Revealing the secrets - Canadian Healthcare Network

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VIMOVO is indicated for the treatment of the signs and symptoms of
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VIMOVO is not recommended for initial treatment of acute pain because
the absorption of naproxen is delayed (as with other modified-release
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For patients with an increased risk of developing cardiovascular (CV)
and/or gastrointestinal (GI) adverse events, other management strategies
that do NOT include the use of NSAIDs should be considered first. Use of
VIMOVO should be limited to the lowest effective dose for the shortest
possible duration of treatment in order to minimize the potential risk for
cardiovascular or gastrointestinal adverse events.
VIMOVO, as an NSAID, does NOT treat clinical disease or prevent its progression.
VIMOVO, as an NSAID, only relieves symptoms and decreases inflammation for
as long as the patient continues to take it.
Evidence from naproxen clinical studies and postmarket experience suggest
that use in the geriatric population is associated with differences in safety.
VIMOVO is contraindicated in the peri-operative setting of coronary artery
bypass graft surgery (CABG); in women in the third trimester of pregnancy or
who are breastfeeding; in patients with severe uncontrolled heart failure, known
hypersensitivity to naproxen, esomeprazole, substituted benzimidazoles or to
any of the components/excipients; history of asthma, urticaria, or allergic-type
reactions after taking ASA or other NSAIDs; active gastric/duodenal/peptic ulcer
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liver disease; severe renal impairment or deteriorating renal disease; known
hyperkalemia and in children and adolescents less than 18 years of age.
WARNING
Risk of cardiovascular (CV) adverse events: ischemic heart disease (IHD), cerebrovascular disease, congestive heart failure (HF) (NYHA II-IV)
Naproxen is a non-steroidal anti-inflammatory drug (NSAID). Use of some NSAIDs is associated with an increased incidence of
cardiovascular adverse events (such as myocardial infarction, stroke or thrombotic events), which can be fatal. The risk may increase
with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.
Caution should be exercised in prescribing NSAIDs such as naproxen, which is a component of VIMOVO (naproxen/esomeprazole), to any
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cerebrovascular disease (including but NOT limited to stroke, cerebrovascular accident, transient ischemic attacks and/or amaurosis fugax)
and/or congestive heart failure (NYHA II-IV).
Use of NSAIDs such as naproxen, which is a component of VIMOVO, can promote sodium retention in a dose-dependent manner, through a
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Randomized clinical trials with VIMOVO have not been designed to detect differences in cardiovascular events in a chronic setting.
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Risk of gastrointestinal (GI) adverse events
Use of NSAIDs such as naproxen, which is a component of VIMOVO, is associated with an increased incidence of gastrointestinal adverse
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The recommended daily dosage of VIMOVO is 375/20 mg or 500/20 mg (naproxen/esomeprazole) twice a day.
The most common adverse reactions seen with naproxen are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe.
Fatalities have occurred, particularly in the elderly.
The most commonly reported adverse reactions for VIMOVO were dyspepsia (11.8%), erosive gastritis (7.2%) and gastritis (6.5%).
See the Product Monograph for full contraindications, warnings, precautions, dosing and administration.
Reference: VIMOVO® Product Monograph. AstraZeneca Canada Inc. January 13, 2011.
11/12
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56
THE MEDICAL POST | UPFRONT
CanadianHealthcareNetwork.ca
OCTOBER 9, 2012
3
Now on the Medical Post's online home:
CanadianH
Canadian
Healthcare
ealthcareN
Network.ca
IN THIS ISSUE
UPFRONT
5 Pertussis immunity drops after
fifth vaccine dose
6 Rounds: The last two weeks
in Canadian medicine
8
MDs question complementary
cancer care
10 What will Ontario’s house calls
plan look like?
12 Editorial: Public supports doctors
over government in fee fight
LIFE
18 Travel:

Rediscovering my
roots in Scotland
23 Dr. Monica Kidd:
Notes to self from
my first year of
practice
24 Wine column:
California
Zinfandels
pair quality
with character
26 The true first
transplant 
New
SCIENCE-ISH:
Are we in
for another
doctor exodus
to the U.S.?
38
PRACTICE
29 Are your record-keeping skills
up to snuff?
30 Finance column:
Should you put all your (nest) eggs
in the corporate basket?
NEWS
43 European Society of Cardiology: Renal denervation
continues to show promise
49 Ontario fee cuts hit family
medicine too, doctors say
51 Canadian Paediatric
Society: Statins deemed
safe for children
60 Inside Dr. Brian Day’s
B.C. Charter challenge
CLASSIFIEDS
62 Job listings
Ergonomics no cure
for ‘chair disease’
Researcher advises more standing and walking
to lessen musculoskeletal and other ills
More trouble for MD who videotaped
nude patient
A doctor who once shot a video of a nude and unconscious
patient is on the verge of having his licence taken away by
the College of Physicians and Surgeons of Ontario. Dr. Justin
Onzuka, who was handed a 16-month sentence for sexually
assaulting two patients, was suspended in 2008 after a hearing
discovered he was addicted to sex and had abused pharmaceutical drugs. According to documents, the physician
videotaped a female patient while working as a resident at
McMaster Hospital, the Toronto Sun reported. The woman
was unconscious and Dr. Onzuka took off her clothes,
“videotaped her and sexually abused her.”
Blog spotlight: Do you treat your
children like patients?
 By Dr. Hari Chana: Have your children ever
suggested they don’t get enough attention from
you when they are sick or hurt compared with
their friends whose parents are not doctors? I
have heard this comment, and so have several
of my colleagues. I used to think my children
didn’t get the same sort of attention as their friends because I
knew they were not in any danger of suffering anything serious;
whereas parents who are not doctors get overly concerned about
a medical ailment and their children get extra attention.
New charges for Canadian doctor
allegedly involved in U.S. fraud
U.S. officials laid a fresh charge against a former Canadian physician accused of taking part in a huge health fraud ring in Texas.
The indictment against Dr. Jacques Roy was issued last month
by a grand jury, which added a charge of obstruction of justice
because Dr. Roy allegedly withheld information. Charges of
making false statements were also levied, the QMI news agency
reported. Prosecutors have said a massive amount of evidence
has been gathered to incriminate Dr. Roy and six others. If convicted, Dr. Roy could be sentenced to life in prison.
BY CHRIS PRITCHARD • Sydney, Australia
station safety in the early
while staring at screens isn’t
1980s, I’ve noticed massive
just a pain in the neck, it’s
changes in the amount of
also responsible for other
computer work performed by
musculoskeletal disorders—
office workers,” she said.
despite improvements in
“Better workstation design,
office ergonomics.
seating and health education
A team led by Karin Grifhaven’t resulted in observable
fiths of the University of Syddecreases in pain over the past
ney’s health sciences faculty
20 to 30 years. Recent research
surveyed 900 office workers
shows prolonged sitting and
and found a correlation
lack of physical activity associbetween time at computers
ated with computer work . . .
and likelihood of musculomay be contributing to cardioskeletal pain.
vascular disease, diabetes and
Of those who spent more
obesity, along with musculothan eight hours a day at
skeletal pain.”
Ergotron and other
a computer, 85% reported
Combating “chair disease”
companies make stand-up
neck pain, 74% shoulder pain
requires more than just using
workstations.
and 70% lower back pain.
ergonomic chairs, she said,
Unprecedented pain is an
recommending bans on interunintended consequence of paperless offices,
nal e-mails between people on the same floor
Griffiths concluded in the August issue of
(thus encouraging walks to colleagues’ desks)
Netherlands-based Work: A Journal of Prevenand more communal stand-up work stations
tion, Assessment & Rehabilitation.
that would allow people to take breaks from
“Since I started assessing offices’ worksitting while working. MP
© Ergotron, Inc. All rights reserved.
SITTING AT DESKS
Online Poll
Other than live events, how would you prefer
to have CME delivered?
Paper-based
14%
Computer
64%
Tablet
21%
Smartphone
0%
Correction
The article “Let family doctors practise how they like, membership urges” in the Sept. 4 issue mispelled the last name of
Dr. Stan Lofsky of Ontario. The Medical Post regrets the error.
The Medical Post online: CanadianHealthcareNetwork.ca
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4
THE MEDICAL POST | upfROnT
OCTOBER 9, 2012
CanadianHealthcarenetwork.ca
Time to give up on Ginkgo biloba
as dementia preventive: MD
No benefit found in new study
but more work ‘urgently’ needed,
French researcher says
BY terrY murraY • Toronto
I
iStockphoto
t’s time to lay to rest any hope that Ginkgo biloba
will prevent Alzheimer’s disease and cognitive
impairment.
That was the opinion of Dr. Lon Schneider, the
director of the University of Southern California’s Alzheimer’s Disease Research Center in Los Angeles, on
the latest major clinical trial on the extract.
“If Ginkgo biloba were a drug, and not marketed as
a food supplement, clinical testing for efficacy against
Alzheimer’s disease and cognitive impairment would
have ended long ago,” Dr. Schneider said in a comment
accompanying publication of the five-year French
GuidAge study in the Lancet Neurology (October).
“Nevertheless, the fact that Ginkgo biloba extract is
widely promoted, derived from a plant and fairly safe
were reasons enough for its use in two landmark prevention trials for Alzheimer’s disease,” Dr. Schneider
wrote, referring to the GuidAge study and the U.S.
Ginkgo Evaluation of Memory study published in 2008.
Calling Ginkgo biloba the “most extensively clinically tested substance for Alzheimer’s disease and cognitive impairment,” he added, “It would be unfortunate if users of Ginkgo biloba . . . are led to believe that
the extract prevents the dementia. Some users will
rationalize that, in the absence of effective treatments,
Ginkgo biloba could still possibly help and, appearing
safe, will not harm them. Other users of Ginkgo
biloba, however, might now consider letting it go.”
GuidAge was a double-blind, randomized, controlled
Seroquel XR
a five-year French trial of more than 2,800
adults showed no statistically significant
differences between those who were given
Ginkgo biloba and those who received placebo.
trial of more than 2,800 French adults age 70 and older
who had reported memory complaints to their primarycare physicians. Half were given 120 mg standardized
Ginkgo biloba extract twice a day and half received
placebo. After five years’ followup, there were no statistically significant differences between the number of
participants in the two groups who had been diagnosed
with probable Alzheimer’s disease, who had a stroke
or other hemorrhagic or cardiovascular event, or died,
according to the report by Dr. Bruno Vellas of Casselardit Hospital in Toulouse.
Dr. Schneider noted that only three of 13 exploratory subgroup analyses showed significant interactions—that men, participants who consumed
alcohol and those who stayed in the trial for at least
four years seemed to benefit from ginkgo compared
with placebo, while women, non-drinkers and people
taking ginkgo for less than four years didn’t.
“These outcomes are unexpected and implausible,”
Dr. Schneider said.
But Dr. Vellas seemed to disagree about the future
of ginkgo studies in Alzheimer’s.
“This is only the third Alzheimer’s prevention trial
to be completed, and is the first to be done outside
the U.S., so further research in this area is urgently
needed,” he was quoted in a release from the Lancet
Neurology.
“While our trial appears to have shown that regular
use of Ginkgo biloba does not protect elderly patients
from progression to Alzheimer’s disease, more studies are needed on long-term exposure. The fact that
prevalence of this debilitating disorder is expected to
quadruple by 2050 suggests that research into preventive therapies for this disease needs to receive urgent
attention.” MP
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THE MEDICAL POST | upfroNt
oCtoBEr 9, 2012
5
Pertussis immunity drops
after fifth vaccine dose
Canadian health
officials to review
vaccine schedules
BY terrY MurraY
toronto
I
mmunity to pertussis
wanes “substantially”
during the five years after
the fifth dose of the combined
diphtheria-tetanus-acellular
pertussis (DTaP) vaccine has
been given, according to a
California study.
The loss of immunity was
such that after the fifth dose
of DTaP, the odds of acquiring pertussis increased by
more than 40% per year, the
researchers reported in the
New England Journal of Medicine (Sept. 13).
That report, as well as pertussis outbreaks across Canada
and a shortage here earlier
this year of DTaP (Quadracel,
which also includes inactivated
polio vaccine), have led Canadian public health authorities
to review pertussis vaccine recommendations in this country.
The California study, headed
by Dr. Nicola Klein at the Kaiser Permanente Vaccine Study
Center in Oakland, was done
to assess the waning of DTaP
protection against pertussis in
a highly vaccinated population
of school-age children who had
received only DTaP rather than
whole-cell pertussis vaccines.
The researchers compared
pertussis risk in 277 children,
four to 12 years old, who were
PCR-positive for pertussis, 3,318 children who were
negative and 6,086 matched
controls. They assessed the
children’s risk of pertussis from
2006 to 2011 in California relative to the time since the fifth
dose of DTaP—a period that
included the large outbreak in
the state in 2010.
Dr. Klein’s group found that
protection wanes after the fifth
dose by an average 42% per
year, but the amount of protection remaining after five years
“depends heavily” on the initial
effectiveness of the vaccine.
“If the initial effectiveness
of DTaP was 90%, it would
decrease to 42% after five
years,” they reported. In the
2010 California outbreak, the
incidence of perThat finding was
tussis was highest
“surprising,” they
among eight- to
added, because it is
11-year-olds who
teenagers who are
had received the full
usually considered
five-dose series of
to be a reservoir for
DTaP in childhood,
pertussis and who
“suggesting that the
have been disproporwaning efficacy of
tionately affected in
Dr. Spika
the fifth dose among
previous outbreaks.
school-age chilCanada’s National
dren played a key role in both
Advisory Committee on
allowing and sustaining the
Immunization (NACI) will be
recent pertussis outbreak,” the
considering the California findresearchers said.
ings as they review pertussis
vaccination recommendations,
according to Dr. John Spika,
director general of the Centre
for Immunization and Respiratory Infectious Diseases in the
Public Health Agency
of Canada.
“We’d asked NACI to review
the pertussis vaccine recommendations but it was primarily in light of the Quadracel
vaccine shortage,” he said in an
interview.
The committee was assessing the effect of substituting
Adacel or another tetanusdiphtheria-acellular pertussis
(Tdap) vaccine with inactivated
polio vaccine for DTaP as the
fifth vaccine dose in light of
the shortage. The Tdap vaccine has a lower dose of pertussis toxoid.
“So the pertussis outbreak
and what is being reported out
of California in this paper adds
another question as NACI considers use of the higher- versus
lower-dose pertussis toxoid
vaccine,” Dr. Spika said. MP
Saskatchewan tweaks rules
for foreign-trained MDs
New rule stipulates one year of postgrad training, ‘reasonable’ clinical experience
BY Deana Driver • regina
physicians in the first year and
SaSkatchewan’S
then widen the process to
medical regulatory body has
conduct 90 assessments a year
approved a new rule for the
and include physicians from all
potential licensure of foreignover the world, whose qualificatrained family physicians from
tions may include only one year
any country. Those who have
of postgraduate training and
only one year of postgraduate
some clinical practice.
training (half as much as their
In preparation for the next
Canadian-trained colleagues)
intake
of SIPPA, the CPSS
and a “reasonable” amount of
Dr. Fourie
council agreed at its September
clinical practice experience can
meeting with a recommendnow apply for assessment to the
ation from its registration committee that
homegrown Saskatchewan International
“family physicians with one year of postPhysician Practice Assessment (SIPPA)
graduate training and three years of
program.
clinical practice experience who are unable
The change is part of Saskatchewan’s
to demonstrate training that covers all
attempt to move toward national
of the required rotations” will be eligible
accreditation standards, said Bryan Salte,
to participate in an assessment program
the associate registrar of the College of
that could lead them to licensure. First,
Physicians and Surgeons of Saskatchewan
they must demonstrate to the registrar
(CPSS) in an interview with the Medical
“an appropriate scope of practice as a
Post. Achieving similar accreditation
family physician” before being accepted
processes “is certainly one of the goals of
into SIPPA.
the various colleges across Canada,” said
Foreign-trained family physicians who
Salte. “It’s driven in part by the fact that
wish
to apply for licensure in Saskatchthe Agreement on Internal Trade says a
ewan must have both the one year of
doctor is a doctor is a doctor. What we
postgraduate training and three years of
are trying to achieve is what gets you
clinical practice experience, said Salte.
into practice in Alberta will be the same
in Saskatchewan and the same in Ontario. Three years was seen by the college council
to be “a reasonable time to have some
That’s a work in process. We’re not there
expectation they could deal appropriately
yet. We’re certainly working toward it.”
with family medicine problems.”
In January 2011, SIPPA began taking
applicants through a two-week orientation
followed by six or 12 weeks of assessment.
This first-year pilot project was meant to
assess physicians from the U.S., U.K.,
Ireland, South Africa, Australia and New
Zealand. The goal was to accept 30
Frustrations
At the spring representative assembly of
the Saskatchewan Medical Association in
May, many assembly delegates expressed
frustration with the continued shortage of
physicians and the delay in licensing
international medical graduates (IMGs) in
the province.
“We do have a system that we believe
is a better system than before,” said outgoing president Dr. Phillip Fourie, a South
African-trained physician, about SIPPA.
The main problems involved with hiring
IMGs were delays in obtaining paperwork,
the high cost of the exam and a recommendation from the assessment program
that the IMGs not bring their families to
Canada until they have passed the program, Dr. Fourie said at the time.
In an e-mail statement supplied to the
Medical Post for this article, current SMA
president Dr. Janet Shannon said, “The
SMA supports the SIPPA process and has
participated in the design. It is a new
process that will require periodic changes
to ensure quality health care for the people
of Saskatchewan. The SMA supports all
quality improvement measures as well as
recruiting high quality physicians for our
province.”
The practical effect of this rule change
by the college will be seen in the January
iteration of SIPPA, said Salte. “In the pilot
phase, it was limited to graduates from
countries like South Africa, Britain and
Ireland, and it was almost all South
Africans.”
Now, many of the people going through
the current program are not South
Africans, he added, noting physicians
from Iran and Egypt are among those
being assessed at present. The variety of
countries represented in the January
process is expected to be greater yet. MP
6
OCTOBER 9, 2012
Rounds
The Last Two Weeks in Canadian Medicine
 CALGARY • New AMA head
with the provincial college over professional lapses.
extends ‘olive branch’ over fees
Though Dr. Gilles Bourdon was barred from surgical
Dr. Michael Giuffre, the newly elected head of the
practice two months ago and has since come under
Alberta Medical Association, said he’s willing to “extend
intense scrutiny over nearly 700 colonoscopies, the
an olive branch” to the province as the two sides work
doctor had other troubles dating back several years. A
toward a new fee deal. Dr. Giuffre, a Calgary physician
college spokesperson said the dearth of proper medical
who took over as AMA president in September, said
MDs need to “realign” with the province and Alberta


Health Services while keeping the interests of patients


first. The province and its 7,200 doctors have been
without a contract for 18 months.
 HALIFAX • N.S. recommends
hospital smoking section
Capital Health CEO Chris Power said it’s hard to swallow a recommendation to put a smoking section back
 TORONTO • Ontario Grits defend
Health Minister Deb Matthews said the legal political
private health donations
donation won’t influence her decision on whether to
mendations after the death of gay activist Raymond
A private health-care company has donated $16,700 to
allow the sale.
Taavel. Andre Denny, a psychiatric patient from the
the Ontario Liberals as it seeks government approval
in a provincial hospital. The section is one of 18 recom-
East Coast Forensic Hospital in Dartmouth, was on a
to purchase a private clinic. The donation was revealed
 MONTREAL • Scandal over
this month on the Elections Ontario website and comes
botched colonoscopies grows
tion that left Taavel dead. The report found that too
as the government weighs Centric Health Corporation’s
The Quebec physician at the centre of a growing scan-
many passes were being handed out for smoking,
$14-million bid to purchase the Shouldice Hospital. But
dal over botched colonoscopies had a history of trouble
sending patients off the grounds.
Vitals

 %
Dispatch
BY JERED STUFFCO
Tuition at Canadian medical schools is up
WHEN DR. ANDRÉ
for doctors is at an all-time high,
HASSPIELER, a Queen’s Univer-
and the physician supply has been
sity graduate, decided to leave
beefed up in the intervening years.
Ontario in 1998 to set up practice
As well, the U.S. is no longer the
in Virginia, the move was precipi-
economic powerhouse it once was.
5.1%
$11,891
two years ago to practise in North
for the 2012-13 year, leaving the average fee at
Among Canadian undergrads, only dentists—at
$16,910 per year—pay more.

one-hour pass when he allegedly got into an alterca-
MDs say U.S. recruiters are
back—but do they have the cash?
tated by phone calls from stateside
In fact, John Philpott, executive
recruiters. Now, according to the
director and CEO of the international
family physician—who returned
firm CanAm Physician Recruiting,
Bay, Ont.—2012 seems like 1998
Dr. Baerlocher
all over again.
“A few months ago,” he told the Medical Post,
Ontario universities have the highest tuition
for in-province medical students, with an average of
$19,700
$3,700 
Quebec is the cheapest at
said, and family doctors would sooner go to
Physician recruiters, Dr. Hasspieler added,
other provinces before the states.
He’s referring to the fact that, at the
Philpott is actually observing a brain drain
occurring in the opposite direction. “We are con-
moment, doctors in Ontario are not at their
tinuously recruiting American primary-care doc-
happiest. Indeed, since his move back to
tors into Canada.” If the sponsorship require-
Canada, war has broken out.
ment for U.S. doctors was lifted, “they would
Physicians like Dr. Hasspieler are reporting
that U.S. offers are trickling in—ranging from
flock to Ontario.”
Still, there is a need for certain sub-spe-
rural to urban work in both community and aca-
cialists in the U.S. and an oversupply in some
demic settings.
areas of medicine in Canada, so Philpott sees
to Canada, it was mostly because, he said,
Canadian physicians who can’t find steady work
here going south.
One interventional radiologist in Barrie, Ont.,
“I heard that things back home were changing,
Dr. Mark Baerlocher, told the Medical Post he’s
that the conditions of practice were much
also been receiving about three U.S. offers per
better, that there were no longer those caps.
week, but he’s taking a wait-and-see approach
“Now, here we go again with talk of freezes,
Source: Statistics Canada
recruiters are wasting their time.”
American offers can’t compete with Ontario
when it comes to primary-care physicians, he
offers. When he decided to move back
$23,338
are being called upon, then U.S.
the ’90s. I get three to four calls per week.”
Dr. Hasspieler said he is entertaining the U.S.
Canada’s highest yearly tuition?
McMaster University’s three-year program:
said, “If Ontario family physicians
“I started getting calls again, just like I did in
“are hot on the trail.”
Courtesy of McMaster University
iStockphotos
notes is “extremely worrisome.”
reductions and a lot of other restrictions, as well
as cuts to services of patients. . . . I’m considering going.”
Working conditions in Ontario aren’t as
dire as they were in the 1990s. Compensation
for now. “(I’m) still hoping that the province
comes up with something that’s fair.
“If that fails, we’ll have to see,” he said.
“After the way that physicians were treated,
the province isn’t viewed as a very physicianfriendly place.”—Julia Belluz
OCTOBER 9, 2012
7
Journal Scan
NEUROLOGY • ‘Minor’ stroke not so minor
A substantial proportion of patients with transient ischemic attack and minor stroke become
Auscultations

disabled, according to Dr. Shelagh Coutts and
colleagues at Foothills Hospital in Calgary. They
followed 499 such patients who were not previ-

and they won’t pay for it.
“I’m sufferingSohere
I’m not happy.
”
ously disabled and had CT scans within 24 hours of symptom
says the province won’t fund her trip to the Mayo Clinic.
have disability as a result of their presenting event; however,
—JENEECE EDROFF, an 18-year-old B.C. philanthropist with neurofibromatosis,
“
I am not naive and I believe we may
be in for a long period of instability.
”
—DR. LINDA SLOCOMBE talks fees in her final letter
as Alberta Medical Association president.
“
After surgery, my surgeon told me,
‘Had I known you were crazy, I wouldn’t
have operated on you.’
”
—A patient quoted in an Ontario Human Rights Commission report on discrimination
among health-care providers.
onset, and found 15% were disabled at 90 days. Of the 463
patients who did not have a recurrent event, 55 were disabled
(12%), compared with 19 of 36 (53%) patients who had a
recurrent event. “In terms of absolute numbers, most patients
recurrent events have the largest relative impact on outcome,”
the researchers wrote. Risk factors for disability included
ongoing symptoms, diabetes, female sex and positive scans.
—Stroke (online Sept. 13)
PEDIATRICS • Trust your gut
Primary-care doctors should trust their instincts
when assessing children presenting with an
acute illness, according to a study of 3,890
patients up to 16 years of age seen at general
or community pediatric practices in Belgium.
Dr. Ann Van den Bruel of the University of Oxford and colleagues
found that of the 3,369 children assessed as having a nonsevere illness, six (0.2%) were later admitted to hospital with a
serious infection. A gut feeling that something was wrong—even
if the clinician was unsure why—increased the likelihood of
severe illness by more than 25 times. Acting on this feeling had

Picture yourself
the potential to prevent two of the six cases being missed, at a
cost of 44 false alarms. Features most associated with gut feeling were the children’s overall response (drowsiness, no laughing), abnormal breathing, weight loss, convulsions and parental
concern that the illness differed from previous experience.
—BMJ (online Sept. 25)
MODELS OF THE PARALYMPIC MOVEMENT As the Canadian team prepared to march
into Paralympic Stadium at Olympic Park for the opening ceremony of the 2012 Paralympic
Games in London, Dr. Richard Goudie caught up with four-time Paralympic swimmer
Donovan Tildesley. Dr. Goudie, a sports medicine physician from Barrie, Ont., had attended
two previous Games and works with the women’s national wheelchair basketball team.
But this time around his responsibilities were much larger—and his role appears to have
had some perks: “Being Chief Medical Officer for the Canadian Paralympic team in London
allowed me to meet all the great athletes, especially the ones who were on the front page
of the Medical Post!” (Donovan is on the cover they are holding, pictured with his father,
Dr. Hugh Tildesley.)
GERIATRICS • Benzos raise risk of dementia
Benzodiazepines could increase seniors’ risk for
dementia, French researchers have warned.
Sophie Billioti de Gage of the University of
Bordeaux and colleagues followed 1,063 men
and women (mean age 78.2 years) who were
free of dementia and did not start taking benzodiazepines until
at least the third year of followup. They confirmed 253 incident
cases of dementia over 15 years. New use of benzodiazepines
was associated with a 50% increase in the risk of dementia, and
the result remained robust after the researchers controlled for
factors such as depression that are considered to be markers for
early dementia. “Considering the extent to which benzodiazepines are now prescribed, physicians and regulatory agencies
should consider the increasing evidence of the potential adverse
effects of this drug class for the general population,” they said.
—BMJ (online Sept. 27)
PREVENTION • Vitamin D in the cold
Hopes for a common cold preventive continue
to be unsatisfied with a New Zealand study
showing monthly megadoses of vitamin D fail
to reduce the incidence or severity of upper respiratory tract infections. Dr. David Murdoch of
the University of Otago and colleagues randomly assigned 322
healthy adults with near-normal vitamin D levels to receive an
initial dose of 200,000 IU oral vitamin D3, then 200,000 IU one
month later, then 100,000 IU monthly, or placebo administered
in an identical dosing regimen, for a total of 18 months. There
were 3.7 URTIs per person in the vitamin D group and 3.8 in
the placebo group—a non-statistically significant difference. Nor
Keep those photos coming! Send submissions to Carol Hilton at: [email protected].
Please include an explanation. Be creative, be funny—and be in the Medical Post!
URTIs, duration of symptoms per episode or severity of URTIs.
—Journal of the American Medical Association (Oct. 3)
iStockphoto
were there differences in the number of workdays missed due to
8
OctOber 9, 2012
THE MEDICAL POST | upfrOnt
canadianHealthcarenetwork.ca
MDs debate merits of
complementary cancer care
‘Integrative oncology’ gets
government funding, but
alarms skeptical physicians
InspireHealth’s eight core clinical staff are all MDs.
They provide patients with one-on-one counselling
and evidence-based treatments such as acupuncture
to reduce side-effects of chemotherapy and radiation.
Staff members also give classes on nutrition, cooking,
exercise, meditation, stress reduction and yoga, and
offer shared-learning groups. The IOCs are non-profit
and are funded through the B.C. government as well
as a mix of membership fees from patients and private
donations.
BY RosemaRY FRei • toronto
courtesy of Dr. Hal Gunn
I
ntegrative oncology clinics (IOCs) that provide
complementary care for cancer patients are
slowly cropping up in Canada, but they have
already sparked concerns among some physicians over
their use of therapies that have not been proven in
clinical trials to be safe and effective.
While any number of practitioners may offer
alternative and complementary treatments for cancer
patients, IOCs focus exclusively on cancer and involve
both MDs and complementary health-care professionals. Unlike their counterparts in the United States,
Canadian IOCs are few in number and largely disconnected from conventional cancer centres. However,
there are some signs this may change. The B.C. government, for example, is funding the expansion of a group
of IOCs in that province.
The non-profit B.C. clinics are under the banner
of InspireHealth, and the first one began operating
in Vancouver in 1997. In June 2011, the provincial
government announced it was providing $2.5 million
in startup money for five new centres across B.C., and
another $2.5 million annually to the IOCs for hiring
additional physicians, nutritionists, exercise therapists
and psychological counsellors.
“Every British Columbian who is facing a battle
with cancer should have access to the integrated cancer care that is provided by InspireHealth,” then-B.C.
health minister Michael de Jong said when the funding was announced.

We help patients
integrate a focus on their
overall health into the
treatment of illness.
—Dr. Hal Gunn

Increasing evidence
“Our focus is on support, empowerment and engagement. We help patients integrate a focus on their
overall health into the treatment of illness,” Dr. Hal
Gunn, InspireHealth’s co-founder and CEO, told
the Medical Post. “That’s been happening in cardiac
care in conventional medicine for 25 years, and
there’s increasing evidence this approach can play an
important role in combating other chronic diseases
including cancer. If we engage people around the time
of their cancer diagnosis, there’s the opportunity to
make significant changes. And I think the B.C. government recognizes that.”
The Samueli Institute in the U.S. has received a
$2.2-million grant from the Hecht Foundation for a
study of InspireHealth’s programs and their impact on
patient quality of life and survival. Cancer patients will
be randomized to either usual care through the BC
Cancer Agency or usual care through the BC Cancer
Agency plus attendance at an InspireHealth IOC.
“That way we’ll be able to rigorously assess the
effectiveness of our program. To our knowledge it’s the
first time a broad integrative program will be assessed
in this way. So it’s really exciting,” said Dr. Gunn.
AndroGel® is indicated for testosterone
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suggestive of hypogonadism if testosterone
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and if other etiologies responsible for the
symptoms have not been excluded.
For additional information please see
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1-800-361-7852
A Promise for Life
THE MEDICAL POST | upfroNt
However, some physicians oppose InspireHealth’s
approach. Dr. Lloyd Oppel,
chairman of the B.C. Medical Association’s Council on
Health Promotion, pitted
himself against IOCs in a PointCounterpoint exchange in the
B.C. Medical Journal (June 2012).
“It is somewhat puzzling
that Dr. Gunn invokes the
endorsement of the privately
funded Samueli Institute as a
demonstration of how InspireHealth is a model of patientcentred care. This may not
satisfy the scientific or semantic
curiosity of skeptical readers
who will note that the Samueli
Institute is headed by people
trained in ‘mind/body methods, spiritual healing, electroacupuncture diagnostics,
homeopathy and bioenergy
therapy,’ ” wrote Dr. Oppel in
his Counterpoint article.
Unproven therapies
“Dr. Gunn’s lengthy exploration (in his Point article) of
the link between lifestyle and
disease is engagingly written,
but it does not address the
concerns expressed about the
effectiveness of the alternative
medicine modalities employed
at InspireHealth. Similarly, the
fact that InspireHealth may be
a non-profit organization with
salaried physicians does not
answer the questions about
the appropriateness of government funding for a clinic that is
charging for unproven cancer
therapies.”
“Alternative medicine
modalities are not used at
InspireHealth,” Dr. Gunn
rebutted. “Patients have the
option of using complementary
modalities such as meditation,
yoga, nutritional counselling
and exercise therapy to support
their health.”
There are also growing pains
in Ontario, where the only other
Canadian IOC exists. Staff at
the Ottawa Integrative Cancer
Centre (OICC), which opened
in March 2012, offer naturopathic medicine, integrative
medical care, family therapy,
physiotherapy, psychiatry,
nutrition, acupuncture, massage therapy, exercise therapy
and yoga. They are also engaged
in research, including participating in a prospective observational trial that will examine
whether intravenous vitamin C
increases survival and quality
of life in patients with breast,
lung, pancreatic and ovarian
cancer, and a double-blind,
multicentre, randomized trial
oCtober 9, 2012

Fortunately, there are
oncologists who are open to
an approach that includes
complementary medicine.
—Dr. Dugald Seely, naturopath
assessing melatonin’s ability to
combat lung cancer.
The OICC’s founder and
executive director, Dr. Dugald
Seely (ND), is active in many
other realms of research, as
shown by his presentation of
several talks and posters at the
October annual meeting of the
Society for Integrative Oncology and his involvement in the
Integrative Canadian Oncology
Research Initiative. That is
part of his overall push to try
to have integrative oncology
accepted by mainstream physicians, as he believes this is in
patients’ best interest.
“Some patients feel there is
value in naturopathic medicine
and so seek their own resources
without communication with
their oncologist, because oncologists often tell patients not
to use naturopathic or other
complementary treatments—
and so there is the potential to
make misguided choices and
have possible harm from interactions,” said Dr. Seely. “One
of our main goals is to bridge
that gap. Fortunately, there are
oncologists who are open to an
approach that includes complementary medicine, such as Dr.
Shailendra Verma at the Ottawa
Hospital and Dr. Stephen
Sagar at McMaster University’s
Juravinski Cancer Centre (in
Hamilton) and we are working toward having access to
patients’ charts and creating
communications protocols
between us.”
Supportive care
Dr. Verma declined an interview request from the Medical
Post, stating he is too busy,
while Dr. Sagar sent an e-mail
with some comments. He said
complementary therapies are
appropriate only for limited,
supportive care, and that use of
complementary therapies for
cancer management should be
led by oncologists and nurses.
“When it comes to naturopathic practice, Dr. Seely is the
exception. He is an excellent

and credible researcher,” wrote
Dr. Sagar. “In fact, we have
teamed up on research projects.
Unfortunately, this standard,
in my opinion, is not reflected
across the naturopathic profession. . . . Therefore, I am
concerned that using the term
‘naturopathic oncology’ is
misleading and could give
patients a false sense of credibility. . . . I (also) have some
concerns that some of the
research on efficacy by Dr. Seely
and me may be over-generalized and be used to give false
credibility to inappropriate
interventions by poorly trained
or uncritical individuals.”
Dr. Lynda Balneaves (RN,
PhD), the principal investigator
of the University of British Columbia and BC Cancer Agency’s
Complementary Medicine
Education and Outcomes
(CAMEO) program, occupies
an intermediate position.
CAMEO’s position is treatments
offered within integrative oncology should be evidence-based
or should be monitored and
evaluated within a clinical trial.
“For example, I.V. vitamin C
is controversial—the sideeffects seem to be minimal, but
the only evidence of benefit is
in vitro and in animals. . . . Just
because there’s no clinical trial
evidence doesn’t mean it doesn’t
work, but it should be offered
only in the context of a trial
rather than as part of standard
care,” Dr. Balneaves told the
Medical Post. “Funding of our
health-care system is becoming more and more limited, so
we can’t afford to be offering
therapies where there is no evidence. But we also shouldn’t be
so dogmatic that we aren’t open
to new possibilities.” MP
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in exactly 100 words. the winner gets $1,000. the organizers of
the annual contest say non-scientific themes are encouraged. The
entry form is available at www.scriptmedical.com. Judges this year
include Medical Post editor Colin Leslie and others.
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10
THE MEDICAL POST | upfrOnt
OctOber 9, 2012
canadianHealthcarenetwork.ca
Call of duty: Will Ontario’s
house-call plan sit well with MDs?
The province is
moving quickly,
but will doctors
play ball?
BY RON STANG
Windsor, Ont.
T
iStockphoto
Though final details are to be confirmed, it looks like Ontario’s new program would
make house call medicine an area of specialization and offer doctors who make house calls
at least 50% of their practice a bigger financial payout.
who wanted to specialize in
home visits.
‘Destined to fail’
Dr. Merrilee Fullerton, pastpresident of the Ottawa Academy of Medicine and a member of the Champlain LHIN
advisory committee, called the
program “destined to fail.”
Dr. Fullerton, who has long
done house calls in rural areas,
said the Seniors Care Strategy
is “centrally arranged” and
“doesn’t address local needs.
“And the needs of downtown Toronto would be hugely
different from Cornwall, Renfrew, Arnprior, Hawkesbury,
and even rural areas in northern Ontario.”
She also thought logistics would make house calls
impractical, given the shortage
of doctors in rural and remote
areas.
This includes driving time
and the lengths of visits, which
can be longer than expected
when dealing with patients
at home.
“It’s not going to be a
15-minute visit, it’s going to be
much longer. In fact, I’ve been
in this situation numerous
times where it’s very difficult
to leave.”
Dr. Fullerton suggested
home visits might work in
small communities or in residential buildings with a high
proportion of seniors, where
“you can see quite a few people
in one setting.”
Still, Dr. Sinha said he is
hopeful about the plan.
He said more than half
of Ontario’s 12,000 primarycare doctors already do some
degree of home visits, but
are reluctant to devote more
time to them because of inad-
equate compensation.
Dr. Sinha pointed to the
50% specialty benchmark
as a way to get more doctors
involved.
“The nice part about this
mechanism is it really gives
those physicians who want to
specialize in this type of practice a real opportunity to do so.”
Concentrations of patients
‘Science-ish’
blog wins CMA
media award
SCieNCe-iSh—a joint project
of the Medical Post, Maclean’s,
and the McMaster Health
forum—has won the canadian
Medical Association’s 2012
Media Award for excellence in
Digital Health reporting. the
blog, written by Medical Post
associate editor Julia belluz
(seen here in the Medical Post’s
newsroom), is being honoured
for a series of articles about
evidence-based health policies,
including “Insite: ‘too early to
tell’ if it works?”, “Where in
canada do doctors make the
most money?” and “Should we
make surgeons get tested for
HIV, hep b and hep c?”
Science-ish appears weekly on
canadianHealthcarenetwork.ca.
colin Leslie
he physician leading
Ontario’s Seniors Care
Strategy says providing
a bigger compensation package
for doctors who take on more
house calls will make it an
attractive proposition as the
province rolls out a plan for
more home-based care.
While exact details have
yet to be released, doctors
who make house calls at least
50% of their practice could be
in line for a bigger payout, the
Medical Post has learned.
According to Dr. Samir
Sinha, who is heading up the
seniors strategy, physicians will
be able to make house calls a
pseudo specialty, and will be
treated “just like” physicians
specializing in other key areas,
like anesthesia, obstetrics and
gynecology or HIV medicine.
Dr. Sinha, also director
of geriatrics at Mount Sinai
Hospital and the University
Health Network in Toronto,
was appointed by the province
in May to develop a plan to provide more medical support for
seniors at home.
After consulting with thousands of health workers, senior
citizens and Ontario’s 14 local
health integration networks
(LHINs), he will release his
report and recommendations
this fall, with implementation
likely coming next year.
Keeping seniors in their
homes not only “honours the
rights” of those who don’t want
to move to an institution, but
it’s also a huge cost saving.
“We’re talking only a few
thousand dollars a year versus
$50,000,” he said.
Per day, home care is estimated to cost $50, versus $150
at a long-term facility and
$1,000 for a hospital bed.
Dr. Sinha said the province
and the Ontario Medical Association are putting the final
touches on a 2004 agreement
that would provide suitable
compensation for doctors
can also help the cause. Dr.
Sinha introduced an acute-care
unit for 250 elderly patients in
Toronto where house calls are
done by an “interprofessional”
team. “We’ve actually been able
to decrease readmissions to
hospitals and decrease (emergency room) visits and our
patients are more likely to die
at home,” he said.
But how it will play out in
practice remains to be seen.
Dr. Andre Rivet, a North Bay,
Ont., family doctor, said house
calls are useful for some cases
but difficult for others.
“If (patients) have abdominal pain, often they would have
to be seen in an emergency
department or an acute clinic to
do blood work,” he said. “But if
you’re just doing routine home
visits for blood pressure checks,
I think the seniors do appreciate that.”
Dr. Jon Johnsen, pastpresident of the Thunder Bay
Medical Society, called house
calls “a very small part of the
solution.”
He stressed that time allocation is key: “My question to
government is always, which
of my other duties would you
like me to give up to do home
visits?” MP
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WARNINGS: As with all ACE inhibitors, please refer to specific warnings regarding
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12
EdiTORial
OCTOBER 9, 2012
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Public supports MDs
over gov’t in fee fight
F
irst, some good news for
Ontario doctors. In a
Nanos telephone survey
of 1,000 Ontarians conducted
between Aug. 11 and 16—
exclusively given to the Medical
Post—49% said the Ontario
Medical Association was the
more reasonable party
compared with 26% saying the
government was being more
reasonable in the debate
between the government and
the province’s doctors.
The Nanos survey, conducted on behalf of the OMA,
also asked the public to rank,
on a scale of one to 10, how
much of a priority it is for the
provincial government to invest
in six areas. The results? Hospitals (8.1 out of 10) and doctors
(7.8 out of 10) beat out—in
descending order of support—
nurses, teachers, pharmacists
and public-sector workers.
Now the bad news: The
profession’s inability in recent
years to deal with fee relativity
continues to produce terrible
headlines. The most recent?
“Six Ontario doctors each
billed taxpayers more than
$3 million last year”appeared
in the Globe and Mail after
the newspaper obtained those
Colin leslie
Editor
numbers under freedom of
information legislation. That
Globe article also reported 27
doctors billed more than
$2 million each in the fiscal
year ending March 31, 2011, and
almost half of those physicians
were ophthalmologists.
When I talk to doctors and
health-policy wonks, it’s clear
there has been a huge loss of
trust in the government. Until
fee negotiations broke off in
the spring, it had seemed physicians in Ontario had a government that genuinely wanted to
work with them to improve the
health-care system.
The government has
expended a lot of goodwill it
will need for the next fee negotiations, four years from now.
The next fee deal? Yes, in many
ways, given Ontario’s financial
situation, the current fee talks
are about money. But many of
the health policy folks I talk to
say soon—probably the next
round—will be the “accountability” negotiations.
Simply put: The public is
paying for physicians’ work and
there are going to be increasing
demands that if your practice
patterns are outside the parameters of similar practices—for
example, if you send a much
higher percentage of patients
for expensive testing than
guidelines suggest—there are
going to be carrots and financial
sticks to bring you in line. This
is going to be incredibly complicated to negotiate because
no one thinks it’s a good idea to
turn doctors into robots; physicians need some autonomy in
their clinical decision-making.
The issue is all moot now.
The governance issues have
not been sorted and the data
systems are not yet ready for
the government to have an
“accountability” negotiations.
But perhaps four years from
now they will.
Follow Colin Leslie on Twitter
at @MedicalPost.
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PHYsiCiAn ADVisoRY BoARD
DR. GILLIAN ARSENAULT
community medicine
DR. BENJAMIN BARANKIN dermatology
DR. BEAU BLOIS emergency medicine
DR. GEORGE BURDEN
family medicine
DR. ALAN BROOKSTONE
information technology
DR. SIMON BRYANT family medicine
DR. PAUL CALDWELL family medicine
DR. ALICE CHENG endocrinology
DR. MICHAEL CLARFIELD sports medicine
DR. LORI CONNORS allergy
DR. MICHAEL CUSSEN community medicine
DR. JANET FRIESEN family medicine
DR. SARAH GILES family medicine
DR. STEVEN GOLUBOFF family medicine
DR. WENDY GRAHAM family medicine
DR. BRIAN HANDS otolaryngology
DR. LARA HAzELTON psychiatry
DR. HASEENA HUSSEIN internal medicine
DR. BARBARA KANE psychiatry
DR. MONICA KIDD family medicine
DR. FAY LEUNG orthopedics
DR. DAVID MARTELL family medicine
DR. JENNIE MICKELSON pediatric urology
DR. MANO MURTY family medicine
DR. DAVID SATOK family medicine
DR. PUNEET SETH family medicine
DR. IRVIN WOLKOFF psychiatry
“Good thing it has a child-proof cap.”
THE MEDICAL POST | OPINION
OCTOBER 9, 2012
13
The case against
Dr. Brian Day’s case
For-profit care is not the
right direction for the health
of all Canadians
AS MANY OF US are aware,
File picture. John Lehmann/Globe and Mail
controversy is brewing over
the Cambie Surgical Centre
in Vancouver.
The British Columbia Medical
Services Commission recently
found that Cambie charged
VANESSA
patients nearly half a million
BRCIC
dollars in illegal billings over just
a 30-day period, including $66,000 in double-billing
to the Medical Services Plan (MSP). Dr. Brian Day, the
owner of this for-profit surgical facility, refuses to stop
these illegal billing practices. He argues—despite the
law stating otherwise—that his patients have a constitutional right to buy their way to the front of the line.
This is a big claim that undermines the core foundation of our public health-care system that allows
us to triage patients based on medical need, not on
ability to pay.
It is undeniable that medicare is underfunded
for some services (but not for most), and that some
patients are waiting too long for procedures. It is true
that medicare is not living up to its full potential,
and we need to change that. It is also true that Dr.
Day has great determination and skill in developing a
for-profit delivery model. But we have no evidence of
whether this model is efficient or whether it delivers
quality care. Privately held companies are not publicly
accountable, so the outcome data from Cambie are not
available for critical peer-review and analysis.
And even if Dr. Day’s for-profit model was found to
be efficient and to provide high-quality care, that does
not mean we need to question the foundation of our
public health system and introduce a two-tiered, profitdriven system in B.C. Instead, why not integrate these
alleged efficiencies into medicare? Since when do doctors run away from the system that pays them, and pays
them well, instead of trying to improve it? I suppose
since they realized they can make millions doing so.
Re: “Advice to new
doctors on how to
talk to patients” (the
Medical Post, Sept. 18)
I thoroughly
Cherry-picking
As a family physician, I know how the game works:
In a fee-for-service system, I will make more money
if I avoid patients with complex-care needs, chronic
pain, multiple comorbidities, patients in poverty, frail
elderly, patients who are “non-compliant,” the list goes
on. Simply put, I make more money if I treat healthier
patients with one problem per visit. But that doesn’t
mean I should do so for my own financial gain. It also
doesn’t mean that I should call into question the laws
Dr. Vanessa Brcic
is a Vancouver family
doctor and an executive board member
with Canadian
Doctors for Medicare. See related
story on page 60.
mihealth.com
Discover more
on page 32
XX
7

how Ontario fee
talks got restarted
tips for discussing
alternative medicine
with patients 30
OMA president outlines new
rule to get it right this time 4
MIH_23842_EarLug_Ads.indd
1
12-04-09 11:22 AM
AD number COR07E
Client:
Merck
Size:
1.875” x 1.1875”
Agency:
Anderson DDB
Publication: Med Post
VOLUME 48 NO. 16 • $82 yEar
ThE INdEpENdENT VOICE fOr CaNada’s dOCTOrs • CaNadIaNhEaLThCarENETWOrK.Ca
sEpTEMbEr 18, 2012
Neonatal revolution
Dr. Shoo Lee’s
global outlook
transforms
Canadian
practice 35
D.W. Dorkin
We also need to
allow sufficient
time for our
patients
There are important reasons why these billing
practices are illegal. Charging patients more than the
approved MSP fee schedule is a violation of both the
B.C. Medicare Protection Act and the Canada Health
Act. Although Dr. Day says he is advocating for people
suffering on wait lists and for personal choice, he also
stands to make millions by continuing these billing
practices. The profit motive can’t be ignored.
LETTERS
The Island
of Tears
PM 40070230

Dr. Brian Day of the Cambie Surgery Centre
performs knee surgery on a patient
at his private clinic.
that deter doctors from cherry-picking certain patients
to enhance their profit margin.
International evidence shows that in a two-tiered
system, patients with less money but more pressing
health-care needs will wait longer for surgery than
healthier, richer patients paying to get to the front of
the line. Why? Profit-driven delivery models lead to
faster (and usually not better) care for a select few,
while everyone else waits longer in a system that is
drained of doctors and nurses. The public system is
further burdened by a caseload of higher relative complexity after the wealthy, healthier and less complex
patients have been skimmed out of the system.
We must remember that medically necessary procedures are generally covered by provincial insurance
plans, paid for by our tax dollars, whether they are delivered through public, not-for-profit settings or private,
for-profit settings. But it costs more to deliver the same
care in for-profit facilities. The Workers’ Compensation
Board of B.C. “paid almost 375% more ($3,222) for an
expedited knee surgery performed in a private clinic
than for a non-expedited knee procedure in a public
hospital ($859),” according to a study published in the
August 2011 Healthcare Policy by epidemiologist Dr.
Mieke Koehoorn (PhD) of the University of British Columbia and colleagues. Yet the return to work of those
treated in the public system was marginally better.
There are two paths for medicare: the path where
the wealthy few get speedy care, and the rest of us wait
longer, or the path of solidarity we’ve already chosen,
where we care for each other based on our health needs,
not our ability to pay. We should continue to choose
our public medicare system and speak up to make it
better—it’s not only the most equitable path, it’s also
the best deal in town.
A visit to Grosse
Ile station 19
Addressing
determinants
of health 50
progressive’ viral DNA
testing lacks funding 8
enjoyed Dr. Murray Waldman’s
john st. Docket#: AZSYM18014
article discussing how to talk
Marmot’s way
Cervical screening
future ‘Truly
Docket Name: Symbicort 2012 ads
Description: print ad
Client: Tetley
Filename: AZSYM18014_SYM_Bootlug_6x1pt5_E_MP
Headline: Symbicort logo
Studio Designer: Newk
Contact: Alisa Pellizzari
Start Date: Jan 11, 2012
cient time to devote
apparently wanted to impress
hadn’t even occurred to me
full attention to each
me: She indicated with pride
that the young student had
individual patient’s
that “her” physicians see on
never seen an otitis media,”
health concerns,
average eight to 10 patients
I would ask her to please
keeping in mind
an hour. Needless to say she
remember that she is talking
that most physical
didn’t make my day! I wonder
about a person, not a disease.
problems also have
whether any of the three “A”s
The habit of referring to a
an emotional or
get addressed at that assem-
person as “the gall bladder in
psychological side.
bly-line facility!—Dr. Mladen
room 23” or the “hip fracture”
Seidl, Toronto
is demeaning and dehuman-
If a doctor is in a hurry—
AD CODE: SYM-4C-SS-ENG-6x1.5 “Cart”
Trim Size: 6" x 1.5"
Creative
(Designer/AD/CD)
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which, unfortunately, has
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Magenta
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Yellow
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Black
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izing, and decreases empathy.
Account Executive
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Pub. Contact: Michael Finley
Studio/Traffic/Production
Manager
Die Line / Fold Marks Inks: DO NOT PRINT
Cover Date: Feb 13, 2012
Format: Front cover bootlug
Fold Marks
Perf Line
Position: N/A
Proof Reading
to patients and hope that most
became an unjustified impera-
new doctors would incorporate
tive of our time—the latter is
his wise suggestions into their
missed and only half a job, or
professional routine.
no job, has been done properly.
Due Date: Jan 31, 2012
Scale: 1:1
Laser is at 100%
Die Line
It is depersonalizing to both
N/A
NOTES: THIS IS NOT A COLOUR PROOF. Refer to pantone chips and process match books for accurate colour samples. No trapping has been done to this file. Our artists have done everything
possible to make this file mechanically perfect. However, before signing approval please check all copy, dimensions and colour space.
Remember to refer
to patients as people,
not as their conditions
that the first “A” (availability)
for a position in a walk-in clinic,
Re: “How to be a great preceptor”
(the Medical Post, Sept. 4)
must also entail allowing suffi-
I met the administrator, who
When the author writes, “It
However, I would just add
Not long ago, while looking
➲
the patient and the physician/learner.—Dr. Elisabeth
Gold, Halifax
Letters: info@medicalpost.
rogers.com
For more doctor views go to the Medical Post’s online home:
www.CanadianHealthcareNetwork.ca/physicians/discussions
IN THE NEXT
ISSUE:
arriving the week
of October 23
Featuring
 Canadian medica
l
students overseas:
Should it be easier
for them to return
home to practise?
 Clinical:
Interscience
Conference on
Antimicrobial Agents
and Chemotherapy
 Practice: Tips for
improving mental
health screening
 Travel: Savouring
the sights, sounds
and flavours of India
Don’t miss the
OCTOBER 23 issue
of
The
Medical
Post
See prescribing information and
study parameters on page 58
XX
ELIQUIS is a trade-mark of Bristol-Myers Squibb Company
used under license by Bristol-Myers Squibb Canada.
Pfizer Canada Inc. Kirkland, Quebec H9J 2M5
Bristol-Myers Squibb Canada, Montreal, Quebec H4S 0A4
Reference: 1. ELIQUIS Product Monograph. Pfizer Canada Inc. and Bristol-Myers Squibb Canada. December 13, 2011.
ELIQUIS (apixaban) is indicated for the prevention of venous thromboembolic events (VTE) in adult patients who have
undergone elective knee or hip replacement surgery.1
Please consult prescribing information for warnings, precautions, adverse events and important patient selection criteria.
ELIQUIS (apixaban) is indicated for the prevention of venous thromboembolic events (VTE) in adult patients who have
undergone elective knee or hip replacement surgery.1
Please consult prescribing information for warnings, precautions, adverse events and important patient selection criteria.
Reference: 1. ELIQUIS Product Monograph. Pfizer Canada Inc. and Bristol-Myers Squibb Canada. December 13, 2011.
See prescribing information and
study parameters on page 58
XX
THE MEDICAL POST
Digging up Scottish roots p.18➾
LIFe
New book explores women’s health challenges p.20➾
OCTOBer 9, 2012
artefactual quiz p.23
Aaron Whitfield
Guiding lights
Drs. Tracy and Bev Burton are giving back to the organization
that helped shape their character in their youth
By Kylie TaggarT
T
15
win physicians Dr. Tracy Burton and Dr. Bev Burton joined the Girl Guides of Canada as
Brownies when they were six, and they’ve never looked back. Not when they went on to
university in their hometown of Lethbridge, Alta., not when they went to medical school
in Calgary, and not when they began to practise family medicine in Pincher Creek, Alta.,
a small town with a population of 3,685.
Now, what Guiding gave to them they are giving back every Monday night in a noisy school gym
in Pincher Creek. The Burtons are among the leaders of a Sparks and Brownie troupe of 40 girls
ages five to nine.
The sisters, now 31 years old, say their experiences in Guides have influenced their lives in a significant way. Bev says Guiding gave her courage and confidence through being able to try new things 
➾
Pr
16
OctOber 9, 2012
THE MEDICAL POST | life
canadianHealthcareNetwork.ca
ADVAlR® & PrADVAlR® DISKUS® (fixed combination of salmeterol
xinafoate and fluticasone propionate) are indicated for the
maintenance treatment of asthma in patients with reversible
obstructive airways disease. ADVAIR® DISKUS® (a dry powder
for inhalation) is specifically indicated for asthma patients
4 years of age and older; and ADVAIR® (an inhalation aerosol)
for asthma patients 12 years of age and older. The dose of
ADVAIR® or ADVAIR® DISKUS® should be titrated to the lowest
dose of fluticasone propionate at which effective control of
symptoms is maintained. Please refer to the Product Monograph
for complete prescribing information.
Aaron Whitfield
ADVAIR® & ADVAIR® DISKUS® are not indicated for patients whose
asthma can be managed by occasional use of a rapid onset,
short duration, inhaled, beta2-agonist or for patients whose
asthma can be successfully managed by inhaled corticosteroids
along with occasional use of a rapid onset, short duration,
inhaled, beta2-agonist.
Dr. Bev Burton (left) says Guides built her confidence as a child by being able to try
new things, while Dr. Tracy Burton says it allowed her to be more extroverted.
from • page 15
in a non-threatening environment. As for Tracy,
she says she gained the self-assurance to become
a bit more extroverted, “which has been a great
skill for my life.” She says the Guiding philosophy
of learning to serve others translated well into
the field of medicine.
Then there all the memories Guiding has
given them. One highlight was a trip they took
while in Rangers—the Guiding program for 15 to
17 year-olds—when they went on an eco-tour of
Costa Rica.
“We got to go right into the jungle,” Tracy says.
“It was fantastic.” At one of the camps their tents
were on platforms with stilts, because of the
“things that could potentially get into your tent.”
Guiding runs in the family. Their mother,
Chris Burton, has been involved in the movement for more than 50 years and recently finished her stint as chief commissioner of the Girl
Guides of Canada. Their father also helped out at
numerous Guide camps.
Although they did their residency in separate
places, the sisters moved to Pincher Creek about
four years ago to practise. They became leaders
within months of moving. They started with a
Sparks troupe (for girls ages five to seven) of eight
girls, but due to a shortage of leaders, the Brownies (ages seven to nine) and Sparks troupes were
combined. Some of the other leaders are parents,
but they also have a nurse, pharmacist, paramedic
and emergency medical technician helping
out. The girls call their leaders by their Guiding
names: Tracy is Razzle and Bev is Dazzle.
A typical one-hour meeting might involve a
warm-up with games and an activity, and closes
with a campfire circle with songs. At one meeting last year they made woven toques. The girls
loved it. “Almost every day throughout the winter you could see at least one kid with a toque on;
they were very distinctive,” Tracy says.
As leaders, they want to give back to the girls
what they gained from the Guiding movement.
“We’re trying to help them be confident
women, to be comfortable with themselves, to
not give into peer pressure or worry about how
they look, to not stop doing something because
of that, and to give them the courage to try
something new,” Tracy explains.
“We also want to give them some role modelling to show them they can become whatever
they want to become,” Bev adds. “It is why it is so
great we have a wide variety of leaders with us so
they know that whatever they set their minds to,
they can do.”
The Burton sisters have also lent their medical expertise to Guiding. In 2010, they served
as camp doctors at a 10-day camp near Guelph,
Ont., for 2,500 Guides from all over the world.
They practised in a tent with “pretty basic” supplies, supported by a number of nurses and other
medical staff.
“There were a lot of blisters, a couple of
broken bones—it happens, they’re kids—and a
lot of homesickness,” Dr. Bev Burton says. “For
the most part it was fairly run-of-the-mill stuff,
sprinkled with some chest pain, a few migraines
thrown in, things where it was good we had a bit
of expertise.”
Three of the doctors the Burtons practise
with have daughters in the Burtons’ Sparks and
Brownies group. One is Dr. Gavin Parker, whose
seven-year-old daughter Mia has been in Sparks
and then Brownies with the Burtons for three
years. He says he admires the level of commitment and energy the Burtons put into Brownies
and Sparks, especially when they do not have
children themselves.
Dr. Parker notes he and his colleagues make
sure the Burtons are able to leave early on
Monday nights by taking any of their walk-in
patients. “There are lots of other extracurricular
things they could be doing that would be purely
for themselves,” he says, “but they elect to spend
that time for the benefit of the young girls in the
community, and I think that is great.”
Even though they are identical twins, the girls
in the Burtons’ troupe have no trouble telling
them apart. “Almost instantly they can tell the
difference,” Tracy says. At work it is sometimes
more difficult, and she says some of the doctors
still have trouble differentiating between the
two. “They don’t always make it easy on us—I’m
pretty sure they share the odd blouse or pair of
shoes,” Dr. Parker says with a laugh.
Drs. Tracy and Bev Burton encourage other
physicians to consider volunteering with the Girl
Guides of Canada, even if time is an issue.
“There are a lot of other positions in Guiding other than just working with the girls (as a
leader), so a lot of physicians would be able to
give their time for those,” Bev says.
If you’re interested in volunteering with the
Girl Guides of Canada, go to www.girlguides.ca/
volunteer-opportunities.
ADVAIR® & ADVAIR® DISKUS® are contraindicated for the primary
treatment of status asthmaticus or other acute episodes of
asthma, or in patients with moderate to severe bronchiectasis.
They contain a long-acting beta2-agonist and should not be used
as a rescue medication. To relieve acute symptoms, a rapid onset,
short duration inhaled bronchodilator (e.g., salbutamol) should
be used. ADVAIR® & ADVAIR® DISKUS® are also contraindicated
for patients with: hypersensitivities to this salmeterol or to any
ingredient in the formulation or component of the container;
cardiac tachyarrhythmias; and untreated fungal, bacterial or
tuberculous infections of the respiratory tract. ADVAIR® DISKUS®
contains lactose (which contains milk protein) and is therefore
contraindicated in patients with an allergy to lactose or milk.
Asthma-Related Death
Long-acting beta2-adrenergic agonists (LABA), such as
salmeterol, one of the active ingredients in ADVAIR® and ADVAIR®
DISKUS®, increase the risk of asthma-related death. Data from
a large placebo-controlled US study that compared the safety of
salmeterol (SEREVENT® Inhalation Aerosol) or placebo added to
patients usual asthma therapy showed an increase in asthmarelated deaths in patients receiving salmeterol (13 deaths out
of 13,176 patients treated for 28 weeks on salmeterol versus
3 deaths out of 13,179 patients on placebo). Post-hoc analysis
of the SMART trial data suggests that the risks may be lower
in patients who were using inhaled corticosteroids (ICS) at
study entry. However, these post-hoc analysis results are not
conclusive. Currently available clinical data are inadequate to
determine whether concurrent use of inhaled corticosteroids
mitigates the increased risk of asthma-related death from LABA.
Available data from controlled clinical trials suggest that LABA
increase the risk of asthma-related hospitalization in pediatric
and adolescent patients.
Therefore, when treating patients with asthma, physicians should
only prescribe ADVAIR® or ADVAIR® DISKUS® for patients not
adequately controlled on a long-term asthma control medication,
such as an inhaled corticosteroid or whose disease severity
clearly warrants initiation of treatment with both an inhaled
corticosteroid and LABA.
Once asthma control is achieved and maintained, assess the
patient at regular intervals and do not use ADVAIR® or ADVAIR®
DISKUS® for patients whose asthma can be adequately controlled
on low or medium dose inhaled corticosteroids.
HPA-axis function and hematological status should be assessed
periodically in asthma patients. Height should also be regularly
monitored in children and adolescents receiving prolonged
treatment with inhaled corticosteroids. Concomitant use of
fluticasone propionate and ritonavir, an HIV protease inhibitor, has
been shown to result in clinically significant systemic
side effects and should be avoided unless the potential benefit
to the patient outweighs the risk. Concomitant use of systemic
ketoconazole (a strong cytochrome P450 3A4 inhibitor)
has been shown to increase exposure to salmeterol, which
may lead to prolongation in the QTc interval. Due to the potential
increased risk of cardiovascular adverse events, the concomitant
use of salmeterol with ketoconazole is not recommended.
In clinical studies, the most common side effects observed in
adolescents and adults with asthma were throat irritation (2%),
hoarseness/dysphonia (2-3%), headache (2%), and candidiasis
(2%) which can be reduced by rinsing and gargling with water
after inhalation; and palpitations (1%). In children aged 4 to 11
with asthma, the only adverse event with an incidence of >2%
was candidiasis.
Reference: 1. Brogan Inc; GPM®; July 2011 to June 2012
83558
08/12
ADVAIR®, DISKUS® and SEREVENT® are registered trademarks, used under license by
GlaxoSmithKline Inc.
™The appearance, namely the colour, shape, and size of the DISKUS® inhalation device,
is used under license by GlaxoSmithKline Inc.
© 2012 GlaxoSmithKline Inc. All rights reserved.
See prescribing summary on page 49
For your asthma patients.
Go ahead.
Breathe.
# 1 dispensed
e
Th
apy
r
e
h
t
o
b
m
co
ICS/LABA
1
.
a
d
a
n
a
in C
THE MEDICAL POST | LIFE
OCTOBER 9, 2012
Photos courtesy of Katherine McIntyre
18
Rediscovering
my roots
in Scotland
Exploring ancestral lands is like a magical trip
back through time
BY KATHERINE MCINTYRE
A
n old letter, written 40 years ago by a long forgotten cousin,
describes his return to “the old country” to find his roots.
This document inspired me to plan a three-generational trip
to discover exactly where in Scotland our ancestors lived, before
they immigrated to Canada.
Packed like sardines in a large rented van that held our group of six plus a mountain of
luggage, we exited from the Glasgow airport. Armed with an assortment of maps and
a GPS guide, we headed for a road that ran between Easter Tulloch and Wester Tulloch overlooking Loch Tay in the Perthshire Highlands. There we would fi
find
nd the McIntyre homestead.
Our first stop was in Inverness, where we had a vast choice of shops ready to outfit us in
our clan’s tartan hats and scarves. Suitably garbed, we continued our journey from Inverness
through rural Scotland’s green and misty hills to historic Kenmore, which was close to our
target: Loch Tay.
Our GPS led us to a narrow, single-lane road cutting through steep, rolling hills, dotted with
docile, woolly sheep. Following the description in my cousin’s letter, which said, “the house is
straight down the hill from the iron mine, half way between Easter Tulloch and Wester Tulloch,”
we found the small overgrown iron mine. And there, directly below it, were the remnants of our
family’s roofless, old stone house overlooking the loch.
From left: All that remains of the original
McIntyre homestead is the roofless foundation
of a stone house overlooking Loch Tay. At the
nearby heritage site Oakbank Crannog, a guide
discusses Iron Age tools. The former castle
of the Marquis of Breadalbane, who cleared
tenants from his land, will soon become a hotel.
➲ For more travel features go to the Medical Post’s online home:
www.CanadianHealthcareNetwork.ca/physicians/life-travel
Why no roof? Their landlord, the Marquis of Breadalbane, burned the roofs of all his tenants’ houses
when he cleared them from their land to pasture his
sheep. A single farm is all that remains of a once thriving community along this part of the loch.
“Are there any McIntyres still around?” we asked the
local farmer. “There’s one,” he replied in his thick Scottish burr, “but he’s out fishing.”
On lichen-covered gravestones in a small cemetery
in nearby Ardeonaig we deciphered family names.
Were they dour Scots? Did they play the bagpipes? Did
they eat haggis? Without these ancestors we wouldn’t
be here, searching for them on the shores of Loch Tay.
Another letter in our files, dated 1855, was from
18-year-old John McIntyre to his brother Donald, who
had gone to Canada to stake out Crown land. “Should
I come by sailing vessel or a steamship?” he wrote.
“Steamships are much quicker but dearer.”
The letter ends, “I received a letter from Donald
Stewart in which he shows that Canada is a lively country, that they spend much of their time in feasting and
drinking and that sports and amusement is carried on
to a great extent.”
Surveying the broken stone house and the green
hills, I mused, “Why is this beautiful loch with its steep
green hills still so empty? And what about the Marquis
who cleared out his tenants for sheep?” Apparently,
in two years he had gambled away his fortune. As for
his former castle, soon it will reopen as the Taymouth
Castle Estate, a posh hotel with its own golf course.
Further down the loch, we discovered Oakbank
Crannog, a demonstration village depicting the
advanced lifestyle of Iron Age residents, who lived
in the area long before the Scottish clans ruled the
country. Archeologists have unearthed old remnants of
their lives, including pieces of hand-woven cloth and
agricultural tools that were well-preserved in the deep,
cold water. It is unclear why they built their round,
wooden houses on stilts in the water instead of on the
secure, dry land.
Our next stop was the Roman Camp Country House
in the scenic village of Callander, situated in Scotland’s
Loch Lomond and Trossachs National Park. Built
in the 17th century as a shooting lodge for an Earl of
OCTOBER 9, 2012
Katherine McIntyre’s granddaughter,
Katie, surveys the countryside around Loch Tay
and her family’s ancestral home (above).
A trip to Scotland wouldn’t be complete without
a little bagpipe music by a piper in a kilt.
IF YOU GO
www.perthshire.co.uk
www.crannog.co.uk
www.romancamphotel.co.uk
19
Moray, it changed hands several times over the years.
For guests it is like coming into a substantial country
home with acres of property and its own private fishing stream. Lavishly furnished with antiques, real log
fireplaces and the Internet for the teens, it was our
treat of the trip.
My room, with its silk bedspreads and heavy
drapes, came with fresh fruit, a decanter of sherry and
a bathroom larger than most hotel rooms. My son and
daughter-in-law’s room had its very own ghost, whose
shadow appeared around midnight and turned on the
lights, and a little later the TV. The manager wasn’t
surprised when they discussed the ghost problem
in the morning. “There are several around. We don’t
know much about them,” he said. “They don’t bother
us.” This was not exactly the Canadian reaction.
One morning at breakfast, at the next table Scotland’s First Minister, Alex Salmond, discussed local
issues with some of his constituents. We would have
been those constituents had our ancestors stayed in
Scotland. Instead we were guests in the lord of the
manor’s hotel.
And did the McIntyres in my family’s letters immigrate to Canada? Indeed, they came by steamship
but their first years were bleak. By 1855 most of the
best land had been claimed. Donald’s land grant was
a piece of virgin forest in Ontario’s Bruce Peninsula.
Their possessions were floated
floated down the Saugeen River
and the family walked through the bush to find their
new home, a cold log cabin far from churches and
schools. They eventually prospered and moved to the
nearby village of Paisley, where they are buried in the
local cemetery. Now their descendants populate Canada from coast to coast.
As for me, the visit to my family’s ancestral home
in Scotland was magical, and we felt as if we had gone
back in time. The green and misty hills and high
streets harken back to the 19th century and are soothing to the eye. Afternoon tea with scones, butter and
jam is restorative. Everyone is courteous, and if it rains
they just use an umbrella and no one ever complains
about the weather.
Katherine McIntyre is a Toronto writer.
Omnaris has shown
a rapid onset of action*...
®
Powerful AR relief. Excellent tolerability profile.
NYC OMN 11032 Med_Post third_pg_tab.indd 1
12-03-20 1:27 PM
CHANGE #
PRODUCTION NOTES
CHANGES BY
APPROVAL
00
COPY DECK #
FILE BUILT AT:
v1
ACCOUNT
ACCOUNT
100%
CREATIVE DIRECTOR
CREATIVE DIRECTOR
SIGNATURE
OMN-2012-03E-TAB
20
OCTOBER 9, 2012
It takes a village
A physician reflects on why
we are failing to make gains
in maternal health
Chris van Es
IN HER NEW BOOK, Dr. Gretchen Roedde
looks back on 25 years of experience working in
women’s health in 15 developing countries, particularly in Africa. The big theme: Why is maternal health, or the United Nations’ “Millennium
Development Goal #5” moving so slowly, with
the least momentum of all these goals? And why
has there been especially little progress in subSaharan Africa? In the following passages from
her book, Dr. Roedde reflects on two experiences
in Tanzania and the gaps and barriers that exist in
providing women there with safe childbirths.
Dr. Roedde’s book hit the Globe and Mail’s
Canadian non-fiction best-seller list last month
in advance of its Sept. 8 release date. She says the
early support likely came from the readings she
has given to non-governmental organizations
and church groups. Dr. Roedde is donating all
proceeds from her book to projects that support
maternal health.
Excerpted with permission from: A Doctor’s
Quest: The Struggle for Mother and Child Health
Around the Globe, © 2012 by Gretchen Roedde. All
rights reserved. Published worldwide by Dundurn
Press (dundurn.com).
BY GRETCHEN ROEDDE
T
1997
he road stretched empty ahead and
behind our pickup truck in a remote
area of Tanzania. A man with a bicycle
was desperately flagging us down. On
the back of the bike was a basket, and
in the basket, his pregnant wife. He was taking her
to hospital, a trip that could take four hours even
without a pregnant woman in the basket, and
probably double that given her current condition.
Labour was well underway.
My Tanzanian colleagues from the national family
planning program and I stopped to help. In her
one antenatal check at four and a half months, she
had been advised to have this baby in the hospital
because this was her sixth delivery with higher risks.
When her contractions began five hours ago, she had
sent a messenger to find her husband on the family
farm, but it took time for him to find a bicycle, as
well as money to pay for her hospital care.
Standing beside the bike, with a toothless face
wreathed in smiles, was the labouring woman’s
mother. My colleagues moved from their seat and
positioned themselves in the open back of the truck
with the husband and his bike. The mother-to-be
and her mother took the bench seat, the older
woman with a bag of worn metal pots and wellwashed rags.
I asked, through the driver who acted as translator, how long the woman had been in labour, how
many times she had given birth. Did the grandmother know how to deliver? She pointed proudly
to the clean, patterned cotton rags and the small
battered tin pots. The labouring woman was silent
and then gave a small, worried sigh.
Turning around, I lifted the pregnant woman’s
skirt to see the baby’s head crowning, as well as
meconium staining, indicating fetal distress. I took
one of our bottles of water, poured it over my hands,
and crossed myself, as did the smiling grandmother.
Then I carefully protected the baby’s head as it
emerged, glistening, the dark hair wet and streaked
with its mother’s blood-tinged mucus. Holding the
baby’s head with my open left hand, I slowed its
arrival and tucked the fingers of my right hand to
feel around the neck. The cord was wrapped around
the baby’s neck twice. Still twisted in my seat, I
untangled the cord and delivered the baby boy while
we were driving. The blue-faced infant didn’t cry
despite my desperate efforts to spank him into some
kind of response. Seconds later a small health centre
miraculously appeared. I asked the driver to run
for a midwife and tell her we had a newly delivered,
unresponsive baby in the truck.
Out came the smiling Tanzanian midwife, wearing a starched white uniform and a blue-banded
hat. She pulled on gloves and carried a metal basin
and a syringe to suction the mucus from the baby’s
mouth and nose. The midwife managed to get the
baby to cry lustily before she delivered the placenta.
Moments later we were helping mother, child and
grandmother into the little clinic. The midwife
took the newborn boy and placed him, naked and
uncovered, on a bare metal weighing scale. She
then laid this newly delivered woman on the concrete floor, took a hose connected to the local water
tank, and washed her down with cold water, cleaning the blood from her legs, genitals and abdomen. 
I washed my hands with iodine
soap, remembering that seven
per cent of adults in that
area were HIV-positive, and
I had delivered the baby with
no gloves.
2006
TANZANIA had reduced the
deaths of children younger
than five years by 40%, but
maternal health had stalled.
Sixty-five per cent of women
with no education delivered
at home, and just over one per
cent of them had access to a
cesarean section because of
user fees, lack of transport or
the distance to a health facility.
I was sitting with “Prof,” a
Tanzanian physician, on the
brown grass under a tree in
front of a mud and cow dung
hut. Wind rustled the leaves. It
had been a three-hour drive on
rutted roads, then a half-hour
walk down a muddy path, to
get to this Masai village.
Prof and I were listening
to Neema, who was shyly
explaining how she had given
birth to her daughter. Her earlobes were adorned with heavy
beaded rings, leaving wide,
gaping, disc-shaped holes.
A large white necklace ruff
accented with blue and yellow
beads circled her neck, while
a burgundy shawl covered her
upper body and breasts over
a bright navy blue wrap. Her
skin glistened with the sheen
of sweat, which gave off an
earthy, slightly sweet smell and
melded with a wafting suggestion of breast milk. These
blended with the wood smoke
from the cooking fire. Flies
buzzed above our heads, darting to the cooking pot. Neema’s
baby was kept close to her body
in a sling. Prof translated.
“I was married at 13. It
was the harvest season. I was
chosen by one of the newly
circumcised warriors. After I
was chosen, I was circumcised.
I was worth many cows! My
father was happy. My husband
is a good man, but I barely
knew him. I had to leave school
to marry. I became pregnant
right away and then learned
from the women in the village how to be brave when I
brought her into the world.
The men had to leave. My
mother and sisters helped me.
They massaged my belly with
oil. They boiled the water over
this fire. It was late at night,
and I could watch the stars
high above me through the
doorway. I was safe.”
Prof moved closer to Neema,
turned slightly away from her
out of politeness. He asked her
difficult questions in a gentle
manner over the next hour.
“Do you know anyone who has
had trouble giving birth? Has
anyone you know from this
village had to go to the hospital
to deliver their babies? Did you
know that the circumcision
you had, the ‘female genital
cutting,’ makes you more at risk
for getting HIV/AIDS or for
bleeding giving birth?”
“You have some strange
ideas,” Neema said. “Once
we are betrothed, we are cut.
We are brave to face this. My
mother paid 10,000 Tanzanian
shillings for me to have this
done so I would be clean for my
husband. And to give birth in a
hospital? We couldn’t do this.
The distance is far. I don’t have
the money! I wouldn’t know

OCTOBER 9, 2012
where to go. But there is no
need. We can manage safely in
the village. I had many women
with me who knew what to
do. Look around you! Look
at all these kids playing and
laughing. They were all born
here. And it was night when
my daughter was born. It isn’t
safe to travel at night.” Neema
lowered her head and her voice
and whispered, “Spirits.”
21
These two encounters,
nearly a decade apart, demonstrate that we need to continue
to close the gap between the
strengths of the village and
those of the health system to
deliver women safely.
Gretchen Roedde is a global
reproductive health consultant
and GP in Temiskaming
Shores, Ont.

Paging . . .
What your colleagues are reading
BOOKS LIKE THE QUEST FOR MENTAL HEALTH (Cambridge University Press,
2011) by Dr. Ian Dowbiggin (PhD) should be placed on syllabi in the pre-clerkship
years at medical schools. They introduce to young minds what is was like to be a
doctor in the past, and what was done by the best and by the most misguided of us.
In knowing this history, a doctor is better prepared to avoid the pitfalls of authority,
but also better able to benefit from the wild ingenuities of our predecessors.
The problem with surveys of medical history is that, by necessity, they are fly-bys
of centuries. Dr. Dowbiggin, a history professor at the University of Prince Edward Island, begins
his book with Rousseau and rockets to the very recent present, and only the dullest of readers
wouldn’t want a character or incident explained in greater, richer detail. Yet his piloting is sure, for
there aren’t moments where one feels he’s circling the jet.
The other problem with historical review is author bias. Dr. Dowbiggin is neutral about distant
events, but as he enters the latter half of the 20th century his skepticism veers into a mild anti-
psychiatry stance—the harsh tone of the last chapter undermines the more masterful treatment
of distant history. Much of what he says about the near-present is true, but a book that partially
rests on an anecdote about an Oprah show featuring Ricky Williams is reliant upon celebrity idiocy
as a gotcha. The problem here is that there are countless other examples of mental health advocates and patients playing a more positive role.
These small criticisms aside, Dr. Dowbiggin has written a near-comprehensive book that discusses the role of physicians but focuses also on individual patients, famous reformers, cataclysmic social changes and the contributions of psychology. The Quest for Mental Health arranges all
these pieces coherently as a narrative that ranges smoothly and (save for its final chapter) provocatively.—Dr. Shane Neilson is a family physician in Erin, Ont.

• What are you reading? Please send your Paging entry to [email protected].
...and powerful
AR relief, too.
1,2
See prescribing summary on page xxx
42
NYC OMN 11032 Med_Post third_pg_tab.indd 2
12-03-20 1:28 PM
OMN-2012-04E-TAB
EFFEXOR® XR is offered
to patients at no additional
cost* versus the generic
version through Pfizer
Strive Payment Assistance!†
Pr
Indicated for:1
- Depression
- Generalized Anxiety Disorder
- Social Anxiety Disorder
- Panic Disorder
Patients must have a valid prescription for EFFEXOR XR
or its generic version
Strive
How does Pfizer
Strive Payment
Assistance work?
Patients enroll in the Pfizer Strive Program at www.PfizerStrive.ca
to receive their personal payment assistance card
Patients present the Pfizer Strive Payment Assistance card
with their prescription and request EFFEXOR XR brand
medication
Pfizer will pay the difference between EFFEXOR XR
and the generic version†
* Refers to the drug cost; dispensing fees not covered.
† Program is not available in Manitoba and Quebec.
To obtain Strive Payment Assistance cards
for your patients, please visit
www.rxhelp.ca
or call 1-866-794-3574.
©2012
Pfizer Canada Inc.
Kirkland, Quebec
H9J 2M5
TM Pfizer Inc, used under license
Effexor ® Wyeth LLC., owner/
Pfizer Canada Inc., Licensee
xx
OCTOBER 9, 2012
23
Notes to self from my first
year of practice
year in practice. Far be it from
me, with my vast (not) clinical
experience, to tell you what
you should do. I’m the young
doctor here. I’d prefer to think
of these as my “Notes to self,” in
no particular order:
Do up narcotic contracts.
Maybe not for a one-time script,
but if someone is back for a
third time, just do it. Blame it
on your own obsessive tendencies, or the college or clinic rules
if you need to wiggle out of the
awkwardness. But do it.
Attend your patients in
labour. Maybe the case room
nurses are more than capable
(and better at pelvic exams than
you are, anyway), and maybe
you’re keeping track of things
regularly over the phone, but
sometimes just showing up
can tip the balance in favour of
a good old-fashioned vaginal
delivery. You’re not sleeping
anyway—who are you kidding?
Wash your hands. Introduce yourself. Ask about your
patients’ social situations. All
that med school 101 stuff still
matters.
Have the “what-to-dowhen” talk with the families
of patients you’re palliating at
home. Encourage them to call
a funeral home. Leave a death
•
MONICA KIDD
Pausing to look
back allows us
to see what we’re
doing well and
where to improve
I
had big plans for the end
of my year-long locum.
In my last week, I would
go through all my patient
encounters and come up with a
tally of how many Pap smears,
ear syringings, mole removals,
smoking cessation talks,
healthy baby visits, et cetera, et
cetera, I had logged in a year of
working in an academic family
practice. I would figure out
what I had missed in followup,
fix what I could and hand the—
what?—two or three things left
over to the new locum
following behind me.
One woman’s optimism is
another woman’s fantasy.
I got through most of the
second day before I gave up.
True, if I were more adept at
our EMR, I may have been able
to expedite my Herculean task.
Instead, I quickly perused my
patient list and came up with a
list of the most pressing things
to tell the team about, then
hoped I’d had the good sense
to put solid plans in place for
people as we went along. I gave
the new locum my list and my
cellphone number, and got on a
plane for my new gig.
A month later, I haven’t
heard from her. I hope no news
is good news.
So, instead of presenting
my grand tally, I thought I’d
take a page from that old
chestnut, Rainer Maria Rilke’s
Letters to a Young Poet (or,
perhaps more appropriately,
Dr. Richard Selzer’s Letters to a
Young Doctor) and share a list
of things I learned over my first
•
•
•

Wash your hands. Introduce
yourself. . . . All that med school 101
stuff still matters.

—Dr. Monica Kidd
certificate. Just like asking about
suicidal ideation, discussing the
logistics of death at home will
not trigger it; it will clear the air.
If a resident is willing to
take on patient problems as
personal projects, generally
speaking, she or he is going
to do just fine. Residents who
start reviewing with, “Mr. X
is just here for . . .” generally
need a little more scrutiny. But
also be wary of the resident
who seems to have asked every
question and examined every
system in 4.7 minutes.
Don’t be afraid to look
stuff up in the Compendium of
Pharmaceuticals and Specialties while in the room with the
patient.
Call patients at home.
Whether it’s to provide a test
result or just to see if they’re
getting better, it doesn’t matter.
They appreciate knowing they
continue to exist for you after
clinic ends.
Of course there’s much more
•
•
•
I learned this year, and I’m still
just digging in on the steepest
part of the learning curve. But
when I started practice I was
terrified by all I didn’t know,
and I’ve been astounded and
humbled by how—er—patient
my patients have been with me.
Packed into my boxes of books
and exam equipment when I
left the clinic were a stack of
photos of babies I’d delivered,
thank you cards, handmade
gifts (someone made me a quilt,
if you can believe it) and e-mail
addresses from former patients
who hoped we could be friends
now that I was no longer their
doctor.
Maybe the most important
thing I learned, as corny as it
sounds, is just what a privilege
being a physician really is.
Monica Kidd is a family physician and this fall starts a new
job as assistant professor in the
Department of Family Medicine
at the University of Calgary.
Artefactual
Test your medical history knowledge
WITH MORE THAN 35,000 OBJECTS
in its collection of medical treasures, the Museum of
Health Care at Kingston in Ontario delights history buffs
with its wide array of unusual devices. Their uses may
surprise you! You might think your office equipment
is ancient, but here you can test your knowledge of
some slightly more archaic tools. Additional quizzes are
available at CanadianHealthcareNetwork.ca, and check
out the museum’s website for even more fascinating
objects at http://artefact.museumofhealthcare.ca.
What is it?
a) Scarificator
b) Lebenswecker
c) Vaccinator
d) Artificial leech
The answer to this quiz can be found on page 31.
The face of the object below
is shown in detail above.
From the Museum of Health Care at Kingston. Used with permission.
Reference: 1. EFFEXOR XR Product Monograph,
Pfizer Canada Inc., July 2012.

Depression: EFFEXOR XR is indicated for the
symptomatic relief of major depressive disorder.
The efficacy of EFFEXOR XR capsules (extended
release) in maintaining an antidepressant
response for up to 26 weeks following response to
8 weeks of acute treatment was demonstrated
in a placebo-controlled trial.
GAD: EFFEXOR XR is indicated for the symptomatic
relief of anxiety causing clinically significant
distress in patients with Generalized Anxiety
Disorder. Anxiety or tension associated with the
stress of everyday life usually does not require
treatment with an anxiolytic. The effectiveness of
EFFEXOR XR in long-term use has been evaluated
for up to 6 months in controlled clinical trials.
Social Anxiety Disorder: EFFEXOR XR is indicated
for the symptomatic relief of Social Anxiety
Disorder, also known as Social Phobia. The
efficacy of EFFEXOR XR capsules as a treatment
for Social Anxiety Disorder was demonstrated in
four 12-week, multicentre, placebo-controlled,
flexible-dose studies and one 6-month, fixed/
flexible-dose study in adult outpatients meeting
DSM-IV criteria for Social Anxiety Disorder.
Panic Disorder: EFFEXOR XR is indicated for
the symptomatic relief of Panic Disorder, with
or without agoraphobia, as defined in DSM-IV.
The efficacy of EFFEXOR XR in prolonging time
to relapse in Panic Disorder for up to 6 months
in responders of a 12-week acute treatment
was demonstrated in a placebo-controlled trial.
The physician who elects to use EFFEXOR XR
for extended periods should periodically
re-evaluate the long-term usefulness of the
drug for the individual patient.
EFFEXOR XR is not indicated for use in children
under 18 years of age. Use of SSRIs and
other newer antidepressant drugs in patients
under the age of 18 may be associated with
behavioural and emotional changes, including
an increased risk of suicidal ideation and
behaviour over that of placebo.
There are clinical trials and post-marketing
reports with SSRIs and other newer antidepressants, in both pediatrics and adults,
of severe agitation-type adverse events
coupled with self-harm or harm to others.
The agitation-type events include: akathisia,
agitation, disinhibition, emotional lability,
hostility, aggression, and depersonalization.
In some cases, the events occurred within
several weeks of starting treatment.
Rigorous clinical monitoring for suicidal ideation
or other indicators of potential for suicidal
behaviour is advised in patients of all ages.
This includes monitoring for agitation-type
emotional and behavioural changes.
An FDA meta-analysis of placebo-controlled
clinical trials of antidepressant drugs in adult
patients ages 18 to 24 years with psychiatric
disorders showed an increased risk of suicidal
behaviour with antidepressants compared
to placebo.
The possibility of fracture should be considered
in the care of patients treated with EFFEXOR XR.
Elderly patients and patients with important
risk factors for bone fractures should be
advised of possible adverse events which
increase the risk of falls, such as dizziness
and orthostatic hypotension, especially at
the early stages of treatment but also soon
after withdrawal.
Patients currently taking EFFEXOR XR should
NOT be discontinued abruptly due to risk of
discontinuation symptoms; rather, a gradual
reduction in dosage should be used.
Please see Product Monograph for complete
Indications, Warnings & Precautions,
Contraindications, Adverse Events, and
Dosage & Administration. Product Monograph
available upon request.

24
OCTOBER 9, 2012
California Zinfandels
pair quality with
character
For the prevention of stroke and systemic embolism in patients with atrial fibrillation,
in whom anticoagulation is appropriate.
Xarelto® is contraindicated in patients: with clinically significant active
bleeding, such as gastrointestinal bleeding, including that associated with
hemorrhagic manifestations, bleeding diathesis, or patients with spontaneous
impairment of hemostasis; with lesions at risk of clinically significant bleeding, eg,
cerebral infarction (hemorrhagic or ischemic) within the last 6 months; active peptic
ulcer disease with recent bleeding; receiving concomitant systemic treatment
with strong inhibitors of both CYP 3A4 and P-glycoprotein (P-gp), such as
ketoconazole, itraconazole, voriconazole, posaconazole, or ritonavir; with hepatic
disease (including Child-Pugh Class B and C) associated with coagulopathy, and
having a clinically relevant bleeding risk; who are pregnant; who are nursing; and
those who are hypersensitive to Xarelto® or to any ingredient in the formulation.
Flourishing in California’s warmer climates, Zinfandel
grapes are found in all of the state’s grape-growing regions.
ing sweet spicy oak and white
pepper notes.
Rock Wall Wine Company
2009 Monte Rosso Reserve
Zinfandel, Sonoma County
(89) has deep berry fruit with
gentle mineral and flower notes.
Peachy Canyon Wines,
2009 Vortex Zinfandel, Paso
Robles (90) has rich, ripe raspberry and wild strawberry fruit
seasoned with pungent Asian
spice notes.

I
t’s a classic American
rags-to-riches story: A
humble immigrant grape
variety from Croatia named
Crljenak Kaštelanski moves to
the United States in the late
19th century, changes its name
to Zinfandel, and becomes
rich, famous and as American
as apple pie.
Four of Zinfandel’s heaviest hitters from Golden State
wineries recently presented an
informative and entertaining
tasting of California Zinfandel
wines in Toronto. The wines,
at prices clustered around $40,
were outstanding. If you can’t
find these bottlings where you
live, other California Zins will
show similar characters with
quality at every price level.
Storybook Mountain
Vineyards 2009 Napa Estate
Zinfandel (score 90+) is a
sweetly ripe wine with brambly
cherry, mineral and wood aromas and flavours.
Robert Biale Vineyards
2009 Grande Vineyard Zinfandel, Napa Valley (score
89+) has pungent mineral and
wood notes around sweetly ripe
black cherry and blackberry
fruit. There’s a late toasty note.
Seghesio Family Vineyards
2009 Cortina Dry Creek
Valley Zinfandel (score 90)
is complex with rich ripe raspberry and plum fruit with vanilla and smoky mineral notes.
Ridge Lytton Springs
2009 Dry Creek Valley (score
90+) offers plush raspberry,
blackberry and plum fruit with
sweet spicy wood and mineral
notes.
Ravenswood 2008 Old
Hill Vineyard, Sonoma Valley Zinfandel (91+) is complex
and elegant with black cherries
and dark chocolate and beguil-
iStockphoto
IRVIN WOLKOFF
Candor/Hope Family
Wines Non-Vintage Candor
Lot 3 (90) features sweet, ripe
wild strawberry, raspberry and
plum fruit with mineral notes.
For more information
about California Zinfandel,
visit the Zinfandel Advocates
& Producers website at http://
zinfandel.org.
Irvin Wolkoff is an oenophile
and psychiatrist in Toronto.
Scenes We’d Like
to See . . .
By Dave Whamond, with respect and apologies
to Rex Morgan, M.D.
Xarelto®, like other anticoagulants, should be used with caution in patients with
an increased bleeding risk. Bleeding can occur at any site during therapy with
Xarelto®. The possibility of a hemorrhage should be considered in evaluating
the condition of any anticoagulated patient. Any unexplained fall in hemoglobin
or blood pressure should lead to a search for a bleeding site. Patients at high
risk of bleeding should not be prescribed Xarelto®. Should severe bleeding
occur, treatment with Xarelto® must be discontinued and the source
of bleeding investigated promptly. Close clinical surveillance (looking for
signs of bleeding or anemia) is recommended throughout the treatment period,
especially in the presence of multiple risk factors for bleeding.
Concomitant use of drugs affecting hemostasis increases the risk of bleeding. Care
should be taken if patients are treated concomitantly with drugs affecting hemostasis
such as nonsteroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid (ASA),
and platelet aggregation inhibitors. Due to the increased bleeding risk, generally
avoid concomitant use with other anticoagulants. Concomitant ASA use (almost
exclusively at a dose of 100 mg or less) with either Xarelto® or warfarin during the
ROCKET AF trial was identified as an independent risk factor for major bleeding.
Safety and efficacy of Xarelto® have not been studied in patients with prosthetic
heart valves, or those with hemodynamically significant rheumatic heart disease,
especially mitral stenosis. There are no data to support that Xarelto® 20 mg (15 mg
in patients with moderate renal impairment) provides adequate anticoagulation in
patients with prosthetic heart valves, with or without atrial fibrillation. Therefore,
the use of Xarelto® is not recommended in this setting.
Strong CYP 3A4 inducers, such as rifampicin, and the anticonvulsants, phenytoin,
carbamazepine, phenobarbitone, should generally be avoided in combination
with Xarelto®.
As with any anticoagulant, patients on Xarelto® who undergo surgery or invasive
procedures are at increased risk for bleeding. In these circumstances, temporary
discontinuation of Xarelto® may be required.
When neuraxial (epidural/spinal) anesthesia or spinal puncture is performed,
patients treated with antithrombotics for prevention of thromboembolic
complications are at risk for developing an epidural or spinal hematoma that may
result in long-term neurological injury or permanent paralysis.

The risk of these events is even further increased by the use of
indwelling epidural catheters or the concomitant use of drugs
affecting hemostasis. Accordingly, the use of Xarelto®, at doses greater
than 10 mg, is not recommended in patients undergoing anesthesia
with post-operative indwelling epidural catheters. The risk may also
be increased by traumatic or repeated epidural or spinal puncture. If
traumatic puncture occurs, the administration of Xarelto® should be
delayed for 24 hours.
Xarelto® should be used with caution in patients with moderate renal impairment
(CrCl 30-49 mL/min), especially in those concomitantly receiving other drugs
which increase rivaroxaban plasma concentrations. Physicians should consider the
benefit/risk of anticoagulant therapy before administering Xarelto® to patients
with moderate renal impairment with a creatinine clearance close to the severe
renal impairment category (CrCl <30 mL/min) or in those with a potential to have
deterioration of renal function to severe impairment during therapy.
The use of Xarelto® is not recommended in patients with severe renal
impairment. Patients who develop acute renal failure while on Xarelto® should
discontinue such treatment.
Bleeding is the most frequent side effect of Xarelto®. In patients with atrial fibrillation
treated with Xarelto® for the prevention of stroke and systemic embolism, major
and nonmajor clinically relevant bleeding occurred in 14.9% of patients per year.
Mucosal major bleeding was more common in the Xarelto® group (2.4%/year)
as compared to the warfarin group (1.6%/year; HR 1.52 (1.25,1.83) P < 0.001).
Most of the mucosal major bleeding was from a gastrointestinal site. The top five
treatment-emergent adverse reactions in the ROCKET AF trial, in patients with
atrial fibrillation, occurring in >1% include: epistaxis (10.1%, Xarelto® vs. 8.6%,
warfarin); dizziness (6.1% vs. 6.3%); edema peripheral (6.1% vs. 6.2%); diarrhea
(5.3% vs. 5.6%); and headache (4.6% vs. 5.1%).
Please see Xarelto® Product Monograph for complete prescribing information.
Reference: 1. Xarelto® (rivaroxaban tablet) Product Monograph, January 2012.
® Bayer, Bayer Cross, Xarelto and Xarelto Diamond Design are trademarks of
Bayer AG, used under license by Bayer Inc.
© 2012, Bayer Inc.
XARELTO :
®
Now for Prevention of Stroke and Systemic
Embolism in Atrial Fibrillation
A Small Tablet
for Your Patients to Remember
(actual size)
One tablet, once daily. No routine coagulation
monitoring*. No special dietary restrictions.
Xarelto® 15 and 20 mg tablets should be taken with food
6 mm film-coated tablet
*The INR is only calibrated and validated for VKA and should not be used for any other anticoagulant, including Xarelto®.
Prothrombin time (PT) values using the Neoplastin® reagent may be useful in determining excess anticoagulant activity in patients who are bleeding.
26
OctOber 9, 2012
The true
first transplant
I
by teRRy MuRRay
courtesy of little company of Mary Hospital
t is widely accepted that the
first human organ transplant—
a kidney—was done in 1954 at
the Peter Bent Brigham Hospital
in Boston.
That’s when a surgical team, led by
Dr. Joseph Murray, removed a kidney
from Ronald Herrick and grafted it
into his identical twin brother Richard.
Richard had Bright’s disease and his kidneys were failing. He lived for another
eight years, dying in 1963 of coronary
artery disease after developing Bright’s
in the transplanted organ. (Ronald Herrick died in 2010, at the age of 79.)
Dr. Murray’s status as having performed the first organ transplant seems
to have been sealed in 1990 when he,
along with Dr. E. Donnell Thomas of
the Fred Hutchinson Cancer Center
in Seattle, received the Nobel Prize
in Physiology or Medicine “for their
discoveries concerning organ and cell
transplantation in the treatment of
human disease.”
But a little-known human kidney
transplant from a cadaveric donor had
been done four years before the Boston
case. In 1950, surgeons at Little Company of Mary Hospital in the Chicago
suburb of Evergreen Park, headed by
Dr. Richard Lawler and Dr. James West,
removed a kidney from a 49-year-old
woman who died of cirrhosis of the
liver, and transplanted it into a 44-yearold woman.
Dr. West, the last surviving member
of that transplant surgical team, died
in late July at his home in Palm Desert,
Calif. He was 98 years old, and had suffered from congestive heart failure. In
an interview just weeks before he died,
Dr. West said he did not begrudge
Dr. Murray the Nobel Prize, but felt
that his work with Dr. Lawler should
be recognized as the first human organ
transplant.
“We didn’t go back to it, but we
established the fact it could be done,” he
told the Medical Post, adding, “It should
be listed as the first one that was done.”
He said the Boston group had been
“lucky” to find a patient with end-stage
kidney disease who had an identical
twin, thereby circumventing the problem of rejection. As for Dr. Murray’s
Nobel Prize, “That was right,” Dr. West
said. “He deserved it, but our group
should have been mentioned.”
Dr. West, whose principal role in the
1950 transplant had been to harvest the
The death of Dr. James West, the last
surviving member of Chicago team that did
controversial kidney transplant in 1950,
revives the memory of this milestone surgery
Dr. Raymond Murphy (from left), Dr. James West and Dr. Richard Lawler,
the surgeons involved in the 1950 kidney transplant, held a reunion
at Little Company of Mary Hospital in 1972.
donor kidney, practised surgery for 40
years. A recovering alcoholic, he pursued additional studies in psychiatry
and substance abuse disorders, and
started the Illinois State Medical Society Panel for the Impaired Physician.
He became physician director of the
Betty Ford Center in Rancho Mirage,
Calif., when it opened in 1982, and
served as its medical director from 1983
to 1989. He then became physician director of the outpatient program, until
his retirement in 2007 at age 93.
However, neither he nor Dr. Lawler,
who had done several years’ research
and experimentation on dogs before
the human case, attempted another
transplant. While both claimed, diplomatically, that they had simply wanted
to kick-start transplantation attempts—
which was indeed one result of their
work—the truth is that the operation
had been controversial, earning them
censure from both their colleagues and
the Catholic church. In addition, Ruth
Tucker, the recipient, had a puzzling
postoperative course.
Opposition
“This was very controversial,” Dr. West
told the Catholic New World, a Chicago newspaper, in 2004. “Even in the
medical community. We had many
doctors who supported it, but many
were against it. The clergy in particular
opposed this procedure—they were
opposed to the idea that you could take
tissue from someone who was dead and
put it in someone who was alive and
it would come back to life. It was like,
once it was dead, it should stay dead.”
Little Company of Mary Hospital
is so named for the order of nuns that
operates it. “The sisters of the Little
Company of Mary knew us well enough
to trust us with doing this radical,
bizarre operation,” Dr. West added.
Tucker had bilateral polycystic
kidney disease. The transplant bought
her another five years—she died of a
coronary thrombosis complicated by
pneumonia—even though the graft was
deemed to have functioned for only two
months at most.
Drs. Lawler and West, as well as urologist Dr. Patrick McNulty and surgeon
Dr. Raymond Murphy, had matched the
recipient and donor for size and blood
group, including Rh status—the best
matching that was possible at that time.
Tucker’s new kidney began putting
out urine almost immediately. By two
months post-transplant, urine production had decreased a bit. An injection
of indigo carmine dye showed that the
graft was still functioning, but a retrograde pyelogram suggested a stricture
was developing at the anastomosis of
the two ureters.
The next day, the surgeons opened
the incision to address the stricture,
but deferred it when they found a small
encapsulated abscess, Dr. Lawler wrote
in Medical World News in 1972. However, he did examine the kidney, finding
it to be “normal in size, colour and feel,”
he said, adding, “There weren’t any visible signs that the homograft was being
rejected.”
Five days later, Tucker was discharged from the hospital—and
immediately set out on a 300-mile road
trip with her family to an American
Legion convention where she “danced
and dined the whole next week away,”
Dr. Lawler reported.
Drs. Lawler and West and their
colleagues reported the transplant in
a “preliminary report” in the Journal
of the American Medical Association
in November 1950, a mere six months
after the procedure, noting that “conclusions to be drawn from this case
are necessarily withheld until there is
more permanency of the graft.” Yet,
a French researcher called the report
a “bombshell” that renewed his own
transplantation attempts.
Tucker’s health remained “excellent,”
Courtesy of little Company of Mary Hospital
but her urine output declined sufficiently
by 9.5 months after the transplant that
Dr. Lawler thought the stricture might be
progressing, and operated on her again.
“To our surprise we didn’t find any
strictures but a much smaller, shrunken
kidney instead,” he said, describing the
toll rejection had taken on the organ.
“It had diminished from normal size to
about that of a large walnut. Although
the tissues still looked alive, the organ
clearly was not producing urine.”
The surgeons left the shrivelled
transplant in place, but didn’t tell
Tucker what they’d found. However, she
learned about it from a Chicago newspaper reporter who had covered the
annual meeting of the American Urological Association in May 1951. There,
Dr. McNulty reportedly said the graft
had never functioned. When the reporter told her this, Tucker said the news
came to her “as a great shock,” but she
“felt fine” and refused to believe it. In
fact, she said she could feel the kidney.
But when a reporter from Time magazine called her, she was reported to have
said, “What a way to get your death sentence—from a newspaper reporter.”
In fact, Dr. Lawler later recalled that
reporters “pestered the life out of the
OCtOber 9, 2012

This was very
controversial. . . .
We had many doctors
who supported it,
but many were
against it.
—Dr. James West

Ruth Tucker (left), received
a kidney from a cadaveric
donor on June 17, 1950,
in Chicago. Dr. James
West (right) in 2006.
Courtesy of the betty ford Center
Tuckers—so much so, I think, that
when she died, the family refused to
allow an autopsy to be performed. So
we’ll never know what finally happened
to the graft.”
He said he couldn’t account for her
survival, but speculated that the graft
“took the load off the other diseased kidney long enough to allow it to eventually
handle most of her body’s requirements.”
Although Dr. McNulty is reported to
have said the transplant was a failure,
Drs. Lawler and West both said in subsequent publications and comments
that the graft had worked for at least
several months.
Dr. Lawler retired in 1979 after 47
years on the staff at Little Company.
27
When he died in 1982 at the age of 86,
his obituary in the New York Times
quoted him as saying the reason he
never attempted another transplant
was that “I just wanted to get it started.”
In the interview shortly before his
death, Dr. West told the Medical Post
the same thing.
But it was the professional and
church censure as well as constant
media scrutiny that caused him to give
up further transplantation attempts,
Dr. Lawler allowed in the Medical World
News article. “Headlines describing the
transplant appeared in newspapers and
magazines around the world and stirred
up a great turmoil in the medical profession,” Dr. Lawler wrote.
“Locally, I was ostracized by much of
the profession. There were so very few
supporters. Some of my good friends
wouldn’t even talk to me for fear that I
would contaminate them. I think some
of this was due to the feeling at the time
that doctors who got their names into
the newspapers were trying to advertise
themselves.”
He added: “For our group to have
done another (transplant) would have
been like waving a red flag in front
of a bull.” MP
®
(sitagliptin phosphate monohydrate
and metformin hydrochloride)
For more information on JANUMET® and JANUVIA®, please contact our
Customer Information Centre at 1-800-567-2594 or your local representative.
© 2011, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved.
® Registered trademarks of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Used under license.
JMT-34770160-JAa
THE MEDICAL POST
oCtober 9, 2012
praCtiCe
How e-mail can aid office efficiency p.33➾
Finance: The safety of savings p.30➾
Practice gem p.34
29
➾
Are your record-keeping skills
up to snuff?
Review these seven tips to see if you’re
meeting requirements • BY WENDY GLAUSER
M
edical record keeping is one of the most important aspects of patient
care, yet it’s also an area where physicians often fall short. From a legal
standpoint, insufficient record keeping can make it seem as if the doctor
didn’t provide the appropriate standard of care, even when he or she did. In other
cases, subjective comments can be misconstrued.
Additionally, as patient care is trusted into ever more hands in the widening
circle of care, the keeping of good, detailed records is becoming even more important in communicating patient needs to multiple providers.
Read on for tips about how to meet modern record-keeping requirements in an
efficient, patient-centred way.
DW Dorken
Write for other
Assessment and Plan—
providers’ eyes
is one way of “concisely putWhile most physicians try to
ting things together,” says
keep good medical records,
Dr. Gabel. The SOAP method
they frequently make the
saves time by making the
mistake of keeping records
data that factored into the
for themselves only, says Dr.
physician’s assessment clear,
Marc Gabel, a Toronto family
without requiring narrative
physician who chaired the
explanations. At the same
working group that updated
time, by having four key areas
Dr. Gabel
the medical records policy of
for the physician to fill out, it
the College of Physicians and
ensures that all the valuable
Surgeons of Ontario this year.
elements are included. (More informa“The most common mistake is not
tion about the SOAP method can be
keeping enough of a record so that the
found here: www.cpso.on.ca/policies/
story of a patient can be followed by
policies/default.aspx?id=1686#TOC9).
someone else who might have to see or
One point that physicians may overcare for that patient,” he says. Physicians look from time to time is that negative
should think of their medical notes as
findings that could be relevant to the
a document explaining their thought
problem should always be included
process to someone who isn’t present
under Objective Data.
during the patient encounter.
Indeed, key updates to
Complete
Ontario’s medical records
medical
policy take into account the
records immediately
greater number of individGetting into the habit of
uals using them by making
completing medical records
cumulative patient profiles (a
at the time of contact can
summary snapshot of critical
save a physician from a legal
or billing issue arising from
details on the patient’s hisnotes that relied on recoltory) mandatory for family
lections, explains Dr. John
physicians. The updates also
Dr. Gray
Gray, CEO of the Canadian
include a new section on proMedical Protective Associacedural medicine, in terms of
tion (CMPA).
what information should be shared and
how it should be shared between referring physicians and consultants.
Be wary of templates
While templates in EMRs cerUse the SOAP method
tainly make life easier, they should be
With more detailed reporting
seen as a tool, not a standalone docurequired as records are shared among
ment, according to Dr. Gabel. “Checkother professionals, the SOAP method
boxes work well for many conditions
for note-taking—or organizing notes
and situations, especially if looking
according to Subjective, Objective,
at things such as whether someone
iStockphoto




It is best to write up medical records at the time of contact with the
patient so you are not relying on recollections later.
smokes,” he says. “But the interaction
with patient cannot be fully summarized with those kinds of checks; a narrative note may be required.”
Narrative notes are more helpful
than checkboxes in cases of anxiety,
for instance, as the severity and context
need to be explained, or when a patient
has a reaction to a medication that is
outside the usual side-effects, Dr. Gabel
notes. “On occasion (templates) have
made it difficult to be able to follow the
care of some patients because
of the lack of detail,” he says.

Don’t leave out e-mail
or phone exchanges
Because advice given over electronic
platforms or the phone tends to occur
outside of a normal day-to-day routine,
it’s easy for these encounters to be forgotten in the record. Dr. Gray reminds
physicians to ensure appropriate
documentation in the medical record
for e-mail or phone consults and to
have patients who use electronic consultation platforms sign a terms of use
agreement so they’re aware that e-mail
exchanges can be included in their
records.
➲ For other practice tips go to the Medical post’s online home:
www.CanadianHealthcareNetwork.ca/physicians/your-practice

Write like a lawyer
Avoid unnecessary notes about
the patient’s character and subjective
remarks or assumptions, which could
appear to others as a personal bias.
“This person smells of alcohol and has
an abnormal gait,” is better than saying, “This person is drunk,” the CMPA
explains in the article “Good notes
vs. bad notes,” which can be found
on its website (www.cmpa-acpm.ca/
cmpapd04/docs/resource_files/infosheets/2000/com_is0011-e.cfm). When
assumptions or inferences have been
made, they should be indicated as such,
rather than stated as fact.
Writing like a lawyer includes knowing the importance of legible notes. As
the CMPA article points out, the courts
can interpret illegible notes as carelessness. Of course, legible notes are also a
must in light of the increasingly interprofessional nature of patient care.

Brush up on requirements
In addition to reading through
your provincial or territorial college’s
policies on medical records, several
resources can help you stay up to date
continued on • page 31
30
OctOber 9, 2012
THE MEDICAL POST | practice
Should you put all your (nest) eggs
in the corporate basket?
The corporation earns $250,000
annually after expenses and
corporate taxes. They need
$150,000 to pay personal taxes
and living expenses. The
remaining $100,000 is invested
at 5%. They both have no other
income or deductions. At age
60, the investment will be
liquidated over 20 years until
they are 80.
ManfreD
PurTzki
Finance
Unsure about
keeping funds in
your corporation
for retirement?
Consider the value
and safety of
savings compared
with investments
T
he reason doctors
incorporate their
practices is to take
advantage of the fact that
income retained in the
corporation is subject to the
low tax rate of small businesses,
resulting in a tax deferral
benefit of about 30%, or
$30,000 on $100,000 (exact
savings depend on the
province). This tax benefit is
repaid when funds are
withdrawn and taxed
personally.
To maximize the tax deferral you would take only the
absolute minimum from the
corporation to fund living
expenses, and invest the surplus in the corporation.
However, a number of doctors I have spoken to recently
are questioning this tax strategy. They fear getting stuck
with a large tax bill on their
corporate withdrawals during
retirement, the time when they
can least afford a big hit on
their already tight budget.
Is it worthwhile to invest in
the corporation and face the
uncertainty of significant personal taxes during retirement,
or pay the tax now by taking
the funds from the corporation
and investing them personally?
Consider the following
scenario:
An Ontario doctor and
spouse are both 45 years of age
and plan to retire at age 60.

Doctors are realizing their lifestyle
expenses during retirement will have to
come mostly from their savings rather
than their investment income.
—Manfred Purtzki
The chart at right compares
the effect of saving personally
outside or inside the corpora-

tion on the couple’s retirement
income.
The illustration shows
that at age 60, the start of the
retirement, the savings in
the company have grown to
$2,008,000, compared with a
personal portfolio balance of
$1,346,000. This results in an
after-tax income of $2,690,000
in the corporation scenario
and $2,035,000 in the personal
scenario. Our couple increased
their after-tax retirement cash
THE MEDICAL POST | praCtiCe
flow by almost one-third by
choosing the option of keeping all surplus funds in their
corporation.
The results vary depending
on your personal situation,
but the overall conclusion will
likely not change.
Portfolio performance
Experiencing dismal returns
on their portfolios, doctors are
realizing that their lifestyle
expenses during retirement
will have to come mostly from
their savings rather than their
Retirement nest-egg
Investments held
outside company
Investments held
inside company
Savings
after year 1
72,000
100,000
5
384,000
542,000
10
830,000
1,203,000
(age 60) 15
1,346,000
2,008,000
20
1,102,000
1,646,000
25
804,000
1,204,000
30
438,000
665,000
35
nil
nil
$2,035,000
$2,690,000
After-tax retirement
income, ages 60 to 80
OCtOber 9, 2012
investment income and capital
gains. To boost the savings you
need to invest the funds in your
corporation.
Invest the tax dollars you
otherwise remit to the treasury, and that will mean more
money in your pocket.
Manfred Purtzki (CA) is the
owner of Purtzki & Associates, with offices in Vancouver
and Nanaimo, B.C. For more
information contact: Manfred@
purtzki.com; 1-888-668-0629;
www.purtzki.com.
31
from • page 29
on record keeping in today’s
increasingly complex care
environment. Some colleges,
including those in British
Columbia and Ontario, offer
CME-accredited medical
record-keeping courses, and
the CMPA provides an online
learning tool to educate
physicians about the legal
and medical ramifications of
records: www.cmpa-acpm.ca/
cmpapd04/docs/ela/flash/
documentation_charting_
profiling-e.cfm. MP
Artefactual
From page 29
BuTrans: Experience the Benefit
Correct answer:
For the management of moderate pain in patients
requiring continuous opioid analgesia.1
(1809-1873), a German
b) Lebenswecker
CARL BAUNSCHEIDT
mechanic and inventor, first
produced the lebenswecker
in 1848. translated most
directly as “life awakener,” the
lebenswecker comprises six
parts (a wooden cap, head
cover, shaft and plunger, and
a metal needle head and
spring), and is used to pierce
the skin without drawing
blood. baunscheidt also sold a
proprietary oil for application
to the punctured area, which
irritated the skin and raised a
blister. He argued that by cre-
BuTrans® is the first and only pain
treatment with 7-day dosing: 2
ating additional pores in the
skin, toxic substances were
more quickly exuded and that
the irritation distracted the
body’s attention away from
• A low starting dose (5 mcg/hr) with flexible dosing (5/10/20 mcg/hr).1
the instigating health issue (a
contemporary medical theory
known as counter-irritation).
BuTrans® (buprenorphine transdermal patch) is indicated for the management of persistent pain of moderate
severity in adults requiring continuous opioid analgesia for an extended period of time. Please refer to
prescribing information for BuTrans®.
the lebenswecker was purported to improve baldness,
Warnings: As with other CNS depressants, patients who have received BuTrans® should be monitored especially
for signs of respiratory depression until a stable maintenance dose is reached. Due to the formation of a
subcutaneous depot of buprenorphine, not only does continued exposure occur after patch removal but, in the
case of removal prior to attainment of peak buprenorphine exposure, buprenorphine plasma levels may continue
to increase after removal of BuTrans® patches. BuTrans® patches are intended for transdermal use on intact skin
only; use on compromised skin can lead to increased exposure to buprenorphine.
BuTrans® has potential for abuse, dependence and diversion.
BuTrans® is contraindicated in patients who are hypersensitive to buprenorphine, opioids or to any ingredient in
the formulation, and in patients suffering from delirium tremens. See Product Monograph for a list of
contraindications. The safety and efficacy of BuTrans® has not been studied in the pediatric population.
Therefore, use of BuTrans® is not recommended in patients under 18 years of age.
toothache and rheumatism,
among other ailments.
by 1854, baunscheidt’s
invention had brought him
fame and wealth, as well as a
string of imitators who aimed
to profit from the lebenswecker’s popularity. initially an
approved distributor of baunscheidt products in Cleveland,
The most common adverse effects in six randomized titration-to-effect clinical placebo-controlled clinical trials
with BuTrans® were anorexia, application site erythema, application site pruritus, asthenia, constipation,
dizziness, dry mouth, headache, hyperhidrosis, insomnia, nausea, somnolence and vomiting.
Ohio, by 1866 John Linden
Product monograph available on request.
called the “resuscitator.” the
was making and selling his
own lebenswecker model
artefact shown on page 23 is
one of Linden’s products.
baunscheidt’s company
produced the lebenswecker
until 1944, when its facilities
5 mcg/hr | 10 mcg/hr | 20 mcg/hr
Helping manage pain management
were damaged during the
Second World War.
—Dr. Pamela Peacock (PhD),
54
curator of the Museum of
Health Care at Kingston.
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THE MEDICAL POST | praCtiCe
OCtOBer 9, 2012
33
Improve office efficiency
with e-mail
pensated time. However, most
doctors who use e-mail will tell
you this concern is overblown,
and that e-mail can improve
office efficiency. E-mailing
patients is an uninsured service
in many cases and physicians
can choose to charge patients.

Doctors who use e-mail will
tell you the concern about increasing
patient demand for financially
uncompensated time is overblown.
—Dr. Jonathan Marcus

JonaThan
Marcus
Finding value
T
he 2010 National
Physician Survey
reported that only 16%
of physicians use e-mail with
patients for clinical purposes
and 5% for “other” purposes.
However, there’s no question that e-mail has revolutionized the way most doctors
share information, both personally and professionally with
colleagues. It’s more efficient
than the alternatives—telephone calls and snail mail.
Why, then, the reluctance
with patients? The main
barriers are:
1. Medico-legal liability.
This includes responding
appropriately and in a timely
fashion to patient concerns, as
well as having patients understand and be able to act on our
responses. Obviously we don’t
want middle-aged men e-mailing questions about their new
onset chest pains.
2. Patient privacy. It can be
hard to ensure the privacy of
e-mail since it can be hacked,
some patients share e-mail
accounts or leave their e-mail
open on their computers, etc.
3. Obtaining patient consent. The Canadian Medical
Protective Association (CMPA)
recommends getting consent
and provides a template for
such a form (http://www.cmpaacpm.ca/cmpapd04/docs/
resource_files/infosheets/2005/
pdf/com_is0586-e.pdf).
4. Fear of increasing patient
demand for financially uncom-
TOO MANY
UPS AND DOWNS?
Glucerna is clinically shown to
lower glycemic response.1,2*
Adjusted mean change in plasma glucose over time1
Adjusted mean change in plasma glucose (mmol/L)
A clear policy
on communication
can ease your
concerns about
using e-mail
to contact patients
With so many concerns, it’s
understandable that few physicians have embraced e-mail
with patients. But many realize that e-communication is
inevitable at some point.
It is possible to gradually
Standard nutritional drink
Glucerna bottle
4.4
3.3
p<0.001††
%
2.2
66 lower
than a standard
nutritional
drink
1.1
0.0
30
60
90
-2.2
240
120
-1.1
Time in minutes
†† At 60 minutes only
Help your patients reduce postprandial
rises in blood glucose and insulin1, 2*
Ideal as a snack or good as a meal replacement, Glucerna nutritional drink
can help your patients manage their diabetes. Glucerna complies with the
Canadian Diabetes Association nutritional guidelines.3
Recommend Glucerna to your patients as part
of their diabetes nutritional management plan.
* Compared to a standard nutritional drink.
References:
1. J.A. Williams, J. Garcia Almeida, M. Matia Martin et al. Lack of Glycemic Response at 120 minutes postprandial
with a New Diabetes Specific Nutritional Formula (Abstract). Clinical Nutrition Supplements. Sept 2009; 4(S2).
LB003. 2. Study BK20, Data on File, Abbott Laboratories, Limited. 3. Canadian Diabetes Association 2008.
Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Canadian Journal
of Diabetes Care; 32 (Suppl. 1) S40-45.
© Abbott Laboratories, Limited
180
OCTOBER 9, 2012
from • page 33
start using e-mail in ways that
reduce the hassle and risk.
Consider sending out batch
e-mails to your entire practice,
such as a quarterly newsletter
or periodic updates such as
when flu shots come in and
how to get one. These can be
sent out in a “no-reply” format
so you don’t have to worry
about responding to patients’
questions online.
You can get a written consent
while patients are visiting your
office. Then create an e-mail
group for your practice. The
consent document for no-reply
e-mail could be much shorter
than the CMPA document
since patients aren’t able to use
e-mail for health questions.
This reduces the privacy and
medico-legal risks and there is
no chance of being drawn into
a time-consuming, uncompensated online discussion.
If you are comfortable
increasing your use of e-mail,
you might consider using it to
THE MEDICAL POST | PRACTICE
communicate simple administrative info such as confirming
appointments, etc. This
would require a slightly more
extended consent document
because you are communicating one-on-one with a patient
about something specific.
It is also possible to set up
e-mail programs such that your
receptionist is able to confirm
if your patients open sent messages. This is helpful when
confirming appointments,
something you can’t do with
voice mail.
And finally, if you want to
use e-mail for more in-depth
communication and allow
patients to contact you with
clinical questions, it’s advisable
to use a consent document
similar to the full CMPA version. If e-mail communication
proves cumbersome in a particular instance, you can always
e-mail a patient to set up a
time for a phone call.
I recommend adding an
e-mail policy to your list of
office policies. If you have a
practice website, it’s helpful
to post it there. You can check
out mine at www.drjonathanmarcus.com/policies/
communications-policy.
E-mail has many advantages

34
over traditional communication vehicles and since it’s possible to start gradually, thereby
reducing risk and hassle, why
not start now?
Jonathan Marcus is a family
Practice Gems
Helping patients understand
why they don’t need antibiotics
THIS IS, VERBATIM, my “You don’t
tion, the neti pot, while gross, really
need antibiotics” talk:
works. Finally, I find ice cream
“There’s good news and bad
especially soothing to a sore
news. The good news is you don’t
throat.
need any of those nasty antibiot-
“If things are getting worse
ics that are expensive and can
rather than better, you develop
cause yeast infections and diar-
a persistent fever that won’t go
rhea. The bad news is you have
away or you become concerned,
a viral illness that will not respond
please come back and see me.”
to antibiotics. I know your throat/ear/
This reassures them that they are
cough is really bothering you. I wish there
were a magic pill to fix it, but there isn’t.
“sick,” tells them why they don’t need antibiotics and makes me really popular with kids!
“In the meantime, we are going to treat
your symptoms. For pain, I suggest aceta-
Dr. Sarah Giles is a locum family physician
miniophen or ibuprofen. For nasal conges-
working in Ontario and Australia.
Rx
NORVASC has been helping physicians treat
hypertension in Canada for 19 years.
NORVA
SC
5 mg o.d
.
NO SUB
STITUT
ION
Today, the Continuity of Care§ Program allows patients to continue
receiving their original NORVASC at no extra cost* vs. the generic.
Along with the Best Life Rewarded† Program rewarding healthy behaviour,
our commitment carries on.
§ This program is currently available in all provinces except for Quebec, Saskatchewan and Manitoba.
To obtain Continuity of Care cards for your patients, visit itrialrx.com or call 1 866 794-3574.
* Refers to the drug acquisition cost; dispensing fees may vary.
© 2012 Pfizer Canada Inc, Kirkland, Quebec H9J 2M5
TM Pfizer Inc, owner/Pfizer Canada Inc, Licensee
† All other trademark(s) are the property of their respective owners.
NOR_13507_MedicalPost_E.indd 1
AD number
Client:
Size:
Agency:
NV HER-1-E
Pfizer
10.0” X 8.0”
Anderson DDB
doctor and entrepreneur
in Toronto. He speaks and
writes on practice management,
emphasizing uninsured
services and practice websites.
Contact him at Jonathan
@DoctorMarcus.ca.
NORVASC ® Pfizer Products Inc, owner/
Pfizer Canada Inc, Licensee
Product Monograph available at: www.pfizer.ca

NORVASC is indicated in the
treatment of mild-to-moderate
essential hypertension and for the
management of chronic stable
angina in patients who remain
symptomatic despite adequate
doses of beta-blockers and/or
organic nitrates, or who cannot
tolerate those agents.
Most common adverse reactions
for hypertension are edema (8.9%)
and headache (8.3%); for angina,
edema (9.9%) and headache
(7.8%).
Rarely, patients, particularly those
with severe obstructive coronary
artery disease, have developed
documented increased frequency,
duration and/or severity of angina
or acute myocardial infarction on
starting calcium channel blocker
therapy or at the time of dosage
increase. The mechanism of this
effect has not been elucidated.
NORVASC is contraindicated in
patients with hypersensitivity to the
drug or other dihydropyridines and
in patients with severe hypotension
(less than 90 mmHg systolic).
Please refer to NORVASC
monograph for full information
about dosing, warnings,
precautions and adverse reactions.
Norvasc Product Monograph,
Pfizer Canada Inc., June 2010.
xx
12-06-27 9:17 AM
THE MEDICAL POST
Science-ish p.38 ➾
OCTOBER 9, 2012
NEWS
European Society of Cardiology p.43 ➾
35
Ontario FP fee cuts p.49 ➾
Private eyes:
Are they watching you?
Does your provincial college hire private investigators
to pose as undercover patients?
MARK CARDWELL
iStockphoto
S
hould Ontario doctors be worried a
new patient is actually a private investigator
working undercover for the province’s
College of Physicians and Surgeons?
Not unless they are suspected of disreputable activities, a spokesperson for the provincial
medical regulatory body suggests.
“The (College of Physicians and Surgeons of
Ontario) uses external or private investigators very
infrequently,” CPSO spokesperson Kathryn Clarke
wrote in a recent e-mail to the Medical Post.
“They are not used in cases where we have a concern about clinical standards, for example, but rather
for matters involving potentially serious misconduct.”
The college’s use of private-hire undercover agents
recently came to light in the case of Dr. Stuart
Lambert. The Toronto-area physician faces the
loss of his medical licence for the second time
in a decade, after being found guilty of several
charges last November.
His penalty hearing was suspended in
August to give the CPSO time to consider
expert testimony in regard to the 60-year-old’s
mental health.
Dr. Lambert first lost his licence in 2002
after pleading guilty to sexually assaulting three
female patients in his Mississauga clinic.
His license was reinstated in June 2009, but
with strict conditions and limitations. He was prohibited from treating female patients and from peddling his own line of skin-care products to patients.
The CPSO opened an investigation into Dr. Lambert’s conduct just weeks after those restrictions were
imposed, however, after it received information he
was still selling his products.
“We retained two external female investigators to
determine whether or not he was breaching the conditions on his licence,” wrote Clarke.
The two agents, identified as Ms. X and Ms. Y
in CPSO disciplinary proceedings, posed as new
patients at Dr. Lambert’s clinic in October 2009.
They surreptitiously filmed him selling Ms. X
skin-care products.
Ms. X also accused Dr. Lambert of touching her
breast and “brushing” her nipple as he reached for a
form he asked her to sign.
Dr. Lambert pleaded guilty to breaching the
terms of his reinstatement regarding treating female
patients, but denied the accusation of sexual assault.
•
Toronto
Despite the lack of video evidence or any overt
reaction to the alleged sexual incident by Ms. X, who
testified that Dr. Lambert was “pleasant and courteous (and) not behaving in a flirtatious or seductive
fashion,” the CPSO’s disciplinary committee found
Dr. Lambert guilty.
“The victim, private investigator Ms. X, was
unequivocal in her testimony regarding what
occurred,” the committee wrote in its 28-page ruling.
The investigator “acknowledged momentarily

There is well-established
case law in Ontario that
does not prohibit . . . the use
of ‘dummy patients.’
—lawyer Matthew Wilton
(not shown)

(that the touch) could have been accidental, but she
quickly concluded it was not,” according to the report.
“The college has proven this allegation of sexual
abuse on a balance of probabilities.”
Clark stated the use of private investigators in the
case “proved to be an effective means of establishing
the facts (and) Dr. Lambert admitted that he had
contravened a number of conditions on his licence.
This approach also spared actual patients from
having to testify at the hearing.”
But has the college gone too far?
Though the college’s use of external private
investigators has raised some eyebrows in medical
circles, Ontario criminal lawyers say the practice
is perfectly legal.
“There is well-established case law in Ontario
that does not prohibit what I call the use of
‘dummy patients’ or ‘clients’ to gather evidence,”
said Matthew Wilton, a Toronto lawyer who frequently defends professionals in disciplinary cases.
Lawyer Marie Henein agreed.
“The CPSO has very broad investigate powers, as
you would expect for any regulatory body that is
tasked with making sure professionals are maintaining standards and keeping the public safe,”
said the Toronto criminal lawyer.
But investigators, she added, must act
appropriately.
“If they entice a doctor into breaking a
law, say like harassing them for illegal drugs,
the analogy in criminal law would be entrapment,” said Henein.
A survey of medical colleges in several other
provinces suggests only Ontario uses private
investigators to gather evidence on members.
“The answer is simple,” said Dr. Charles Bernard,
president and general manager of the Quebec
College of Physicians. “We have not and do not use
private investigators to gather evidence on doctors
(in regard to) professional complaints, period.”
Bruce Thorne, director of policy and communications for the College of Physicians and Surgeons of
Nova Scotia is equally categorical.
“This college,” he wrote in an e-mail, “does not
and has not employed investigative techniques.”
Dr. William Pope, registrar and CEO of the College
of Physicians & Surgeons of Manitoba, wrote that his
organization “used (a private investigator) once to try
to find a former member, but it was unsuccessful.”
Kelly Eby, a spokesperson for the College of
Physicians & Surgeons of Alberta wrote, “I cannot
speak for anything before 1995 or so (because we
don’t have anyone on staff who worked here before
then), but in recent memory, the college has not
used undercover investigators to review physicianrelated complaints.” MP
36
OCTOBER 9, 2012
THE MEDICAL POST | NEWS
Revealing
the secrets
of sudden
death
Dr. Kristopher
Cunningham
the genetic underpinnings
of unexplained deaths to benefit
the living—but can proponents
of the technique overcome
high costs and an antiquated
coroner system?
BY STEPHEN STRAUSS
•
Toronto
O
f all the anxious times in a medical practice, few rank
higher than the moment a doctor must tell grieving
family members that the cause of death of a loved
one has been assigned to what is sometimes called
the “Nowhere Man” file.
After a physical autopsy of the body, after biological and toxicological
screens, no explanation can be arrived at to explain the sudden demise
of what was previously a seemingly healthy and often young person. It is
a causal blank that Dr. Kristopher Cunningham, a forensic pathologist
with the Ontario Forensic Pathology Service (OFPS) in Toronto, said
has occurred in upwards of 4% of all cases referred to them.
However, the unsettling “death of unknown cause” determination
may, if not become a thing of the past, be significantly reduced if what
are called “molecular autopsies” become standard procedure.
The term refers to the more sophisticated genetic tests developed
almost daily that have linked many unexplained deaths to mutations
that cause the heart to suddenly stop functioning. A paper published 
Photos by D.W. Dorken
Molecular autopsy uncovers
OCTOBER 9, 2012
37
in the June Mayo Clinic Proceedings indicated that
when molecular autopsies were performed on tissues
taken from 173 people whose deaths had previously
been unexplained, 26% had genetic mutations linked
with long QT syndrome or ventricular tachycardia.
(The study, led by Mayo Clinic cardiologist Dr. Michael
Ackerman, encompassed cases sent to the Windland
Smith Rice Sudden Death Genomics Laboratory from
September 1998 through October 2010.)
However, what is much more significant from a clinical perspective is that the discovery of a lethal mutation
in the dead person holds out two benefits for the living.
The first is the subsequent testing of blood relatives to
determine whether they also carry the deadly stretch of
DNA. But, just as importantly, in many instances there
are readily available treatments and lifestyle changes—
beta-blockers, defibrillators, reduction in strenuous
exercise—that can dramatically lower the risk of similar
deaths occurring in affected family members.
Saving lives
Dr. Kathy Hodgkinson (PhD), an assistant professor of
clinical epidemiology at Memorial University of Newfoundland in St. John’s, N.L., said the implantation of
defibrillators in often symptomless teenage boys who
carry a Newfoundland-centred mutation for arrhythmogenic right ventricular cardiomyopathy has meant the
early death rates in carrier families has fallen to onetenth of what family bibles suggest they were in the past.
That success reflects the leading role Canada has
played in the field. The first reported molecular autopsy in this country was performed at the University
of Ottawa Heart Institute in 2007. In 2010, the rapid
advances in the area—upward of 50 genes or mutations can now be tested for at once—led the OFPS to
announce as part of a five-year-plan that “our goal is to
develop an approach that makes the ‘molecular autopsy’ part of the core service of the OFPS.”
That is happening in 2012. The OFPS has created a
new facility “designed for collecting and purifying and
storing DNA of individuals who die,” Dr. Cunningham
told the Medical Post. This not only makes it the sole
pathology office in the country with the capacity to conduct molecular autopsies, but ranks it with the Mayo
Clinic and the New York City medical examiner’s office
as world leaders in the effort to routinize the process.
While all of this sounds like the fulfilment of the
promise of a genetically based medical practice that
a decade or two ago seemed imminent, for molecular
autopsies to become standard practice across the
country they must circumvent numerous obstacles.
To begin with, they must navigate a coroner/medical examiner system that was not set up to facilitate
what is in effect becoming a 21st-century branch of
family medicine. “Coroners may not be physicians
in some jurisdictions,” said Dr. Andrew Krahn, chief
of cardiology at the University of British Columbia
in Vancouver. “This means that coroners may not be
conscious (of the fact) that finding the true cause of a
mysterious death affects the future of living relatives.”
And even if they are aware that a test can have
implications for the living, in many places they don’t
have the funds to routinely order a molecular autopsy
after foul play has been eliminated. Art Erasmus, a coroner in Terrace, B.C., said when he suspects a genetic
heart condition underlies an unexplained death, he
phones Dr. Laura Arbour (PhD), a geneticist at UBC.
She and her team have been studying long QT syndrome, which is common among First Nations populations in his area. Erasmus then almost plaintively asks
Dr. Arbour, “Does your research budget allow for me to
send you a blood sample to test for long QT?”
Another difficulty for present practices relates to
how bodies are traditionally preserved in formaldehyde for physical autopsies. “It destroys the DNA
The Ontario Forensic Pathology Service
has created a facility  purposely designed
for collecting and purifying and storing DNA
of individuals who die.
—Dr. Kristopher Cunningham
A vial used to separate DNA from tissue samples.
required for testing, so we need to have medical
examiners become more savvy,” said Dr. Heidi Rehm
(PhD), director of the Harvard-affiliated Laboratory
for Molecular Medicine at the Partners Healthcare
Center for Personalized Genetic Medicine, a Boston
laboratory that tests for gene mutations for a number
of provinces in this country. As a response, her laboratory has stopped accepting any formaldehyde-soaked
samples from coroners and medical examiners.
Long-term preservation is also vital as the discovery
of an ever-increasing number of mutations associated
with sudden cardiac death means the periodic retesting of an initially negative sample will likely become
standard practice in the future.
Cost-effectiveness
However, the issue overriding everything is: At what
point does a reduction in the numbers of “deaths
of unknown cause” and the subsequent potential
increase in future health benefits for living family
members make molecular autopsies cost-effective?
To date, provinces in this country and insurance
companies in the United States have been quite
resistant to routinely paying for molecular autopsies.
Indeed, they are in some cases backtracking on previous approval protocols. Until last year, Ontario regularly approved out-of-country tests on dead people’s
tissues. “Now if someone is dead their OHIP coverage
is deemed expired, and so the ministry has decided
not to pay for any new out-of-country tests on their tissues,” said Dr. Robert Hamilton, an electrophysiologist
at the Hospital for Sick Children in Toronto.
Payers’ reluctance is understandable in a costconscious era. Depending on what genes are being
screened for, the cost of a molecular autopsy from a
U.S. laboratory can range from $2,500 to $9,000.
What is also disconcerting is that finding a mutated
gene that has killed one person is not the same as being
able to definitively say that living family members with
the same mutation will necessarily die suddenly and
young. Studies of the Gitxsan First Nation of northern
B.C. have found that while roughly 1% of the 5,400 tribe
members bear a mutation associated with long QT
syndrome, about one-third of carriers seem to have no
heart conditions, 15% die suddenly and the rest show a
variety of heart-related symptoms. Then there’s the fact
that various mutations of “unknown significance” are
regularly found in generalized genetic screens.
However, conducting tests on living family members
alone is fundamentally inefficient because you have to
screen for all possible mutations, and not test for the
existence of the specific mutation or mutations that a
molecular autopsy shows likely killed a blood relative.
As a consequence, members of the Canadian
Cardiovascular Society and Canadian Heart Rhythm
Society published a paper in the Canadian Journal of
Cardiology (March 2011) recommending what might
be called a yes/no approach to molecular autopsies. In
autopsy-negative, unexpected sudden (maybe cardiacrelated) deaths, they said, “Genetic testing of retained
tissue is recommended only when there is evidence
of a clinical phenotype in family members.”
But technology may revise this cost/benefit equation. What Harvard Partners and other laboratories
around the world are aiming for in the near future is an
inexpensive test that screens not for all mutations but
only for those whose significance is already known. The
hoped for price is one that Dr. Rehm said she was told
cost-conscious payers won’t openly challenge: $500. MP
Research for this article was funded in part by a Canadian
Institutes of Health Research journalism grant.
38
OCTOBER 9, 2012
THE MEDICAL POST | nEws
are we in for another
doctor exodus to the u.S.?
Canadian-trained physicians
into the U.S. So Science-ish
wondered, based on the data
about the MD workforce, are
we poised for a doctor exodus?
Dr. Arthur Sweetman, the
Ontario research chair in
health human resources at
McMaster University, pointed
out that where doctors do their
residencies is one of the biggest
determining factors for where
they will practise. To break
from that, a number of key
conditions need to be in place.
Number one is, “If you’re looking to move, it’s not because
things are bad here. You’re
looking to move to some place
where things are better.”
In the 1990s, when Canada
lost doctors to the States,
compensation here wasn’t
competitive with that in the
U.S. But that simply isn’t the
case now. In fact, doctor salaries in Ontario, even inflationadjusted, are the highest they
have been in 20 years.
According to this recent
report, “On a per-physician
basis, the mean payments to
physicians in Ontario, having
remained fairly flat between
1992/93 and 2003/04, rose
by around $100,000 between
2004/05 and 2009/10” (all
unadjusted dollars). Family
doctors saw the greatest pay
increase: more than $1.5 billion
collectively between 1992/93
and 2009/10. On a per physician basis, that meant billings
rose to $300,000 by 2010 from
julia Belluz
Science-ish
Ontario MDs
are threatening
to leave en masse.
But what does it
actually take for
a doctor to quit
Canada?
BY julia Belluz
Toronto
a
nyone who has read
the news from Canada
in the last six months
knows there is a serious labour
struggle going on between
doctors and governments. In
Ontario, the situation has been
particularly fraught. Heated
negotiations over physician
fees—against the backdrop of a
$13-billion deficit—have led
some of the province’s MDs to
warn that, if things don’t
change, they’re going to leave
for greener pastures.
Radiologists and cardiologists have made public threats,
and even idealistic medical students are chiming in. As Stephanie Kenny, from the University
of Ottawa’s class of 2013, told
Science-ish in an e-mail, “The
average medical school student today will graduate with
$150,000 of debt and will spend
13 years in training after high
school before becoming a fully
licensed physician.” Though
she would “love to practise in
Ontario,” she added “there is
a perfect storm brewing that
is making this a difficult and
unpalatable place to work.”
Now, Ontario Health Minister Deb Matthews has said she
isn’t buying the chatter. But it’s
not that far-fetched: Canada
has experienced doctor brain
drains in the past. In the 1990s,
when the government capped
spending on physicians,
there was a steady trickle of
Constipation affects up to 95% of patients taking opioids.1
®
DUAL THERAPEUTIC EFFECT
Controlled release oxycodone for the relief of moderate
to severe pain, combined with controlled release naloxone for
relief of opioid-induced constipation...in one tablet.2*
THE MEDICAL POST | News
less than $200,000 in the early
1990s. Meanwhile, with the
U.S. economy stagnating and
the future of health care there
looking uncertain, its hiring
climate is not what it was.
Another part of the story is
that in the 1990s there was a
physician shortage, and governments in Canada cut medical school enrolment by 10%.
Currently, the Canadian MD
supply is at an all-time high.
First-year medical school
enrolment has almost doubled
and data from the Canadian
Institute for Health Information show that the number of
doctors practising in Canada is
greater than it has ever been,
with 69,699 active physicians
(compared with 37,252 in 1980).
While we don’t know yet
how this supply increase is
going to play out, and Canadians still report shortages of
family doctors, some are predicting that we are headed for
an oversupply.
Or, as Steven Lewis, a
Saskatoon-based health-care
analyst, put it, “Some few (doc-
OCTOBeR 9, 2012
tors) might get juicy
roots and (their)
offers with guarannot wanting to have
teed incomes, but
to start over with
we’re way beyond
whole new patient
the physician supply
rosters, relationships
crunch of the 1990s.”
with facilities and
Lewis cites demoreferral networks,”
graphics as another
he wrote in an
major reason why
e-mail. “Even those
we’re unlikely to
motivated to move
Dr. Rachlis
see doctors leave en
for income reasons
masse: “There’s a
have to recognize the
fairly large middle-aged bulge
transaction costs.”
in the physician supply, and
On the West Coast, Dr. Morthat group is highly unlikely to
ris Barer, of the Barer-Stoddart
leave given their community
Report and the director of the
Demonstrated analgesic efficacy of OxyContin®
demonstrated no statistically significant difference compared to
OxyContin for average pain scores (p=0.406).2,3†
®
®
Reduced constipation with naloxone
demonstrated a statistically significant improvement in bowel function
at 4 weeks compared to OxyContin®, as measured by Bowel Function Index
®
vs.
(p<0.0001), with improvements already seen after 1 week. [
®
®
OxyContin : -14.9; 95% CI: -17.9, -11.9 at 4 weeks,
vs. OxyContin®
-13.8 (44.16 vs. 57.96) mean BFI at 1 week (p<0.0001)].2,3†
®
®
*
(oxycodone hydrochloride/naloxone hydrochloride) is a controlled release tablet having a dual therapeutic effect.
®
is indicated for the relief of moderate to severe pain in adults who require continuous
The oxycodone component in
®
is indicated for the relief of
around-the-clock opioid analgesia for several days or more. The naloxone component in
opioid-induced constipation (OIC).
®
. The most
Adverse events often observed with other drugs with opioid-agonist activity, were also seen with
frequently observed were nausea which tends to reduce with time, as well as constipation, diarrhea, fatigue, headache and
®
is contraindicated in: patients hypersensitive to oxycodone or naloxone, other opioid analgesics, or to
hyperhidrosis.
any ingredient in the formulation; patients with gastrointestinal obstruction or diseases affecting bowel transit or suspected
surgical abdomen; acute pain or perioperative pain; acute alcoholism or convulsive disorders; CNS depression; concomitant MOA
inhibitors (or within 14 days of such therapy); pregnant or breast-feeding women; and moderate to severe hepatic impairment.
®
is 80 mg oxycodone/40 mg naloxone, however, dosage limitations may be imposed by
The maximum daily dose of
adverse effects as well. If they occur, please refer to prescribing information.
Warning: Opioid analgesics should be prescribed and handled with a degree of caution appropriate to the use of a drug with
®
, as it may increase the chance of
abuse potential. Patients should be cautioned not to consume alcohol while taking
®
should not be administered rectally due to the possible increased systemic
experiencing dangerous side effects.
®
40/20 mg
availability of naloxone by this route and the potential for the occurrence of severe withdrawal effects.
tablets are for use in opioid tolerant patients only. There is potential for fatal respiratory depression in a single dose greater than
40 mg of oxycodone, or total daily doses greater than 80 mg of oxycodone, when administered to patients intolerant of the
®
should not be used to treat patients with constipation not related to opioid
respiratory depressant effects of opioids.
®
tablets should be swallowed whole and should not be broken, chewed, dissolved or crushed since this can lead
use.
to the rapid release and absorption of a potentially fatal dose of oxycodone.
Product monograph available on request.
†
Multicentre, randomized, double-blind, double-dummy, active-controlled, parallel group study in patients with chronic back pain and osteoarthritis. BFI = 3-item
questionnaire using (NAS) Numerical Analogue Scale (0-100) = low numbers for good bowel function. Pain Intensity Score (0-10) = average pain over last 24 hours over
®
10/5, 20/10, 40/20 mg q12h vs. OxyContin® 10, 20, 40 mg q12h, placebo q12h. IR oxycodone q4-6h p.r.n. for breakthrough pain. 80/40 mg
12 weeks. (
®
4.13 vs. OxyContin® 3.94 at 12 weeks, (-0.19).
maximum per day.)2,3 Average pain over last 24 hours was not statistically different and remained constant.
®
vs. OxyContin® 0.10 difference, p=0.406; 95% CI: - 0.14, 0.34; pain intensity (NRS) Numerical Rating Scale 0-10).3 Bowel function improvement was
(
®
®
. (Clinically meaningful difference in mean BFI scores >12 change.) (BFI mean at week 4:
40.9 vs.
statistically significant in favour of
OxyContin® 53.3).3 (12 weeks) (n=265).2,3
®
®
Controlled release oxycodone/naloxone HCl tablets
10/5 mg, 20/10 mg, 40/20 mg
®
is a registered Trademark of Purdue Pharma.
OxyContin® is a registered Trademark of Purdue Pharma.
© 2011 Purdue Pharma. All rights reserved.
44
39
University of British Columbia’s Centre for Health Services
and Policy Research, has
been studying the physician
workforce for decades. He too
thinks the talk of an exodus is
just that—talk. “My sense is
that doctors need to be really
put off by circumstances before
they will actually leave.”
Even the brain drains of the
past weren’t as dire as they were
made out to be in the media,
Dr. Barer adds, and if you look
at the big picture, there have
been more doctors coming into
this country than leaving.
Dr. Michael Rachlis, a
Toronto-based health-policy
analyst, made a similar point
when he noted that Canada is
experiencing more of a doctor
boom than bust right now.
“The top year for loss of doctors to the U.S. was in 1978,” he
wrote in an e-mail. “In the last
few years there has been a net
gain of MDs.”
Of course, there are always
doctors who flee their homelands for ideological reasons—
such as the glut of Brits who
immigrated to Canada after the
National Health Service was
established in 1948. “But major
moves of this sort are more
frequently associated with
being handed great opportunities elsewhere, or being
really unhappy about some
mix of those circumstances (at
home),” Dr. Barer said. There’s
nowhere better for Canadian
physicians to go right now.
Still, things change. The
very fact that we are paying to
train so many doctors here may
indeed lead to an oversupply,
and this could eventually force
physicians to go—especially
to the U.S. if the need for
primary-care physicians kicks
in with his health bill. For now,
Dr. Barer attributes doctors’ exit
threats to the fact that “health
policy in this country is often
the product of prior public
theatre.”
In other words, when labour
groups aren’t getting what they
want behind closed doors, they
appeal to the public. However,
Dr. Barer quipped, “The problem is that doctors have rarely,
in the past, managed to secure
public sympathy.”
Science-ish is a joint project of
Maclean’s, the Medical Post and
the McMaster Health Forum.
Julia is an associate editor at the
Medical Post. Got a tip? Message her at [email protected] or on Twitter
@juliaoftoronto.
PRESCRIBING SUMMARY
PAtIENt SElECtIoN CRItERIA
tHERAPEUtIC ClASSIFICAtIoN:
Antidepressant/anxiolytic
INDICAtIoNS AND ClINICAl USE
Adults
Pr
EFFEXOR ® XR is indicated for:
Depression: EFFEXOR XR is indicated for the symptomatic relief of major depressive disorder. The short-term efficacy of
EFFEXOR XR has been demonstrated in placebo-controlled trials of up to 12 weeks. The efficacy of EFFEXOR XR in maintaining
an antidepressant response for up to 26 weeks following response to 8 weeks of acute treatment was demonstrated in a
placebo-controlled trial (see Product Monograph, ClINICAl tRIAlS, DEPRESSIoN).
Generalized Anxiety Disorder (GAD): EFFEXOR XR is indicated for the symptomatic relief of anxiety causing clinically
significant distress in patients with GAD. Anxiety or tension associated with the stress of everyday life usually does not require
treatment with an anxiolytic. The effectiveness of EFFEXOR XR in long-term use has been evaluated for up to 6 months in
controlled clinical trials (see Product Monograph, ClINICAl tRIAlS, Generalized Anxiety Disorder).
Social Anxiety Disorder (Social Phobia): EFFEXOR XR is indicated for the symptomatic relief of Social Anxiety Disorder,
also known as Social Phobia. Social Anxiety Disorder is characterized by a marked and persistent fear of one or more social
or performance situations, in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure
to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared
situations are avoided or endured with intense anxiety or distress. Fear, anxious anticipation, distress in the feared situation(s),
or avoidance of social and/or performance situations that does not interfere significantly with the person’s normal routine,
occupational or academic functioning, or social life usually does not require treatment with an anxiolytic.
The efficacy of EFFEXOR XR capsules as a treatment for Social Anxiety Disorder (also known as Social Phobia) was demonstrated
in four 12-week, multicentre, placebo-controlled, flexible-dose studies and one 6-month, fixed/flexible-dose study in adult
outpatients meeting DSM-IV criteria for Social Anxiety Disorder. These studies evaluating EFFEXOR XR doses in a range of
75 to 225 mg/day demonstrated that EFFEXOR XR was significantly more effective than placebo for the Liebowitz Social
Anxiety Scale Total score, Clinical Global Impressions of Severity of Illness rating, and Social Phobia Inventory (see Product
Monograph, ClINICAl tRIAlS, Social Anxiety Disorder).
Panic Disorder : EFFEXOR XR is indicated for the symptomatic relief of Panic Disorder, with or without agoraphobia, as
defined in DSM-IV. Panic Disorder is characterized by the occurrence of unexpected panic attacks and associated concern
about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in
behaviour related to the attacks.
Panic Disorder (DSM-IV) is characterized by recurrent, unexpected panic attacks, i.e., a discrete period of intense fear or discomfort,
in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: 1) palpitations, pounding
heart, or accelerated heart rate; 2) sweating; 3) trembling or shaking; 4) sensations of shortness of breath or smothering;
5) feeling of choking; 6) chest pain or discomfort; 7) nausea or abdominal distress; 8) feeling dizzy, unsteady, light-headed, or faint;
9) derealization (feelings of unreality) or depersonalization (being detached from oneself); 10) fear of losing control; 11) fear of
dying; 12) paresthesias (numbness or tingling sensations); 13) chills or hot flushes.
The efficacy of EFFEXOR XR in the treatment of Panic Disorder was established in two 12-week placebo-controlled trials in adult
outpatients with Panic Disorder (DSM-IV). The efficacy of EFFEXOR XR in prolonging time to relapse in Panic Disorder for up to
6 months in responders of a 12-week acute treatment was demonstrated in a placebo-controlled trial (see Product Monograph,
ClINICAl tRIAlS, Panic Disorder).
long-term Use of EFFEXoR XR: The physician who elects to use EFFEXOR XR for extended periods in the treatment of
Depression, GAD, Social Anxiety Disorder, or Panic Disorder should periodically re-evaluate the long-term usefulness of the
drug for the individual patient (see DoSAGE AND ADMINIStRAtIoN).
CoNtRAINDICAtIoNS
Hypersensitivity: Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container.
Monoamine oxidase Inhibitors (MAoIs): EFFEXOR XR should not be used in combination with MAOIs or within 2 weeks
of terminating treatment with MAOIs. Treatment with MAOIs should not be started until 2 weeks after discontinuation of
EFFEXOR XR therapy.
Adverse reactions, some serious, have been reported when EFFEXOR XR therapy is initiated soon after discontinuing an MAOI
and when an MAOI is initiated soon after discontinuation of EFFEXOR XR. These reactions have included tremor, myoclonus,
diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome,
seizures and death. In patients receiving antidepressants with pharmacological properties similar to venlafaxine in combination
with an MAOI, there have also been reports of serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor,
these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital
signs, and mental status changes that include extreme agitation progressing to delirium and coma. Some cases presented
with features resembling neuroleptic malignant syndrome. Severe hypothermia and seizures, sometimes fatal, have been
reported in association with the combined use of tricyclic antidepressants and MAOIs. These reactions have also been reported
in patients who have recently discontinued these drugs and have been started on an MAOI.
SPECIAl PoPUlAtIoNS
Pregnant Women: There are no adequate and well-controlled studies with venlafaxine in pregnant women. Therefore,
venlafaxine should only be used during pregnancy if clearly needed. Patients should be advised to notify their physician if
they become pregnant or intend to become pregnant during therapy.
Post-marketing reports indicate that some neonates exposed to venlafaxine, SSRIs (Selective Serotonin Reuptake Inhibitors),
or other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization,
respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings
have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia,
hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either
a direct toxic effect of SSRIs and other newer antidepressants, or, possibly a drug discontinuation syndrome. It should be
noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS and PRECAUtIoNS,
Serotonin Syndrome/Neuroleptic Malignant Syndrome). When treating a pregnant woman with EFFEXOR XR during
the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DoSAGE AND
ADMINIStRAtIoN, treatment of Pregnant Women During the third trimester).
Nursing Women: Because venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), have been reported to be
excreted in human milk, lactating women should not nurse their infants while receiving venlafaxine. If the mother is taking
EFFEXOR XR while nursing, the potential for discontinuation effects in the infant upon cessation of nursing should be considered.
Geriatrics (> 65 years of age): Caution should be exercised in treating the elderly. In Phase II and III clinical trials, no overall
differences in effectiveness and safety were observed between these geriatric patients and younger patients, and other
reported clinical experience has not identified differences in response between the elderly and younger patients. However,
greater sensitivity of some older individuals cannot be ruled out.
Pediatrics (<18 years of age): EFFEXoR XR is not indicated for use in children under 18 years of age (see WARNINGS
AND PRECAUtIoNS, General, Potential Association with Behavioural and Emotional Changes, Including Self-Harm).
SAFEtY INFoRMAtIoN
PotENtIAl ASSoCIAtIoN WItH BEHAVIoURAl AND EMotIoNAl CHANGES, INClUDING SElF-HARM.
Pediatrics: Placebo-Controlled Clinical trial Data: Recent analyses of placebo-controlled clinical trial
safety databases from SSRIs and other newer antidepressants suggest that use of these drugs in patients
under the age of 18 may be associated with behavioural and emotional changes, including an increased
risk of suicidal ideation and behaviour over that of placebo. the small denominators in the clinical trial
database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety
profiles among the drugs in the class.
Adults and Pediatrics: Additional Data: there are clinical trial and post-marketing reports with SSRIs and other
newer antidepressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with
self-harm or harm to others. the agitation-type events include: akathisia/psychomotor restlessness, agitation,
disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred
within several weeks of starting treatment.
Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised
in patients of all ages. this includes monitoring for agitation-type emotional and behavioural changes.
An FDA meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients ages 18 to
24 years with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared
to placebo.
Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety,
agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor
restlessness), hypomania, mania, other unusual changes in behaviour, worsening of Depression, and suicidal
ideation, especially when initiating therapy or during any change in dose or dosage regimen. the risk of suicide
attempt must be considered, especially in depressed patients (see oVERDoSAGE).
Discontinuation Symptoms: Patients currently taking EFFEXoR XR should Not be discontinued abruptly, due to
risk of discontinuation symptoms (see WARNINGS and PRECAUtIoNS, Discontinuation Symptoms). At the time
that a medical decision is made to discontinue an SSRI or other newer antidepressant drug, a gradual reduction
in the dose wherever possible, rather than an abrupt cessation, is recommended.
Bone Fracture Risk
Epidemiological studies show an increased risk of bone fractures following exposure to some antidepressants,
including SSRIs/SNRIs. the risks appear to be greater at the initial stages of treatment, but significant increased
risks were also observed at later stages of treatment. the possibility of fracture should be considered in the
care of patients treated with EFFEXoR XR. Elderly patients and patients with important risk factors for bone
fractures should be advised of possible adverse events which increase the risk of falls, such as dizziness and
orthostatic hypotension, especially at the early stages of treatment but also soon after withdrawal. Preliminary
data from observational studies show association of SSRIs/SNRIs and low bone mineral density in older
men and women. Until further information becomes available, a possible effect on bone mineral density with
long-term treatment with SSRIs/SNRIs, including EFFEXoR XR, cannot be excluded, and may be a potential
concern for patients with osteoporosis or major risk factors for bone fractures.
General
Allergic Reactions: Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic
phenomenon.
Hypertension: General: Dose-related increases in blood pressure have been reported in some patients treated with
venlafaxine. Also, rare cases of hypertensive crisis and malignant hypertension have been reported in normotensive and
treated-hypertensive patients in post-marketing experience (see Acute Severe Hypertension and Sustained Hypertension
in the Supplemental Product Information section). Caution should be exercised in patients whose underlying conditions
might be compromised by increases in blood pressure.
Serotonin Syndrome: As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur
with venlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter
systems (see Serotonin Syndrome/Neuroleptic Malignant Syndrome, and DRUG INtERACtIoNS, Serotonergic Drugs).
Cardiac Disease: Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recent history
of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many
clinical studies during the product’s clinical trials. Therefore it should be used with caution in these patients. No case of sudden
unexplained death or serious ventricular arrhythmia, which are possible clinical sequelae of QTc prolongation, was reported
in EFFEXOR XR premarketing studies. Increases in heart rate can occur, particularly with higher doses. Caution should be
exercised in patients whose underlying conditions might be compromised by increases in heart rate.
Concomitant Illness: Clinical experience with venlafaxine in patients with concomitant systemic illness is limited. Caution
is advised in administering venlafaxine to patients with diseases or conditions that could affect hemodynamic responses or
metabolism (see also WARNINGS AND PRECAUtIoNS, General, Hypertension). Patients should be questioned about
any prescription or “over-the-counter drugs, herbal or natural products or dietary supplements” that they are taking, or planning
to take, since there is a potential for interactions.
Endocrine and Metabolism
Serum Cholesterol Elevation: Clinically relevant increases in total serum cholesterol were recorded in 5.3% of venlafaxinetreated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled trials in Major Depressive
Disorders (see Product Monograph, Monitoring laboratory Changes, Serum Cholesterol Elevation). Consistent with
the above findings, elevations of High Density Lipoprotein Cholesterol (HDL), Low Density Lipoprotein Cholesterol (LDL) and
the overall ratio of Total Cholesterol/HDL have been observed in placebo-controlled clinical trials for Social Anxiety Disorder
(SAD) and Panic Disorder. Measurement of serum cholesterol levels (including a complete lipid profile/fractionation and an
assessment of the patient’s individual risk factors) should be considered especially during long-term treatment.
Hepatic/Biliary/Pancreatic
In patients with hepatic impairment, the pharmacokinetic disposition of both venlafaxine and ODV is significantly altered.
Dosage adjustment is necessary in these patients (see Recommended Dose, Patients with Hepatic Impairment,
Patients with Renal Impairment).
Neurologic
Seizures: EFFEXOR XR should be used cautiously in patients with a history of seizures, and should be promptly discontinued
in any patient who develops seizures. Seizures have also been reported as a discontinuation symptom (see also WARNINGS
AND PRECAUtIoNS, Discontinuation Symptoms; ADVERSE REACtIoNS, Discontinuation Symptoms; DoSAGE
AND ADMINIStRAtIoN, Discontinuing Venlafaxine).
Serotonin Syndrome/Neuroleptic Malignant Syndrome: On rare occasions, serotonin syndrome or neuroleptic malignant
syndrome (NMS)-like events have occurred in association with treatment with SSRIs, including venlafaxine, particularly when
given in combination with other serotonergic drugs (including SSRIs, SNRIs, and triptans), with drugs that may impair metabolism
of serotonin (including MAOIs [including linezolid, an antibiotic, and methylene blue]), neuroleptics/antipsychotics, or other
dopamine antagonist drugs. As these syndromes may result in potentially life-threatening conditions, treatment with venlafaxine
should be discontinued if patients develop a combination of symptoms possibly including hyperthermia, rigidity, myoclonus,
autonomic instability (e.g., tachycardia, labile blood pressure) with possible rapid fluctuations of vital signs, neuromuscular
aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea),
mental status changes including confusion, irritability, and extreme agitation progressing to delirium and coma, and supportive
symptomatic treatment should be initiated. Serotonin syndrome, in its most severe form, can resemble NMS. Due to the risk
of serotonergic syndrome or NMS, venlafaxine should not be used in combination with MAOIs or serotonin-precursors (such
as L-tryptophan, oxitriptan) and should be used with caution in patients receiving other serotonergic drugs (triptans, lithium,
tramadol, St. John’s Wort, most tricyclic antidepressants), or neuroleptics/antipsychotics (see CoNtRAINDICAtIoNS and
DRUG INtERACtIoNS, Serotonergic Drugs).
If concomitant treatment with venlafaxine and other agents that may affect the serotonergic and/or dopaminergic neurotransmitter
systems is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose
increases.
The concomitant use of venlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended.
Renal: In patients with renal impairment (GFR=10-70 mL/min), the pharmacokinetic disposition of both venlafaxine and ODV
is significantly altered. Dosage adjustment is necessary in these patients (see DoSAGE AND ADMINIStRAtIoN,
Patients with Renal Impairment and Recommended Dose, Patients with Renal Impairment).
For additional information on Warnings and Precautions, see the Supplemental Product Information section.
ADVERSE REACtIoNS (see full listing in the Product Monograph)
Commonly observed Adverse Reactions
During Depression, GAD, Social Anxiety Disorder, and Panic Disorder trials, the most commonly observed adverse events
(incidence of 5% and at a rate at least twice that of placebo) associated with the use of EFFEXOR XR were: nausea (30-46%),
somnolence (12-29%), dizziness (20-27%), asthenia (19-25%), dry mouth (12-24%), insomnia (23%), anorexia (8-22%),
abnormal male ejaculation (7-18%), sweating (10-15%), nervousness (9-14%), dysmenorrhea (12-13%), constipation (8-12%),
yawn (5-12%), pharyngitis (11%), libido decreased (5-10%), impotence (6-8%), abnormal vision (5-8%), male anorgasmia
(5-8%), abnormal dreams (6-7%), tremor (5-7%), paresthesia (6%), twitching (5%), vasodilatation (5-8%). In GAD, there has
been evidence of adaptation to some adverse events with continued therapy (e.g., dizziness and nausea). In Depression, some
side effects tend to be dose-related.
To monitor drug safety, Health Canada, through the Canada Vigilance Program, collects information on serious and unexpected
effects of drugs. If you suspect a patient has had a serious or unexpected reaction to this drug, you may notify Canada Vigilance
by telephone at 1-866-234-2345.
ADMINIStRAtIoN
DoSAGE AND ADMINIStRAtIoN
Dosing Considerations
General: EFFEXoR XR is not indicated for use in children under 18 years of age (see WARNINGS AND PRECAUtIoNS,
Potential Association with Behavioural and Emotional Changes, Including Self-Harm).
Discontinuing Venlafaxine: When discontinuing venlafaxine after more than 1 week of therapy, it is generally recommended
that the dose be tapered gradually to minimize the risk of discontinuation symptoms. Discontinuation symptoms have been
assessed both in patients with Depression and in those with GAD. Abrupt discontinuation, dose reduction, or tapering of
venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which
increased with higher dose levels and with longer duration of treatment. Reported symptoms include but are not limited to
the following: aggression, agitation, anorexia, anxiety, asthenia, confusion, convulsions, impaired coordination and balance,
diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headache, hypomania, insomnia,
nausea, nightmares, nervousness, paresthesia, electric shock sensations, sensory disturbances (including shock-like electrical
sensations), sleep disturbances, somnolence, sweating, tinnitus, vertigo, and vomiting. Where such symptoms occurred, they
were usually self-limiting but in a few patients continued for several weeks. It is therefore recommended that the dosage of
EFFEXOR XR be tapered gradually whenever possible and the patient monitored. The period required for tapering may depend
on the dose, duration of therapy, and the individual patient. If venlafaxine has been used for more than 6 weeks, tapering
over at least a 2-week period is recommended (see WARNINGS AND PRECAUtIoNS, PotENtIAl ASSoCIAtIoN WItH
BEHAVIoURAl AND EMotIoNAl CHANGES, INClUDING SElF-HARM and also Discontinuation Symptoms; ADVERSE
REACtIoNS, Discontinuation Symptoms).
Switching Patients to or from a Monoamine oxidase Inhibitor: At least 14 days should elapse between
discontinuation of an MAOI and initiation of therapy with EFFEXOR XR. In addition, at least 14 days should be allowed after
stopping EFFEXOR XR before starting an MAOI (see CoNtRAINDICAtIoNS).
Switching Patients from Immediate Release tablets: Depressed patients who are currently being treated at a therapeutic
dose with immediate release tablets may be switched to EFFEXOR XR at the nearest equivalent dose (mg/day), e.g.,
37.5 mg immediate release two times a day to 75 mg EFFEXOR XR once daily. However, individual dosage adjustments may
be necessary.
Recommended Dose and Dosage Adjustment
ADUltS:
Patients with Major Depressive Disorder: The recommended dose for EFFEXOR XR is 75 mg/day, administered
once daily with food, either in the morning or in the evening. For some patients, it may be desirable to start at 37.5 mg/day
for 4 to 7 days to allow new patients to adjust to the medication before increasing to 75 mg/day. Each capsule should be
swallowed whole with water. It should not be divided, crushed, chewed, or placed in water.
While the relationship between dose and antidepressant response for EFFEXOR XR has not been adequately explored, patients
not responding to the initial 75 mg may benefit from dose increases. Depending on tolerability and the need for further clinical
effect, the dose should be increased by up to 75 mg/day up to a maximum of 225 mg/day as a single dose for moderately
depressed outpatients. Dose increments should be made at intervals of approximately 2 weeks or more, but not less than
4 days. There is very limited experience with EFFEXOR XR at doses higher than 225 mg/day, or in severely depressed inpatients.
Patients with Generalized Anxiety Disorder (GAD): The recommended starting dose of EFFEXOR XR is 37.5 mg/day
administered as a single dose, taken with food, for 4 to 7 days. The usual dose is 75 mg/day administered as a single dose.
Subsequent dosage increments of up to 75 mg/day may be considered, if clinically warranted. Dose increments should be
made as needed at intervals of not less than 4 days. The maximum recommended daily dose is 225 mg/day as a single dose.
Patients with Social Anxiety Disorder (Social Phobia): For most patients, the recommended dose for EFFEXOR XR is
75 mg/day, administered in a single dose. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days,
to allow new patients to adjust to the medication before increasing to 75 mg/day. Depending on tolerability and if clinically
warranted, dose increases should be in increments of up to 75 mg/day, as needed, up to a maximum of 225 mg/day. Dose
increments should be made at intervals of not less than 4 days.
Panic Disorder: It is recommended that initial single doses of 37.5 mg/day of EFFEXOR XR be used for 7 days. The recommended
treatment dose is 75 mg/day, administered in a single dose. Although a dose response relationship for effectiveness in
patients with Panic Disorder was not clearly established in fixed-dose studies, certain patients not responding to 75 mg/day
may benefit from dose increases to a maximum of 225 mg/day. Dose increases should be in increments of up to 75 mg/day,
as needed, and should be made at intervals of at least 7 days.
Maintenance/Continuation/Extended Treatment: There is no body of evidence available to answer the question of how
long a patient should continue to be treated with EFFEXOR XR for Depression, GAD, Social Anxiety Disorder, or Panic Disorder.
During long-term therapy for any indication, the EFFEXOR XR dosage should be maintained at the lowest effective dose and
the need for continuing treatment should be periodically reassessed.
Depression: It is generally agreed that acute episodes of major Depression require several months or longer of sustained
pharmacotherapy beyond response to the acute episode. Whether the dose needed to induce remission is identical to the
dose needed for maintenance is unknown. Maintenance of efficacy of EFFEXOR XR has been shown in a placebo-controlled
study in which patients responding during 8 weeks of acute treatment with EFFEXOR XR were assigned randomly to placebo
or to the same dose of EFFEXOR XR (75, 150, or 225 mg/day, in the morning [i.e., qAM]) during 26 weeks of maintenance
treatment (see Product Monograph, ClINICAl tRIAlS, Depression).
It is not known whether or not the dose of EFFEXOR XR needed for maintenance treatment is identical to the dose needed
to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment
and the appropriate dose for such treatment.
Social Anxiety Disorder: In patients with Social Anxiety Disorder, there are no efficacy data beyond 6 months of treatment
with EFFEXOR XR. The need for continuing medication in patients with Social Anxiety Disorder who improve with EFFEXOR
XR treatment should be periodically reassessed.
Panic Disorder: In one study in Panic Disorder, in which patients who were responders in the final 2 weeks of a
12-week acute treatment with EFFEXOR XR were assigned randomly to placebo or to the same dose of EFFEXOR XR (75, 150,
or 225 mg/day) during 6 months of maintenance treatment, patients continuing EFFEXOR XR treatment showed a significantly
longer time to relapse than patients switched to placebo.
Special Patient Populations:
treatment of Pregnant Women During the third trimester: When treating a pregnant woman with EFFEXOR XR during
the third trimester, the physician should carefully consider the potential risks and benefits of treatment.
Elderly Patients: No dose adjustment is recommended for elderly patients solely on the basis of their age. As with any
antidepressant or anxiolytic drug for treatment of Social Anxiety Disorder or Panic Disorder, however, caution should be exercised
in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.
Patients with Hepatic Impairment: Given the decrease in clearance and increase in elimination half-life for both venlafaxine
and ODV that is observed in patients with hepatic cirrhosis compared with normal subjects (see Product Monograph, ACtIoN
AND ClINICAl PHARMAColoGY, Hepatic Insufficiency), the total daily dose should be reduced by about 50% in
patients with mild to moderate hepatic impairment. For such patients, it may be desirable to start at 37.5 mg/day. Because
of individual variability in clearance in these patients, individualization of dosage may be desirable. Since there was much
individual variability in clearance between patients with cirrhosis, it may be necessary to reduce the dose by even more than
50%, and individualization of dosing may be desirable in some patients.
Patients with Renal Impairment: Given the decrease in clearance for venlafaxine and increase in elimination half-life
for both venlafaxine and ODV that is observed in patients with renal impairment (GFR=10-70 mL/min) compared to normal
subjects (see Product Monograph, ACtIoN AND ClINICAl PHARMAColoGY, Renal Insufficiency), the total daily
dose should be decreased by 25% to 50%. In patients undergoing hemodialysis, the total daily dose must be reduced
by 50% and withheld until the dialysis treatment is completed (4 hrs). For such patients, it may be desirable to start at
37.5 mg/day. Since there is so much individual variability in clearance among patients with renal impairment, individualization
of dosing may be desirable.
Missed Dose: If a dose is missed, it should not be made up by doubling the dose next time. The next dose should be
taken as scheduled.
Administration: Administer once daily with food, either in the morning or in the evening.
Discontinuation Symptoms: Discontinuation symptoms have been assessed both in patients with Depression and those with anxiety. Abrupt discontinuation, dose reduction,
or tapering of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose
level and with longer duration of treatment. If venlafaxine is used until or shortly before birth, discontinuation effects in the newborn should be considered.
Discontinuation effects are well known to occur with antidepressants, and therefore, it is recommended that the dosage be tapered gradually whenever possible and the
patient monitored. Time to event onset after dose reduction or discontinuation can vary in individual patients and range from the same day to several weeks (see also
ADVERSE EVENtS, Discontinuation Symptoms; DoSAGE AND ADMINIStRAtIoN, Discontinuing Venlafaxine).
Psychomotor Impairment: In healthy volunteers receiving an immediate release venlafaxine formulation at a stable regimen of 150 mg/day, some impairment of psychomotor
performance was observed. Patients should be cautioned about operating hazardous machinery, including automobiles, or engaging in tasks requiring alertness until they
have been able to assess the drug’s effect on their own psychomotor performance.
Dependence/tolerance: In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA)
receptors. It has no significant CNS-stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability.
While venlafaxine has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behaviour in the clinical trials.
However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed.
Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of
venlafaxine (e.g., development of tolerance, incrementation of dose, drug-seeking behaviour).
Changes in Appetite and Weight: Treatment-emergent anorexia and weight loss were more commonly reported for venlafaxine-treated patients than for placebo-treated
patients in Depression and GAD, Social Anxiety Disorder and Panic Disorder trials. Significant weight loss, especially in underweight depressed/GAD patients, may be an
undesirable result of treatment. Venlafaxine is not recommended for weight loss alone or in combination with other products such as phentermine or sibutramine. Based on
the known mechanisms of action, the potential harm of co-administration includes the possibility of serotonin syndrome (see DRUG INtERACtIoNS, Serotonergic Drugs).
Gastrointestinal: Results of testing in healthy volunteers demonstrated differences in the gastrointestinal tolerability of different formulations of venlafaxine. Data from
healthy volunteers showed reduced incidence and severity of nausea with EFFEXOR XR capsules, compared with immediate release tablets.
Genitourinary
Hyponatremia: Cases of hyponatremia may occur with venlafaxine, usually in volume-depleted or dehydrated patients. Elderly patients, patients taking diuretics, and patients
who are otherwise volume depleted, may be at greater risk for this event. The hyponatremia appeared to be reversible when venlafaxine was discontinued.
Inappropriate Antidiuretic Hormone Secretion: Cases of Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion may occur with venlafaxine, usually in
volume-depleted or dehydrated patients. Elderly patients, patients taking diuretics, and patients who are otherwise volume depleted, may be at greater risk for this event.
Hematologic
Abnormal Bleeding: SSRIs and SNRIs, including EFFEXOR XR, may increase the risk of bleeding events by causing abnormal platelet aggregation. Concomitant use of
acetylsalicylic acid (ASA), nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to the risk. Case reports and epidemiological studies
(case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding.
Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of EFFEXOR XR and NSAIDs, ASA, or other drugs that affect coagulation
(see DRUG INtERACtIoNS, Drugs Affecting Platelet Function). Caution is advised in patients with a history of bleeding disorder or predisposing conditions
(e.g., thrombocytopenia).
Immune
Venlafaxine and O-desmethylvenlafaxine produced only limited effects in immunological studies, which were generally at doses greater than those required to produce
antidepressant effects in animals.
ophthalmologic
Glaucoma: As with other SSRIs/SNRIs, EFFEXOR XR can cause mydriasis and should be used with caution in patients with raised intraocular pressure or those with
narrow angle glaucoma.
Psychiatric
Suicide: The possibility of a suicide attempt in seriously depressed patients is inherent to the illness and may persist until significant remission occurs. Close supervision
of patients should accompany initial drug therapy, and consideration should be given to the need for hospitalization of high-risk patients. Patients, their families, and their
caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia
(psychomotor restlessness), hypomania, mania, other unusual changes in behaviour, worsening of Depression, and suicidal ideation, especially when initiating therapy or
during any change in dose or dosage regimen. The risk of suicide attempt must be considered, especially in depressed patients; the smallest quantity of drug, consistent
with good patient management, should be provided to reduce the risk of overdose with this drug. The same precautions observed when treating patients with Depression
should be observed when treating patients with GAD or Social Anxiety Disorder (see WARNINGS AND PRECAUtIoNS, PotENtIAl ASSoCIAtIoN WItH BEHAVIoURAl
AND EMotIoNAl CHANGES, INClUDING SElF-HARM).
Insomnia and Nervousness: Treatment-emergent insomnia and nervousness were more commonly reported for patients treated with venlafaxine than with placebo
(see ADVERSE REACtIoNS) in Depression, GAD, Social Anxiety Disorder, and Panic Disorder studies.
Activation of Mania/Hypomania: As with all antidepressants, EFFEXOR XR should be used cautiously in patients with a history or family history of bipolar disorder. A
major depressive episode may be the initial presentation of bipolar disorder. Patients with bipolar disorder may be at an increased risk of experiencing manic episodes
when treated with antidepressants alone. Therefore, the decision to initiate symptomatic treatment of Depression should only be made after patients have been adequately
assessed to determine if they are at risk for bipolar disorder.
DRUG INtERACtIoNS
overview
Venlafaxine is not highly bound to plasma proteins; therefore, administration of venlafaxine to a patient taking another drug that is highly protein-bound should not cause increased
free concentrations of the other drug. The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is
advised if the concomitant administration of venlafaxine and such drugs is required. As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.
Drug-Drug Interactions
Monoamine Oxidase Inhibitors : See CoNtRAINDICAtIoNS and DoSAGE AND ADMINIStRAtIoN, Switching Patients to or from a Monoamine oxidase Inhibitor.
Serotonergic Drugs: Based on the known mechanism of action of venlafaxine and the potential for serotonin syndrome, a potentially life threatening condition,
caution is advised when venlafaxine is co-administered with other drugs that may affect the serotonergic neurotransmitter systems (such as triptans, selective
serotonin reuptake inhibitors, other SNRIs, linezolid (an antibiotic which is a reversible non-selective MAOI; see CoNtRAINDICAtIoNS), lithium, sibutramine, or
fentanyl (and its analogues, dextromethorphan, tramadol, tapentadol, meperidine, methadone, and pentazocine), or with serotonin precursors, such as tryptophan
supplements). Rare post-marketing reports describe patients with symptoms suggestive of, or diagnostic of, serotonin syndrome, following the combined use of
an SSRI with 5HT1-agonists (triptans) or lithium. If concomitant treatment with EFFEXOR XR and an SSRI, an SNRI, a triptan (e.g., almotriptan, sumatriptan,
rizatriptan, naratriptan, zolmitriptan), tricyclic antidepressants, or other drugs or agents with serotonergic activity (including but not limited to fenfluramine,
tryptophan, and sibutramine; the antibiotic linezolid; methylene blue [a surgical dye]; St. John’s Wort) is clinically warranted, appropriate observation of the patient
for acute and long-term adverse events is advised (see also WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Changes in Appetite and Weight;
and WARNINGS AND PRECAUTIONS, Neurologic, Serotonin Syndrome/Neuroleptic Malignant Syndrome).
There exist no clinically significant drug-drug interactions with lithium and diazepam. Potential interactions do exist with alcohol, cimetidine, haloperidol, imipramine, metoprolol,
risperidone, indinavir, and ketoconazole. See the Product Monograph for complete information.
Drugs That Inhibit Cytochrome P450 Isoenzymes
CYP2D6 Inhibitors: The potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism and venlafaxine. Concomitant use of CYP2D6
inhibitors and venlafaxine may reduce the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of
ODV. As venlafaxine and ODV are both pharmacologically active, no dosage adjustment is required when venlafaxine is co-administered with a CYP2D6 inhibitor.
CYP3A3/4 Inhibitors: Concomitant use of CYP3A4 inhibitors and venlafaxine may increase levels of venlafaxine and ODV (see Ketoconazole, above). Therefore, caution is
advised when combining venlafaxine with a CYP3A4 inhibitor.
CYP2D6 and 3A4 Inhibitors: Interactions between concomitant intake of inhibitors of both CYP2D6 and CYP3A3/4 with venlafaxine have not been studied. However, this
concomitant use would be expected to increase venlafaxine plasma concentrations. Because the two primary metabolic pathways for venlafaxine are through CYP2D6 and,
to a lesser extent, CYP3A3/4, concomitant intake of inhibitors of both of these isoenzymes is not recommended during treatment with venlafaxine.
Post-marketing Reports of Drug-Drug Interactions: There have been reports of elevated clozapine levels that were temporally associated with adverse events
including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when
venlafaxine was given to patients receiving warfarin therapy.
Electroconvulsive Therapy: There are no clinical data on the use of electroconvulsive therapy combined with EFFEXOR XR treatment.
Drug-Herb Interactions
St. John’s Wort: In common with SSRIs, pharmacodynamic interactions between EFFEXOR XR and the herbal remedy St. John’s Wort may occur and may result in an
increase in undesirable effects.
Drug-lifestyle Interactions
Interference with Cognitive and Motor Performance: In healthy volunteers receiving an immediate release venlafaxine formulation at a stable regimen of 150 mg/day, some
impairment of psychomotor performance was observed. Patients should be cautioned about operating hazardous machinery, including automobiles, or engaging in tasks
requiring alertness until they have been able to assess the drug’s effect on their own psychomotor performance.
oVERDoSAGE
For management of a suspected drug overdose, contact your regional Poison Control Centre.
Among the patients included in the premarketing evaluation of venlafaxine extended release capsules, there were 2 reports of acute
overdosage with EFFEXOR XR in Depression trials, either alone or in combination with other drugs. One patient took a combination of 6 g of EFFEXOR XR and 2.5 mg
of lorazepam. This patient was hospitalized, treated symptomatically, and recovered without any untoward effects. The other patient took 2.85 g of EFFEXOR XR.
This patient reported paresthesia of all four limbs but recovered without sequelae. There were 2 reports of acute overdose with EFFEXOR XR in anxiety trials.
One patient took a combination of 0.75 g EFFEXOR XR and 200 mg of paroxetine and 50 mg of zolpidem. This patient was described as being alert, able to communicate,
and a little sleepy. This patient was hospitalized, treated with activated charcoal, and recovered without any untoward effects. The other patient took 1.2 g of
EFFEXOR XR. This patient recovered and no other specific problems were found. The patient had moderate dizziness, nausea, numb hands and feet, and hot-cold
spells 5 days after the overdose. There were no reports of acute overdose with EFFEXOR XR in Social Anxiety Disorder trials. There were 2 reports of acute overdose
with EFFEXOR XR in Panic Disorder trials. One patient took 0.675 g of EFFEXOR XR once and the other patient took 0.45 g of EFFEXOR XR for 2 days. No signs
or symptoms were associated with either overdose and no actions were taken to treat them.
Post-marketing Experience with EFFEXoR (Dosage Form Unknown)
In post-marketing experience, overdose with venlafaxine was reported predominantly in combination with alcohol and/or other drugs. The most commonly reported events
in overdose include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, convulsion, and vomiting. Other events reported include
electrocardiographic changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, delayed rise in
plasma creatine kinase levels, rhabdomyolysis, liver necrosis, serotonin syndrome, vertigo, and death. Muscle enzymes should be monitored in patients with venlafaxine
overdose to detect development of rhabdomyolysis at an early stage and to initiate appropriate treatment. According to post-marketing overdose reports with venlafaxine
(where overdose amounts were provided), fatal acute overdoses have been reported with venlafaxine alone at doses as low as approximately 1 gram.
Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI
antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher burden of
suicide risk factors than SSRI patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage
as opposed to some characteristics of venlafaxine-treated patients is not clear. Prescriptions for venlafaxine should be written for the smallest quantity of drug consistent
with good patient management, in order to reduce the risk of overdose.
overdosage Management: Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate
airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is
not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in
symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange
transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known.
In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control centre for current information on
the treatment of any overdose.
For a copy of the Product Monograph or full Prescribing Information, please contact: Pfizer Canada Medical Information at 1-800-463-6001 or visit www.pfizer.ca.
SUPPlEMENtAl PRoDUCt INFoRMAtIoN
WARNINGS AND PRECAUtIoNS
Acute Severe Hypertension: Cases of severe elevated blood pressure requiring immediate treatment have been reported in post-marketing experience, including reports
of hypertensive crisis and malignant hypertension. The reports included normotensives and treated-hypertensive patients as well. Pre-existing hypertension should be
controlled before treatment with venlafaxine. All patients should have their blood pressure evaluated before starting venlafaxine and monitored regularly during treatment.
Patients should be told to consult their doctors if they have symptoms associated with acute severe hypertension, such as headache (particularly in the back of head/neck
when waking up), stronger heart beat and possibly more rapid, palpitations, dizziness, easy fatigability, blurred vision, chest pain.
Sustained Hypertension: Venlafaxine treatment has been associated with sustained hypertension. Sustained increases in blood pressure could have adverse
consequences. Therefore, it is recommended that patients have their blood pressure monitored before starting venlafaxine and then regularly during treatment.
For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered after a
benefit-risk assessment is made.
© 2012
Pfizer Canada Inc.
Kirkland, Quebec
H9J 2M5
TM Pfizer Inc, used under license
Effexor ® Wyeth LLC., owner/
using OMNARIS over several months or longer should be examined
periodically for possible changes in the nasal mucosa.
®
Prescribing Summary
ADVERSE REACTIONS:
Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted
under very specific conditions the adverse reaction rates observed in the clinical
trials may not reflect the rates observed in practice and should not be compared
to the rates in the clinical trials of another drug. Adverse drug reaction information
from clinical trials is useful for identifying drug-related adverse events and for
approximating rates.
In controlled clinical studies, a total of 2013 patients ages 12 years and older
received treatment with OMNARIS . In studies of 2 to 6-weeks duration,
677 patients were treated with OMNARIS 200 mcg daily, and in a study of up
to one year in duration, 441 patients were treated with OMNARIS 200 mcg
daily. The overall incidence of adverse events for patients treated with
OMNARIS was comparable to that in patients treated with the placebo.
Approximately 2% of patients treated with OMNARIS 200 mcg in clinical
trials discontinued because of adverse events; this rate was similar for
patients treated with placebo. Table 1 displays adverse events, assessed as
likely or definitely related to treatment by the investigator, that occurred with
an incidence of 1% or greater in clinical trials of 2 to 6-weeks in duration. In
a 52-week long-term safety trial that included 663 adolescent and adult
patients (227 males and 436 females) with perennial allergic rhinitis, the
adverse event profile over the treatment period was similar to the adverse
event profile in trials of shorter duration. Adverse events considered likely or
definitely related to OMNARIS that were reported at an incidence of 1% or
greater are presented in Table 2. No patient experienced a nasal septal
perforation or nasal ulcer during long-term use of OMNARIS nor was there
any evidence of HPA-axis suppression in this study.
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IMPORTANT: Before making prescribing decisions, please refer to the
complete Product Monograph at www.nycomed.ca.
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Patient Selection Criteria
INDICATIONS AND CLINICAL USE: OMNARIS (ciclesonide nasal spray) is
indicated for the treatment of seasonal allergic rhinitis, including hayfever,
and perennial allergic rhinitis in adults and adolescents 12 years of age and
older.
®
Special Populations:
Geriatrics (>65 years of age): A total of 31 patients 65 years of age and older
(age range 65 to 75 years) have been treated with OMNARIS 200 mcg/day for
up to 1 year. The adverse reactions reported in this population were similar in
type and incidence to those reported by younger patients, but greater
sensitivity of some older individuals cannot be ruled out. Based on available
data for OMNARIS , no adjustment of dosage of OMNARIS in geriatric
patients is warranted.
Pediatrics: OMNARIS is not presently approved for use in patients younger
than 12 years of age. A total of 91 patients 12-17 years of age were treated
with OMNARIS for up to one year. No differences in the rate or incidence of
adverse events were observed.
Pregnant Women: There are no adequate and well-controlled studies with
OMNARIS in pregnant women. As with other corticosteroids, ciclesonide
should only be used during pregnancy when the potential benefit to the mother
justifies the potential risk to the mother, fetus or infant. Infants born to mothers
who received corticosteroids during pregnancy should be observed carefully for
hypoadrenalism. The extent of exposure in pregnancy during clinical trials: Very
Limited: individual cases only.
Nursing Women: It is unknown if ciclesonide is excreted in human milk. As
with other corticosteroids, OMNARIS should only be used in nursing women
when the potential benefit to the mother justifies the potential risk to the
mother and/or infant.
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CONTRAINDICATIONS: OMNARIS is contraindicated in patients with a
hypersensitivity to any of the ingredients. OMNARIS should be used with
caution, if at all, in patients with active or quiescent tuberculosis infections of
the respiratory tract.
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DRUG INTERACTIONS:
Overview: In vitro data indicate that cytochrome P450 3A4 is the major enzyme
involved in the metabolism of the active metabolite of ciclesonide (M1) in man.
Based on in vitro studies in human liver microsomes, the active metabolite (M1)
did not significantly inhibit or induce the metabolism of other drugs. Based on
in vitro human hepatocyte studies, ciclesonide and M1 had no significant effect
on the induction of major cytochrome P450 isozymes. In vitro studies also
demonstrated that the plasma protein binding of des-ciclesonide was not
affected by warfarin or salicylic acid, indicating that protein binding-based drug
interactions are unlikely. The serum levels of ciclesonide and its active
metabolite M1, are negligible following administration of ciclesonide nasal
spray. Therefore, the potential for clinically relevant drug-drug interactions is
very low. However, co-administration with potent inhibitors of the cytochrome
P450 3A4 system (e.g., protease inhibitors for the treatment of HIV infections
such as, ritonavir or nelfinavir) should be considered with caution because
there might be an increase in systemic drug levels of the active metabolite M1.
To report an adverse reaction contact Nycomed Canada Inc. by phone at
1-866-295-4636, or Health Canada at 1-866-234-2345.
®
Administration
Recommended Dose and Dosage Adjustment: Adults and Adolescents
(12 Years of Age and Older): The recommended dose of OMNARIS is 200 mcg
per day administered as 2 sprays (50 mcg/spray) in each nostril once daily. The
maximum total daily dosage should not exceed 2 sprays in each nostril
(200 mcg/day).
Missed Dose: It is very important that OMNARIS is used regularly. If a dose is
missed, the next dose should be taken when it is due and patients should not
exceed the prescribed daily dosage.
Administration: Prior to initial use, OMNARIS must be shaken gently and then
the pump must be primed by actuating 8 times. If not used for 4 or more
consecutive days, it should be shaken gently and reprimed with 1 spray or until a
fine spray appears. It is recommended that the applicator tip be wiped with a clean
tissue following daily use. It is also recommended that the applicator be cleaned
weekly using warm water and reprimed with one spray or until a fine mist appears.
OMNARIS delivers 50 mcg of ciclesonide per spray. Each bottle of OMNARIS
contains 120 metered sprays after initial priming. The bottle should be discarded
after 120 sprays following initial priming, since the amount of ciclesonide
delivered per spray thereafter may be substantially less than the labeled dose. If
more than 6 months have elapsed since the bottle was removed from the foil
pouch, it should be discarded. Do not spray in eyes.
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Safety Information
SUMMARY OF WARNINGS AND PRECAUTIONS:
Immune: Patients who are on drugs that suppress the immune system are
more susceptible to infections than healthy individuals. Chickenpox and
measles, for example, can have a more serious or even fatal course in children
or adults on corticosteroids. In children or adults who have not had these
diseases, particular care should be taken to avoid exposure. How the dose,
route, and duration of corticosteroid administration affects the risk of
developing a disseminated infection is not known. The contribution of the
underlying disease and/or prior corticosteroid treatment to the risk is also not
known. If exposed to chickenpox, prophylaxis with varicella zoster immune
globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with
pooled intramuscular immunoglobulin (IG) may be indicated. If chickenpox
develops, treatment with antiviral agents may be considered. Because of the
inhibitory effect of corticosteroids on wound healing, patients who have
experienced recent nasal septal ulcers, nasal surgery, or nasal trauma should
not use a nasal corticosteroid until healing has occurred.
Infection: In clinical studies with corticosteroids administered intranasally, the
development of localized infections of the nose and pharynx with Candida
albicans have been reported only rarely. When such an infection develops, it
may require treatment with appropriate local therapy and discontinuation of
treatment with the intranasal steroid. Therefore, patients using intranasal
corticosteroids over several months or longer should be examined periodically
for evidence of Candida infection or other signs of adverse effects on the nasal
mucosa. OMNARIS should be used with caution, if at all, in patients with
untreated local or systemic fungal or bacterial infections; systemic viral or
parasitic infections; or ocular herpes simplex.
Systemic Effects: Rarely, immediate hypersensitivity reactions or contact
dermatitis may occur after the administration of intranasal corticosteroids. Rare
instances of wheezing, nasal septum perforation, cataracts, glaucoma, and
increased intraocular pressure have been reported following the intranasal
application of corticosteroids. The risk of glaucoma was evaluated by
assessments of intraocular pressure in 390 adolescent or adult patients receiving
treatment with OMNARIS 200 mcg daily for up to 52 weeks. In this trial, no
significant differences in intraocular pressure changes were observed between
OMNARIS and placebo-treated patients. Additionally, no significant
differences between OMNARIS 200 mcg and placebo-treated patients were
noted during the 52-week study of 577 patients in which thorough
ophthalmologic assessments were performed including evaluation of cataract
formation using slit lamp examinations. Although systemic effects have been
minimal with recommended doses of OMNARIS , any such effect is likely to be
dose dependent. Therefore, larger than recommended doses of OMNARIS
should be avoided. When used at excessive doses, systemic corticosteroid
effects such as hypercorticism and adrenal suppression may occur. If such
changes occur, the dosage of OMNARIS should be discontinued slowly,
consistent with accepted procedures for discontinuing oral corticosteroid
therapy. Physicians should closely follow the growth of children and adolescents
taking corticosteroids by any route, and weigh the benefits of corticosteroid
therapy against the possibility of growth suppression if growth appears slowed.
To minimize the systemic effects of intranasal corticosteroids each patient
should be titrated to his/her lowest effective dose.
Systemic Steroid Replacement by a Topical Steroid: The replacement of a
systemic corticosteroid with a topical corticosteroid can be accompanied by
signs of adrenal insufficiency. In addition, some patients may experience
symptoms of corticosteroid withdrawal, e.g., joint and/or muscular pain,
lassitude, and depression. Patients previously treated for prolonged periods
with systemic corticosteroids and transferred to topical corticosteroids should
be carefully monitored for acute adrenal insufficiency in response to stress. In
those patients who have asthma or other clinical conditions requiring long-term
systemic corticosteroid treatment, rapid decreases in systemic corticosteroid
dosages may cause a severe exacerbation of their symptoms.
Monitoring and Laboratory Tests: As with any long-term treatment, patients
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Study Reference
1. OMNARIS (ciclesonide nasal spray) Product Monograph. Nycomed
Canada Inc. June 2011. 2. Patel P, et al. Onset of action of ciclesonide once
daily in the treatment of seasonal allergic rhinitis. Ear Nose Throat J
2008;87(6):340-345, 353.
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SUPPLEMENTAL PRODUCT INFORMATION
ADVERSE REACTIONS
Table 1: Common Adverse Reactions (1-10%) in Controlled Clinical Trials 2 to 6-weeks in
Duration in Patients 12 Years of Age and Older with Seasonal or Perennial Allergic Rhinitis
1
®
OMNARIS 200 mcg
n=677
(%)
Placebo
n=674
(%)
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Adverse Reaction
2.7
2.1
Nasal Passage Irritation
2.4
2.2
Headache
1.3
0.7
Epistaxis
2
3
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1
Assessed as likely or definitely related to the treatment by investigator.
2
Epistaxis (e.g., frank bleeding, blood-tinged mucus and blood flecks).
3
Nasal passage irritation includes nasal discomfort.
Table 2: Common Adverse Reactions (1-10%) in a 52-week Study in Adult and Adolescent
Patients with Perennial Allergic Rhinitis
1
OMNARIS 200 mcg
n=441
(%)
Placebo
n=222
(%)
®
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Adverse Reaction
®
8.4
6.3
Nasal passage irritation
4.3
3.6
Headache
1.6
0.5
Epistaxis
2
3
®
1
Assessed as likely or definitely related to the treatment by investigator.
2
Epistaxis (e.g., frank bleeding, blood-tinged mucus and blood flecks).
3
Nasal passage irritation includes nasal discomfort.
The following less common adverse reactions (assessed as possibly related to treatment by the investigator) were
reported in controlled clinical trials 2 to 52 weeks in duration in patients 12 years of age and older with
Seasonal Allergic or Perennial Allergic Rhinitis treated with OMNARIS 200 mcg:
Less Common Clinical Trial Adverse Drug Reactions ( 0.1% to <1%):
®
Gastrointestinal: dry mouth (0.2%), dyspepsia (0.2%)
Infections: candidiasis (0.2%), rhinitis (0.2%)
Investigations: laboratory test abnormal NOS (0.2%), white blood cell count increased (0.3%)
Nervous System: dysgeusia (0.2%)
Respiratory, Thoracic and Mediastinal: nasal dryness (0.4%), pharyngolaryngeal pain (0.4%),
rhinorrhoea* (0.3%), nasal septum disorder (0.2%), throat irritation* (0.2%)
*occurred at rates placebo
Special Populations: The incidence of adverse events did not differ appreciably based on age, gender or race.
Abnormal Hematologic and Clinical Chemistry Findings: Examination of the percentage of patients with normal
values at baseline and values above or below the normal range at the end of treatment did not demonstrate any
trends with respect to changes in hematology and biochemistry values.
DRUG INTERACTIONS:
Drug-Drug Interactions: A drug interaction study with orally inhaled ciclesonide and oral erythromycin, a
substrate and weak inhibitor of cytochrome P450 3A4, had no relevant effect on the pharmacokinetics of either
M1 or erythromycin. In a drug interaction study at steady state with orally inhaled ciclesonide and oral
ketoconazole, a potent cytochrome P450 3A4 inhibitor, the exposure of the active metabolite M1 increased
approximately 3.5-fold, while levels of ciclesonide remained unchanged. Due to the low systemic exposure of
intranasal ciclesonide relative to orally inhaled ciclesonide, clinically relevant drug interactions with OMNARIS ,
except with very potent inhibitors of the cytochrome P450 3A4 system, are not expected.
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Drug-Food Interactions: Interactions with food have not been established. Drug-food interactions are unlikely for
intranasal corticosteroids.
Drug-Herb Interactions: Interactions with herbal products have not been established.
Drug-Laboratory Interactions: Interactions with laboratory tests have not been established. Drug-laboratory
interactions are unlikely for intranasal corticosteroids.
DOSAGE CONSIDERATIONS:
Dosing Considerations: The therapeutic effects of corticosteroids, unlike those of decongestants, are not
immediate. Since the effect of OMNARIS depends on its regular use, patients should be instructed to take the
nasal inhalation at regular intervals and not, as with other nasal sprays, as they feel necessary.
®
The full Product Monograph is available at www.nycomed.ca or by contacting:
Nycomed Canada Inc.
435 North Service Road West, 1st Floor
Oakville, ON L6M 4X8
© 2012 Nycomed Canada Inc. All rights reserved.
Registered Trademark of Nycomed GmbH. Used under licence.
®
OCTOBeR 9, 2012
43
Renal denervation
continues to show promise
EUROPEAN SOciEty Of cARDiOLOGy
Procedure
for refractory
hypertension
found to work in
a variety of settings
ies that first highlighted the
possibility of controlling drugresistant hypertension by renal
artery denervation.
“Although longer-term
results are required, renal
denervation should be conBy ED SUSmAN
sidered for all patients with
Munich
treatment-resistant hypertension, as it is likely to lower their
blood pressure and reduce
n a series of small
their chances of myocardial
studies, researchers at
the European Society of
infarction and stroke,” Dr.
Cardiology annual meeting
Mylotte said at a press briefing
here found renal sympathetic
dedicated to new research on
denervation improves ejection
renal denervation
fraction in patients with heart
Dr. Michael Bohm, a profesfailure, has durable effects on
sor of medicine at Saarland
uncontrolled hypertension and
University in Homburg,
even benefits patients with
Germany, reported that in
psychological symptoms.
the SYMPLICITY HTN2 trial,
In the treatment of
renal denervation resulted in
heart failure, patients who
reductions in blood pressure
underwent renal
that lasted at least 18
denervation with
months.
radiofrequency ablaThe researchers
tion achieved a starandomized 106
tistically significant
patients: 52 who
improvement in left
received immediventricular ejection
ate ablation and 54
fraction, from 25%
who served as conat baseline to 31%
trols but were later
after 12 months,
allowed to cross over
Dr. taborsky
while patients given
to renal denervation.
optimal medical
In the treatment
treatment had minimal and
group, systolic blood pressure
non-significant changes: from
had decreased by 32 mmHg
26% to 28%.
and diastolic pressure by
The difference between the
12 mmHg at six months—and
groups was also significant,
those reductions were maintained at 18 months.
said Dr. Mylos Taborsky, an
Among patients who
associate professor of medicine
crossed over to treatment,
at University Hospital Olosystolic blood pressure lowermouc in the Czech Republic.
ing was 25 mmHg
In a second study,
at six months and
Dr. Darren Mylotte,
a clinical fellow in
28 mmHg at 18
cardiology at the
months; diastolic
Cardiovascular Instiblood pressure
tute of Paris South,
decline was 8 mmHg
reported systolic
at six months and
blood pressure reduc11 mmHg at 18
tions of 23 mmHg
months. The differto 31 mmHg from
ences observed all
Dr. mylotte
baseline and diastolic
achieved statistical
blood pressure reducsignificance.
tions of 10 mmHg to 14 mmHg
“At 18 months followup
from baseline six months after
there are no device-related
the procedure.
serious adverse effects and no
He scrutinized outcomes in
detrimental effects on the renal
35 consecutive patients treated
vasculature following treatin a community hospital with
ment,” Dr. Bohm said, noting
the catheter-based ablation
that cases of hypotension were
technique and found his outnot observed in the trial.
comes were similar to those
In a fourth study, Dr. Denise
Fischer (PhD), a staff psycholoseen in the SYMPLICITY stud-
Courtesy of the University Health Network
i
Doctors at toronto General Hospital discuss the renal denervation procedure, which
European studies have found improves ejection fraction in patients with heart failure
and has durable effects on uncontrolled hypertension, among other benefits.
gist at Saarland University Hospital, reported that renal sympathetic denervation improves
anxiety, depression, quality of
life and stress in patients with
resistant hypertension.
Commenting
on the
studies,
Dr. David
Holmes,
the immediate
pastpresident
Dr. fischer
of the
American
College of Cardiology and a
professor of medicine at the
Mayo Clinic College of Medicine in Rochester, Minn., said,
“Denervation disrupts the
sympathetic nervous system,
but that may not be germane
to long-term problems because
the drugs that we have used
also upset that pathway. So we
ies in clinical research at the
have been doing it biochemically, rather than with a device. University of Minnesota in
Minneapolis and a spokesman
“The relevant information
for the American Heart Assoto take home from these pretty
ciation. He said the system was
darn small studies is that,
useful when humans required a
number one, renal denervation
rapid fight-or-flight
appears to be safe
mechanism when
and the technique
faced with hungry
is not inherently
beasts on the plains
dangerous; the
of Africa, but probinformation that we
ably is not helpful
have available shows
in a 60-year-old man
this intervention
with high blood
can change blood
pressure in the right
pressure.
direction.
“There are
Dr. Holmes
“We need larger
people, and it seems
studies—and they
an increasing numare underway—that can posber, who have uncontrollable
sibly determine the mechanhypertension,” he said. “They
isms of those effects.”
get on four or five or six mediThat ablation of the renal
cations and they have all the
artery nerves may not have
side-effects. These are complex
adverse long-term effects
patients. They stop taking their
is due to the nature of the
medications and they bounce
sympathetic nervous system,
back in the hospital. In that
explained Dr. Russell Luepker,
context, renal denervation
the director of graduate studcould be a real boon.” MP
®
®
Controlled release oxycodone/naloxone HCl tablets
10/5 mg, 20/10 mg, 40/20 mg
Prescribing Summary
THERAPEUTIC CLASSIFICATION: Opioid Analgesic/Opioid Antagonist
INDICATIONS AND CLINICAL USE: Adults: Targin® (oxycodone hydrochloride/naloxone hydrochloride) is a controlled release tablet
having a dual therapeutic effect. The oxycodone component in Targin® is indicated for the relief of moderate to severe pain in adults who
require continuous around-the-clock opioid analgesia for several days or more. The naloxone component in Targin® is indicated for the
relief of opioid-induced constipation (OIC). Geriatrics (> 65 years of age): In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, concomitant disease and other drug therapy. The dosage should be adjusted to the intensity of the pain and the sensitivity of
the individual patient. Pediatrics (< 18 years of age): The safety and efficacy of Targin® has not been studied in the pediatric
population. Therefore, use of Targin® is not recommended in patients under 18 years of age.
CONTRAINDICATIONS:
Targin® (oxycodone hydrochloride/naloxone hydrochloride controlled release tablets) is contraindicated in:
• Patients who are hypersensitive to the active substances (oxycodone or naloxone) or other opioid analgesics or to any ingredient
in the formulation. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product
Monograph.
• In patients with known or suspected mechanical gastrointestinal obstruction (e.g., bowel obstruction, strictures) or any
diseases/conditions that affect bowel transit (e.g., ileus of any type).
• Administration by the rectal route is contraindicated (see WARNINGS AND PRECAUTIONS).
• Patients with suspected surgical abdomen (e.g., acute appendicitis or pancreatitis).
• Patients with mild, intermittent or short duration pain that can be managed with other pain medications.
• The management of acute pain, including use in outpatient or day surgeries.
• The management of perioperative pain.
• Patients with acute asthma or other obstructive airway, and status asthmaticus.
• Patients with acute respiratory depression, elevated carbon dioxide levels in the blood, and cor pulmonale.
• Patients with acute alcoholism, delirium tremens, and convulsive disorders.
• Patients with severe CNS depression, increased cerebrospinal or intracranial pressure, and head injury.
• Patients taking monoamine oxidase (MAO) inhibitors (or within 14 days of such therapy).
• Women who are breast-feeding, pregnant, or during labour and delivery.
• Opioid-dependent patients and for narcotic withdrawal treatment.
• Patients with moderate to severe hepatic impairment (Child-Pugh Class B & C).
Safety Information
WARNINGS AND PRECAUTIONS:
General
Targin® (oxycodone hydrochloride/naloxone hydrochloride controlled release tablets) should be swallowed whole. Taking
broken, chewed, dissolved or crushed Targin® tablets could lead to the rapid release and absorption of a potentially fatal
dose of oxycodone.
Targin® should not be administered rectally due to the possible increased systemic availability of naloxone by this route
and the potential for the occurrence of severe withdrawal effects (see CONTRAINDICATIONS). Targin® 40/20 mg tablets
are for use in opioid tolerant patients only (see also DOSAGE AND ADMINISTRATION).
A single dose greater than 40 mg of oxycodone, or total daily doses greater than 80 mg of oxycodone, may cause fatal
respiratory depression when administered to patients who are not tolerant to the respiratory depressant effects of opioids
(see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS).
Patients for whom Targin® is prescribed should not give Targin® to anyone else as such inappropriate use may have severe
medical consequences, including death.
Targin® should not be used to treat patients with constipation not related to opioid use.
Patients should be cautioned not to consume alcohol while taking Targin®, as it may increase the chance of experiencing dangerous side effects. There is no
clinical experience in patients with cancer associated with peritoneal carcinomatosis or with sub-occlusive syndrome in advanced stages of digestive and pelvic
cancers. Therefore, the use of Targin® in this population is not indicated. Gastrointestinal Diarrhea is a possible effect of naloxone. If severe or persistent
diarrhea lasts for more than 3 days during treatment, patients should be advised to contact their physician. Abuse of Opioid Formulations If abused
parenterally, intranasally or rectally by individuals dependent on opioid agonists, Targin® is expected to produce marked withdrawal symptoms – because of
the systemic opioid receptor antagonist characteristics of naloxone by these routes – or to intensify withdrawal symptoms already present.Targin® consists of
a dual polymer matrix intended for oral use only. Abuse can lead to overdose and death. This risk is increased when the tablets are crushed, dissolved, broken
or chewed, and with concurrent consumption of alcohol or other CNS depressants. With parenteral abuse, the tablet excipients, especially talc, can be expected
to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Dependence/Tolerance As
with other opioids, tolerance and physical dependence may develop upon repeated administration of Targin® and there is a potential for development of
psychological dependence. Targin® tablets should therefore be prescribed and handled with the degree of caution appropriate to the use of a drug with abuse
potential. Abuse and addiction are separate and distinct from physical dependence and tolerance. In addition, abuse of opioids can occur in the absence of true
addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Tolerance, as well as physical
dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse. Concerns about abuse,
addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients
with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients. Opioids, such as
oxycodone, should be used with particular care in patients with a history of alcohol and drug abuse. Drug abuse is usually not a problem in patients with pain
in which opioids are appropriately indicated. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid
antagonist. Patients on prolonged therapy should be withdrawn gradually from the drug if it is no longer required for pain control.Use in Drug and Alcohol
Addiction Targin® is an agonist/antagonist combination product with no approved use in the management of addictive disorders.NeurologicInteraction
with Other Central Nervous System Depressants: Oxycodone should be used with caution and in a reduced dosage during concomitant administration of other
opioid analgesics, general anaesthetics, phenothiazines and other tranquilizers, sedative-hypnotics, tricyclic antidepressants and other CNS depressants, including alcohol.
Respiratory depression, hypotension and profound sedation or coma may result. Severe pain antagonizes the subjective and respiratory depressant actions of opioid
analgesics. Should pain suddenly subside, these effects may rapidly become manifest. Patients who are scheduled for chordotomy or other interruption of pain
transmission pathways should not receive Targin® within 24 hours of the procedure. Head Injury: The respiratory depressant effects of oxycodone, and the
capacity to elevate cerebrospinal fluid pressure, may be greatly increased in the presence of an already elevated intracranial pressure produced by trauma. Also,
oxycodone may produce confusion, miosis, vomiting and other side effects which obscure the clinical course of patients with head injury. In such patients,
oxycodone must be used with extreme caution and only if it is judged essential. Withdrawal Effects: Withdrawal symptoms may occur following abrupt
discontinuation of therapy. These symptoms may include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, runny nose,
sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and
yawning. Patients on prolonged therapy should be withdrawn gradually from the drug if it is no longer required for pain control. In patients who are appropriately
treated with opioid analgesics and who undergo gradual withdrawal from the drug, these symptoms are usually mild.CardiovascularTargin® should be used
with caution in patients with pre-existing cardiovascular disease. Oxycodone administration may result in severe hypotension in patients whose ability to maintain
adequate blood pressure is compromised by reduced blood volume or concurrent administration of drugs, such as phenothiazines or certain anaesthetics.
Oxycodone may produce orthostatic hypotension in ambulatory patients. Oxycodone, like all opioid analgesics of the morphine-type, should be administered
with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. Respiratory
DepressionOxycodone should be used with extreme caution in patients with substantially decreased respiratory reserve, pre-existing respiratory depression,
hypoxia or hypercapnia. Such patients are often less sensitive to the stimulatory effects of carbon dioxide (CO2) on the respiratory centre and the respiratory
depressant effects of oxycodone may reduce respiratory drive to the point of apnea. Pre- and Post-Operative Use Targin® is contraindicated for
perioperative use, within 24 hours before or after surgery. Targin® is not indicated for pain in the postoperative period if the pain is mild
or not expected to persist for an extended period of time. In the case of planned chordotomy or other pain-relieving operations, patients should not
be treated with Targin® within 24 hours before or after the operation. Thereafter, if Targin® is to be continued after the patient recovers from the post-operative
period, a new dose should be used in accordance with the changed need for pain relief. Psychomotor ImpairmentTargin® may impair the mental and/or
physical abilities needed for certain potentially hazardous activities such as driving a car or operating machinery. Patients usingTargin® should not drive or operate
dangerous machinery unless they are tolerant to the effects of the drug. Patients should also be cautioned about the combined effects of Targin® with other CNS
depressants, including other opioids, phenothiazines, sedative/hypnotics and alcohol. Special Populations Special Risk Groups: Oxycodone should be
administered with caution and in a reduced dosage to debilitated patients, and in patients with Addison's disease, cholelithiasis, hypothyroidism, toxic psychosis,
pancreatitis, prostatic hypertrophy or urethral stricture. Nursing Women: Oxycodone passes into the breast milk. It is not known whether naloxone is excreted
in human milk. Since the safety of Targin® in infants and newborns has not been studied, Targin® is contraindicated in nursing mothers. Pregnancy, Labour
and Delivery: Oxycodone and naloxone pass into the placenta. Targin® is contraindicated during pregnancy, labour and delivery due to impaired uterine
contractility and the risk of neonatal respiratory depression. There are no adequate data from the use ofTargin® in pregnant women or during childbirth. Animal
studies have not been performed with oxycodone and naloxone in combination. While animal reproduction studies have revealed no evidence of harm to the
fetus due to oxycodone, safe use in pregnancy has not been established. Long-term administration of oxycodone during pregnancy may lead to withdrawal
symptoms in the newborn. Geriatrics (> 65 years of age): In general, dose selection for an elderly patient should be cautious, usually starting at the low
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. The
dosage should be adjusted to the lowest Targin® dose which will achieve the overall treatment goal of satisfactory pain relief with acceptable side effects.
Pediatrics (< 18 years of age): Targin® has not been studied in children and is not recommended for patients less than 18 years of age. The safety and
efficacy of Targin® in children have not been established. Hepatic Impairment: A clinical trial has shown that plasma concentrations of both oxycodone and
naloxone are elevated in patients with hepatic impairment. Naloxone concentrations were affected to a higher degree than oxycodone. The clinical relevance of
this is under investigation. Caution must be exercised when administeringTargin® to patients with mild hepatic impairment.Targin® is contraindicated in patients
with moderate and severe hepatic impairment(see CONTRAINDICATIONS). Renal Impairment:A clinical trial has shown that plasma concentrations
of both oxycodone and naloxone are elevated in patients with renal impairment. Naloxone concentrations were affected to a higher degree than oxycodone.
The plasma concentrations obtained in patients with mild, moderate and severe renal impairment are comparable to those in mildly hepatic impaired patients.
The clinical relevance of this is under investigation, but caution should be exercised when administeringTargin® to patients with renal impairment. “In Vitro”
Dissolution Studies of Interaction with Alcohol In-vitro data show that in presence of ethanol, at concentrations up to 40%, the controlled-release
characteristics of the Targin® formulation were maintained and no breakdown of the controlled release mechanism was observed.
ADVERSE REACTIONS: Clinical Trial Adverse Drug Reactions The pre-marketing pivotal clinical program of Targin®
(oxycodone hydrochloride/naloxone hydrochloride controlled release tablets) included exposure to 520 patients. A summary of
adverse events occurring at an incidence of 1% or more is given below which includes all events, whether considered by the clinical
investigator to be related to the study drug or not (see CLINICAL TRIALS for methodological details of the trials). Nausea was
a very common adverse effect in patients taking Targin®. Nausea is a common effect associated with other drugs with opioid-agonist
activity and tends to reduce with time. Adverse effects, including constipation, diarrhea, fatigue, headache and hyperhidrosis,
often observed with other drugs with opioid-agonist activity, were also seen with Targin® treatment.
Adverse Event Reports in Targin® Pivotal Clinical Trials (≥1%)
(% of patients on Targin® (n = 520) / % of patients on Oxycodone CR (n = 446) / % of patients on Placebo * (n = 235): Ear and labyrinth disorders:
vertigo 1.7/1.8/5.1. Gastrointestinal disorders:abdominal pain: 3.3/2.7/3.8; abdominal pain upper: 1.9/2.7/2.1; constipation: 6.5/10.5/8.9; diarrhea:
6.2/5.4/6.0; dry mouth: 2.5, 1.6, 2.1; dyspepsia: 1.4/3.4/3.0; flatulence: 1.2, 0.5, 0.9; nausea: 12.3/14.8/14.9; vomiting: 5.4/5.6/6.0.General disorders
and administrative site conditions:asthenia: 1.4/0.0/0.9; chills: 1.2/0.7/0.9; drug withdrawal syndrome: 0.2/1.4/0.4; fatigue: 5.4/5.8/4.3; malaise:
0.2/0.7/1.7; edema peripheral: 1.7/1.8/0.0; pain: 2.3/1.6/2.1; pyrexia: 0.4/0.0/1.3. Infections and infestations: bronchitis: 1.5/1.1/0.0; cystitis:
0.2/1.4/1.3; gastroenteritis: 1.9/2.2/0.0; influenza: 1.2/1.6/0.4; nasopharyngitis: 2.9/4.7/4.3; sinusitis: 1.2/0.0/0.0; upper respiratory tract infection:
0.0/1.6/0.0; urinary tract infection: 3.5/2.2/1.3; viral infection: 1.5/1.4/1.3. Injury, poisoning and procedural complications:Contusion: 0.0/0.2/1.7.
Investigations:blood cholesterol increased: 0.0/0.0/1.7; blood glucose increased: 1.9/0.2/0.4; blood triglycerides increased: 0.6/2.0/1.7; blood uric acid
increased: 0.2/0.2/2.6; gamma-glutamyltransferase increased: 0.6/1.1/0.4; lymphocyte count decrease: 0.0/0.2/1.3. Metabolism and nutrition
disorders: anorexia: 0.8/1.1/0.9; decreased appetite: 0.6/0.2/1.3; hyperglycemia: 1.2/1.4/0.0; hyperlipidemia: 1.2/0.2/0.0; hypertriglyceridemia:
1.4/0.2/1.3; hyperuricemia: 1.2/1.1/0.0. Musculoskeletal and connective tissue disorders:arthralgia: 1.5/2.2/2.1; back pain: 3.3/2.5/0.0; neck pain:
0.0/1.4/0.0; osteoarthritis: 1.2/1.6/0.0; pain in extremity: 1.5/1.1/0.0. Nervous system disorders: dizziness: 4.2/8.1/4.3; headache: 6.2/6.3/9.8;
migraine: 1.4/0.2/0.4; sciatica: 1.5/0.0/0.0; somnolence: 1.2/1.1/0.0; tremor: 1.0/1.1/0.4. Psychiatric disorders: depression: 1.9/2.5/0.0; insomnia:
2.1/2.5/3.4; nervousness: 0.6/0.0/1.3; restlessness: 0.8/0.2/2.6; sleep disorder: 0.6/0.2/1.7.Skin and subcutaneous tissue disorders:hyperhidrosis:
6.5/4.3/6.4; pruritus: 2.9/4.0/3.0; rash: 1.2/0.5/0.0. Vascular disorders:hot flush: 1.0/2.0/0.9; hypertension: 0.6/1.4/1.7.
* Placebo patients received immediate-release oxycodone or combination preparations with codeine 30mg as
rescue medication in pivotal clinical trials.
Less Common Clinical Trial Adverse Drug Reactions (< 1%): Other less common (< 1%) adverse drug reactions reported and
considered in any way related to Targin® in randomized pivotal clinical trials are summarized in the Product Monograph (see Adverse
Reactions section in the Product Monograph).
To report a suspected adverse reaction, please contact:
Purdue Pharma
575 Granite Court
Pickering, ON
Canada L1W 3W8
Tel: 905-420-6400
1-800-387-5349
DRUG INTERACTIONS Overview Interaction with Central Nervous System (CNS) DepressantsTargin® (oxycodone hydrochloride/naloxone
hydrochloride controlled release tablets) should be dosed with caution and started in a reduced dosage (1/3 to 1/2 of the usual dosage) in patients
who are currently taking other central nervous system depressants (e.g., alcohol, other opioids, sedatives, hypnotics, anti-depressants, sleeping aids,
phenothiazines, neuroleptics, anti-histamines and anti-emetics), pyrazolidone and beta-blockers, as they may enhance the CNS-depressant effect (e.g.,
respiratory depression) of Targin®. Drug-Drug Interactions No interaction studies have been performed with Targin®. Administration with
Mixed Activity Agonist/Antagonist OpioidsMixed activity agonist/antagonist opioid analgesics (i.e., pentazocine, nalbuphine, butorphanol, and
buprenorphine) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure μ-opioid agonist
analgesic, such as the oxycodone in Targin®. In this situation, mixed activity agonist/antagonist analgesics may reduce the analgesic effect
of oxycodone and/or may precipitate withdrawal symptoms in these patients. Drugs Metabolized by Cytochrome P450 Isozymes In vitro
metabolism studies indicate that no clinically relevant interactions are to be expected between oxycodone and naloxone. At therapeutic
concentrations, Targin® is not expected to cause clinically relevant interactions with other concomitantly administered drugs metabolized over
the CYP isomers CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6 and CYP2E1. Oxycodone is metabolized, in part, by CYP3A4 therefore caution is
advised when Targin® is administered with CYP3A4 inhibitors/inducers. In addition, the likelihood of clinically relevant interactions between
acetaminophen or acetylsalicylic acid and the combination of oxycodone and naloxone in therapeutic concentrations is minimal. MAO Inhibitors
MAO inhibitors intensify the effects of opioid drugs which can cause anxiety, confusion and decrease respiration. Targin® is contraindicated in
patients receiving MAO inhibitors or who have used them within the previous 14 days (see CONTRAINDICATIONS). Warfarin and Other
Coumarin Anticoagulants Clinically relevant changes in International Normalized Ratio (INR or Quick-value) in both directions have been
observed in individuals when oxycodone and coumarin anticoagulants are co-administered.
Administration
DOSAGE AND ADMINISTRATION: Dosing Considerations: Targin® (oxycodone hydrochloride/naloxone hydrochloride controlled
release tablets) should be swallowed whole. Taking broken, chewed, dissolved or crushed Targin® tablets could lead to the
rapid release and absorption of a potentially fatal dose of oxycodone. Patients who are currently taking oral oxycodone can
be switched to Targin® based on an equivalent oxycodone dose. For conversion from other opioids/opioid preparations,
patients should be initiated on the lowest available Targin® strength, provided with adequate rescue medication, with dose
titration to achieve satisfactory pain relief with acceptable side effects. Targin® doses must be individualized and should be
assessed at regular intervals. Targin® 40/20 mg tablets are for use in opioid tolerant patients only. A single dose greater than
40 mg of oxycodone, or total daily doses greater than 80 mg of oxycodone, may cause fatal respiratory depression when
administered to patients who are not tolerant to the respiratory depressant effects of opioids at equivalent doses (see WARNINGS
AND PRECAUTIONS and DRUG INTERACTIONS). Targin® is contraindicated for rectal administration (see CONTRAINDICATIONS).
Targin® is contraindicated in the perioperative period, within 24 hours before or after surgery. Targin® is not indicated for
pain in the postoperative period if the pain is mild or not expected to persist for an extended period of time. In the case of
planned chordotomy or other pain-relieving operations, patients should not be treated with Targin® within 24 hours before or after the operation.
Thereafter, if Targin® is to be continued after the patient recovers from the post-operative period, a new dose should be used in accordance
with the changed need for pain relief. In steady-state studies, the analgesic efficacy of Targin® is equivalent to the OxyContin® controlled
release oxycodone formulation. In clinical studies with Targin®, only patients who had previously been dosed on oxycodone were switched to
Targin®. To date, there is no clinical experience evaluating switching from other analgesics to Targin®. Targin® doses must be individualized
based upon the status of each patient and should be assessed at regular intervals after application. Proper optimization of doses scaled to the
individual’s pain should aim at the regular administration of the lowest dose of Targin® which provides pain relief. The dosage of the drug
must be individualized according to the response and tolerance of the patient. Targin® should be taken at the determined dosage twice daily
(every 12 hours) according to a fixed time schedule. Single doses should not exceed 40 mg oxycodone and 20 mg naloxone. The
maximum daily dose of Targin® is 80 mg oxycodone hydrochloride and 40 mg naloxone hydrochloride. For patients requiring
higher doses of Targin®, administration of supplemental controlled-release oxycodone at the same time intervals should be considered. In the
case of supplemental oxycodone dosing, the beneficial effect of naloxone on bowel function may be impaired. In general, the lowest effective
opioid analgesic dose should be selected. After discontinuation of therapy with Targin®, with a subsequent switch to another opioid, symptoms
associated with reduced bowel motility can be expected. The controlled release tablets may be taken with or without food with sufficient liquid
(with 4 to 6 oz. of water). The empty matrix tablet remnants may be visible in the stool. Adults (over 18 years) Patients Not Receiving Opioids
at the Time of Initiation of Targin® Treatment (Opioid-Naïve) The usual initial adult dose for patients who have not previously received opioid
analgesics is Targin® 10/5 mg every 12 hours. Patients Currently Receiving Opioids Patients who are currently taking oxycodone can
be switched to Targin® based on an equivalent oxycodone dose. Discontinue all other around-the-clock oxycodone analgesic
medications when Targin® therapy is initiated. In clinical studies with Targin®, only patients who had previously been dosed on oxycodone
were switched to Targin®. Patients receiving other oral oxycodone formulations may be transferred to Targin® tablets at the same total daily
dosage, equally divided into two 12-hourly Targin® tablet doses and reassessed with dose adjustments made accordingly. To date, there is no clinical
experience to refer to for switching other opioid analgesics to Targin®. Patients already receiving oxycodone, and tolerant to the respiratory
depressant effects, may be started on higher dose than the usual initial adult dose of 10/5 mg every 12 hours depending on their previous
oxycodone dose. Not to exceed the maximum daily dose of Targin®, 80 mg oxycodone hydrochloride and 40 mg naloxone hydrochloride. For
conversion from other opioids/opioid preparations, discontinue all other round-the-clock opioid analgesic preparations.
Patients should be initiated on the lowest available Targin® strength, provided with adequate rescue medication, with dose
titration to achieve satisfactory pain relief with acceptable side effects. Targin® doses must be individualized and should be
assessed at regular intervals. Targin® should be gradually titrated until adequate pain relief and acceptable side effects have been
achieved. The maximum daily dose of Targin® is 80 mg oxycodone hydrochloride and 40 mg naloxone hydrochloride. Dose
Titration Proper optimization of doses scaled to the relief of the individual's pain should aim at regular administration of the lowest dose of
Targin® which will achieve the overall treatment goal of satisfactory pain relief with acceptable side effects. Dose adjustments may be made
every 1-2 days until a stable dose is reached. Subsequent increases in Targin® dosage must be individualized according to the pain relief and
tolerance of the patient with adequate rescue medication, as required (see Management of Breakthrough Painsection of the Product Monograph).
If breakthrough pain repeatedly occurs at the end of the dosing interval it is generally an indication for a dosage increase
rather than more frequent administration. The maximum daily dose of Targin® is 80 mg oxycodone hydrochloride and 40
mg naloxone hydrochloride.Management of Breakthrough PainSome patients taking Targin® according to a fixed time schedule may require
immediate-release analgesics as "rescue" medication for breakthrough pain. Immediate-release oxycodone or combination preparations with
codeine 30 mg may be given. Alternatively, non-opioid analgesics may be used. Targin® is a controlled release formulation and therefore is
not intended for use as rescue medication. For the treatment of breakthrough pain with an immediate-release opioid, a single dose of “rescue
medication” should approximate one sixth of the equivalent daily dose of oxycodone hydrochloride. The need for more than two rescue
medication doses per day (24 hours) is usually an indication that the dose of Targin® requires upward adjustment. This adjustment may be
made every 1-2 days until a stable dose is reached. The aim is to establish a patient-specific 12 hour dose that will maintain adequate analgesia
and minimize side effects for as long as pain therapy is necessary. Reducing the dosing frequency from every 12 hours is not recommended.
Managing Expected Opioid Adverse Experiences Many patients receiving opioids, especially those who are opioid-naïve, will experience
side effects. Clinical trials have shown that these effects are generally most bothersome during initial treatment and can be minimized by
starting Targin® at 10/5 mg every 12 hours and gradually increasing the dose as needed. Other opioid related side effects such as sedation
and nausea are usually self-limited and often do not persist beyond the first few days. If nausea persists and is unacceptable to the patient,
treatment with anti-emetics or other modalities may relieve these symptoms and should be considered. Missed Dose If the patient forgets to
take one or more doses, they should take their next dose at the next scheduled time and in the normal amount. Discontinuation Careful and
regular monitoring are required to establish required maintenance of treatment. When the patient no longer requires therapy with Targin®,
doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient. Withdrawal symptoms
may occur following abrupt discontinuation of therapy. These symptoms may include body aches, diarrhea, gooseflesh, loss of appetite, nausea,
nervousness or restlessness, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase
Study References
1. Pereira J, Bruera E et al. Alberta Hospice Palliative Care Resource Manual. A project of the Alberta Cancer
Board with financial support provided by Alberta Cancer Foundation. Division of Palliative Care Medicine,
University of Alberta, 2001:1-87.
2. Targin® Product Monograph, Purdue Pharma, March 2010.
3. Lowenstein O et al. Combined prolonged-release oxycodone and naloxone improves bowel function in
patients receiving opioids for moderate-to-severe non-malignant chronic pain: a randomized controlled trial.
Expert Opin Pharmacother 2009;10(4):531-543.
Supplemental Product Information
Information for Physicians to Convey to Patients
A patient information sheet should be provided when Targin® tablets are dispensed to the patient.
Patients receiving Targin® should be given the following instructions by the physician:
1. Patients should be informed that accidental ingestion or use by individuals (including children) other than the patient
for whom it was originally prescribed, may lead to severe, even fatal, consequences.
2. Patients should be advised that Targin® contains oxycodone, an opioid pain medicine.
3. Patients should be advised that Targin® should only be taken as directed. The dose of Targin® should not be adjusted
without consulting with a physician.
4. Targin® should be swallowed whole (not broken, chewed, dissolved or crushed) due to the risk of fatal oxycodone
overdose.
5. Patients should be warned not to administer Targin® by the rectal route, as severe withdrawal effects may occur.
6. Diarrhea is a possible effect of naloxone. Patients should be advised to contact their physician if the diarrhea is severe or
persistent.
7. Patients should be advised to report episodes of breakthrough pain and adverse experiences occurring during therapy.
Individualization of dosage is essential to make optimal use of this medication.
8. Patients should not combine Targin® with alcohol or other central nervous system depressants (sleep aids,
tranquilizers) because dangerous additive effects may occur resulting in serious injury or death.
9. Patients should be advised to consult their physician or pharmacist if other medications are being used or will be used with
Targin®.
10. Patients should be advised that if they have been receiving treatment with Targin® and cessation of therapy is indicated,
it may be appropriate to taper the Targin® dose, rather than abruptly discontinue it, due to the risk of precipitating
withdrawal symptoms.
11. Patients should be advised of the most common adverse reactions that may occur while taking Targin®: nausea,
constipation, diarrhea, hyperhidrosis, fatigue, vomiting, headache and dizziness.
12. Patients should be advised that Targin® may cause drowsiness, dizziness, or lightheadedness and may impair mental
and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery).
Patients started on Targin® or patients whose dose has been adjusted should be advised not to drive a car or operate
machinery unless they are tolerant to the effects of Targin®.
13. Patients should be advised that Targin® is a potential drug of abuse. They should protect it from theft or misuse.
14. Patients should be advised that Targin® should never be given to anyone other than the individual for whom it was
prescribed.
15. Patients should be advised that Targin® 40/20 mg is for use only in individuals tolerant to the effect of equivalent
doses of oxycodone.
16. Women of childbearing potential who become or are planning to become pregnant should be advised to consult a
physician prior to initiating or continuing therapy with Targin®. Women who are breast-feeding or pregnant should
not use Targin®.
17. Patients should be advised that they may pass empty matrix tablet remnants in the stool, and that this should not
be a concern since the analgesic medication, oxycodone, has already been released.
ADVERSE REACTIONS
Post-Market Adverse Drug Reactions
In a two year non-interventional open-label, prospective, observational study (Study 9002) performed in Europe, 7,836
pain patients with severe pain for at least 4 months received Targin® and were monitored over a period of 4 weeks.
Approximately 25% of the patients (n=1,963) were opioid naïve with the remaining 5,849 patients previously pre-treated
with opioids. The most frequently reported adverse drug reactions in the total population were nausea (3.1%), constipation
(3.1%), dizziness (2.4%), abdominal distension (1.9%), diarrhea (1.9%), abdominal pain (1.4%), vomiting (1.1%) and
irregular bowel movements (1.1%). All these adverse drug reactions are consistent with the expected adverse event profile
of the opioid analgesic class of drugs. (see Adverse Reactions section in the Product Monograph).
OVERDOSAGE
Symptoms
Depending on the history of the patient, an overdose of Targin® (oxycodone hydrochloride/naloxone hydrochloride
controlled release tablets) may be manifested by symptoms that are either triggered by oxycodone (opioid receptor
agonist) or by naloxone (opioid receptor antagonist).
Symptoms of oxycodone overdose include miosis, respiratory depression, somnolence progressing to stupor, skeletal
muscle flaccidity, bradycardia as well as hypotension. Coma, non-cardiogenic pulmonary oedema and circulatory failure
may occur in more severe cases and may lead to a fatal outcome.
Symptoms of a naloxone overdose alone are unlikely due to the low systemic availability of naloxone by the oral route.
Withdrawal symptoms due to an overdose of naloxone should be treated symptomatically in a closely-supervised
environment.
Treatment
Primary attention should be given to the establishment of adequate respiratory exchange through the provision of a patent
airway and controlled or assisted ventilation. Clinical symptoms suggestive of an oxycodone overdose may be treated by the
administration of opioid antagonists (e.g., naloxone 0.4-2 mg intravenously). Administration should be repeated at 2-3 minute
intervals, as clinically necessary. It is also possible to apply an infusion of 2 mg naloxone in 500 mL of 0.9% sodium chloride or
5% dextrose (0.004 mg/mL naloxone). The infusion should run at a rate aligned to the previously administered bolus doses
and to the patient's response.
Consideration may be given to gastric lavage.
Supportive measures (artificial ventilation, oxygen, vasopressors and infusions) should be employed, as necessary, to
manage the circulatory shock accompanying an overdose. Cardiac arrest or arrhythmias may require cardiac massage
or defibrillation. Artificial ventilation should be applied if necessary. Fluid and electrolyte metabolism should be
maintained.
SPECIAL HANDLING INSTRUCTIONS: Store at Room Temperature (15-30°C). Keep in a cool dry place. Protect from
light, heat and humidity. Keep Targin® out of sight and reach of children.
DOSAGE FORMS AND PACKAGING: Targin® 10/5 mg are white, oblong tablets with a film coating, marked OXN
on one side and 10 on the other. Targin® 20/10 mg are pink, oblong tablets with a film coating, marked OXN on one
side and 20 on the other. Targin® 40/20 mg are yellow, oblong tablets with a film coating, marked OXN on one side
and 40 on the other. All strengths will be available in blisters (10s, 14s, 20s, 28s, 30s, 50s, 56s, 60s, 98s and 100s)
and opaque plastic bottles of 50, 60, 100 and 250’s (see DOSAGE FORMS, COMPOSITION AND PACKAGING in
the Product Monograph).
Targin® is a registered Trademark of Purdue Pharma
03/10
TA01/12-292E
OCTOBeR 9, 2012
45
CAR DIOLOGY
Psoriasis doubles
risk of developing
new-onset diabetes
Researcher calls for annual screening in patients
with the skin disease BY ED SuSmAn • Munich
istockphoto
in sweating, palpitations, unexplained fever, weakness and yawning. Patients on prolonged therapy should
be withdrawn gradually from the drug if it is no longer required for pain control. In patients who are
appropriately treated with opioid analgesics and who undergo gradual withdrawal from the drug, these
symptoms are usually mild. If treatment discontinuation is required, the dose of opioid may be decreased as
follows: one-half of the previous daily dose given every 12 hours or immediate release oxycodone every 6
hours for the first two days, followed by a 25% reduction every two days.
OVERDOSAGE (see Supplemental Product Information)
For management of suspected drug overdose, contact your Regional Poison Control Centre.
The risk of developing diabetes doubled among people diagnosed with severe psoriasis,
and was nearly 50% higher even in patients with mild psoriasis, researchers found.
D
octors should check psoriasis patients
was 4,465,643. The researchers identified 52,613
for glucose intolerance, researchers
individuals who developed psoriasis after 1997;
said here, after finding an association
of those, 45,829 were described as having
between the skin disease and new-onset
mild psoriasis and 6,784 were diagnosed with
diabetes.
severe psoriasis.
The risk of developing diabetes doubled
The incidence rate of diabetes was 3.67
among people diagnosed with severe psoriasis,
per 1,000 person-years in the reference group,
and was nearly 50% higher even in patients with
compared with 6.93 for those with mild psoriasis
mild psoriasis, said Dr. Ole Ahlehoff, a physician
and 9.65 for severe psoriasis. “The results reflect
and postdoctoral fellow in cardiology at Copenmainly type 2 diabetes,” Dr. Ahlehoff said.
hagen University Hospital.
After adjusting for age, sex, comAt the European Society of
orbidities and level of income, the
Cardiology meeting here, Dr. Ahlehoff
relative risk of developing diabetes
described how he and colleagues
was 49% greater in patients with mild
used a Danish medical database to
psoriasis and 2.13 times greater in the
study information on about 4.5 milsevere psoriasis patients—both statislion people.
tically significant findings.
“Psoriasis is a common inflamma“The median followup of patients
tory disease affecting approximately
diagnosed with psoriasis was about six
125 million people worldwide,” Dr.
years, so that would indicate there is a
Ahlehoff said in a media briefing.
short time span between diagnosis of
Dr. Ahlehoff
He noted that previous studies have
psoriasis and subsequent diagnosis of
shown that patients with psoriasis
new-onset diabetes,” Dr. Ahlehoff said.
have a twofold increased risk of myocardial
“Screening for diabetes and cardiovascular risk
infarction, stroke and death.
factors in patients with psoriasis is warranted.”
“Diabetes and psoriasis share an underlying
He suggested that screening psoriasis
inflammatory process and an abundance of risk
patients once a year for diabetes, along with
factors, and therefore it is not surprising that
other classical cardiovascular risk factors such
psoriasis has been proposed as a risk factor for
as cholesterol and blood pressure levels, would
new-onset diabetes,” he explained.
be reasonable.
“We therefore set out to test this hypothesis in
Dr. Ahlehoff said his findings support the
a nationwide study of the entire Danish populahypothesis that inflammation increases the risk
tion since diagnosis of a risk factor for diabetes
for new-onset diabetes.
may allow for early detection and treatment.”
“It would be interesting to know if psoriasis
The study involved individuals who were 10
was treated, could you diminish the incidence
years of age or older in 1997 and were followed
of diabetes,” Dr. Gordon Tomaselli, a professor
for 13 years, until 2009. The researchers started
and the director of cardiology at the Johns
with a cohort of 4,614,807 and excluded 96,551
Hopkins University School of Medicine in Balwho had prevalent diabetes, creating a study
timore and the past-president of the American
cohort of 4,518,256 people. The reference popuHeart Association, said in commenting on
lation (those who did not develop psoriasis)
the study. MP
Prescribing Summary
The information provided in this prescribing summary is limited to
the Atrial Fibrillation indication. Please see the XARELTO Product
Monograph for the complete prescribing information pertaining to
all approved indications.
THERAPEUTIC CLASSIFICATION: Anticoagulant
INDICATIONS AND CLINICAL USE
XARELTO (rivaroxaban) is indicated for the prevention of stroke
and systemic embolism in patients with atrial fibrillation, in whom
anticoagulation is appropriate.
Geriatrics
Clinical studies have included patients with an age >65 years (see
WARNINGS AND PRECAUTIONS – Geriatrics (>65 Years of Age), Renal
Impairment, and DOSAGE AND ADMINISTRATION – Renal Impairment,
Geriatrics (>65 years of age)). Safety and efficacy data are available (see
CLINICAL TRIALS in Product Monogaph).
Pediatrics
The safety and efficacy of XARELTO have not been established in children
less than 18 years of age. Therefore, XARELTO is not recommended in this
patient population.
CONTRAINDICATIONS
•Clinicallysignificantactivebleeding,suchasgastrointestinalbleeding,
including that associated with hemorrhagic manifestations, bleeding
diathesis, or patients with spontaneous impairment of hemostasis
•Lesionsatriskofclinicallysignificantbleeding,eg,cerebralinfarction
(hemorrhagic or ischemic) within the last 6 months, active peptic ulcer
disease with recent bleeding
•Concomitant systemic treatment with strong inhibitors of both CYP
3A4 and P-glycoprotein (P-gp), such as ketoconazole, itraconazole,
voriconazole, posaconazole, or ritonavir (see WARNINGS AND
PRECAUTIONS – Drug Interactions, Interaction with strong inhibitors of
both CYP 3A4 and P-gp)
•Hepatic disease (including Child-Pugh Class B and C) associated
with coagulopathy, and having a clinically relevant bleeding risk (see
WARNINGS AND PRECAUTIONS – Hepatic Impairment)
•Pregnancy(seeWARNINGSANDPRECAUTIONS–SpecialPopulations,
Pregnant Women)
•Nursing women (see WARNINGS AND PRECAUTIONS – Special
Populations, Nursing Women)
•Hypersensitivity to XARELTO (rivaroxaban) or to any ingredient in the
formulation, see DOSAGE FORMS, COMPOSITION AND PACKAGING in
Product Monogaph.
Safety Information
WARNINGS AND PRECAUTIONS
Bleeding
XARELTO, like other anticoagulants, should be used with caution in
patientswithanincreasedbleedingrisk.Bleedingcanoccuratanysite
during therapy with XARELTO. The possibility of a hemorrhage should be
considered in evaluating the condition of any anticoagulated patient. Any
unexplained fall in hemoglobin or blood pressure should lead to a search
for a bleeding site.
Patients at high risk of bleeding should not be prescribed XARELTO (see
CONTRAINDICATIONS).
Should severe bleeding occur, treatment with XARELTO must be
discontinued and the source of bleeding investigated promptly.
Close clinical surveillance (looking for signs of bleeding or anemia) is
recommended throughout the treatment period, especially in the presence
of multiple risk factors for bleeding (see Table 1 below).
Table 1 – Factors Which Increase Hemorrhagic Risk
Factors increasing
rivaroxaban
plasma levels
Severe renal impairment (CrCl <30 mL/min)
Concomitant systemic treatment with strong
inhibitors of both CYP 3A4 and P-gp
Pharmacodynamic NSAID
interactions
Platelet aggregation inhibitors, including ASA,
clopidrogrel, prasugrel, ticagrelor
Diseases/
procedures
with special
hemorrhagic risks
Congenital or acquired coagulation disorders
Thrombocytopenia or functional platelet defects
Uncontrolled severe arterial hypertension
Active ulcerative gastrointestinal disease
Recent gastrointestinal bleeding
Vascular retinopathy, such as hypertensive or diabetic
Recent intracranial hemorrhage
Intraspinal or intracerebral vascular
abnormalities
Recent brain, spinal or ophthalmological surgery
Others
Age > 75 years
Concomitant use of drugs affecting hemostasis increases the risk of
bleeding. Care should be taken if patients are treated concomitantly with
drugs affecting hemostasis such as nonsteroidal anti-inflammatory drugs
(NSAIDs), acetylsalicylic acid (ASA), and platelet aggregation inhibitors. Due
to the increased bleeding risk, generally avoid concomitant use with other
anticoagulants (see DRUG INTERACTIONS in SUPPLEMENTAL PRODUCT
INFORMATION). Concomitant ASA use (almost exclusively at a dose of
100 mg or less) with either XARELTO or warfarin during the ROCKET AF
trial was identified as an independent risk factor for major bleeding (see
also DRUG INTERACTIONS in SUPPLEMENTAL PRODUCT INFORMATION).
Unfractionated heparin may be administered concomitantly at doses
necessary to maintain a patent central venous or arterial catheter.
Cardiovascular
In a dedicated clinical trial, no QTc prolonging effects were observed with XARELTO.
Patients with valvular disease
Safety and efficacy of XARELTO have not been studied in patients with
prosthetic heart valves, or those with hemodynamically significant
rheumatic heart disease, especially mitral stenosis. There are no data
to support that XARELTO 20 mg (15 mg in patients with moderate renal
impairment) provides adequate anticoagulation in patients with prosthetic
heart valves, with or without atrial fibrillation. Therefore, the use of
XARELTO is not recommended in this setting.
Of note, in the pivotal Phase III ROCKET AF trial that evaluated XARELTO
in the prevention of stroke in atrial fibrillation, 14% of patients had other
valvular disease including aortic stenosis, aortic regurgitation, and/or
mitral regurgitation. Patients with a history of mitral valve repair were
also not excluded from the study. Mitral valve repair rates are not known
in ROCKET AF, since information on mitral valve repair status was not
specifically collected in this study.
Drug Interactions
Interaction with strong inhibitors of both CYP 3A4 and P-gp
The use of XARELTO is contraindicated in patients receiving concomitant
systemic treatment with strong inhibitors of both CYP 3A4 and P-gp, such
as ketoconazole, itraconazole, voriconazole, posaconazole, or ritonavir.
These drugs may increase XARELTO plasma concentrations to a clinically
relevant degree, ie, 2.6-fold on average, which increases bleeding risk.
Interaction with moderate CYP 3A4 inhibitors
The azole anti-mycotic, fluconazole, a moderate CYP 3A4 inhibitor, has
less effect on rivaroxaban exposure and may be co-administered (see
DRUG INTERACTIONS in SUPPLEMENTAL PRODUCT INFORMATION).
Interaction with strong CYP 3A4 inducers
Strong CYP 3A4 inducers, such as rifampicin, and the anticonvulsants,
phenytoin, carbamazepine, phenobarbitone, should generally be avoided
in combination with XARELTO (see DRUG INTERACTIONS – Drug-Drug
Interactions in SUPPLEMENTAL PRODUCT INFORMATION).
Hepatic Impairment
Patients with significant hepatic disease, eg, acute clinical hepatitis,
chronic active hepatitis, liver cirrhosis, were excluded from clinical trials.
Therefore, XARELTO is contraindicated in patients with hepatic disease
(includingChild-PughClassBandC)associatedwithcoagulopathy,and
having a clinically relevant bleeding risk.
The limited data available for patients with mild hepatic impairment without
coagulopathy indicate that there is no difference in pharmacodynamic
response or pharmacokinetics as compared to healthy subjects.
Surgery/Procedural Interventions
As with any anticoagulant, patients on XARELTO who undergo surgery
or invasive procedures are at increased risk for bleeding. In these
circumstances, temporary discontinuation of XARELTO may be required.
Pre-Operative Phase
If an invasive procedure or surgical intervention is required, XARELTO should
be stopped at least 24 hours before the intervention, if possible, due to
increased risk of bleeding, and based on clinical judgment of the physician.
If the procedure cannot be delayed, the increased risk of bleeding should
be assessed against the urgency of the intervention. Although there are
limited data, in patients at higher risk of bleeding or in major surgery where
complete hemostasis may be required, consider stopping XARELTO two to
four days before surgery, depending on clinical circumstances.
Peri-Operative Spinal/Epidural Anesthesia, Lumbar Puncture
When neuraxial (epidural/spinal) anesthesia or spinal puncture is
performed, patients treated with antithrombotics for prevention of
thromboembolic complications are at risk for developing an epidural
or spinal hematoma that may result in long-term neurological injury or
permanent paralysis.
The risk of these events is even further increased by the use of
indwelling epidural catheters or the concomitant use of drugs
affecting hemostasis. Accordingly, the use of XARELTO, at doses
greater than 10 mg, is not recommended in patients undergoing
anesthesia with post-operative indwelling epidural catheters. The
risk may also be increased by traumatic or repeated epidural or
spinal puncture. If traumatic puncture occurs, the administration of
XARELTO should be delayed for 24 hours.
Patients who have undergone epidural puncture and who are receiving
XARELTO should be frequently monitored for signs and symptoms of
neurological impairment, eg, numbness or weakness of the legs, bowel
or bladder dysfunction. If neurological deficits are noted, urgent diagnosis
and treatment is necessary.
The physician should consider the potential benefit versus the risk before
neuraxial intervention in patients anticoagulated or to be anticoagulated for
thromboprophylaxis and use XARELTO only when the benefits clearly outweigh
the possible risks. An epidural catheter should not be withdrawn earlier
than 18 hours after the last administration of XARELTO. XARELTO should be
administered not earlier than 6 hours after the removal of the catheter.
Post-procedural Period
XARELTO should be restarted following an invasive procedure or surgical
intervention as soon as adequate hemostasis has been established and
the clinical situation allows.
Renal Impairment
Following oral dosing with XARELTO, there is a direct relationship between
the pharmacodynamic effects and the degree of renal impairment. For
more details see ACTION AND CLINICAL PHARMACOLOGY – Renal
Insufficiency in Product Monograph.
XARELTO should be used with caution in patients with moderate renal
impairment (CrCl 30-49 mL/min), especially those concomitantly receiving
other drugs which increase rivaroxaban plasma concentrations (see DOSAGE
AND ADMINISTRATION, Renal Impairment and DRUG INTERACTIONS – DrugDrug Interactions in SUPPLEMENTAL PRODUCT INFORMATION).
Physicians should consider the benefit/risk of anticoagulant therapy before
administering XARELTO to patients with moderate renal impairment with
a creatinine clearance close to the severe renal impairment category
(CrCl <30 mL/min), or in those with a potential to have deterioration of renal
function to severe impairment during therapy.
There are insufficient safety data in patients with severe renal impairment
(CrCl <30 mL/min) as these patients were excluded from pivotal Phase III
trials. Therefore, the use of XARELTO is not recommended in patients
with severe renal impairment. Patients who develop acute renal failure
while on XARELTO should discontinue such treatment.
Due to the high plasma protein binding, ie, about 95%, XARELTO is not
expected to be removed by dialysis.
Lactose Sensitivity
XARELTO contains lactose. Patients with rare hereditary problems of
lactose or galactose intolerance, eg, the Lapp lactase deficiency or
glucose-galactose malabsorption, should not take XARELTO.
Special Populations
Pregnant Women
No data are available on the use of XARELTO in pregnant women.
Based on animal data, use of XARELTO is contraindicated throughout
pregnancy (see CONTRAINDICATIONS).
If XARELTO is to be used in women of childbearing potential, pregnancy
should be avoided.
Nursing Women
No data are available on the use of XARELTO in nursing mothers.
In rats, XARELTO is secreted into breast milk. Therefore, XARELTO
may only be administered after breastfeeding is discontinued (see
CONTRAINDICATIONS).
Geriatrics (>65 Years of Age)
Increasingageisassociatedwithdecliningrenalfunction.Bothofthese
factors have been observed to result in increased systemic exposure to
rivaroxaban, and consequently increased bleeding (see WARNINGS AND
PRECAUTIONS – Renal Impairment, and DOSAGE AND ADMINISTRATION
– Renal Impairment).
Use with caution in elderly patients, especially those taking concomitant
medications that increase systemic exposure of rivaroxaban (see
WARNINGS AND PRECAUTIONS – Drug Interactions, and DRUG
INTERACTIONS in SUPPLEMENTAL PRODUCT INFORMATION).
Pediatrics (<18 Years of Age)
less than 18 years of age. Therefore, XARELTO is not recommended in this
patient population.
Monitoring and Laboratory Tests
The prothrombin time (PT), measured in seconds, is influenced by
XARELTO in a dose-dependent way with a close correlation to plasma
concentrations if the Neoplastin® reagent is used. In patients who are
bleeding, measuring the PT using the Neoplastin® reagent may be useful
to assist in determining an excess of anticoagulant activity (see DOSAGE
AND ADMINISTRATION – Considerations for INR Monitoring of VKA Activity
During Concomitant XARELTO Therapy).
Although XARELTO therapy will lead to an elevated INR, depending
on the timing of the measurement, the INR is not a valid measure
to assess the anticoagulant activity of XARELTO. The INR is only
calibrated and validated for VKA and should not be used for any
other anticoagulant, including XARELTO.
At recommended doses, XARELTO affects the measurement of the aPTT
and Heptest®. These tests are not recommended for the assessment of
the pharmacodynamic effects of XARELTO.
Converting patients from warfarin to XARELTO, or from XARELTO to
warfarin, increases PT by the Neoplastin® reagent in seconds (or INR
values) more than additively, eg, individual INR values up to 12 may be
observed, during concomitant therapy, whereas effects on aPTT and
endogenous thrombin potential are additive.
Anti-Factor-Xa activity is influenced by XARELTO in a dose-dependent
fashion. If it is desired to test the pharmacodynamic effects of XARELTO
during the switching period, tests of anti-Factor-Xa activity can be used
as they are not affected by warfarin. Use of these tests to assess the
pharmacodynamic effects of XARELTO requires calibration and should not
be done unless XARELTO-specific calibrators and controls are available.
ADVERSE REACTIONS
Prevention of Stroke and Systemic Embolism in Patients with Atrial
Fibrillation (SPAF)
In the pivotal double-blind ROCKET AF study, a total of 14,264 patients with
atrial fibrillation at risk for stroke and systemic embolism were randomly
assigned to treatment with either rivaroxaban (7,131) or warfarin (7,133)
in 45 countries. Patients received XARELTO 20 mg orally once daily
(15 mg orally once daily in patients with moderate renal impairment [CrCl
30-49 mL/min]) or dose-adjusted warfarin titrated to a target INR of 2.0 to
3.0. The safety population included patients who were randomized and took
at least 1 dose of study medication. In total, 14,236 patients were included
in the safety population, with 7,111 and 7,125 patients in rivaroxaban
and warfarin groups, respectively. The median time on treatment was
19 months and overall treatment duration was up to 41 months.
The incidence of adverse events resulting in permanent discontinuation of study
drug was 15.8% in the rivaroxaban group and 15.2% in the warfarin group.
Bleeding
Due to the pharmacological mode of action, XARELTO is associated with
an increased risk of occult or overt bleeding from any tissue and organ
(seeWARNINGSAND PRECAUTIONS – Bleeding, Drug Interactions).The
risk of bleeding may be increased in certain patient groups, eg, patients
with uncontrolled severe arterial hypertension and/or on concomitant
medication affecting hemostasis (see WARNINGS AND PRECAUTIONS
–Bleeding,Table1).Thesigns,symptoms,andseverity(includingfatal
outcome) will vary according to the location and degree or extent of
the bleeding and/or anemia. Hemorrhagic complications may present
as weakness, paleness, dizziness, headache or unexplained swelling,
dyspnea, and unexplained shock. In some cases as a consequence of
anemia, symptoms of cardiac ischemia like chest pain or angina pectoris
have been observed. Known complications secondary to severe bleeding
such as compartment syndrome and renal failure due to hypoperfusion
have been reported for XARELTO. Therefore, the possibility of a
hemorrhage should be considered in evaluating the medical condition in
any anticoagulated patient.
Major or severe bleeding may occur and, regardless of location, may lead
to disabling, life-threatening or even fatal outcomes.
Since the adverse event profiles of the patient populations treated with
XARELTO for different indications are not interchangeable, a summary
description of major and total bleeding is provided in Table 2 for stroke
prevention in atrial fibrillation.
Table 2 – ROCKET AF – Time to the First Occurrence of Bleeding Events
While on Treatment (Up to Last Dose Plus 2 Days) – Safety Analysis
XARELTO
Warfarin
n (%/year) n (%/year)
Major and Non1475 (14.91)
major Clinically
Relevant Bleedinga
Major Bleedingb
1449
(14.52)
HR (95% CI); P-value
1.03 (0.96,1.11); 0.442
395 (3.60)
386 (3.45) 1.04 (0.90,1.20); 0.576
Hemoglobin Drop
305 (2.77)
254 (2.26) 1.22 (1.03,1.44); 0.019*
Transfusion
(> 2 units)
183 (1.65)
149 (1.32) 1.25 (1.01,1.55); 0.044*
Critical Organ
Bleedc
91 (0.82)
133 (1.18) 0.69 (0.53,0.91); 0.007*
Intracranial
Hemorrhage
55 (0.49)
84 (0.74)
0.67 (0.47,0.94); 0.019*
Fatal Bleed
27 (0.24)
55 (0.48)
0.50 (0.31,0.79); 0.003*
1151
(11.37)
1.04 (0.96,1.13); 0.345
Non-major
Clinically Relevant 1185 (11.80)
Bleeding
a Principal Safety Endpoint: composite of major and nonmajor clinically
relevant bleeding events.
b A major bleeding event was defined as overt bleeding associated with
a fall in hemoglobin of 2 g/dL or more; or leading to a transfusion
of 2 or more units of packed red blood cells or whole blood; or that
occurred in a critical site: intracranial, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, retroperitoneal;
or contributing to death.
c Critical organ bleeding are cases where CEC bleeding site = intracranial,
intraocular, pericardial, intra-articular, intramuscular with compartment
syndrome or retroperitoneal.
Note: Hazard ratio (95% CI) and P-value from Cox proportional hazard
model with treatment group as covariate.
*
Statistically significant at nominal 0.05 (two-sided)
Mucosal major bleeding was more common in the XARELTO group (2.4%/year)
as compared to the warfarin group (1.6%/year; HR 1.52 (1.25,1.83) P<0.001).
Most of the mucosal major bleeding was from a gastrointestinal site.
Intracranial hemorrhage and upper gastrointestinal hemorrhage resulting
in death were observed in 24/55 (43.6%) and 1/204 (0.5%) respectively,
in XARELTO patients who experienced these adverse events, compared
to 42/84 (50.0%) and 3/125 (2.4%) respectively, in warfarin patients who
experienced these same events.
Clinical Trial Adverse Drug Reactions
The most common identified treatment-emergent adverse drug reactions in
the pivotal Phase III study, ROCKET AF, for prevention of stroke and systemic
embolism in patients with atrial fibrillation are presented in Table 3.
Table 3 – Treatment-Emergent Adverse Reactions Occurring in >1%
of Any Treatment Group – ROCKET AF – Safety Analysis
XARELTO
(N=7111)
n (%)
Warfarin
(N=7125)
n (%)
Blood and lymphatic system disorders
Anemia
219 (3.08)
143 (2.01)
Eye disorders
Conjunctival hemorrhage
104 (1.46)
151 (2.12)
Gastrointestinal disorders
Diarrhea
379 (5.33)
397 (5.57)
Gingival bleeding
263 (3.70)
155 (2.18)
Nausea
194 (2.73)
153 (2.15)
Rectal hemorrhage
149 (2.10)
102 (1.43)
Abdominal pain upper
127 (1.79)
120 (1.68)
Vomiting
114 (1.60)
111 (1.56)
Dyspepsia
111 (1.56)
91 (1.28)
Abdominal pain
107 (1.50)
118 (1.66)
Gastrointestinal hemorrhage
100 (1.41)
70 (0.98)
General disorders and administration site conditions
Edema peripheral
435 (6.12)
444 (6.23)
Fatigue
223 (3.14)
221 (3.10)
Asthenia
125 (1.76)
106 (1.49)
Pyrexia
72 (1.01)
87 (1.22)
Injury, poisoning and postprocedural complications
Contusion
196 (2.76)
291 (4.08)
Investigations
Alanine aminotransferase increased
144 (2.03)
112 (1.57)
Musculoskeletal, connective tissue, and bone disorders
Pain in extremity
191 (2.69)
208 (2.92)
Nervous system disorders
Dizziness
433 (6.09)
Headache
324 (4.56)
Syncope
130 (1.83)
Renal and urinary disorders
Hematuria
296 (4.16)
Respiratory tract disorders
Epistaxis
721 (10.14)
Hemoptysis
99 (1.39)
Skin and subcutaneous tissue disorders
Ecchymosis
159 (2.24)
Pruritus
120 (1.69)
Rash
112 (1.58)
Vascular disorders
Hematoma
216 (3.04)
Hypotension
141 (1.98)
449 (6.30)
363 (5.09)
108 (1.52)
242 (3.40)
609 (8.55)
100 (1.40)
234 (3.28)
118 (1.66)
129 (1.81)
330 (4.63)
130 (1.82)
NB:Incidenceisbasedonnumberofsubjects, not number of events.
Treatment-Emergent = events that start on or after the first dose of study
medication and up to 2 days after the last dose of study medication.
For more details on adverse events reported during clinical trials, see
adverse reactions in the supplemental product information.
You can report any suspected adverse reactions associated with the use of
health products to the Canada Vigilance Program by one of the following 3 ways:
Report online: www.healthcanada.gc.ca/medeffect
Call toll-free at: 1-866-234-2345
Complete a Canada Vigilance Reporting Form and:
Fax toll-free to: 1-866-678-6789
Mail to: Canada Vigilance Program
Health Canada
Postal Locator 0701D
Ottawa ON K1A 0K9
Bayer Inc.
You can report any suspected adverse reactions associated with the
useofhealthproductstoBayerInc.by:
Toll-free telephone: 1-800-265-7382
Mail:BayerInc.,77BelfieldRoad,Toronto,OntarioM9W1G6Canada
Administration
DOSAGE AND ADMINISTRATION
Prevention of Stroke and Systemic Embolism in Patients with Atrial
Fibrillation
The recommended dose is one 20 mg tablet of XARELTO taken once daily
with food. For patients with moderate renal impairment (CrCl 30-49 mL/
min), the recommended dose is 15 mg once daily with food (see Renal
Impairment below).
The recommended maximum daily dose is 20 mg.
Acute myocardial infarction (AMI): Consideration should be given to
discontinuing XARELTO in the setting of acute myocardial infarction should
the treatment of myocardial infarction involve invasive procedures, such
as percutaneous coronary revascularization, or coronary artery bypass
surgery. Similar consideration should be given if thrombolytic therapy is
to be initiated, because bleeding risk may increase. Patients with acute
myocardial infarction should be treated according to current clinical
guidelines. In this setting, XARELTO may be resumed, when deemed
clinically appropriate, for the prevention of stroke and systemic embolism
upon completion of these revascularization procedures.
Concomitant use of ASA or clopidogrel with XARELTO in patients with
atrial fibrillation increases the risk of bleeding. Concomitant use of ASA
or other antiplatelet agents based on medical need to prevent myocardial
infarction should be undertaken with caution. Close clinical surveillance
is recommended.
Other situations requiring thrombolytic therapy: XARELTO should be
discontinued in situations such as acute ischemic stroke where current clinical
practice calls for administering thrombolytic therapy. XARELTO treatment may
be subsequently resumed as soon as is deemed clinically appropriate.
Cardioversion: Few patients in ROCKET AF underwent electrical
cardioversion for atrial fibrillation. The utility of XARELTO for preventing
post-cardioversion stroke and systemic embolism is unknown.
Hepatic Impairment
XARELTO is contraindicated in patients with hepatic disease (including
Child-Pugh Class B and C) associated with coagulopathy, and having
clinically relevant bleeding risk. Patients with severe hepatic impairment
or chronic hepatic disease were excluded from pivotal clinical trials.
The limited clinical data for patients with moderate hepatic impairment
indicate a significant increase in the pharmacological activity. XARELTO
should be used with caution in these patients (see CONTRAINDICATIONS,
WARNINGS AND PRECAUTIONS – Hepatic Impairment).
The limited data available for patients with mild hepatic impairment without
coagulopathy indicate that there is no difference in pharmacodynamic
response or pharmacokinetics as compared to healthy subjects.
Renal Impairment
XARELTO should be used with caution in patients receiving other drugs
which increase XARELTO plasma concentrations. Physicians should
consider the benefit/risk of anticoagulant therapy before administering
XARELTO to patients with moderate renal impairment with a creatinine
clearance close to the severe renal impairment category (CrCl <30 mL/
min) or with a potential to have deterioration of renal function during
therapy. Consideration should be given to following renal function carefully
in these patients (see WARNINGS AND PRECAUTIONS – Renal Impairment,
and DRUG INTERACTIONS – Drug-Drug Interactions in SUPPLEMENTAL
PRODUCT INFORMATION).
There are limited safety data in patients with severe renal impairment (CrCl
<30 mL/min) as these patients were excluded from pivotal Phase III trials.
Patients who develop acute renal failure while on XARELTO should
discontinue such treatment.
XARELTO 15 mg and 20 mg tablets should be taken with food.
Gender, Ethnicity, or Body Weight
No dose adjustment is required.
Geriatrics (>65 years of age)
No dose adjustment is generally required for the elderly. Increasing age
may be associated with declining renal function (see WARNINGS AND
PRECAUTIONS – Renal Impairment, and DOSAGE AND ADMINISTRATION
– Renal Impairment).
Pediatrics (<18 years of age)
less than 18 years of age; therefore, XARELTO is not recommended in this
patient population.
Switching from Parental Anticoagulants to XARELTO
XARELTO can be started when the infusion of full-dose intravenous heparin
is stopped or 0 to 2 hours before the next scheduled injection of full-dose
subcutaneous low-molecular-weight heparin (LMWH) or fondaparinux. In
patients receiving prophylactic heparin, LMWH or fondaparinux, XARELTO
can be started 6 or more hours after the last prophylactic dose.
Switching from XARELTO to Parenteral Anticoagulants
Discontinue XARELTO and give the first dose of parenteral anticoagulant at
the time that the next XARELTO dose was scheduled to be taken.
Switching from Vitamin K Antagonists (VKA) to XARELTO
To switch from a VKA to XARELTO, stop the VKA and determine the INR. If
the INR is ≤ 2.5, start XARELTO at the usual dose. If the INR is > 2.5, delay
the start of XARELTO until the INR is ≤ 2.5 (see Considerations for INR
Monitoring of VKA Activity During Concomitant XARELTO Therapy).
Switching from XARELTO to a VKA
As with any short-acting anticoagulant, there is a potential for inadequate
anticoagulation when transitioning from XARELTO to a VKA. It is important
to maintain an adequate level of anticoagulation when transitioning
patients from one anticoagulant to another.
XARELTO should be continued concurrently with the VKA until the INR is
≥ 2.0. For the first 2 days of the conversion period, the VKA can be given
in the usual starting doses without INR testing (see Considerations for
INR Monitoring of VKA Activity During Concomitant XARELTO Therapy).
Thereafter, while on concomitant therapy, the INR should be tested just
prior to the next dose of XARELTO, as appropriate. XARELTO can be
discontinued once the INR is >2.0. Once XARELTO is discontinued, INR
testing may be done at least 24 hours after the last dose of XARELTO, and
should then reliably reflect the anticoagulant effect of VKA.
Considerations for INR Monitoring of VKA Activity During Concomitant
XARELTO Therapy
In general, after starting VKA therapy, the initial anticoagulant effect is
not readily apparent for at least 2 days, while the full therapeutic effect
is achieved in 5-7 days. Consequently, INR monitoring in the first 2 days
after starting a VKA is rarely necessary. Likewise, the INR may remain
increased for a number of days after stopping VKA therapy.
Although XARELTO therapy will lead to an elevated INR, depending on the
timing of the Measurement, the INR is not a valid measure to assess the
anticoagulant activity of XARELTO. The INR is only calibrated and validated for
VKA and should not be used for any other anticoagulant, including XARELTO.
When switching patients from XARELTO to a VKA, the INR should only be
used to assess the anticoagulant effect of the VKA, and not that of XARELTO.
Therefore, while patients are concurrently receiving XARELTO and VKA
therapy, if the INR is to be tested, it should not be before 24 hours after
the previous dose of XARELTO, and should be just prior to the next dose
of XARELTO, since at this time the remaining XARELTO concentration in
the circulation is too low to have a clinically important effect on the INR.
If INR testing is done earlier than just prior to the next dose of XARELTO,
the reported INR will not reflect the anticoagulation effect of the VKA only,
because XARELTO use may also affect the INR, leading to aberrant readings.
Missed Dose
It is essential to adhere to the dosage schedule provided.
If a dose is missed, the patient should take XARELTO immediately and
continue on the following day with the once daily intake as before.
A double dose should not be taken to make up for a missed tablet.
OVERDOSAGE
For management of suspected drug overdose, contact your
regional Poison Control Centre.
Overdose following administration of XARELTO may lead to hemorrhagic
complications due to its pharmacodynamic properties.
Rare cases of overdose up to 600 mg have been reported without bleeding
complications or other adverse reactions. No further increase in average
plasma exposure is expected due to limited absorption at supratherapeutic
doses of 50 mg or above because of a solubility ceiling effect.
A specific antidote for XARELTO is not available. The use of activated
charcoal to reduce absorption in case of XARELTO overdose may be
considered. Administration of activated charcoal up to 8 hours after
overdose may reduce the absorption of XARELTO.
Due to the high plasma protein binding, XARELTO is not expected to be
removed by dialysis.
Management of Bleeding
Should bleeding occur in a patient receiving XARELTO, the next
administration should be delayed, or treatment should be discontinued
as appropriate. XARELTO has a half-life of approximately 5 to 13 hours.
Management should be individualized according to the severity and location
of the hemorrhage. Appropriate symptomatic treatment should be used
as needed, such as mechanical compression, eg, for severe epistaxis,
surgical hemostasis with bleeding control procedures, fluid replacement
and hemodynamic support, blood products (packed red cells or fresh frozen
plasma, depending on associated anemia or coagulopathy) or platelets.
If bleeding cannot be controlled by the above measures, consider
administration of one of the following procoagulants:
•activatedprothrombincomplexconcentrate(APCC)
•prothrombincomplexconcentrate(PCC)
•recombinantFactor-VIIa(rFVIIa)
However, there is currently very limited experience with the use of these
products in individuals receiving XARELTO.
In a randomized, double-blind, placebo-controlled study, a non-activated
prothrombin complex concentrate (PCC) given to 6 healthy male
subjects who had previously received XARELTO, completely reversed
its anticoagulant effect within 15 minutes, based on coagulation tests.
Although this study may have important clinical implications, this effect of
PCC has not yet been confirmed in patients with active bleeding who have
been previously treated with XARELTO.
Protamine sulfate and vitamin K are not expected to affect the anticoagulant
activity of XARELTO. There is no experience with antifibrinolytic agents
(tranexamic acid, aminocaproic acid) in individuals receiving XARELTO.
There is neither scientific rationale for benefit or experience with the
systemic hemostatics, eg, desmopressin and aprotinin in individuals
receiving XARELTO.
The PT, measured in seconds, is influenced by XARELTO in a dosedependent way with a close correlation to plasma concentrations if the
Neoplastin® reagent is used. In patients who are bleeding, measuring
the PT (Neoplastin® reagent) may be useful to assist in determining an
excess of anticoagulant activity. INR should not be used to assess the
anticoagulant effect of XARELTO (see WARNINGS AND PRECAUTIONS –
Monitoring and Laboratory Tests).
References
XARELTOProductMonograph,BayerInc.,January2012.
Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in
Nonvalvular Atrial Fibrillation. New Engl J Med. 2011;365:883-891.
ADVERSE REACTIONS
Less Common Clinical Trial Adverse Drug Reactions
Incidence is ≥0.1% to <1% unless specified.
Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation
Cardiac disorders: tachycardia
Eye disorders: eye hemorrhage, vitreous hemorrhage
Gastrointestinal disorders: melena, upper gastrointestinal hemorrhage, hemorrhoidal hemorrhage,
hematochezia, mouth hemorrhage, lower gastrointestinal hemorrhage, anal hemorrhage, gastric ulcer
hemorrhage, gastritis hemorrhagic, gastric hemorrhage, hematemesis, abdominal discomfort, abdominal
pain lower, dry mouth
General disorders and administration site conditions: malaise
Hepatobiliary disorders: hepatic function abnormal, hyperbilirubinemia, jaundice ( 0.01% to <0.1%)
Immune system disorders: hypersensitivity, anaphylaxis ( 0.01% to <0.1%)
Injury, poisoning, and procedural complications: post-procedural hemorrhage, wound hemorrhage,
traumatic hematoma, incision site hemorrhage, subdural hematoma, subcutaneous hematoma,
periorbital hematoma
Investigations: hemoglobin decreased, hematocrit decreased, blood bilirubin increased, liver function
test abnormal, aspartate aminotransferase increased, hepatic enzyme increased, blood urine present,
creatinine renal clearance decreased, blood creatinine increased, blood urea increased, blood alkaline
phosphatase increased, lipase increased, bilirubin conjugated increased (with or without concomitant
increase of ALT) ( 0.01% to <0.1%)
Musculoskeletal, connective tissue, and bone disorders: hemarthrosis, muscle hemorrhage ( 0.01%
to <0.1%)
Nervous system disorders: loss of consciousness, hemorrhagic stroke, hemorrhage intracranial
Renal and urinary disorders: renal impairment
Reproductive system disorders: vaginal hemorrhage, metrorrhagia
Skin and subcutaneous tissue disorders: dermatitis allergic, rash pruritic, rash erythemateous, rash
generalized, pruritus generalized, urticaria, skin hemorrhage
Vascular disorders: hemorrhage, bleeding varicose vein
In other clinical studies with XARELTO, occurrences of vascular pseudoaneurysm formation following
percutaneous intervention have been observed. Very rare cases of adrenal hemorrhage have been
reported.
DRUG INTERACTIONS
XARELTO (rivaroxaban) neither inhibits nor induces CYP 3A4 or any other major CYP isoenzymes.
Concomitant use of drugs affecting hemostasis increases the risk of bleeding. Care should be taken
if patients are treated concomitantly with drugs affecting hemostasis such as nonsteroidal antiinflammatory drugs (NSAIDs), acetylsalicylic acid, and platelet aggregation inhibitors. Due to the
increased bleeding risk, generally avoid concomitant use with other anticoagulants (see WARNINGS AND
PRECAUTIONS – Bleeding).
Drug-Drug Interactions
The use of XARELTO is contraindicated in patients receiving concomitant systemic treatment with strong
inhibitors of both CYP 3A4 and P-gp (such as ketoconazole, itraconazole, voriconazole, posaconazole, or
ritonavir). These drugs may increase XARELTO plasma concentrations to a clinically relevant degree, ie,
2.6-fold on average, which may lead to bleeding. The azole anti-mycotic fluconazole, a moderate CYP
3A4 inhibitor, has less effect on rivaroxaban exposure and may be co-administered with caution (see
CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS – Drug Interactions.
Drugs strongly inhibiting only one of the XARELTO elimination pathways, either CYP 3A4 or P-gp, are
expected to increase XARELTO plasma concentrations to a lesser extent. The expected increase is
considered less clinically relevant (see Table 5).
Table 5 – Established or Potential Drug-Drug Interactions
Concomitant Drug
Class: Drug Name
Azole antimycotic:
ketoconazole
Ref. Effect
Clinical Comment
CT
Coadministration of XARELTO with the azole-antimycotic ketoconazole
(400 mg od) a strong CYP 3A4 and P-gp inhibitor, led to a 2.6-fold
increase in mean XARELTO steady state AUC and a 1.7-fold
increase in mean XARELTO Cmax, with significant increases in its
pharmacodynamic effects.
The use of XARELTO is contraindicated in patients
receiving systemic treatment with ketoconazole (see
CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS –
Drug Interactions, Renal Impairment).
CT
Administration of the moderate CYP 3A4 inhibitor fluconazole (400
mg once daily) led to a 1.4-fold increase in mean XARELTO AUC and a
1.3-fold increase in mean Cmax.
Protease inhibitor:
ritonavir
CT
Coadministration of XARELTO with the HIV protease inhibitor ritonavir
(600 mg bid), a strong CYP 3A4 and P-gp inhibitor, led to a 2.5-fold
increase in mean XARELTO AUC and a 1.6-fold increase in mean
XARELTO Cmax, with significant increases in its pharmacodynamic
effects.
The use of XARELTO is contraindicated in patients
receiving systemic treatment with ritonavir (see
CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS –
Drug Interactions, Renal Impairment).
Anti-infectives:
erythromycin
CT
Erythromycin (500 mg tid), which inhibits CYP 3A4 and P-gp
moderately, led to a 1.3-fold increase in mean XARELTO AUC and Cmax.
clarithromycin
CT
Clarithromycin (500 mg bid), considered a strong CYP 3A4 inhibitor
and moderate P-gp inhibitor, led to a 1.5-fold increase in mean
rivaroxaban, and a 1.4-fold increase in Cmax.
The use of XARELTO in combination with clarithromycin may
increase the risk of bleeding particularly in patients with
underlying disease conditions, and elderly. Caution is required.
rifampicin
CT
Coadministration of XARELTO with the strong CYP 3A4 and P-gp
inducer rifampicin led to an approximate 50% decrease in mean
XARELTO AUC, with parallel decreases in its pharmacodynamic effects.
Strong CYP 3A4 inducers should generally be avoided in
combination with XARELTO, as such use can be expected to
result in inadequate anticoagulation.
Anti-convulsants:
phenytoin
carbamazepine
phenobarbitone
T
The concomitant use of XARELTO with strong CYP 3A4 inducers, eg,
phenytoin, carbamazepine, or phenobarbitone, may also lead to a
decreased XARELTO plasma concentration.
Strong CYP 3A4 inducers should generally be avoided in
combination with XARELTO, as such use can be expected to
result in inadequate anticoagulation.
Nonsteroidal Antiinflammatory
Drugs (NSAID):
naproxen
CT
Coadministration with naproxen did not affect XARELTO bioavailability
and pharmacokinetics. No clinically relevant prolongation of bleeding
time was observed when 500 mg naproxen was pre-administered
24 hours before concomitant administration of single doses of
XARELTO 15 mg and naproxen 500 mg in healthy subjects.
Concomitant use with XARELTO increases the risk of bleeding.
Promptly evaluate any signs or symptoms of blood loss (see
WARNINGS AND PRECAUTIONS – Drug Interactions).
For patients in the ROCKET AF trial, concomitant ASA use
(almost exclusively at 100 mg or less) was identified as an
independent risk factor for major bleeding with both XARELTO
and warfarin.
Antiplatelet drugs:
clopidogrel
CT
In two drug interaction studies of 11 and 13 healthy subjects,
clopidogrel 300 mg was pre-administered 24 hours before
concomitant administration of single doses of XARELTO 15 mg and
clopidogrel 75 mg in healthy subjects. Clopidogrel with or without
XARELTO led to an approximately 2-fold increase in the median
bleeding time (normal range 2-8 minutes). In these studies, between
30% and 40% of subjects who received both XARELTO and clopidogrel
had maximum bleeding times of up to 45 minutes. XARELTO alone
did not lead to a change in bleeding time at 4 hours or 2 days after
administration. There was no change in the pharmacokinetics of
either drug.
Concomitant use with XARELTO increases the risk of bleeding.
Promptly evaluate any signs or symptoms of blood loss (see
WARNINGS AND PRECAUTIONS – Drug Interactions).
Antithrombotic:
enoxaparin
CT
After combined administration of enoxaparin (40 mg single dose) with
XARELTO (10 mg single dose), an additive effect on anti-Factor-Xa
activity was observed, without any additional effects on clotting
tests (PT, aPTT). Enoxaparin did not affect the bioavailability and
pharmacokinetics of XARELTO.
Coadministration of XARELTO at doses ≥10 mg with other
anticoagulants or antithrombotic therapy has not been
adequately studied in clinical trials. Due to the increased
bleeding risk, generally avoid concomitant use with other
anticoagulants (see WARNINGS AND PRECAUTIONS –
Drug Interactions).
Legend: CT=Clinical Trial; T=Theoretical
No pharmacokinetic interaction was observed between warfarin and XARELTO.
There were no mutual pharmacokinetic interactions observed between XARELTO and midazolam (substrate of CYP 3A4), digoxin (substrate of P-gp), or atorvastatin (substrate
of CYP 3A4 and P-gp).
Coadministration of the proton pump inhibitor, omeprazole, the H2-receptor antagonist, ranitidine, the antacid, aluminum hydroxide/magnesium hydroxide, or naproxen,
clopidogrel, or enoxaparin did not affect XARELTO bioavailability or pharmacokinetics.
Drug-Food Interactions
XARELTO 15 mg and 20 mg should be taken with food.
Grapefruit juice is a moderate CYP 3A4 inhibitor. Therefore, an increase in XARELTO exposure following grapefruit juice consumption is not expected to be clinically relevant.
Drug-Herb Interactions
The concomitant use of XARELTO with other strong CYP 3A4 inducers, eg, St. John’s Wort, may lead to a decreased XARELTO plasma concentration. Strong CYP 3A4 inducers
should generally be avoided in combination with XARELTO, as such use can be expected to result in inadequate anticoagulation.
Drug-Laboratory Interactions
Although various clotting parameter tests (PT, aPTT, Heptest®) are affected by the mode of action of XARELTO, none of these clotting tests have been demonstrated to reliably
assess the anticoagulant activity of rivaroxaban following XARELTO administration under usual conditions (see WARNINGS AND PRECAUTIONS – Monitoring and Laboratory
Tests).
The PT, measured in seconds, is influenced by XARELTO in a dose-dependent way with a close correlation to plasma concentrations if the Neoplastin® reagent is used. In
patients who are bleeding, measuring the PT (Neoplastin® reagent) in seconds, but not INR, may be useful to assist in determining an excess of anticoagulant activity (see
WARNINGS AND PRECAUTIONS – Monitoring and Laboratory Tests).
Please see XARELTO Product Monograph for complete prescribing information.
Complete Product Monograph, prepared for health professionals, can be found at: http://www.bayer.ca or by contacting the sponsor at 1-800-265-7382.
® Bayer, Bayer Cross, XARELTO, and XARELTO Diamond Design
are registered trademarks of Bayer AG, used under license by Bayer Inc.
All other trademarks are the property of their respective owners.
© 2012, Bayer Inc.
Bayer Inc.
77 Belfield Road
Toronto, Ontario M9W 1G6
THE MEDICAL POST |news
CaRdIOLOGY
Richer doesn’t always
mean healthier
istockphoto
fluconazole
48
Wealthier people tend to eat more fruit and vegetables, but also
consume more fats and meat protein, a study has found.
Study reveals
income’s variable
effects on lifestyle
than swimming against the tide.”
Physical activity showed a similar
variation by income. “As countries
become wealthy or individuals
become wealthy, physical activity
BY Ed SuSman • Munich
decreases,” Dr. Yusuf said, and the
ndividuals with higher
decline in exercise, he suggested,
incomes tend to eat more fruit is the prime cause of the obesity
and green vegetables, but they epidemic. With the exception of
also consume more fats and meat
marathon runners, Dr. Yusuf said,
proteins.
regular exercise may not be enough
In the massive Proto offset the increase in
spective Urban and Rural
fat and protein consumpEpidemiological (PURE)
tion observed in the
study, lead investigawealthier countries.
tor Dr. Salim Yusuf, a
Other lifestyle choices
professor of medicine
had a less straightforward
at McMaster University
relationship with wealth.
in Hamilton, described
“Smoking among women
findings gleaned from
does not depend on
interviews with 154,000
(gross domestic product)
dr. Yusuf
people in 17 countries,
but on other cultural facincluding Canada.
tors,” Dr. Yusuf said.
“Because people take more pro“In Asian countries and in
tein and fat in the rich countries,
Muslim countries, women (typthey tend to take less carbohydrates,” ically) don’t smoke. In men there
Dr. Yusuf said during a press briefing is a clear inverse relationship from
at the European Society of Cardiolabout 45% of men in the poorest
ogy meeting here. “Carbohydrates
countries smoking to about 20% in
represent about 50% of the diet in
the rich countries. The emphasis
richer countries and about 65% of
should be on getting people to quit
the diet in poorer countries.”
smoking. If you can get them to quit
then their children will not start.”
Wealthy eat more fat
“In countries and societies where
In one-third of the countries—the
there is wealth, it is important to
poorer ones on the list—the popumaintain levels of physical activity,”
lation consumed less than the recDr. Deepak Bhatt, a professor of
ommended five servings or
medicine at Brigham and Women’s
500 g/day of fruit and vegetables.
Hospital and Harvard Medical
But in some of the richer nations,
School in Massachusetts, said in
the population consumed up to
commenting on the study.
900 g/day of these “healthy foods.”
“As countries go from rural to
On the other hand, the wealthier
becoming more industrialized
countries consumed more fats, more . . . it is important to remind such
saturated fats and more protein.
communities of the importance
Dr. Yusuf said the study results
of daily physical activity. Likewise,
have “huge policy implications. . . .
in impoverished communities it is
In the right environment it is easy
important to set up mechanisms by
for people to do the right thing. It is
which people there can have access
called swimming with the tide rather to fresh produce.” MP
I
OCTOBeR 9, 2012
49
Ontario fee cuts hit
family medicine too, doctors say
BY Julia Belluz
Toronto
O
n the face of it,
when the Ontario
government unilaterally imposed 37 changes to
the physician fee schedule in
May, it seemed specialists in
the province would feel most of
the burn. After all, it was the
slashing of fees paid for diagnostic radiology tests, cataract
surgery and preoperative
echocardiograms that made
headlines.
But family physicians are
also reporting their bottom
lines have taken a hit. The
biggest change has been the
reduction of the intermediate
assessment fee for an office visit
(A007), one of family medicine’s most common. It was
reduced by a dollar, to $33.70.
According to an Ontario
health ministry website, “Over
the years, physicians have been
claiming an increasingly higher
number of office visits using
this more expensive office visit
code rather than using the lower
fee for a minor assessment.”
Doctors say a dollar a visit
may not sound like much, but
“it adds up,” said Dr. André Hasspieler, a North Bay, Ont., family
doctor. “If you see 40 people a
day, you’re billing 35 A007s.”
Still, Dr. Hasspieler said he
feels the worst is yet to come. “I
think the government is trying
to divide and conquer: Hit the
specialists first and then family
practice is next.”
low back pain tests
The government also
announced changes to fees
related to the use of CT/MRI
tests for low back pain, another
well-trodden area for family
doctors. Now, physicians who
are ordering CT/MRIs will
need to show that the test is
medically necessary.
Dr. Michelle Greiver, who is
part of the North York Family
Health Team in Toronto, told
the Medical Post, “We all started
receiving letters from the
diagnostic imaging facilities,
reminding us that we can’t refer
people for MRIs of the back if
they don’t have red flags.”
She said family doctors have
interpreted this to mean that
if they refer a patient
for an MRI of the
back and the patient
doesn’t fit certain
criteria, the doctor
is responsible for the
payment. As such,
the change has had
the ministry’s desired
effect on doctors.
“It makes you
Dr. Greiver
pain all the time.”
Dr. Jim Stewart, head of
the family medicine section of
the Ontario Medical Association, said he keeps discovering
“quirks and nuances” in the
fee schedule that make certain
procedures unaffordable.
For example, according
to the ministry of health,
“Physicians will no longer be
think, ‘Does this
patient need a referral or not?’ Which is
not a bad thing. But
it was fairly draconian measure,” Dr.
Greiver said. “That’s
the major one that
impacted family
docs because we see
patients with back
paid a separate fee for routine
screening for using an electrocardiogram and/or a pulmonary function test when these
tests are given during a routine
annual health visit, unless
there are symptoms of heart or
lung disease.”
Dr. Stewart said this change
makes doing those procedures
“prohibitive.” MP
Currently available clinical data are inadequate to determine whether concurrent use of inhaled
corticosteroids mitigates the increased risk of asthma-related death from LABA. Available data
from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization
in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians
should only prescribe ADVAIR® or ADVAIR® DISKUS® for patients not adequately controlled on a
long-term asthma control medication, such as an inhaled corticosteroid or whose disease
severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA.
Once asthma control is achieved and maintained, assess the patient at regular intervals and do
not use ADVAIR® or ADVAIR® DISKUS® for patients whose asthma can be adequately controlled
on low or medium dose inhaled corticosteroids.
Pr
ADVAIR® DISKUS® / PrADVAIR®
salmeterol xinafoate/fluticasone propionate dry powder for inhalation/
salmeterol xinafoate/fluticasone propionate inhalation aerosol
Prescribing Summary
ADVAIR® should not be used to treat acute symptoms of asthma. It is crucial to inform patients of this
and prescribe rapid onset, short duration inhaled bronchodilator (e.g., salbutamol) to relieve the acute
symptoms of asthma. Patients should be clearly instructed to use rapid onset, short duration, inhaled β2agonists only for symptomatic relief if they develop asthma symptoms while taking ADVAIR®. When
beginning treatment with ADVAIR®, patients who have been taking rapid onset, short duration, inhaled β2agonists on a regular basis (e.g., q.i.d) should be instructed to discontinue the regular use of these drugs
and use them only for symptomatic relief if they develop acute symptoms of asthma while taking ADVAIR®.
Discontinuance: Treatment with inhaled corticosteroids should not be stopped abruptly in patients
with asthma due to risk of exacerbation. In this case, therapy should be titrated down gradually, under
physician supervision. For patients with COPD, cessation of therapy may be associated with symptomatic
decompensation and should be supervised by a physician.
Cardiovascular And Other Effects: Although clinically not significant, a small increase in QTc
interval has been reported with therapeutic doses of salmeterol. It is not known if this becomes
clinically significant when concomitant medications causing similar effects are prescribed and/or in
the presence of heart diseases, hypokalemia, or hypoxia. Large doses of inhaled or oral salmeterol
(12 to 20 times the recommended dose) have been associated with clinically significant prolongation
of the QTc interval, which has the potential for producing ventricular arrhythmias.
Fatalities have been reported following excessive use of aerosol preparations containing sympathomimetic
amines, the exact cause of which is unknown. Cardiac arrest was reported in several instances.
No clinically significant effect on the cardiovascular system is usually seen after the administration
of inhaled salmeterol in recommended doses. Cardiovascular effects such as increased blood pressure
and heart rate may occasionally be seen with all sympathomimetic drugs, especially at higher than
therapeutic doses. Central nervous system effects (increased excitement) can occur after the use of
salmeterol. Occurrence of cardiovascular or central nervous system effects may require discontinuation
of the drug. For this reason, salmeterol xinafoate/fluticasone propionate, like all sympathomimetic
amines, should be used with caution in patients with cardiovascular disorders, especially coronary
insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders or thyrotoxicosis;
and in patients who are unusually responsive to sympathomimetic amines.
In individual patients any β2-adrenergic agonist may have a clinically significant cardiac effect. As
has been described with other beta-adrenergic agonist bronchodilators, clinically significant changes
in systolic and/or diastolic blood pressure, pulse rate, and electrocardiograms have been seen infrequently
in individual patients in controlled clinical studies with salmeterol.
Ear/Nose/Throat: Symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking,
have been reported rarely in patients receiving salmeterol.
Endocrine And Metabolism (Systemic Steroid Replacement by Inhaled Steroid): Particular care is
needed in patients who are transferred from systemically active corticosteroids to inhaled corticosteroids
because deaths due to adrenal insufficiency have occurred in patients with asthma during and after
transfer. For the transfer of patients being treated with oral corticosteroids, inhaled corticosteroids
should first be added to the existing oral steroid therapy which is then gradually withdrawn.
Patients with adrenocortical suppression should be monitored regularly and the oral steroid reduced
cautiously. Some patients transferred from other inhaled steroids or oral steroids remain at risk of
impaired adrenal reserve for a considerable time after transferring to inhaled fluticasone propionate.
After withdrawal from systemic corticosteroids, a number of months are required for recovery of
hypothalamic-pituitary-adrenal (HPA) function. During this period of HPA suppression, patients may
exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery or infections,
particularly gastroenteritis. Although inhaled fluticasone propionate may provide control of asthmatic
symptoms during these episodes, it does not provide the systemic steroid which is necessary for
coping with these emergencies. The physician may consider supplying oral steroids for use in times
of stress (e.g. worsening asthma attacks, chest infections, and surgery).
During periods of stress or a severe asthmatic attack, patients who have been withdrawn from systemic
corticosteroids should be instructed to resume systemic steroids immediately and to contact their
physician for further instruction. These patients should also be instructed to carry a warning card
indicating that they may need supplementary systemic steroids during periods of stress or a severe
asthma attack. To assess the risk of adrenal insufficiency in emergency situations, routine tests of
adrenal cortical function, including measurement of early morning and evening cortisol levels, should
be performed periodically in all patients. An early morning resting cortisol level may be accepted as
normal only if it falls at or near the normal mean level.
Systemic Effects: Systemic effects may occur with any inhaled corticosteroid, particularly at high
doses prescribed for long periods; these effects are much less likely to occur than with oral corticosteroids.
Possible systemic effects include Cushing’s syndrome, Cushingoid features, and adrenal suppression,
For complete prescribing information, please refer to the full Product Monograph at
http://www.gsk.ca
ASTHMA: ADVAIR® is indicated for the maintenance treatment of asthma in patients with reversible
obstructive airways disease. ADVAIR®/ADVAIR® DISKUS® is not indicated for patients whose asthma
can be managed by occasional use of a rapid onset, short duration, inhaled β2 -agonist, or for
patients whose asthma can be successfully managed by inhaled corticosteroids along with occasional
use of a rapid onset, short duration, inhaled β2 -agonist.
Long-acting β2-adrenergic agonists (LABA), such as salmeterol, one of the active ingredients in
ADVAIR® and ADVAIR® DISKUS®, increase the risk of asthma-related death. Available data from
controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in
pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should
only prescribe ADVAIR® or ADVAIR® DISKUS® for patients not adequately controlled on a long-term
asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly
warrants initiation of treatment with both an inhaled corticosteroid and LABA.
Once asthma control is achieved and maintained, assess the patient at regular intervals and do not
use ADVAIR® or ADVAIR® DISKUS® for patients whose asthma can be adequately controlled on low or
medium dose inhaled corticosteroids. ADVAIR® contains a long-acting β2-agonist and should not be
used as a rescue medication. To relieve acute asthmatic symptoms, a rapid onset, short duration
inhaled bronchodilator (e.g. salbutamol) should be used.
CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD): ADVAIR® 250 DISKUS® and ADVAIR® 500
DISKUS® are indicated for the maintenance treatment of COPD, including emphysema and chronic
bronchitis, in patients where the use of a combination product is considered appropriate. ADVAIR®
DISKUS® should not be used as a rescue medication. Physicians should reassess patients several
months after the initiation of ADVAIR® DISKUS® and if symptomatic improvement has not occurred,
ADVAIR® DISKUS® should be discontinued.
Geriatrics: There is no need to adjust the dose in elderly patients.
Pediatrics (< 4 years of age): At present, there is insufficient clinical data to recommend the use of
ADVAIR® DISKUS® in children younger than 4 years of age and the use of ADVAIR® inhalation aerosol
in children younger than 12 years of age.
CONTRAINDICATIONS
• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component
of the container.
• Patients with IgE mediated allergic reactions to lactose (which contains milk protein) or milk
(ADVAIR® DISKUS® users only).
• Patients with cardiac tachyarrhythmias.
• Patients with untreated fungal, bacterial or tuberculous infections of the respiratory tract.
• In the primary treatment of status asthmaticus or other acute episodes of asthma, or in patients
with moderate to severe bronchiectasis.
Safety Information
General: Information concerning a study regarding salmeterol, a component of ADVAIR®/
ADVAIR® DISKUS®
ASTHMA-RELATED DEATH
Long-acting β2-adrenergic agonists (LABA), such as salmeterol, one of the active ingredients in
ADVAIR® and ADVAIR® DISKUS®, increase the risk of asthma-related death. Data from a large
placebo-controlled US study that compared the safety of salmeterol (SEREVENT® Inhalation
Aerosol) or placebo added to patients usual asthma therapy showed an increase in asthma-related
deaths in patients receiving salmeterol (13 deaths out of 13, 176 patients treated for 28 weeks
on salmeterol versus 3 deaths out of 13, 179 patients on placebo). Post-hoc analysis of the
SMART trial data suggests that the risks may be lower in patients who were using inhaled
corticosteroids (ICS) at study entry. However, these post-hoc analysis results are not conclusive.
1
50
OCTOBER 9, 2012
time to tell kids the truth
about tanning beds: mD
CaNaDIaN PaeDIatrIC SOCIety
Impossible to tan
without risking
carcinogenesis
by terry murray
London, Ont.
I
t’s time to apply what’s
been learned about the
cancer risk of tobacco
smoking to the cancer risk of
indoor suntanning, according
to a public health official.
As with cigarette packaging,
promotion of tanning salons
should be accompanied not
by pictures of young, healthy
women, but with warning
signs showing pictures of
late-stage melanoma or cold
sores, caused by reactivation
of latent herpes virus infection, Dr. Richard Stanwick, the
chief medical health officer for
the Vancouver Island Health
Authority, told the annual
conference of the Canadian
Paediatric Society here.
It’s important to restrict
children and teenagers’ use of
tanning beds because risk is
cumulative, Dr. Stanwick said.
He cited a recent casecontrol study in Minnesota
showing that melanoma risk
increased “markedly” with
frequency and duration of use,
with the highest risk associated with more than 50 hours
(three times increased risk),
more than 100 sessions (2.7
times) and more than 10 years
(2.5 times).
Seven other studies involving nearly 7,400 cases showed
that first exposure to sunbeds
before age 35 increased melanoma risk by 75%, he added.
The tanning industry widely
promotes tanning salons for
acquiring a “base tan” before
a trip to Mexico, for example.
But that provides the equivalent of SPF-3 photoprotection,
and “is like exposing yourself
to secondhand smoke so you
can become a better smoker,”
he said.
“Tanning without risk of
carcinogenesis is probably scientifically impossible.”
Proponents of tanning salons argue that indoor tanning
is an aid to vitamin D synthesis. But Dr. Stanwick countered
that vitamin D synthesis
requires minimal
exposure and time.
“The farmer’s tan
for about 15 minutes
a day is all you really
need. And with that
sort of exposure,
a dermatologist
Dr. Stanwick
knows where to look
for potential skin
cancers of different
types. . . . You can
also get your vitamin
D for six cents a day
out of a bottle.”
The intensity of
exposures from tanning beds is
higher than from natural sunlight in this part of the world,
he added.
Dr. Stanwick also cited a
“distressing” recent paper from
New Brunswick showing that
by Grade 12, one-third of girls
growth retardation in children and adolescents, decrease in bone mineral density (BMD), cataract and
glaucoma. It is important therefore, that the dose of inhaled corticosteroid is titrated to the lowest
dose at which effective control is maintained.
The long-term effects of fluticasone propionate in human subjects are still unknown. The local effect
of the drug on developmental or immunologic processes in the mouth, pharynx, trachea, and lungs is
unknown. There is also no information about the possible long-term systemic effects of the agent.
Long-term use of orally inhaled corticosteroids may affect normal bone metabolism resulting in a loss
of bone mineral density. In patients with major risk factors for decreased bone mineral content, such
as chronic alcohol use, tobacco use, age, sedentary lifestyle, strong family history of osteoporosis, or
chronic use of drugs that can reduce bone mass (e.g., anticonvulsants and corticosteroids), ADVAIR®
may pose an additional risk.
Effects of treatment with ADVAIR® DISKUS® 50/500 mcg, fluticasone propionate 500 mcg, salmeterol
50 mcg, or placebo on BMD was evaluated in a subset of 658 patients (females and males 40 to 80
years of age) with COPD in a 3 year study (SCO30003). BMD evaluations were conducted at baseline
and at 48, 108 and 158 weeks. There were no significant differences between any of the treatment
groups at 3 years. A slight reduction in BMD measured at the hip was observed in all treatment groups
(ADVAIR® DISKUS® -3.2%, fluticasone propionate-2.9%, salmeterol-1.7%, placebo-3.1%). Fracture
risk was estimated for the entire population of patients with COPD in study SCO30003 (N=6,184).
There were no significant differences between any of the treatment groups. The probability of a
fracture over 3 years was 6.3% for ADVAIR® DISKUS®, 5.4% for fluticasone propionate, 5.1% for
salmeterol, and 5.1% for placebo.
During post-marketing use, there have been reports of clinically significant drug interactions in
patients receiving intranasal or inhaled fluticasone propionate and ritonavir, resulting in systemic
corticosteroid effects including Cushing’s syndrome and adrenal suppression. Therefore, concomitant
use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the
patient outweighs the risk of systemic corticosteroid side-effects.
The results of a drug interaction study conducted in healthy subjects indicated that concomitant use
of systemic ketoconazole (a strong cytochrome P450 3A4 inhibitor) increased exposure to salmeterol
in some subjects. This increase in plasma salmeterol exposure may lead to prolongation in the QTc
interval. Due to the potential increased risk of cardiovascular adverse events, the concomitant use of
salmeterol with ketoconazole is not recommended. Caution should also be exercised when other
CYP3A4 inhibitors are co-administered with salmeterol (e.g. ritonavir, atazanavir, clarithromycin,
indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin).
Metabolic Effects: Doses of the related β2-adrenoceptor agonist salbutamol, when administered
intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis.
Administration of β2-adrenoceptor agonists may cause a decrease in serum potassium, possibly
through intracellular shunting, which has the potential to increase the likelihood of arrhythmias. The
effect is usually seen at higher therapeutic doses and the decrease is usually transient, not requiring
supplementation. Therefore, salmeterol/fluticasone propionate should be used with caution in patients
predisposed to low levels of serum potassium.
The possibility of impaired adrenal response should always be borne in mind in emergency and elective
situations likely to produce stress and appropriate corticosteroid treatment must be considered.
Certain individuals can show greater susceptibility to the effects of inhaled corticosteroid than do
most patients.
In common with other beta-adrenergic agents, salmeterol can induce reversible metabolic changes
(hyperglycemia, hypokalemia). There have been very rare reports of increases in blood glucose levels
and this should be considered when prescribing to patients with a history of diabetes mellitus.
There is an enhanced effect of corticosteroids on patients with hypothyroidism.
Hematologic (Eosinophilic Conditions): In rare cases, patients on inhaled fluticasone propionate
may present with systemic eosinophilic conditions, with some patients presenting with clinical
features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with
systemic corticosteroid therapy. These events usually, but not always, have been associated with the
reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone
propionate. Cases of serious eosinophilic conditions have also been reported with other inhaled
corticosteroids in this clinical setting. Physicians should be alerted to eosinophilia, vasculitic rash,
worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their
patients. A causal relationship between fluticasone propionate and these underlying conditions has
not been established.
Hepatic/Biliary/Pancreatic: There is an enhanced effect of corticosteroids on patients with cirrhosis.
Hypersensitivity: Immediate hypersensitivity reactions may occur after administration of salmeterol,
as demonstrated by rare cases of urticaria, angioedema, rash and bronchospasm, and very rare cases
of anaphylactic reactions, anaphylactic shock.
Immune (Candidiasis): Therapeutic dosages of fluticasone propionate frequently cause the appearance
of Candida albicans (thrush) in the mouth and throat. The development of pharyngeal and laryngeal
candidiasis is a cause for concern because the extent of its penetration into the respiratory tract is
unknown. Patients may find it helpful to rinse the mouth and gargle with water after using ADVAIR®.
Symptomatic candidiasis can be treated with topical anti-fungal therapy while continuing to
use ADVAIR®.
Infection: Corticosteroids may mask some signs of infection and new infections may appear. A decreased
resistance to localised infection has been observed during corticosteroid therapy. This may require
treatment with appropriate therapy or stopping the administration of fluticasone propionate until the
infection is eradicated. Patients who are on drugs that suppress the immune system are more susceptible
were using tanning salons, and
one-third of them were going
with their mothers.
“You don’t allow Johnny to
walk into a bar with Dad and
order a triple Scotch,” he said.
“It’s just not acceptable and we
want this to be the same.” MP
to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious
or even fatal course in susceptible children or adults on corticosteroids. In such children or adults
who have not had these diseases, particular care should be taken to avoid exposure. How the dose,
route, and duration of corticosteroid administration affect the risk of developing a disseminated infection
is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk
is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG)
may be indicated. If exposed to measles, prophylaxis with intramuscular pooled immunoglobulin (IG) may
be indicated. If chickenpox develops, treatment with antiviral agents may be considered.
For patients with asthma or COPD, consideration should be given to additional corticosteroid therapy
and to antibiotics if an exacerbation is associated with an infection.
For COPD patients, it is important that even mild chest infections be treated immediately since these
patients may be more susceptible to damaging lung infections than healthy individuals. Patients
should be instructed to contact their physician as soon as possible if they suspect an infection.
Physicians should recommend that COPD patients receive an annual influenza vaccination.
In a 3 year study of 6,184 patients with COPD (SCO30003) there was an increased reporting of any
adverse event of pneumonia in patients receiving ADVAIR® 50/500 mcg compared with placebo (16%
on ADVAIR® DISKUS® 50/500 mcg, 14% on fluticasone propionate 500 mcg, 11% on salmeterol 50 mcg
and 9% on placebo). Physicians should remain vigilant for the possible development of pneumonia
in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap.
Ophthalmologic: For patients at risk, monitoring of ocular effects (cataract and glaucoma) should
also be considered in patients receiving maintenance therapy with ADVAIR®.
Effects of treatment with ADVAIR® DISKUS® 50/500 mcg, fluticasone propionate 500 mcg, salmeterol 50
mcg, or placebo on development of cataracts or glaucoma was evaluated in a subset of 658 patients with
COPD in a 3 year (SCO30003) study. Ophthalmic examinations were conducted at baseline and at 48, 108
and 158 weeks. The presence of cataracts and glaucoma at baseline was similar across treatment
groups (61% to 71% and 5% to 8%, respectively). New cataracts were diagnosed in all treatment
groups (26% on ADVAIR® DISKUS® 50/500 mcg, 17% on fluticasone propionate, 15% on salmeterol,
and 21% on placebo). A few new cases of glaucoma were diagnosed (2% on ADVAIR® DISKUS® 50/500
mcg, 5% on fluticasone propionate, none on salmeterol, and 2% on placebo). There were no significant
differences in the development of glaucoma or cataracts between any of the treatment groups.
Respiratory: As with other inhalation therapy, paradoxical bronchospasm may occur characterized
by an immediate increase in wheezing after dosing. This should be treated immediately with a rapid
onset, short duration inhaled bronchodilator (e.g. salbutamol) to relieve acute asthmatic symptoms.
ADVAIR® should be discontinued immediately, the patient assessed, and if necessary, alternative
therapy instituted.
Special Populations:
Use In Women
Pregnant Women: There are no adequate and well-controlled studies with ADVAIR® in pregnant
women. ADVAIR® should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
In animal studies, some effects on the fetus, typical for a beta-agonist, occurred at exposure levels
substantially higher than those that occur with therapeutic use. Extensive use of other beta-agonists
has provided no evidence that effects in animals are relevant to human use.
Like other glucocorticoids, fluticasone propionate is teratogenic to rodent species. Adverse effects
typical of potent corticosteroids are only seen at high systemic exposure levels; administration by
inhalation ensures minimal systemic exposure. The relevance of these findings to humans has not yet
been established since well-controlled trials relating to fetal risk in humans are not available. Infants
born of mothers who have received substantial doses of glucocorticoids during pregnancy should be
carefully observed for hypoadrenalism.
Use in Labour and Delivery: There are no well-controlled human studies that have investigated
effects of salmeterol on preterm labour or labour at term. Because of the potential for beta-agonist
interference with uterine contractility, use of ADVAIR® during labour should be restricted to those
patients in whom the benefits clearly outweigh the risks.
Nursing Women: Plasma levels of salmeterol after inhaled therapeutic doses are very low (85 to
200 pg/mL) in humans and therefore levels in milk should be correspondingly low. Studies in lactating
animals indicate that salmeterol is likely to be secreted in only very small amounts in breast milk.
Glucocorticoids are excreted in human milk. The excretion of fluticasone propionate into human
breast milk has not been investigated. When measurable plasma levels were obtained in lactating
laboratory rats following subcutaneous administration, there was evidence of fluticasone propionate
in the breast milk. However, plasma levels in patients following inhaled fluticasone propionate at
recommended doses are likely to be low.
Since there is no experience with use of ADVAIR® by nursing mothers, a decision should be made
whether to discontinue nursing or to discontinue the drug, taking into account the importance of the
drug to the mother.
Pediatrics: (≥4 years of age): In adolescents and children, the severity of asthma may vary with age
and periodic reassessment should be considered to determine if continued maintenance therapy with
ADVAIR® is still indicated.
The safety and efficacy of ADVAIR® DISKUS® in children younger than 4 years of age have not been
established. The safety and efficacy of ADVAIR® inhalation aerosol in children younger than 12 years
of age have not been established.
Geriatrics: As with other β2-agonists, special caution should be observed when using salmeterol in
elderly patients who have concomitant cardiovascular disease that could be adversely affected by
2
OCTOBeR 9, 2012
51
Canadian PaEdiaTRiC SOCiETY
Statins deemed safe
for children
Montreal doctors
suggest pediatric
use is fine with
regular monitoring
for adverse events
bY TERRY muRRaY
London, Ont.
considered first-line therapy for
elevated LDL cholesterol in
children as young as eight.
But since that time, there
have been no studies examining the impact of the recommendations in statin-treated
children, according to Dr.
a
“firestorm of
controversy” greeted
the 2008
recommendation from the
American Academy of
Pediatrics that statins be
this class of drug. Based on available data, no adjustment of salmeterol dosage in geriatric patients
is warranted.
Monitoring And Laboratory Tests (Monitoring Control of Asthma or COPD): ADVAIR® should not
be introduced in acutely deteriorating asthma or COPD, which is a potentially life threatening
condition. Increasing use of rapid onset, short duration inhaled bronchodilators to control symptoms
indicates deterioration of asthma control. Sudden and progressive deterioration in asthma control is
potentially life-threatening and the treatment plan should be re-evaluated. Also, where current
dosage of ADVAIR® has failed to give adequate control of reversible obstructive airways disease the
patient should be reviewed by a physician. Before introducing ADVAIR®, adequate education should
be provided to the patient on how to use the drug and what to do if asthma flares up.
During long-term therapy, HPA axis function and haematological status should be assessed periodically.
For patients at risk, monitoring of bone and ocular effects (cataract and glaucoma) should also be
considered in patients receiving maintenance therapy with ADVAIR®. It is recommended that the
height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored.
ADVERSE REACTIONS
Adverse Drug Reaction Overview
As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in
wheezing after dosing. This should be treated immediately with a rapid onset, short duration inhaled
bronchodilator. ADVAIR® should be discontinued immediately, the patient assessed and alternative
therapy instituted if necessary.
The type and severity of adverse reactions associated with salmeterol xinafoate and fluticasone propionate
may be expected with ADVAIR®. There is no incidence of additional adverse events following combined
administration of the two compounds.
Salmeterol Xinafoate: The pharmacological side effects of β2-agonist treatment, such as tremor,
subjective palpitations and headache, have been reported, but tend to be transient and reduce with
regular therapy.
Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles) may
occur in some patients.
There have been reports of arthralgia and hypersensitivity reactions, including rash, urticaria,
bronchospasm, edema, angioedema, anaphylactic reaction and anaphylactic shock.
There have been reports of oropharyngeal irritations as well as common reports of muscle cramps.
Symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported
rarely in patients receiving salmeterol.
Clinically significant changes in blood glucose and/or serum potassium were seen rarely during
clinical studies with long-term administration of salmeterol at recommended doses.
Fluticasone Propionate: In general, inhaled corticosteroid therapy may be associated with dose
dependent increases in the incidence of ocular complications, reduced bone density, suppression of
HPA axis responsiveness to stress, and inhibition of growth velocity in children. Such events have been
reported rarely in clinical trials with fluticasone propionate.
Possible systemic effects include Cushing’s syndrome, Cushingoid features and adrenal suppression.
Glaucoma may be exacerbated by inhaled corticosteroid treatment. In patients with established
glaucoma who require long-term inhaled corticosteroid treatment, it is prudent to measure intraocular
pressure before commencing the inhaled corticosteroid and to monitor it subsequently. In patients
without established glaucoma, but with a potential for developing intraocular hypertension (e.g. the
elderly), intraocular pressure should be monitored at appropriate intervals.
In elderly patients treated with inhaled corticosteroids, the prevalence of posterior subcapsular and
nuclear cataracts is probably low but increases in relation to the daily and cumulative lifetime dose.
Cofactors such as smoking, ultraviolet B exposure, or diabetes may increase the risk. Children may be
less susceptible.
A reduction of growth velocity in children or teenagers may occur as a result of inadequate control of
chronic diseases such as asthma or from use of corticosteroids for treatment. Physicians should
closely follow the growth of children and adolescents taking corticosteroids by any route and weigh
the benefits of corticosteroid therapy and asthma control against the possibility of growth suppression
if any child’s or adolescent’s growth appears slowed.
Osteoporosis and fracture are the major complications of long-term treatment with parenteral or oral
steroids. Inhaled corticosteroid therapy is also associated with dose-dependent bone loss although
the degree of risk is very much less than with oral steroid. This risk may be offset by estrogen replacement
in post-menopausal women, and by titrating the daily dose of inhaled steroid to the minimum
required to maintain optimal control of respiratory symptoms. It is not yet known whether the peak
bone density achieved during youth is adversely affected if substantial amounts of inhaled
corticosteroid are administered prior to 30 years of age.
Failure to achieve maximal bone density during youth could increase the risk of osteoporotic fracture
when those individuals reach 60 years of age and older.
Hoarseness and candidiasis (thrush) of the mouth and throat can occur in some patients receiving
inhaled fluticasone propionate. These may be relieved by rinsing the mouth and gargling with water
after use of ADVAIR®. Symptomatic candidiasis can be treated with topical anti-fungal therapy while
still continuing with ADVAIR®.
There have been uncommon reports of cutaneous hypersensitivity reactions. There have also been
rare reports of hypersensitivity reactions manifesting as angioedema (mainly facial and oropharyngeal
edema), respiratory symptoms (dyspnea and/or bronchospasm) and very rarely, anaphylactic reactions.
There have been very rare reports of anxiety, sleep disorders and behavioural changes, including
hyperactivity and irritability (predominantly in children and adolescents)
Silvana Barone. So she and
her colleagues at Ste-Justine
Hospital in Montreal studied
the children receiving pharmacological treatment for
familial hypercholesterolemia
(FH) at the lipid disorders
clinic—admittedly, a condition
Eosinophilic Conditions: In rare cases, patients on inhaled fluticasone propionate may present with
systemic eosinophilic conditions, with some patients presenting with clinical features of vasculitis
consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid
therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal
of oral corticosteroid therapy following the introduction of fluticasone propionate. Cases of serious
eosinophilic conditions have also been reported with other inhaled corticosteroids in this clinical setting.
Physicians should be alerted to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac
complications, and/or neuropathy presenting in their patients. A causal relationship between fluticasone
propionate and these underlying conditions has not been established.
Asthma: Long-acting β2-adrenergic agonists, such as salmeterol, one of the active ingredients in ADVAIR®
and ADVAIR® DISKUS®, increase the risk of asthma-related death. Data from a large, placebo-controlled
US study that compared the safety of salmeterol (SEREVENT® Inhalation Aerosol) or placebo added to usual
asthma therapy showed an increase in asthma-related death in patients receiving salmeterol Post-hoc
analysis of the SMART trial data suggests that the risks may be lower in patients who were using inhaled
corticosteroids (ICS) at study entry. However, these post-hoc analysis results are not conclusive. Currently
available clinical data are inadequate to determine whether concurrent use of inhaled corticosteroids
mitigates the increased risk of asthma-related death from LABA.
Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related
hospitalization in pediatric and adolescent patients.
Clinical Trial Adverse Drug Reactions
To report an adverse event, you may notify Health Canada by phone at 1-866-234-2345, or
by toll-free fax at 1-866-678-6789 or by email at [email protected].
Asthma
Use in adolescents and adults: There have been very rare reports of anxiety, sleep disorders and
behavioural changes including hyperactivity and irritability (predominantly in children and adolescents).
There have been uncommon reports of contusions (skin bruising).
ADVAIR® DISKUS®: In clinical trials involving 1824 adult and adolescent patients, the most commonly
reported adverse events with the combination salmeterol xinafoate/fluticasone propionate ADVAIR® were:
hoarseness/dysphonia, throat irritation, headache, candidiasis of mouth and throat and palpitations
(see Table 1).
ADVAIR® Inhalation Aerosol: In clinical trials, the most commonly reported adverse events with the
combination salmeterol xinafoate/fluticasone propionate inhalation aerosol were: hoarseness/dysphonia,
throat irritation and headache. All other adverse events with a reasonable possibility of being related to
study drug were reported in ≤ 1% of subjects (see Table 2)
Use in children: A total of 257 pediatric patients participated in the clinical development programme
and received either the combination 50 mcg salmeterol xinafoate/100 mcg fluticasone propionate
ADVAIR® or concurrent therapy (with salmeterol and fluticasone propionate administered via separate
inhalers). Only one drug-related adverse event, candidiasis, was reported with an incidence of 2% or
more in the ADVAIR® group. The combination product was generally well tolerated and the safety
profile was comparable to that observed in the concurrent therapy group.
There have been very rare reports of anxiety, sleep disorders and behavioural changes including
hyperactivity and irritability (predominantly in children and adolescents).
COPD
Clinical trial adverse drug reaction data is provided for two 24-week studies, a 52-week study and a
3-year study.
24-week studies: In clinical trials involving 2054 adults, the most commonly reported adverse
events with ADVAIR® DISKUS® after 24 weeks were: upper respiratory tract infection, throat irritation,
headache and musculoskeletal pain (see Table 3). These adverse reactions were mostly mild to
moderate in severity.
Other COPD Clinical Trial Adverse Drug Reactions (1-3%)
Cardiovascular: arrhythmias, hypertension, palpitations
Drug Interaction, Overdose and Trauma: contusions, fractures, hematomas, lacerations and wounds
Ear/Nose/Throat: ear/nose/throat infections, ear/nose/throat signs and symptoms, ear signs and
symptoms, epistaxis, laryngitis, nasal sinus disorders, pharyngitis/throat infections, rhinorrhea/post
nasal drip, sputum abnormalities
Endocrine and Metabolism: diabetes mellitus, hypothyroidism
Gastrointestinal: constipation, dental discomfort and pain, diverticulosis, dyspeptic symptoms,
gastrointestinal infections, gum signs and symptoms, hyposalivation, oral discomfort and pain; oral
lesions, regurgitation and reflux
Hepatic/Biliary/Pancreatic: abnormal liver function tests
Immune: bacterial infections, candidiasis unspecified site, viral infections
Neurologic: anxiety, situational disorders, sleep disorders, syncope, tremors, vertigo
Non-Site Specific: bone and skeletal pain, edema and swelling, non-site specific pain, non-specific
condition, soft tissue injuries
Ophthalmologic: dry eyes, eye infections, lacrimal disorders, ocular pressure disorders, visual disturbances
Per-Operative Considerations: postoperative complications
Respiratory: breathing disorders, bronchitis, lower respiratory hemorrhage, lower respiratory signs
and symptoms, pneumonia
Skin: fungal skin infections and skin infections
52-week study: After 52 weeks of treatment with ADVAIR® DISKUS® (50/500 mcg), fluticasone
propionate 500 mcg, salmeterol 50 mcg and placebo in 1465 patients with COPD, the most commonly
reported drug related adverse event was candidiasis of the mouth and throat (ADVAIR® DISKUS®
3
for which statin use is not so
controversial—to describe its
impact on lipid profiles and to
document adverse effects.
Dr. Barone, a pediatrics
resident, presented the findings at the annual conference
here of the Canadian Paediatric
Society here.
The American Academy
of Pediatrics report recommended a targeted approach,
including a fasting lipid profile
on all children and adolescents
with a positive family history of
either premature cardiovascular disease or high lipid levels,
as well as those with unknown
family history or other classic risk factors such as being
overweight or obese, smoking
cigarettes, and having hypertension and/or diabetes. It then
advised statin treatment for
patients with high LDL levels
despite lifestyle interventions
with diet and exercise.
“This clinical report set off
a firestorm of controversy with
members of the public, the lay
media and medical professionals, voicing serious concern
about the potential overprescription of statins, the use of
statins as a panacea for the obesity epidemic in children and
the belief that these were ‘adult’
medications with risk of serious
side-effects,” Dr. Barone said.
notable improvement
But her retrospective chart
review of 68 statin-treated children (whose average age was
12 years at the start of treatment), between October 2009
and February 2010 inclusive,
showed that use of the drug
class was associated with a significant improvement in lipid
profile with few adverse effects.
Compared with 146 patients
not treated with statins, fasting
lipid profiles at initial clinic
visit showed the statin-treated
group had significantly higher
total cholesterol (average
7.7 mmol/l), LDL (6.14 mmol/l)
and apolipoprotein B (1.56 g/l)
levels, but significantly lower
HDL levels (1.04 mmol/l) and
comparable triglycerides
(1.04 mmol/l).
Duration of statin therapy
averaged 1.8 years, but was
as long as eight years. Fifty
52
OCTOBER 9, 2012
Canadian PaEdiaTRiC SOCiETY
nearly 6% of adverse events
after varicella vaccine are ‘serious’
Getting other
vaccines at same
time increases
the rate, but
causation isn’t
clear
BY TERRY MURRaY
London, Ont.
events following immunization
(AEFIs) were reported during
the period, of which 325, or
5.8%, were considered serious.
Those figures represented a
rate of 151 AEFI reports per
100,000 vaccine doses distributed, and a rate of 8.8 serious
AEFIs per 100,000, she said.
However, the serious AEFIs,
most of which were seizures,
varied by the vaccines given
and the age of the children
receiving them, she added.
“We found the concomitant
administration of MMR contributed disproportionately to
the AEFI reports of seizures,”
she said.
When reports of adverse
events were restricted to children who had received the
single-antigen varicella vaccine
alone, the percentage of serious
events dropped to 3.9%.
Comparison of the Canadian findings with U.S. data
from the Vaccine Adverse
Events Reporting System
showed the types of AEFIs to
be similar, although rates in
Canada were higher. However,
Canadian reporting rates are
four- to five-fold higher than in
the U.S., which would account
for our higher rate of all AEFIs,
while inclusion of IMPACT
data boosted our rate of serious
AEFIs, Dr. Anyoti said.
She noted better reporting
by physicians is also needed.
Of all AEFI reports, 68% came
from public health; only 2%
came from physicians. MP
a
lthough most adverse
reactions reported
after varicella
vaccination have been mild
and expected, nearly 6% of
them have been serious and
the most common serious
events have been seizures.
Those were the findings
of a review of reports to the
Canadian Adverse Events
Following Immunization
Surveillance System (CAEFISS)
from 1999 to 2010, reported
at the annual conference here
of the Canadian Paediatric
Society.
The reports to the voluntary CAEFISS program were
supplemented by IMPACT
(Immunization Monitoring
Program ACTive), a pediatric hospital-based national
active surveillance network
for adverse events following
immunization.
The events reported had
temporal relationships to
vaccination but have not been
followed up to determine
causality, said Dr. Helen
Anyoti, a physician in the vaccine safety section of the Public Health Agency of Canada in
Ottawa. However, the data will
provide a baseline to assess any
changes once new strategies
for varicella immunization are
adopted across the country.
Combination vaccine
The National Advisory Committee on Immunization and
other groups have recommended a two-dose varicella
vaccination schedule, and
the use of the combination
measles-mumps-rubella-varicella (MMRV) vaccine. Only a
single-antigen varicella vaccine
was used during the study period, although sometimes at the
same time as MMR and other
vaccines were given. In other
words, MMRV was not used
during the period under investigation, Dr. Anyoti said.
A total of 5,568 adverse
50/500 mcg, 6%; fluticasone propionate 500 mcg, 6%; salmeterol 50 mcg, 1%; placebo, 1%).
3-year study: Study SCO30003 provided safety data on 6,184 patients with moderate to severe COPD
who were randomised and received at least one dose of study medication and treated for up to 3 years;
defined as the Safety population. The safety profile of ADVAIR® over the three-year treatment period was
comparable to that seen in previous studies of shorter duration, confirming the long-term tolerability of
ADVAIR®. All three active treatments were well tolerated and the adverse events reported were generally
those expected based on clinical experience with these treatments, with the exception of pneumonia.
The estimated 3 year probability of having pneumonia reported as an adverse event was 12.3% for
placebo, 13.3% for salmeterol, 18.3% for fluticasone propionate and 19.6% for ADVAIR® (Hazard ratio
for ADVAIR® vs placebo: 1.64, 95% CI: 1.33 to 2.01, p < 0.001). There was no increase in pneumonia
related deaths for ADVAIR®; deaths while on treatment that were adjudicated as primarily due to
pneumonia were 7 for placebo, 9 for salmeterol, 13 for fluticasone propionate and 8 for ADVAIR®. There
was no significant difference in probability of bone fracture (5.1% placebo, 5.1% salmeterol, 5.4%
fluticasone propionate and 6.3% ADVAIR®; Hazard ratio for ADVAIR® versus placebo: 1.22, 95% CI:
0.87 to 1.72, p=0.248). The incidence of adverse events of eye disorders, bone disorders, and HPA axis
disorders was low and there was no difference observed between treatments. There was no evidence of
an increase in cardiac events for ADVAIR®, salmeterol, and fluticasone propionate.
Post-Market Adverse Drug Reactions: There have been uncommon reports of cutaneous hypersensitivity
reactions. There have also been rare reports of hypersensitivity reactions manifesting as angioedema
(mainly facial and oropharyngeal edema), respiratory symptoms (dyspnea and/or bronchospasm) and
very rarely, anaphylactic reactions, anaphylactic shock.
There have been very rare reports of anxiety, sleep disorders and behavioural changes, including
hyperactivity and irritability (predominantly in children and adolescents). Very rarely, hyperglycemia
and hypertension have been reported.
Particularly with previous or concurrent use of systemic steroids (e.g., IV or oral), there have also been
very rare cases of osteonecrosis reported.
DRUG INTERACTIONS
Overview
Use ADVAIR® with caution in patients receiving other medications causing hypokalemia and/or
increased QTc interval (diuretics, high dose steroids, anti-arrhythmics, astemizole, terfenadine) since
cardiac and vascular effects may be potentiated.
Salmeterol Xinafoate: Co-administration of repeat dose ketoconazole (a cytochrome P450 3A4 inhibitor) and
salmeterol in healthy subjects resulted in a significant increase in plasma salmeterol exposure (1.4-fold
increase in Cmax and 15-fold increase in AUC). This increase in plasma salmeterol exposure may cause a
prolongation of the QTc interval.
Fluticasone Propionate: Under normal circumstances, low plasma concentrations of fluticasone propionate
are achieved after inhaled dosing, due to extensive first pass metabolism and high systemic clearance
mediated by cytochrome P450 3A4 in the gut and liver. Hence, clinically significant drug interactions involving
fluticasone propionate are unlikely.
A drug interaction study of intranasal fluticasone propionate in healthy subjects has shown that ritonavir (a
highly potent cytochrome P450 3A4 inhibitor) can greatly increase fluticasone propionate plasma
concentrations, resulting in markedly reduced serum cortisol concentrations. During post-marketing use,
there have been reports of clinically significant drug interactions in patients receiving intranasal or inhaled
fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome
and adrenal suppression. Therefore, concomitant use of fluticasone propionate and ritonavir should be
avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects.
This study has shown that other inhibitors of cytochrome P450 3A4 produce negligible (erythromycin) and
minor (ketoconazole) increases in systemic exposure to fluticasone propionate without notable reductions in
serum cortisol concentrations. However, there have been a few case reports during world-wide post-market
use of adrenal cortisol suppression associated with concomitant use of azole anti-fungals and inhaled
fluticasone propionate. Therefore, care is advised when co-administering potent cytochrome P450 3A4
inhibitors (e.g. ketoconazole) as there is potential for increased systemic exposure to fluticasone propionate.
regular use of a rapid onset, short duration (4 hour) inhaled or oral bronchodilator (e.g. salbutamol).
Rapid onset, short duration β2-agonists should be used only to relieve acute symptoms of asthma.
Patients should be regularly reassessed so that the strength of ADVAIR® they are receiving remains
optimal and is only changed on medical advice. The dose should be titrated to the lowest dose of
fluticasone propionate at which effective control of symptoms is maintained.
There is no need to adjust the dose in the otherwise healthy elderly or in patients with impaired renal
function. Because salmeterol is predominantly cleared by hepatic metabolism, patients with hepatic
disease should be closely monitored.
Recommended Dose and Dose Adjustment
Asthma
Asthma
ADVAIR
ADVAIR®®DISKUS
DISKUS®®: :
COPDCOPD
Children
4-11
Children
4-11
years
of of
ageage
years
Adults
andand
Adults
≥18≥18
Adults
Adults
adolescents
≥12≥12yearsyears
of age
adolescents
of age
years
of age
years
of age
inhalation
inhalation
OneOne
inhalation
twice OneOne
inhalation
OR OR
– –
twice daily
daily
twicetwice
dailydaily
inhalation One inhalation
One inhalationOR OR
OneOne
inhalation
––
twicetwice
dailydaily
twicetwice
dailydaily
inhalation One inhalation
One inhalation
OneOne
inhalation
––
twicetwice
dailydaily
twicetwice
dailydaily
ADVAIR®®100
100DISKUS
DISKUS®®
ADVAIR
250DISKUS
DISKUS®®
ADVAIR®®250
ADVAIR
500DISKUS
DISKUS®®
ADVAIR®®500
ADVAIR
ADVAIR®®Inhalation
InhalationAerosol:
Aerosol: Asthma
Asthma
ADVAIR
Adults
adolescents
≥12
years
Adults
andand
adolescents
≥12
years
of of
ageage
125
ADVAIR®®125
ADVAIR
250
ADVAIR®®250
ADVAIR
inhalations
twice
daily
TwoTwo
inhalations
twice
daily
inhalations
twice
daily
TwoTwo
inhalations
twice
daily
OR OR
It is intended that each prescribed dose of ADVAIR® Inhalation Aerosol be given by a minimum of two
inhalations twice daily. However, the prescribed dose of ADVAIR® DISKUS® may be given by a single
inhalation twice daily.
Use with Spacer Devices: Spacer devices may be used in patients who have difficulty coordinating
the actuation of a metered dose inhaler (MDI) with inhalation. The dosage of ADVAIR® inhalation
aerosol should be adjusted according to individual response. For patients whose asthma has been
stabilized without the use of a spacer device, continuation of therapy with a spacer may require a
dosage adjustment.
Two small single dose pharmacokinetic studies were conducted in subjects with asthma to investigate
the performance of various spacer devices. The studies showed that following the administration of
ADVAIR® inhalation aerosol, the exposure to both fluticasone propionate (FP) and salmeterol
xinafoate (SAL) was significantly higher (up to 4 fold) when used with the AeroChamber Max spacer,
compared to the MDI alone. Exposure to FP and SAL was also increased with the use of the
AeroChamber Plus and Ventahaler spacers, but to a lesser degree than that seen with the AeroChamber
Max spacer. The long term safety and clinical effect of using a spacer device with ADVAIR® inhalation
aerosol was not evaluated in these studies.
Missed Dose: If a single dose is missed, instruct the patient to take the next dose when it is due.
Administration: ADVAIR® is to be administered by oral inhalation only.
The patient should be made aware that for optimum benefit ADVAIR® should be taken regularly, even
when asymptomatic.
As a general rule, rinsing the mouth and gargling with water after each inhalation can help in preventing
the occurrence of candidiasis. Cleansing dentures has the same effect.
Adverse Reactions
Asthma:
1
) (Safety
Population)
Table 1:1: Number
Number(and
(andpercentage)
percentage)ofofpatients
patientswith
with
drug-related
adverse
events
(incidence
≥1)1%
drug-related
adverse
events
(incidence
≥ 1%
(Safety
Population)
Adverse
Adverseevents
events
Administration
Salmeterol
xinafoate
andand Fluticasone
Salmeterolxinafoate/
xinafoate/ Salmeterol
Salmeterol
xinafoate
FluticasoneSalmeterol
Salmeterol Placebo
Placebo
fluticasone
propionate
fluticasonepropionate
propionate Fluticasone
Fluticasone
propionate propionate
propionate xinafoate
xinafoate
combination
concurrent
therapy
alonealone
alonealone
combinationproduct
product
concurrent
therapy
Number
Numberof ofpatients
patients
Dosing Considerations: Long-acting β2-adrenergic agonists (LABA), such as salmeterol, one of the
active ingredients in ADVAIR® and ADVAIR® DISKUS®, increase the risk of asthma-related death.
Therefore, when treating patients with asthma, physicians should only prescribe ADVAIR® or ADVAIR®
DISKUS® for patients not adequately controlled on a long-term asthma control medication, such as an
inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an
inhaled corticosteroid and LABA.
Once asthma control is achieved and maintained, assess the patient at regular intervals and do not
use ADVAIR® or ADVAIR® DISKUS® for patients whose asthma can be adequately controlled on low or
medium dose inhaled corticosteroids.
ADVAIR® should not be used to treat acute symptoms of asthma or COPD. It is crucial to inform patients
of this. For asthma, a rapid onset, short duration β2-agonist should be prescribed for this purpose. Medical
attention should be sought if patients find that rapid onset, short duration relief bronchodilator treatment
becomes less effective or if they need more inhalations than usual. Sudden worsening of symptoms
may require increased corticosteroid dosage, which should be administered under medical supervision.
As twice-daily regular treatment, ADVAIR® provides twenty-four hour bronchodilation and can replace
644
644
486486
110(17(17%)%)
110
81 (17
81 (17
%) %)
Hoarseness/dysphonia
1515(2(2%)%)
11%)
(2 %)
11 (2
8 (2 8%)(2 %) 1 (<11 (<1
%) %)
Throatirritation
irritation
Throat
1414(2(2%)%)
10%)
(2 %)
10 (2
(<1 %)
8 (2 8%)(2 %) 1 (<11 (<1
%) %)1 (<11 %)
Candidiasisof ofmouth
mouthand
Candidiasis
and throat
throat
1515(2(2%)%)
(2 %)
9 (29%)
5 (1 5%)(1 %)
0
0
0
0
Headaches
Headaches
0
event
AnyAnyevent
339 339
180 180
175 175
50 %)
(15 %) 9 (5 %)
9 (5 %) 5 (3 %)
5 (3 %)
50 (15
0
0
1616(2(2%)%)
11%)
(2 %)
11 (2
3 (<1
3 (<1
%) %)
0
0
0
2 2
Asthma
Asthma
9 9(1(1%)%)
11%)
(2 %)
11 (2
3 (<1
3 (<1
%) %)
0
0
0
0
Palpitations
Palpitations
7 7(1(1%)%)
4 (<1
4 (<1
%) %)
2 (<1
1 (<1
2 (<1
%) %) 1 (<1
%) %)
0
0
Cough
Cough
(<1%)%)
6 6(<1
2 (<1
2 (<1
%) %)
5 (1 5%)(1 %) 1 (<11 (<1
%) %)
0
0
Breathingdisorders
disorders
Breathing
(<1%)%)
6 6(<1
2 (<1%)
2 (<1%)
4 (1 4%)(1 %)
0
0
0
0
CandidiasisCandidiasis-unspecified
siteunspecified site
(<1%)%)
6 6(<1
3 (<1
3 (<1
%) %)
4 (1 4%)(1 %)
0
0
Upperrespiratory
respiratorytract
tract
Upper
infection
infection
5 (<1%)%)
5 (<1
(1 %)
5 (15%)
2 (<1
2 (<1
%) %)
0
0
11
2
2 (1 %)
2 (1 %)
0
0
in any
any integrated
integratedtreatment
treatmentgroup;
group;2asthma
asthmawaswasnotnotrecorded
recorded
adverse
in those
studies
included
treatment
with salmeterol
in
as as
an an
adverse
eventevent
in those
studies
whichwhich
included
treatment
with salmeterol
xinafoate
aloneororplacebo
placebo(unless
(unlessit itwas
wasa serious
a seriousadverse
adverse
event)
xinafoate alone
event)
4
OCTOBER 9, 2012
53
CANADIAN PAEDIATRIC SOCIETY
Switching from codeine to morphine
in kids: It’s possible
Changing approach
requires constant
education and
engaging staff
early in the process
BY TERRY MURRAY
London, Ont.
Now, physicians in the
Northern Alberta Children’s
Cancer Program have success-
1
Table
with
drug-related
adverse
events
(incidence
≥ 1%≥1)1%
(Safety
Population)
Table 2:2: Number
Number(and
(andpercentage)
percentage)ofofpatients
patients
with
drug-related
adverse
events
(incidence
) (Safety
Population)
Adverse
Adverseevents
events
Number
Numberof ofpatients
patients
AnyAnyevent
event
Salmeterol
Fluticasone
Salmeterol
Salmeterolxinafoate/
xinafoate/
Fluticasone
Salmeterol
fluticasone
propionate
MDI propionate
alone
alonealone
fluticasone
propionate
propionate
alone xinafoate
xinafoate
combination
product
MDI combination product
622
614614
274 274
622
6767(11(11%)%)
71 (11
%) %)
29 (11
71 (11
29 %)
(11 %)
Throat
Throatirritation
irritation
Candidiasis
Candidiasisof ofmouth
mouth
andandthroat
throat
Headaches
Headaches
Cough
Cough
Placebo
Placebo
176 176
9 (5 %)
9 (5 %)
1313(2(2%)%)
1313(2(2%)%)
7 (17%)
(1 %)
14 (2
14%)
(2 %)
3 (2 3%)(2 %)
10 (410%)(4 %)
0 (0 %)
0 (0 %)
3 (2 %)
3 (2 %)
8 (1
8 (1%)%)
8 (18%)
(1 %)
0 (0 0%)(0 %)
1 (<11 %)
(<1 %)
1111(2(2%)%)
3 (<1
3 (<1%)%)
11 (2
11%)
(2 %)
3 (<1
%) %)
3 (<1
5 (2 5%)(2 %)
6 (2 6%)(2 %)
3 (2 %)
3 (2 %)
1 (<11 %)
(<1 %)
6 (1
6 (1%)%)
2 (<1
%) %)
2 (<1
1 (<1
%) %)
1 (<1
0 (0 %)
0 (0 %)
Hyposalivation
Hyposalivation
11
in any
dose
inhaler
any integrated
integratedtreatment
treatmentgroup;
group;MDI
MDI==metered
metered
dose
inhaler
COPD:
COPD:
®
® ® in patients
Table
incidence
in controlled
clinical
trialstrials
withwith
ADVAIR
DISKUS
with COPD
DISKUS® in patients
with COPD
Table 3:3:Overall
Overalladverse
adverseexperiences
experienceswith
with≥ ≥3%3%
incidence
in controlled
clinical
ADVAIR
Adverse
AdverseEvent
Event
AnyAnyevent
event
®®
ADVAIR
ADVAIR
®®
DISKUS
DISKUS
50/500
50/500mcg
mcg
(n(n==169)
169)
%%
® ®
ADVAIR
Fluticasone
ADVAIR
Fluticasone Fluticasone
Fluticasone Salmeterol
Salmeterol Placebo
Placebo
® ®
propionate
DISKUS
propionate propionate
propionate 50 mcg
(n = 576)
50 mcg (n = 576)
DISKUS
50/250
mcgmcg 500500
% %
mcgmcg
250 250
mcg mcg (n =(n341)
50/250
= 341)
178)
391)391) (n =(n399)
% %
(n (=
n=
178) (n =
= 399)
(n =
%%
%%
% %
7878
7070
80 80
74 74
68 68
69 69
Upper
Upperrespiratory
respiratory
tract
tractinfection
infection
1717
1212
18 18
16 16
11 11
15 15
Nasal
Nasalcongestion/
congestion/
blockage
blockage
44
33
7 7
4 4
4
4
3
Throat
Throatirritation
irritation
1111
88
9 9
9 9
7
7
6
6
Upper
Upperrespiratory
respiratory
inflammation
inflammation
99
22
7 7
5 5
5
5
5
5
Sinusitis
Sinusitis
33
33
3 3
6 6
4
4
2
2
Sinusitis/sinusinfection
Sinusitis/sinus
infection
44
22
2 2
2 2
1
1
2
2
1
1
Ear,
Ear,nose,
nose,and
andthroat
throat
33
55
5 5
5 5
Candidiasismouth/throat
mouth/
Candidiasis
throat
77
1010
12 12
6 6
2
2
<1 <1
88
66
9 9
5 5
5
5
4
3
<1 <1
Lowerrespiratory
respiratory
Lower
Viralrespiratory
respiratoryinfections
Viral
infections
4
4
2
2
Neurology
Neurology
33
44
2 2
2 2
4
Headaches
Headaches
1818
1616
17 17
13 13
14 14
Gastrointestinal
Gastrointestinal
Nausea& vomiting
& vomiting
Nausea
44
22
4 4
4 4
3
3
3
3
Non-sitespecific
specific
Non-site
Fever
Fever
44
44
3 3
3 3
1
1
3
3
44
88
33
33
3 3
2 2
3 3
2 2
2
2
3
3
3
3
1
1
44
1212
00
99
3 3
9 9
2 2
10 10
1
1
Musclecramps
cramps
Muscle
& spasms
& spasms
Musclepain
pain
Muscle
Musculoskeletalpain
pain
Musculoskeletal
12 12
The initial barriers that
were there diminished over
time and really . . . did not
hinder change.
—Dr. Mark Belletrutti
fully piloted a switch from
codeine to oral morphine, which
they reported to the recent
annual conference of the Canadian Paediatric Society here.
Publications since about
2008 have noted that approximately 30% of people are ultrarapid metabolizers of codeine
due to polymorphisms in the
cytochrome P450 isoenzyme
CYP2D6. This has resulted in
increased adverse effects, especially in children, including at
least two deaths, said Dr. Mark
Belletrutti. Adverse events have
been primarily reported in
patients receiving the drug after
tonsillectomy for sleep apnea.
Genetic testing for the
CYP2D6 polymorphism isn’t
commercially available, so at
least one pediatric hospital—
Toronto’s Hospital for Sick
Children—removed the drug
from its formulary.
But when physicians at
Stollery Children’s Hospital in
Edmonton began to explore
ways to eliminate codeine
use, they found no one had
reported details of their success, said Dr. Belletrutti, an
assistant professor of pediatric
hematology and oncology at

Dizziness
Dizziness
Musculoskeletal
Musculoskeletal
Malaise& fatigue
& fatigue
Malaise

For nearly five years, calls
have been growing to discontinue the use of codeine in
children, but there have been
no publications suggesting
how the drug can be successfully removed from a hospital
formulary.
11 11
<1 <1
10 10
Clinical Pearls
Diagnosing chronic cough in kids
ONE OF THE MOST COMMON referral
OVERDOSAGE
ADVAIR® should not be used more frequently than twice daily (morning and evening) at the recommended dose. Fatalities have been reported
in association with excessive use of inhaled sympathomimetic drugs. Large doses of inhaled or oral salmeterol (12 to 20 times the recommended
dose) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular
arrhythmias.
There are no data available from clinical trials on overdose with ADVAIR®, however data on overdose with individual drugs is given below.
The expected signs and symptoms of salmeterol overdosage are those typical of excessive beta2-adrenergic stimulation, including tremor,
headache, tachycardia, increases in systolic blood pressure, cardiac arrhythmias, hypokalemia, hypertension and, in extreme cases, sudden
death. Treatment should be symptomatic; cardiac and respiratory function should be monitored and support provided if necessary. The
preferred antidote is the judicious use of a cardioselective beta-blocking agent. Cardioselective beta-blocking drugs should be used with
caution, bearing in mind the danger of inducing an asthmatic attack. Serum potassium level should be monitored. If ADVAIR® therapy has to be
withdrawn due to overdose of the beta-agonist component of the drug; provision of appropriate replacement steroid therapy should be
considered.
Acute inhalation of fluticasone propionate doses in excess of those approved may lead to temporary suppression of the hypothalamic-pituitaryadrenal axis. This does not usually require emergency action, as normal adrenal function typically recovers within a few days.
If higher than approved doses are continued over prolonged periods, significant adrenocortical suppression is possible. There have been very
rare reports of acute adrenal crisis occurring in children exposed to higher than approved dosages (typically 1000 mcg daily and above), over
prolonged periods (several months or years); observed features included hypoglycemia and sequelae of decreased consciousness and/or
convulsions. Situations which would potentially trigger acute adrenal crisis include exposure to trauma, surgery or infection or any rapid
reduction in dosage. Patients receiving higher than approved dosages should be managed closely and the dose reduced gradually.
For management of a suspected drug overdose, contact your regional Poison Control Centre.
questions I get is for “the child with
The full Product Monograph is available at http://www.gsk.ca or by contacting:
GlaxoSmithKline Inc.
7333 Mississauga Road
Mississauga, Ontario L5N 6L4
1-800-387-7374
© 2011 GlaxoSmithKline Inc.
Date of revision: May 20, 2011.
sometimes associated with wheezing? Any of
84911
these suggest a diagnosis of asthma.
of the pharynx? These suggest chronic
sinusitis.
chronic cough.” The first step is to
• Paroxysms of cough, which can be
decide if the cough is truly chronic,
followed by facial plethora, a “whoop”
or whether it’s recurrent. Canadian
and/or vomiting, suggest pertussis.
kids can easily get eight to 12 colds
Pertussis is having a resurgence now.
per year, and it’s common for the
cough from one cold to practically blend
• In infants, or children who have
developmental delay, look for evidence
into the next. A chronic cough is usually defined
of gastroesophageal reflux, which can cause
as one lasting at least a month. Here are some
chronic cough.
clinical pearls for dealing with chronic cough
• A “Canada goose,” very forced “honking”
in children:
type of cough that goes away at night is typical
• Does the cough transiently improve with
of psychogenic cough.—Dr. Tom Kovesi,
bronchodilators, or improve after several weeks’
pediatric respirologist, Children’s Hospital
therapy with inhaled steroids? Is it at least
of Eastern Ontario in Ottawa.
• Is the cough associated with persistent nasal
5

the University of Alberta.
“Our hospital system is
structured in a way that removing codeine from the formulary
was not a practical or achievable goal,” he said. “We’re a
children’s hospital that’s integrated into the larger university
hospital system, so a complete
formulary removal was proving
to be quite difficult.”
But the Northern Alberta
Children’s Cancer Program,
a heavy prescriber of codeine
because use of acetaminophen
and ibuprofen is necessarily
limited in a cancer population,
volunteered to conduct a pilot
study on removal of the drug.
Within two months of instituting the change, the number
of patients for whom codeine
was prescribed dropped by
more than 91% (to three in
May 2011 from 35 children two
months before the change
in March that year), and the
number of doses prescribed
declined by more than 97% (to
seven from 249 doses during the
same time). By the end of a year,
codeine prescribing had been
eliminated, Dr. Belletrutti said.
“We felt the key to success was a well-planned,
multifaceted education and
implementation strategy,” he
said. “We engaged frontline
staff and prescribers early on
in the planning process, and
continued to engage them
throughout the process. We
had multiple forums of information available to explain
these issues to our families.
And just within our program
itself, we had a good, strong
presence of early adopters—
people who were innovative
and were change agents, which
helped the process and brought
everybody along in a comfortable fashion.”
A survey of health professionals in the program, done
before implementation and
after three and six months,
showed three factors were
initially seen as potential barriers to the change, but turned
out not to be problematic:
• the need for increased use
of Alberta’s triplicate prescription program;
• misconceptions by healthcare workers and parents about
the addictive potential and
potency of morphine; and
• during the transition, some
patients would still be using
codeine while others were
using morphine, which had
the potential for confusion,
especially among families.
“The initial barriers that were
there diminished over time and
really, in the grand scheme of
things, did not hinder change,”
Dr. Belletrutti said. MP
discharge, postnasal drip or cobblestoning
Want to share a clinical tip from your practice?
Please limit the submission to approximately 200
words and e-mail it to andrew.skelly@medicalpost.
rogers.com. We will pay for published pearls.

®
Buprenorphine transdermal delivery system
5 mcg/hr | 10 mcg/hr | 20 mcg/hr
Prescribing Summary
THERAPEUTIC CLASSIFICATION: Opioid Analgesic
INDICATIONS AND CLINICAL USE: Adults BuTrans® (buprenorphine transdermal patch) is indicated for:
• the management of persistent pain of moderate intensity in adults requiring continuous opioid analgesia for an extended period of time.
Geriatrics (> 65 years of age): In elderly patients, BuTrans® may have altered pharmacokinetics due to poor fat stores, muscle wasting or
altered clearance (see DOSAGE AND ADMINISTRATION). Therefore, it may be appropriate, according to clinical judgment, to initiate these
patients on the lowest available BuTrans® strength with dose titration to achieve satisfactory pain relief with acceptable side effects. Pediatrics
(< 18 years of age): The safety and efficacy of BuTrans® has not been studied in the pediatric population. Therefore, use of BuTrans® is
not indicated in patients under 18 years of age.
CONTRAINDICATIONS:
BuTrans® (buprenorphine transdermal patch) is contraindicated in:
• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing of
excipients, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph;
• Patients who have ileus of any type;
• Patients with suspected surgical abdomen (e.g., acute appendicitis or pancreatitis);
• Patients with mild, intermittent or short duration pain that can otherwise be managed;
• The management of acute pain, including use in out-patient or day surgeries;
• The management of peri-operative pain relief, or in other situations characterized by rapidly varying analgesic requirements (see WARNINGS
AND PRECAUTIONS,
Perioperative Considerations);
• Patients with acute asthma or other obstructive airway, and status asthmaticus;
• Patients with acute respiratory depression, elevated carbon dioxide levels in the blood, and cor pulmonale;
• Patients with acute alcoholism or alcohol dependence, delirium tremens, and convulsive disorders;
• Patients with severe CNS depression, increased cerebrospinal or intracranial pressure, and head injury;
• Patients taking monoamine oxidase (MAO) inhibitors (or within 14 days of such therapy);
• Women during pregnancy, labour and delivery or breast-feeding;
• Opioid dependent patients and for narcotic withdrawal treatment;
• Patients suffering from myasthenia gravis;
• Patients who have severe hepatic insufficiency.
Safety Information
General
BuTrans® (buprenorphine transdermal patch) should ONLY be prescribed to patients who require continuous opioids for pain
management. Initiation doses higher than the 5 mg patch should not be used in opioid naïve patients (see DOSAGE AND
ADMINISTRATION – Patients Not Already Taking Opioids [Opioid Naïve]). BuTrans® is not indicated for use in children under
18 years of age, as dosage requirements for the safe and efficacious use of BuTrans® have not been established for this patient
population. BuTrans® should only be prescribed by persons knowledgeable in the continuous administration of potent opioids,
in the management of patients receiving potent opioids for treatment of pain, and in the detection and management of respiratory
depression including the use of opioid antagonists. Since serum buprenorphine concentrations decline gradually after patch
removal (approximately 50% in 12 hours [range 10-24 h]), patients who have experienced serious adverse events should be
monitored for at least 24 hours after BuTrans® removal or until the adverse reaction has subsided. Due to the formation of a
subcutaneous depot of buprenorphine, not only does continued exposure occur after patch removal but, in the case of removal
prior to attainment of peak buprenorphine exposure, buprenorphine plasma levels may continue to increase after removal of
BuTrans® patches. As with other CNS depressants, patients who have received BuTrans® should be monitored especially for signs
of respiratory depression until a stable maintenance dose is reached. BuTrans® patches are intended for transdermal use on intact
skin only; use on compromised skin can lead to increased exposure to buprenorphine. Placing BuTrans® in the mouth, chewing
it, swallowing it, or using it in any way other than indicated may cause choking or overdose that could result in death.
Patients should be cautioned not to consume alcohol while using BuTrans® as it may increase the chance of experiencing dangerous side effects. Risk
of Unintentional Increase of Drug ExposurePatients with Fever:A pharmacokinetic study showed no alteration of buprenorphine plasma concentrations
in subjects with mild fever induced by endotoxin administration. However, because increased blood flow to the skin may enhance absorption, patients
with severe febrile illness should be monitored for side effects and may require dose adjustment. Application of External Heat: While wearing the
BuTrans® transdermal patch, patients should be advised to avoid exposing the BuTrans® site to external heat sources, such as heating pads, electric
blankets, heated water beds, heat or tanning lamps, hot water bottles, hot baths, saunas, hot whirlpool spa baths and sunbathing, as an increase in
absorption of buprenorphine may occur and result in serious medical consequences. Accidental Exposure to BuTrans®:Serious medical consequences,
including death, may occur if people are accidentally exposed to buprenorphine transdermal patch. Examples of accidental exposure include transfer
of a buprenorphine transdermal patch while hugging, sharing a bed, or moving a patient. Acute Abdominal Conditions As with other μ-opioid
receptor agonists, the administration of BuTrans® may obscure the diagnosis or clinical course in patients with acute abdominal conditions.
Cardiovascular Hypotensive Effects: BuTrans® should be administered with caution to patients at risk for hypotension. Buprenorphine, like other
opioids, may cause severe hypotension in patients with depleted blood volume or after agents acting on vasomotor tone such as phenothiazines or general
anesthetics. Patients receiving BuTrans® as their first around-the-clock opioid may be at increased risk of hypotension or orthostatic syncope, similar to
that seen with other opioids. Concomitant Use of CYP3A4 Inhibitors The concomitant use of BuTrans® with cytochrome P450 3A4 inhibitors such
as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, verapamil, diltiazem, amiodarone, amprenavir,
fosamprenavir, aprepitant, fluconazole, erythromycin and grapefruit juice may result in an increase in buprenorphine plasma concentrations, which could
increase dose related toxicity, including potential fatal respiratory depression. In this situation, special patient care and observation is appropriate (see
DRUG INTERACTIONS). Concomitant Use of CYP3A4 Inducers The interaction between buprenorphine and CYP3A4 enzyme inducers has not
been studied. Co-administration of BuTrans® and enzyme inducers (e.g., phenobarbital, carbamazepine, phenytoin, and rifampin) could lead to
increased clearance which might result in reduced efficacy. Dependence/ToleranceBuTrans® can produce drug dependence of the opiate type.
Diversion of buprenorphine has been reported. Buprenorphine is a partial μ-opioid agonist. Chronic use of buprenorphine can result in the
development of a limited degree of physical dependence. Withdrawal (abstinence syndrome), is generally mild, begins after two days and may last up
to two weeks. Reports of physical dependence and withdrawal syndrome with BuTrans® treatment are uncommon. BuTrans® should not be prescribed
for patients with known physical dependence on other opioids. Due to its antagonist component, BuTrans® may not substitute for other opioids in such
patients as it may precipitate an abstinence syndrome depending on the level of physical dependence, and the timing and dose of buprenorphine. Caution
should be exercised when prescribing BuTrans® to patients known to have, or suspected of having, problems with other drug or alcohol abuse or
serious mental illness. BuTrans® has no approved use in the management of addictive disorders. All buprenorphine products have some potential for
opioid abuse and dependence. However, reports of abuse with BuTrans® are uncommon. The development of addiction to opioid analgesics in properly
managed patients with pain has been reported to be uncommon, which is consistent with the clinical trial results and post-marketing experience for
BuTrans®. However, data are not available to establish the true incidence of addiction in chronic pain patients. Careful record-keeping of prescribing
information, including quantity, frequency, and renewal requests is strongly advised. Patients should be advised to properly store and dispose of the
product. Hepatic/Biliary/PancreaticBecause buprenorphine is extensively metabolized by the liver, the activity of BuTrans® may be increased and/or
extended in those individuals with impaired hepatic function or those receiving other agents known to decrease hepatic clearance. Patients with severe
hepatic impairment may accumulate buprenorphine during BuTrans® treatment. Consideration of alternate therapy should be given, and BuTrans®
should not be used in such patients (see Special Populations; Hepatic Impairment). Buprenorphine has been shown to increase intracholedochal
pressure, as do other opioids, and cause spasm of the Sphincter of Oddi and should be used with caution in patients with biliary tract disease, including
acute pancreatitis. Opioids may also cause an increase in serum amylase concentration. Immune Allergic Reactions: Cases of acute and chronic
hypersensitivity to buprenorphine have been reported in clinical trials in buprenorphine marketed products. The most common signs and symptoms
include rashes, hives and pruritus. Cases of bronchospasm, angioneurotic edema and anaphylactic shock have also been reported. A history of
hypersensitivity to buprenorphine or any component of the formulation is a contraindication to BuTrans® use. Application Site Skin Reactions In
rare cases, severe application site skin reactions with signs of marked inflammation including “burn,” “discharge,” and “vesicles”
have occurred. Time of onset varies, ranging from days to months following the initiation of BuTrans treatment. Instruct patients
to promptly report the development of severe application site reactions and to discontinue therapy.
Neurologic Interaction with Other Central Nervous System Depressants: Buprenorphine, like all opioid analgesics, should be dosed
with caution in patients who are concurrently taking other CNS depressants that may cause respiratory depression, hypotension, profound
sedation, or may potentially result in coma or death. Such agents include alcohol, antihistamines, antipsychotics, benzodiazepines, centrally acting
anti-emetics, general anaesthetics, other opioid analgesics, phenothiazines and sedatives or hypnotics. When such combined therapy is
contemplated, a substantial reduction in the dose of one or both agents should be considered and patients carefully monitored (see DRUG
INTERACTIONS). Head Injury and Increased Intracranial Pressure: BuTrans® should not be used in patients who may be particularly
susceptible to the intracranial effects of CO2 retention such as those with evidence of increased intracranial pressure, impaired consciousness, shock,
or coma. Respiratory depression may be exacerbated in the presence of head injury, intracranial lesions (e.g., space occupying tumours) or
increased intracranial pressure. Pupillary responses and effects on consciousness resulting from buprenorphine may mask neurologic signs of
increasing intracranial pressure. Opioids may obscure the clinical course of patients with head injury.
Opiate Withdrawal Effects Buprenorphine is a partial agonist at the µ-opioid receptor and chronic administration produces
dependence of the opiate type, characterized by withdrawal upon abrupt discontinuation or rapid taper. The withdrawal
syndrome is generally milder than seen with full agonists and may be delayed in onset.
Peri-operative Considerations BuTrans® is contraindicated for peri-operative pain relief, or in other situations characterized by rapidly varying
analgesic requirements. In the case of planned chordotomy or other pain-relieving operations, patients should not be treated with BuTrans®
for at least 48 hours before the operation and BuTrans® should not be used in the immediate post-operative period. Thereafter, if BuTrans®
is to be continued after the patient recovers from the post-operative period, a new dosage should be administered in accordance with the
changed need for pain relief. The risk of withdrawal in opioid-tolerant patients should be addressed as clinically indicated (see Opiate
Withdrawal Effects). The administration of analgesics in the peri-operative period should be managed by healthcare providers with adequate
training and experience (e.g., by an anesthesiologist) (see CONTRAINDICATIONS). Potential for Abuse and Diversion BuTrans®
patches contain a large amount of a potent opioid, buprenorphine, which along with other opioids has potential for abuse and associated risk
of fatal overdose due to respiratory depression. The high buprenorphine content in BuTrans® patches may be a target for abuse and diversion,
with alternative routes of administration potentially resulting in overdose due to uncontrolled delivery of the opioid. This risk should be considered
when prescribing or dispensing BuTrans® in situations where the healthcare professional is concerned about increased risk of misuse, abuse
or diversion. Concerns about abuse, addiction and diversion should not prevent the proper management of pain. Patients should be assessed
for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients receiving opioids should be routinely monitored
for signs of misuse and abuse. Since BuTrans® may be diverted for non-medical use, careful record keeping of prescribing information,
including quantity, frequency, and renewal requests, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic
re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs (see
Dependence/Tolerance). Psychomotor Impairment Opioid analgesics, including buprenorphine, can have a depressant effect on mental
and/or physical responses. Caution must be exercised in activities requiring mental alertness such as driving a car or operating heavy machinery,
especially when doses are being adjusted or when other CNS active drugs are being added to the treatment regimen. This impairment may be
potentiated by concomitant depressant medications such as other opioids, phenothiazines, alcohol, sedatives, hypnotics, or other CNS depressants.
Patients using BuTrans® should not drive or operate dangerous machinery unless they are tolerant to the effects of the drug. Respiratory
Depression As with other potent opioids, clinically significant respiratory depression may occur in patients receiving buprenorphine. Some cases
of death due to respiratory depression have been reported, particularly when addicts have intravenously abused buprenorphine, usually in
combination with benzodiazepines, or with concomitant administration of buprenorphine with other depressants such as alcohol or other
opioids. Opioids, including buprenorphine, should be used with caution in patients with compromised respiratory function (e.g., chronic
obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia or pre-existing respiratory depression), in
the elderly and in debilitated patients. Particular caution is advised if BuTrans® is to be administered to patients taking, or recently receiving,
drugs with CNS/respiratory depressant effects. IN THE CASE OF OVERDOSE, THE PRIMARY MANAGEMENT SHOULD BE THE
REESTABLISHMENT OF ADEQUATE VENTILATION WITH MECHANICAL ASSISTANCE OF RESPIRATION, IF REQUIRED.
NALOXONE MAY NOT BE EFFECTIVE IN REVERSING ANY RESPIRATORY DEPRESSION PRODUCED BY BUPRENORPHINE
(see OVERDOSAGE). Respiratory depression is a risk of starting opioid agonist medications, especially in elderly, debilitated patients.
Respiratory depression usually follows large initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents
that depress respiration. Although BuTrans® is a partial opioid agonist, buprenorphine may cause hypoventilation at analgesic doses, especially
in patients who have an underlying pulmonary condition or who receive usual doses of opioids or other CNS drugs associated with hypoventilation
in addition to BuTrans® (see DRUG INTERACTIONS regarding the use of concomitant CNS active drugs). Comparative effects of BuTrans®
have not been evaluated, but in clinical trials (up to doses of BuTrans® 40 mcg/hr), respiratory failure was reported as a rare adverse event
(i.e., <0.1%, but at least in more than 1 patient [see ADVERSE REACTIONS]). If respiratory depression from BuTrans® occurs, it may persist
beyond the removal of the patch. Patients with hypoventilation should be observed for at least several hours and until their respiratory rate
has recovered. In patients with respiratory depression, symptomatic treatment following standard intensive care measures should be instituted
(see OVERDOSAGE). Use in Patients with Chronic Pulmonary Disease: Buprenorphine should be used with caution in patients with
chronic pulmonary disease, patients with decreased respiratory reserve and others with potentially compromised respiration. Normal analgesic
doses of opioids may further decrease respiratory drive in these patients to the point of respiratory failure.
Special Populations Special Risk Groups: Use of BuTrans®, like all opioid analgesics, is associated with increased potential risks and should
be used only with caution in the following conditions: adrenocortical insufficiency (e.g., Addison’s disease); CNS depression or coma; high-risk
debilitated patients; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture and toxic psychosis. The administration of
buprenorphine, like other opioid analgesics, may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Buprenorphine
may aggravate convulsions in patients with convulsive disorders and may induce or aggravate seizures in some clinical settings. Pregnant
Women: There is no data from the use of BuTrans® in pregnant women. Rodent studies with some opioids, including buprenorphine, have
indicated the possibility of embryotoxic effects. In humans, it is not known whether buprenorphine can cause fetal harm when administered during
pregnancy or can affect reproductive capacity. Towards the end of pregnancy high oral doses of buprenorphine may induce respiratory depression
in the neonate even after a short period of administration. Long-term administration of buprenorphine during the last three months of pregnancy
may cause a withdrawal syndrome in the neonate. Buprenorphine crosses the placental barrier and has been detected in newborn blood, urine
and meconium. BuTrans® should not be used during pregnancy or in women of childbearing potential who are not using effective contraception.
(see CONTRAINDICATIONS). Labour and Delivery:The safety of BuTrans® given during labour and delivery has not been established. (see
CONTRAINDICATIONS). Nursing Women: Buprenorphine has been detected in low concentrations in human milk, thus nursing mothers
treated with BuTrans® should not breast-feed or the use of BuTrans® during lactation should be avoided. (see CONTRAINDICATIONS).
Gender: No differences in plasma buprenorphine concentrations were detected between males and females treated with BuTrans®. Geriatrics
(> 65 years of age): The pharmacokinetic profile of BuTrans® is similar in healthy elderly and younger adult subjects. Elderly subjects trended
toward higher plasma concentrations of buprenorphine immediately after removal of BuTrans®. In a pharmacokinetic study in healthy volunteers,
mean plasma concentrations changed from 88.11 pg/mL at the time of patch removal at steady state to a peak of 90.77 pg/mL one hour after
patch removal in younger adults (n=12). By three hours after patch removal, mean plasma levels had declined to less than 88.11 pg/mL (i.e.,
73.76 pg/mL). Mean plasma concentrations in healthy elderly adults (n=12) changed from 90.68 pg/mL at patch removal to a peak of
99.56 pg/mL 12 hours after patch removal. By 18 hours after patch removal, mean plasma concentrations had declined to less than 90.68 pg/mL
(i.e., 84.18 pg/mL) in healthy elderly adults. Both groups subsequently eliminated buprenorphine at similar rates. In a safety study evaluating
the recommended dose-escalation schedule, the pharmacokinetics in healthy elderly were similar to healthy younger adults. Pediatrics (< 18
years of age): BuTrans® has not been studied in children and is not indicated for patients less than 18 years of age. The safety and efficacy of
BuTrans® in children have not been established. Renal Impairment: A pharmacokinetic study showed that pharmacokinetic parameters for
buprenorphine were similar in patients with severe renal impairment compared with normal adults. This study confirmed with multiple-dose use,
that the accumulation of buprenorphine metabolites did not decrease the clearance of the parent molecule in chronic use. Therefore, no special
dose adjustment of buprenorphine is necessary in patients with renal impairment. Hepatic Impairment: In a pharmacokinetic study utilizing
intravenous buprenorphine, there were no differences in clearance of buprenorphine between mild to moderate hepatically impaired subjects
relative to healthy adult subjects. These data show no need for dosage adjustment when using BuTrans® in patients with mild to moderate
hepatic impairment. Patients with severe hepatic impairment may accumulate buprenorphine during BuTrans® treatment. Consideration of
alternate therapy should be given, and BuTrans® should not be used in such patients.
ADVERSE REACTIONS: Adverse Drug Reaction Overview Serious adverse drug reactions which may be associated with BuTrans®
(buprenorphine transdermal patch) therapy in clinical use are those observed with other opioid analgesics, including respiratory depression
(especially when used with other CNS depressants) and hypotension. Care must be exercised when using BuTrans® in patients who are using
benzodiazepines or other agents with CNS activity. The adverse drug reactions seen on initiation of therapy with BuTrans® in clinical studies
are those often observed with other opioid analgesics (nausea, vomiting, dizziness, somnolence, constipation, pruritus and dry mouth). The
frequency of these events depends on the dose, the clinical setting, the patient’s level of opioid tolerance, and factors specific to the individual.
They should be expected and managed as part of opioid analgesic therapy. The most common adverse effects in six randomized titrationto-effect placebo-controlled clinical trials with BuTrans® were anorexia, application site erythema, application site reactions, asthenia,
constipation, dizziness, dry mouth, headache, hyperhidrosis, insomnia, nausea, somnolence and vomiting. Opioid-agonist related adverse
events tend to reduce over time, except for constipation. Clinical Trial Adverse Drug Reactions The stated frequencies of adverse events
represent the proportion of individuals who experienced at least once, a treatment-emergent adverse event regardless of causality. An event
was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
This document plus the full product monograph, prepared for health professionals can be found at: http://www.purdue.ca/products or by
contacting the manufacturer, Purdue Pharma, at: 1-800-387-5349.
Adverse events ≥ 1% for parallel-design titration-to-effect clinical trials
% of patients on BuTrans® (n=392)/ % of patients on placebo (n=261): Ear and labyrinth disorders: tinnitus: 1.3/0.4. Eye disorders: vision
blurred: 1.5/0.4. Gastrointestinal disorders: constipation: 13.5/5.4; diarrhea: 3.1/1.9; dry mouth: 7.1/1.5; nausea: 22.7/7.7; stomach
discomfort: 2.0/1.1; vomiting: 11.2/1.5. General disorders and administration site conditions: application site erythema: 7.1/1.5; application
site pain: 1.5/0.8; application site pruritus: 15.1/11.9; application site vesicles: 1.0/0; asthenia: 1.3/1.1; fatigue: 5.1/1.1; pain: 1.5/1.5; peripheral
edema: 7.4/3.4; pyrexia: 1.5/0.4. Infections and infestations: influenza: 1.3/0.4; sinusitis: 1.0/0.4; urinary tract infection: 2.6/2.3. Injury,
poisoning and procedural complications: fall: 3.8/1.5; skin laceration: 1.3/1.1. Investigations: blood pressure increased: 1.0/0.4.
Metabolism and nutrition disorders: anorexia: 2.0/0.8. Musculoskeletal and connective tissue disorders: arthralgia: 2.0/1.9; back
pain: 2.6/1.5; joint swelling: 2.6/0.8; muscle spasms: 1.3/0.8; muscular weakness: 1.0/0.4; pain in extremity: 2.8/2.3. Nervous system
disorders: dizziness: 16.3/7.7; headache: 16.1/11.5; hypoesthesia: 2.3/0.8; migraine: 1.0/0.8; paraesthesia: 2.0/0.8; tremor: 2.0/0.4;
somnolence: 13.5/4.6. Psychiatric disorders: agitation: 1.0/0.0; anxiety: 1.8/0.8; depression: 1.3/0.8; disorientation: 1.0/0.4; insomnia:
2.8/1.9; nervousness: 1.0/0.4. Respiratory, thoracic and mediastinal disorders: cough: 1.3/0.4; dyspnea: 2.8/1.1. Skin and subcutaneous
tissue disorders: hyperhidrosis: 4.3/1.1; pruritus: 4.1/0.8; pruritus generalized: 1.5/0.8; rash: 2.0/1.1.
Adverse events ≥1% for crossover-design titration-to-effect clinical trials
% of patients on BuTrans® (n= 146)/ % of patients on placebo (n=133): Cardiac disorders: palpitations: 3.4/0.8. Ear and labyrinth
disorders: tinnitus: 1.4/0; vertigo: 1.4/0. Gastrointestinal disorders: abdominal pain upper: 3.4/2.3; constipation: 21.9/ 13.5; dry mouth:
10.3/1.5; gastroesophageal reflux disease: 1.4/0.0; nausea: 45.9/18.0; vomiting: 18.5/4.5. General disorders and administration site
conditions: application site bruising: 1.4/0; application site pain: 2.1/1.5; application site pruritus: 25.3/24.8; application site rash: 3.4/3.0;
asthenia: 12.3/8.3; fatigue: 9.6/3.0; influenza-like illness: 2.1/0; peripheral edema: 8.9/0. Immune system disorders: urticaria: 1.4/0.
Infections and infestations: influenza: 2.1/1.5; urinary tract infection: 2.1/0. Metabolism and nutrition disorders: anorexia: 13.0/11.
Musculoskeletal and connective tissue disorders: Musculoskeletal stiffness: 1.4/0.8; myalgia: 2.1/0. Nervous system disorders:
dizziness: 27.4/6.0; headache: 11.6/6.0; migraine: 2.7/1.5; paraesthesia: 1.4/0.8; somnolence: 24.0/6.0; tremor: 4.1/2. Psychiatric
disorders: agitation: 2.7/1.5; anxiety: 2.1/0.8; nightmare: 1.4/0.8. Skin and subcutaneous tissue disorders: erythema: 1.4/0;
hyperhidrosis: 16.4/9.0; pruritus: 1.4/0. Surgical and medical procedures: endodontic procedure: 1.4/0.
Vascular disorders: hot flush: 4.1/1.5.
Adverse events ≥ 1% for patients shown to be tolerant and responsive to a BuTrans® (5 – 20
mcg/h) patch during a run-in period of 3 weeks maximum, prior to randomization % of patients on
BuTrans® (n=164)/ % of patients on placebo (n=162): Gastrointestinal disorders: abdominal pain; 1.2/0;
constipation: 7.1/5.2; diarrhea: 1.5/1.5; dry mouth: 2.8/2.1; nausea: 8.9/8.9; vomiting: 2.1/0.9. General
disorders and administration site conditions: application site erythema: 3.1/1.5; application site pruritus:
4.6/3.4; application site rash: 2.1/0.6; fatigue: 2.5/1.5; peripheral edema: 3.4/0.6. Infections and infestations:
urinary tract infection: 1.2/0.3. Musculoskeletal and connective tissue disorders: back pain: 2.5/2.1; pain
in extremity: 1.2/1.2. Nervous system disorders: dizziness: 6.1/3.7. Psychiatric disorders: anxiety: 1.2/0.3.
In clinical trials in which BuTrans® was compared to active controls, expected opioid effects (nausea, vomiting, dry
mouth, pruritus, dizziness, somnolence), on initiation of therapy in non-tolerant individuals, reached their maximum
1 - 2 days after BuTrans® application and usually decreased with continued use.
Less Common Clinical Trial Adverse Drug Reactions (< 1%): Other less common (< 1%) adverse drug
reactions reported and considered in any way related to BuTrans® in randomized clinical trials are summarized
in the Product Monograph (see Adverse Reactions section in the Product Monograph).
DRUG INTERACTIONS Overview Additive Effects of Other CNS Depressants: BuTrans® (buprenorphine
transdermal patch) should be dosed with caution in patients who are currently taking other CNS depressants or other
drugs that may cause respiratory depression, hypotension, profound sedation, or may potentially result in coma. Such
agents include alcohol, antihistamines, antipsychotics, anxiolytics, barbiturates, benzodiazepines, centrally acting antiemetics, clonidine and related substances, general anaesthetics, neuroleptics, other opioid derivatives (analgesic and
antitussive), phenothiazines and sedatives or hypnotics. When such combined therapy is contemplated, a substantial
reduction in the dose of one or both agents should be considered and patients carefully monitored (see WARNINGS
AND PRECAUTIONS, Neurologic – Interaction with Other Central Nervous System Depressants). Patients
should also be warned that these combinations increase central nervous system depression and can make driving
vehicles and operating machinery hazardous (see WARNINGS AND PRECAUTIONS, Psychomotor Impairment).
Drug-Drug Interactions CYP 3A4 Inhibitors: Buprenorphine is primarily metabolized by glucuronidation and to
a lesser extent (about 30%) by CYP3A4. Concomitant treatment with CYP3A4 inhibitors (e.g., ritonavir, ketoconazole,
itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, verapamil, diltiazem, amiodarone, amprenavir,
fosamprenavir, aprepitant, fluconazole, erythromycin and grapefruit juice) may lead to elevated plasma concentrations
with an increase in dose related toxicity of buprenorphine including potentially fatal respiratory depression (see
WARNINGS AND PRECAUTIONS, Concomitant Use of CYP3A4 Inhibitors). The interaction between
buprenorphine and CYP3A4 enzyme inducers has not been studied. Co-administration of BuTrans® and enzyme
inducers (e.g., phenobarbital, carbamazepine, phenytoin, and rifampin) could lead to increased clearance which might
result in reduced efficacy. MAO Inhibitors: MAO inhibitors intensify the effects of opioid drugs which can cause
anxiety, confusion and decreased respiration. Buprenorphine is contraindicated in patients receiving MAO inhibitors or
who have used them within the previous 14 days (see CONTRAINDICATIONS, WARNINGS AND
PRECAUTIONS). Warfarin: The potential may exist for INR elevation in patients who are concomitantly taking
warfarin. Anesthetics: Reductions in hepatic blood flow induced by some general anesthetics (e.g., halothane) and
other drugs may result in a decreased rate of hepatic elimination of buprenorphine. Flunitrazepam: Deaths have been
reported in the addict population when buprenorphine was coadministered with flunitrazepam. This adverse drug
interaction cannot be explained by a pharmacokinetic drug-drug interaction. Caution must be exercised with the
combined use of buprenorphine and flunitrazepam and a dosage reduction in one or both drugs should be considered.
Drug-Herb Interactions Interactions with herbal products have not been established. Drug-Laboratory Interactions
Interactions with laboratory tests have not been established.
Administration
DOSAGE AND ADMINISTRATION:
General
BuTrans® (buprenorphine transdermal patch) should only be prescribed by persons knowledgeable in
the continuous administration of potent opioids, in the management of patients receiving potent opioids
for treatment of pain, and in the detection and management of respiratory depression including the use
of opioid antagonists. Dosing Considerations BuTrans® is intended to be used for the continual release of
buprenorphine transdermally over a 7-day period per patch, for the management of persistent pain of moderate
intensity. BuTrans® can be used in either opioid naïve patients or patients previously treated with PRN (as needed)
analgesics when the analgesic requirement has progressed to a need for continuous opioid analgesia. BuTrans® doses
must be individualized based upon the status of each patient and should be assessed at regular intervals after application.
Proper optimization of doses scaled to the relief of the individual’s pain should aim at the regular administration of
the lowest dose of BuTrans® which provides pain relief with acceptable side effects. The dosage of the drug must be
individualized according to the response and tolerance of the patient. An important factor to be considered in determining
the appropriate dose is the extent of pre-existing opioid tolerance (see Conversion from Opioid or Fixed-Ratio
Opioid/Non-Opioid Combination Drugs). Initiation on the lowest available strength of BuTrans® with appropriate
dose titration is suggested for the elderly and other groups discussed in WARNINGS AND PRECAUTIONS. The patch
should be worn for 7 days continuously before changing to a new patch at the same dose. A new skin area should be
selected when changing to a new patch. After the patch is removed, a 3-week interval is required before the same area
can be re-used. When returning to a previously used area, after at least 3 weeks, a different skin site should be used
if possible. (See PART III: CONSUMER INFORMATION – PROPER USE OF THIS MEDICATION– Where to
apply BuTrans® in the product monograph). BuTrans® should not be used in individuals less than 40 kg in
weight. BuTrans® may have altered pharmacokinetics due to poor fat stores, muscle wasting or altered clearance. Opioid
analgesics may be only partially effective in relieving dysesthetic pain, postherpetic neuralgia, stabbing pains, activityrelated pain and some forms of headache. That is not to say that patients with these types of pain should not be given
an adequate trial of opioid analgesics, but it may be necessary to refer such patients at an early time to other forms of
pain therapy. BuTrans® has potential for abuse and diversion (see WARNINGS AND PRECAUTIONS).
Initial BuTrans Dose Selection BuTrans® is designed to allow for once weekly dosing, i.e., dosing every 7 days.
Treatment with BuTrans® should generally be initiated at the lowest available dose (BuTrans® 5).
Patients Not Already Taking Opioids (Opioid-Naïve) In situations when it is clinically indicated to initiate opioid
therapy with a maintenance (around-the-clock) opioid in an opioid naïve patient, clinical trials have shown that such
patients may successfully initiate opioid therapy with BuTrans®. The lowest dose available (BuTrans® 5) should
always be used as the initial dose and titrated as required. If the patient requires rescue medication, see
Management of Patients Requiring Rescue Medication section. Conversion from Opioid or Fixed-Ratio
Opioid/Non-Opioid Combination Drugs BuTrans® has been studied as an alternative opioid analgesic in patients
taking up to 80 mg of oral morphine-equivalents a day. Such patients should be started on BuTrans® 5 or
BuTrans® 10 and be provided with adequate rescue medication and titrated as required (see Management
of Patients Requiring Rescue Medication).Patch ApplicationBuTrans® should be applied to non-irritated, intact
skin of the upper outer arm, upper chest, upper back or the side of the chest. BuTrans® should be applied to a relatively
hairless or nearly hairless skin site. If none are available, the hair at the site should be clipped, not shaven. Application
should be rotated to a different area whenever a patch is replaced or added. Application areas should be re-used at no
less than 3-week intervals (See PART III: CONSUMER INFORMATION – PROPER USE OF THIS MEDICATION
– Where to applyBuTrans® in the product monograph). If the application site must be cleaned, it should be done
with clear water only. Soaps, alcohol, oils, lotions or abrasive devices must not be used. The skin site must be dry before
the patch is applied. BuTrans® should be immediately applied after removal from the sealed pouch. Following removal
of the protective layer, the transdermal patch should be pressed firmly in place with the palm of the hand for approximately
30 seconds, making sure the contact is complete, especially around the edges. If the edges of the patch begin to peel off,
the edge may be taped down with suitable skin tape. Bathing, showering or swimming should not affect the patch. While
wearing BuTrans®, patients should be advised to avoid exposing the patch site to direct external heat sources (see
WARNINGS AND PRECAUTIONS). Dose TitrationProper optimization of doses scaled to the relief of the individual's
pain should aim at regular administration of the lowest dose of controlled release buprenorphine (BuTrans®) which will
achieve the overall treatment goal of satisfactory pain relief with acceptable side effects. On average, steady-state blood
levels are achieved after 3 days. It is recommended that doses of BuTrans® be slowly titrated – with dosage
adjustment generally separated by 7 days. The dose of BuTrans® should not be increased before 3 days
as the plasma concentrations continue to increase following application. Subsequent increases of BuTrans®
dosage must be individualized according to the pain relief and tolerance of the patient with adequate rescue
medication, as required (see Management of Patients Requiring Rescue Medication). If pain repeatedly
occurs at the end of the dosing interval it is generally an indication for a dosage increase rather than more frequent
administration of controlled release buprenorphine (BuTrans®). The maximum recommended patch dose is 20
mcg/h every 7 days. To increase the dose, the patch that is currently being worn should be removed, disposed of
properly, and the next higher strength of BuTrans® should be used. Application areas should be rotated whenever a patch
is replaced or added. Application sites should be re-used at no less than 3-week intervals. It is recommended that no more
than two patches be applied at the same time (See PART III: CONSUMER INFORMATION – PROPER USE OF
THIS MEDICATION – Where to apply BuTrans® in the product monograph). No change in dose titration is
required in patients with renal impairment or mild to moderate hepatic impairment. Patients with severe hepatic
impairment may accumulate buprenorphine and BuTrans® should not be used in such patients. Management of
Patients Requiring Rescue Medication During initiation, titration, and treatment with BuTrans, patients may
continue their existing NSAID or acetaminophen regimen as needed. In clinical trials with BuTrans®, acetaminophen
and acetaminophen with codeine combinations were used as rescue medications. If episodes of pain are encountered
with appropriate adjustments of the BuTrans® dose, fentanyl products should not be used as rescue medication in
patients taking BuTrans®. Selection of rescue medication should be based on individual patient conditions. For
patients whose dose has been titrated to the recommended maintenance dose, without attainment of adequate
analgesia, the total daily dose may be increased, unless precluded by side effects. If dose limiting adverse events occur
before the therapeutic goal of mild or no pain is achieved, the events should be treated with appropriate medications
such as laxatives or anti-nauseants. Once adverse events are under control, upward titration should continue to an
acceptable level of pain control. If adequate pain control cannot be achieved with the maximum patch dose of
BuTrans® 20 mcg/h every 7 days, the patient should be converted to an alternative around-the-clock μ-opioid
agonist, and the dose of the alternative analgesic further titrated, as appropriate. Managing Expected Opioid
Adverse Experiences Many patients receiving opioids, especially those who are opioid naïve, will experience side
effects. Clinical trials have shown that these effects are most bothersome during the initial application and can be
minimized by starting at BuTrans® 5 and gradually increasing the dose as needed. Although the side effects from
BuTrans® are often transient, some may require treatment. Adverse events such as constipation should be anticipated
and treated with a stimulant laxative and/or stool softener. Patients do not usually become tolerant to the constipating
effects of opioids. Other opioid related side effects such as sedation and nausea are usually self-limited and often do
not persist beyond the first few days. If nausea persists and is unacceptable to the patient, treatment with anti-emetics
or other modalities may relieve these symptoms and should be considered. Discontinuation of BuTrans Therapy
After removal of BuTrans®, plasma concentrations decrease gradually, and the analgesic effect is maintained for a
certain amount of time. This needs to be considered when use of BuTrans® is to be followed by other opioids. As a
general rule, a subsequent opioid should not be administered within 24 hours of removal of a BuTrans® patch. As
part of an overall strategy to suitably manage pain in this period, the use of appropriate rescue medication and/or
careful monitoring during this time should be considered. Buprenorphine concentrations decline, decreasing
approximately 50% in 12 hours (range 10-24 h). Safety and HandlingThe buprenorphine contained in BuTrans®
is supplied in sealed transdermal patches. If the adhesive from the drug accidentally contacts the skin other than
intended application site, the area should be washed with water. Do not use soap, alcohol or other solvents to remove
the adhesive because they may enhance the absorption of the drug. When changing the patch, remove the used
BuTrans® patch, fold it over itself, and discard it (flush down the toilet or consult with a pharmacist about other
disposal options). OVERDOSAGE (see Supplemental Product Information)For management of suspected
drug overdose, contact your Regional Poison Control Centre.
Study References
1. BuTrans® product monograph, Purdue Pharma, March 2012.
2. Purdue Pharma, March 24, 2010.
Supplemental Product Information
Information for Physicians to Convey to Patients
A patient information sheet is included in the package of BuTrans® patches dispensed to the patient.
Patients receiving BuTrans® patches should be given the following instructions by the physician:
1. Patients should be informed that accidental ingestion or use by individuals (including children) other than the patient for whom it was originally
prescribed, may lead to severe, even fatal, consequences.
2. Patients should be advised that BuTrans® patches contain buprenorphine, an opioid pain medicine.
3. Patients should be advised that each BuTrans® patch should be worn continuously for 7 days. After 7 days, the old patch should be removed prior to
applying a new patch.
4. Patients should be advised to wear only 1 patch at a time, unless a 15 mcg/h dosage is prescribed, requiring the use of 2 patches simultaneously (1
patch of 10 mcg/h and 1 patch of 5 mcg/h).
5. Patients should be advised that the application area should be rotated whenever a patch is replaced. A 3-week interval is required before the same area
can be re-used as a strategy to prevent skin irritation and/or reduce the potential for increased drug absorption. After 3 weeks, when returning to a
previously used area, patients should vary the skin site used within the area if possible.
6. Patients should be advised that BuTrans® patches should be applied to intact, non-irritated and non-irradiated skin on a flat surface such as the upper
chest, upper back, side of chest, or upper outer arm. Additionally, patients should be advised of the following:
➢ If BuTrans® is part of an overall strategy to suitably manage pain in patients with cognitive impairment, the potential of each patient to remove
the patch(es) and place them in the mouth or on others should be considered when recommending rotation sites;
➢ Hair at the application site should be clipped (not shaved) prior to patch application;
➢ If the site of BuTrans® application must be cleansed prior to application of the patch, do so with clear water;
➢ Allow the skin to dry completely prior to patch application;
➢ Do not use soaps, oils, lotions, alcohol, or any other agents that may irritate the skin or alter its characteristics.
7. Patients should be advised that BuTrans® should be applied immediately upon removal from the sealed package and after removal of the protective
liner.
Additionally, patients should be advised of the following:
➢ The BuTrans® patch should not be used if the seal is broken, or if it is altered, cut, or damaged in any way prior to application. The transdermal
patch should be pressed firmly in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges;
➢ The patch should not be folded.
8. Patients should be advised that while wearing the patch, they should avoid exposing the BuTrans® application site to direct external heat sources, such
as:
➢ heating pads;
➢ electric blankets;
➢ heat lamps;
➢ saunas;
➢ hot tubs;
➢ heated water beds.
9. Patients should be advised that there is a potential for temperature-dependent increase in buprenorphine release from the patch that could result in an
overdose of buprenorphine. If patients develop a high fever while wearing the patch they should contact their physician.
10. Patients should be advised that if they experience problems with adhesion of the BuTrans® patch, they may tape the edges of the patch with first aid
tape.
11. Patients should be advised that if the patch falls off before 7 days a new patch may be applied to a different skin site.
12. When BuTrans® is no longer needed (used or unused), patients should be advised to fold the patch (so that the adhesive side adheres to itself) and
immediately flush it down the toilet, or consult with a pharmacist about other disposal options.
13. Patients should be instructed that, if the drug adhesive layer accidentally contacts the skin other than the intended application site, the area should be
washed clean with clear water and not soap, alcohol, or other chemicals, because these products may increase the ability of buprenorphine to go through
the skin.
14. Patients should be advised that the dose of BuTrans® should NEVER be adjusted without the prescribing health care professional’s instruction.
15. Patients should be advised that BuTrans® may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g.,
driving, operating machinery).
16. Patients should be advised to refrain from any potentially dangerous activity when initially starting on BuTrans® or when their dose is being adjusted,
until it is established that they have not been adversely affected.
17. Patients should be advised that BuTrans® should not be combined with alcohol or other centrally acting agents, such as: sleep medications, tranquilizers,
sedatives and hypnotics because dangerous additive effects may occur, resulting in serious injury or death.
18. Patients should be advised to consult their physician or pharmacist if other medications are being, or will be, used with BuTrans®.
19. Patients should be advised of the potential for severe constipation.
20. Patients should be advised that if they have been receiving treatment with BuTrans® and cessation of therapy is indicated, it may be appropriate to
taper the BuTrans® dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. Withdrawal symptoms are generally
milder than seen with full agonists, and begin after two days and may last up to two weeks.
21. Patients should be advised that BuTrans® contains buprenorphine, a drug with a potential for abuse.
22. Patients, family members and caregivers should be advised to protect BuTrans® from theft or misuse in the work or home environment.
23. Patients should be advised that BuTrans® should never be given to anyone other than the individual for whom it was prescribed because of the risk of
death or other serious medical problems to that person, for whom it was not intended.
24. Patients should be instructed to keep BuTrans® in a secure place out of sight and reach of children due to the risk of fatal respiratory depression.
25. Women of childbearing potential who become or are planning to become pregnant should be advised to consult a physician prior to initiating or
continuing therapy with BuTrans®.
26. Patients should be informed that, if the patch dislodges and accidentally sticks to the skin of another person, they should immediately take the patch
off, wash the exposed area with water (and not soap, alcohol, or other chemicals, because these products may increase the ability of buprenorphine to
go through the skin) and seek immediate medical attention for the accidentally exposed individual.
Post-Market Adverse Drug Reactions
Other adverse reactions (≥ 1% frequency) not observed in clinical trials, that have been reported in post-marketing data include vasodilation. (See Adverse
Reactions section in the Product Monograph).
OVERDOSAGE
Symptoms
The manifestations of BuTrans® (buprenorphine transdermal patch) overdose are an extension of its pharmacologic actions, but in overdose the antagonist
properties may predominate. Symptoms include respiratory depression, sedation, drowsiness, nausea, vomiting and marked miosis. Respiratory depression
has been absent in some cases of buprenorphine overdose. However, respiratory depression, including apnea, and cardiovascular collapse have occurred in
other overdose situations. Treatment Support: Establish and maintain a patent airway, assist or control respiration as indicated, and maintain adequate
body temperature and fluid balance. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Topical
Exposure: Remove any patch in contact with the patient and dispose of it properly. Ingestion of BuTrans®: Administer activated charcoal (either 1g/kg
or 50 g) with an accompanying cathartic (e.g., 70% sorbitol, 1 mL/kg) to reduce buprenorphine absorption. Opioid Antagonist: A specific opioid antagonist
such as naloxone may reverse the effects of buprenorphine. The dose of naloxone required to antagonize the respiratory depressant effects of BuTrans®
may be in the range of 5 to 12 mg intravenously which is significantly higher than that used for a narcotic such as morphine. The onset of naloxone effect
may also be delayed by 30 minutes or more. Maintenance of adequate ventilation is essential when managing a BuTrans® overdose and more important
than specific antidote treatment with a narcotic antagonist, such as naloxone.
SPECIAL HANDLING INSTRUCTIONS: BuTrans® (buprenorphine transdermal patch) should be kept in a safe place out of the sight and reach of children
before and after use. Do not give to others. BuTrans® patches should not be divided, cut or damaged in any other way. The buprenorphine contained in
BuTrans® is supplied in sealed transdermal patches. If the adhesive from the drug accidentally contacts the skin other than the intended application site, the
area should be washed with water. Do not use soap, alcohol or other solvents to remove the adhesive because they may enhance the absorption of the drug.
When changing the patch, remove the used BuTrans®, fold it over itself, and discard it (flush down the toilet) immediately upon removal, or consult with a
pharmacist about other disposal options. DOSAGE FORMS, COMPOSITION AND PACKAGING: Patch Components and Structure BuTrans®
(buprenorphine transdermal patch) is a rectangular or square, beige coloured patch consisting of a protective liner and functional layers. Proceeding from
the outer surface toward the surface adhering to the skin, the layers are (1) a beige coloured web backing layer of polyester material; (2) an adhesive matrix
rim without buprenorphine; (3) a separating foil over the adhesive matrix; (4) the buprenorphine containing adhesive matrix with inactive ingredients
including aluminum acetylacetonate, levulinic acid, oleyl oleate, polyacrylate (dry solids), povidone; and (5) a release liner. Before use, the release liner covering
the adhesive layer is removed and discarded (see DOSAGE FORMS, COMPOSITION AND PACKAGING in the Product Monograph).
®
Purdue Pharma is the owner of the Trademark BuTrans
03/12
news 55
Lipid
profiles
improved
in kids
from • page 51
patients were taking atorvastatin, 11 were on rosuvastatin
and seven on simvastatin; 17
previously or concomitantly
took bile-acid sequestrants.
When the researchers compared the statin-treated children’s initial findings to their
most favourable lipid profile
(defined as the profile with
the lowest LDL levels), they saw
a 29% decrease in total cholesterol and a 40% decrease in
LDL—both significant changes
and “pretty much consistent
with what we see in the literature on the use of statins in children with FH,” Dr. Barone said.
The statin-treated group
also showed a significant
decrease in ApoB (35%) and
a significant increase in HDL
(22%), although the “slight”
decrease in triglycerides (not
quite 4%) was not significant.
Adverse effects
When it came to adverse effects,
two patients (3%) reported
myalgia and headache, with
creatine kinase levels of 183 IU/l
and 93 IU/l, respectively, at the
time of presentation. Treatment
was stopped in two patients—
one who had reported headache
and another with asymptomatic
elevation of aminotransferase.
The range of creatine kinase
levels went as high as 858 IU/l
in one patient who was a football player who had recently
“undergone vigorous physical
activity,” she said.
The statin was changed
in three patients to achieve
acceptable LDL levels—from
atorvastatin to rosuvastatin for
one, and from rosuvastatin to
atorvastatin for two.
The study confirmed the
favourable effect of statin treatment on lipid profiles in children with FH and suggested
statins can be used safely in
children with regular clinical
and laboratory monitoring for
potential adverse effects, Dr.
Barone said. It also provides a
basis for further research examining the application of clinical
guidelines to other populations of dyslipidemic children
including those with dyslipidemia due to overweight/
obesity and the metabolic
syndrome, she added. MP
Modified Release Tablets
375 mg enteric-coated naproxen/20 mg immediate release esomeprazole & 500 mg
enteric-coated naproxen/20 mg immediate release esomeprazole
Prescribing Summary
THERAPEUTIC CLASSIFICATION: NSAID and H+, K+-ATPase inhibitor
INDICATIONS AND CLINICAL USE: Adults: VIMOVO (naproxen/esomeprazole) is
indicated for the treatment of the signs and symptoms of osteoarthritis (OA), rheumatoid
arthritis (RA) and ankylosing spondylitis (AS) and to decrease the risk of developing gastric
ulcers in patients at risk for developing NSAID-associated gastric ulcers. VIMOVO is not
recommended for initial treatment of acute pain because the absorption of naproxen is
delayed (as with other modified release formulations of naproxen). For patients with an
increased risk of developing cardiovascular (CV) and/or gastrointestinal
(GI) adverse events, other management strategies that do NOT include
the use of NSAIDs should be considered first (see CONTRAINDICATIONS and
WARNINGS AND PRECAUTIONS). Use of VIMOVO should be limited to the
lowest effective dose for the shortest possible duration of treatment in
order to minimize the potential risk for cardiovascular or gastrointestinal
adverse events (see CONTRAINDICATIONS and WARNINGS AND
PRECAUTIONS). VIMOVO, as a NSAID, does NOT treat clinical disease or prevent its progression.
VIMOVO, as a NSAID, only relieves symptoms and decreases inflammation for as long as the patient
continues to take it. Geriatrics (>65 years of age): Evidence from naproxen clinical studies and
postmarket experience suggest that use in the geriatric population is associated with differences in
safety (see WARNINGS AND PRECAUTIONS; Special Populations and Product Monograph, CLINICAL
TRIALS). Pediatrics (<18 years of age): VIMOVO should not be used in children or adolescents under
18 years of age. The safety and efficacy of VIMOVO in this population has not been established.
CONTRAINDICATIONS: VIMOVO is contraindicated in: the peri-operative setting of
coronary artery bypass graft surgery (CABG) (although VIMOVO has NOT been studied in this
patient population, a selective COX-2 inhibitor NSAID studied in such a setting has led to an
increased incidence of cardiovascular/thromboembolic events, deep surgical infections and
sternal wound complications); the third trimester of pregnancy, because of risk of premature
closure of the ductus arteriosus and prolonged parturition; women who are breastfeeding,
because of the potential for serious adverse reactions in nursing infants; patients with severe
uncontrolled heart failure; patients with known hypersensitivity to naproxen, esomeprazole,
substituted benzimadazoles or to any of the components/excipients (see DOSAGE FORMS,
COMPOSITION AND PACKAGING); patients with history of asthma, urticaria, or allergic-type
reactions after taking ASA or other NSAIDs (i.e. complete or partial syndrome of
ASA-intolerance – rhinosinusitis, urticaria/angioedema, nasal polyps, asthma) (fatal
anaphylactoid reactions have occurred in such individuals). Individuals with the above medical
problems are at risk of a severe reaction even if they have taken NSAIDs in the past without
any adverse reaction. The potential for cross-reactivity between different NSAIDs must be
kept in mind [see WARNINGS AND PRECAUTIONS; Hypersensitivity Reactions, Anaphylactoid
Reactions]); patients with active gastric/duodenal/peptic ulcer, active GI bleeding; patients
with cerebrovascular bleeding or other bleeding disorders; patients with inflammatory bowel
disease; patients with severe liver impairment or active liver disease; patients with severe
renal impairment (creatinine clearance <30 mL/min or 0.5 mL/sec) or deteriorating renal
disease (individuals with lesser degrees of renal impairment are at risk of deterioration of
their renal function when prescribed NSAIDs and must be monitored) (see WARNINGS AND
PRECAUTIONS; Renal); patients with known hyperkalemia (see WARNINGS AND
PRECAUTIONS; Renal, Fluid and Electrolyte Balance) and children and adolescents less than
18 years of age.
Safety Information
Serious Warnings and Precautions
Risk of Cardiovascular (CV) Adverse Events: Ischemic Heart Disease,
Cerebrovascular Disease, Congestive Heart Failure (NYHA II-IV) (See
WARNINGS AND PRECAUTIONS; Cardiovascular).
Naproxen is a non-steroidal anti-inflammatory drug (NSAID). Use of some
NSAIDs is associated with an increased incidence of cardiovascular
adverse events (such as myocardial infarction, stroke or thrombotic
events) which can be fatal. The risk may increase with duration of use.
Patients with cardiovascular disease or risk factors for cardiovascular
disease may be at greater risk.
Caution should be exercised in prescribing NSAIDs such as naproxen,
which is a component of VIMOVO (naproxen/esomeprazole), to any
patient with ischemic heart disease (including but NOT limited to acute
myocardial infarction, history of myocardial infarction and/or angina),
cerebrovascular disease (including but NOT limited to stroke,
cerebrovascular accident, transient ischemic attacks and/or amaurosis
fugax) and/or congestive heart failure (NYHA II-IV).
Use of NSAIDs such as naproxen, which is a component of VIMOVO, can
promote sodium retention in a dose-dependent manner, through a renal
mechanism, which can result in increased blood pressure and/or
exacerbation of congestive heart failure (see also WARNINGS AND
PRECAUTIONS; Renal, Fluid and Electrolyte Balance).
Randomized clinical trials with VIMOVO have not been designed to
detect differences in cardiovascular events in a chronic setting.
Therefore, caution should be exercised when prescribing VIMOVO.
Risk of Gastrointestinal (GI) Adverse Events (see WARNINGS AND
PRECAUTIONS, Gastrointestinal and Product Monograph, CLINICAL TRIALS)
Use of NSAIDs such as naproxen, which is a component of VIMOVO, is
associated with an increased incidence of gastrointestinal adverse
events (such as peptic/duodenal ulceration, perforation, obstruction
and gastrointestinal bleeding).
General: Frail or debilitated patients may tolerate side effects less well and therefore
special care should be taken in treating this population. To minimize the potential risk
for an adverse event, the lowest effective dose should be used for the
shortest possible duration. As with other NSAIDs, caution should be used in the
treatment of elderly patients who are more likely to be suffering from impaired renal, hepatic
or cardiac function. For high-risk patients, alternate therapies that do not involve NSAIDs
should be considered. VIMOVO, which contains naproxen, is NOT recommended for use with
other NSAIDs, with the exception of low-dose ASA for cardiovascular prophylaxis, because of
the absence of any evidence demonstrating synergistic benefits and the potential for additive
adverse reactions (see DRUG INTERACTIONS; Drug/Drug Interactions, Acetylsalicylic acid
(ASA) or other NSAIDs). VIMOVO should not be used concomitantly with other naproxen
containing drugs since they all circulate in plasma as the naproxen anion. Concomitant
administration with atazanavir or nelfinavir is not recommended (see DRUG INTERACTIONS).
In the presence of any alarm symptom (e.g., significant unintentional weight loss, recurrent
vomiting, dysphagia, hematemesis or melena), and/or when gastric ulcer is suspected or
present, malignancy should be excluded, as treatment may alleviate symptoms and delay diagnosis.
Special Populations: Pregnant Women: VIMOVO is CONTRAINDICATED for use
during the third trimester of pregnancy because of risk of premature
closure of the ductus arteriosus and the potential to prolong parturition
(see Product Monograph, TOXICOLOGY). Caution should be exercised in
prescribing VIMOVO during the first and second trimesters of pregnancy.
Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or the embryofetal
development. Data from epidemiological studies suggest an increased risk of miscarriage and
of cardiac malformation after use of a prostaglandin synthesis inhibitor in early pregnancy. In
animals, administration of a prostaglandin synthesis inhibitor has been shown to result in
increased pre- and post-implantation loss and embryo-fetal lethality. In addition, increased
incidences of various malformations, including cardiovascular, have been reported in animals
given a prostaglandin synthesis inhibitor during the organogenetic period. VIMOVO, which
contains naproxen, is not recommended in labour and delivery because naproxen-containing
products, through their prostaglandin synthesis inhibitory effect, may adversely affect fetal
circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage.
Nursing Women: See CONTRAINDICATIONS. Pediatrics (<18 years of age): See
CONTRAINDICATIONS. Geriatrics: Patients older than 65 years and frail or debilitated patients
are more susceptible to a variety of adverse reactions from NSAIDs. The incidence of these
adverse reactions increases with dose and duration of treatment. In addition, these patients
are less tolerant to ulceration and bleeding. Most reports of fatal GI events are in this
population. Older patients are also at risk of lower esophageal injury including ulceration and
bleeding. For such patients, consideration should be given to a starting dose lower than the
one usually recommended, with individual adjustment when necessary and under close
supervision. Of the total number of patients who received VIMOVO (n=1157) in clinical trials,
387 were ≥65 years of age, of which 85 patients were 75 years and over. No meaningful
differences in efficacy (reduction in gastric ulcer rates or pain relief) or safety were observed
between these subjects and younger subjects. Elderly patients in the VIMOVO group compared
with the naproxen group (n=426) were consistently observed to have significantly lower
gastric ulcer rates, 1.5% vs 28.5% in patients ≥65 years of age (p<0.001), and 0% vs 19.2%
in patients ≥75 years of age (p=0.019). VIMOVO non-inferiority to celecoxib for pain relief
was maintained in elderly patients >65 years of age, generally considered to be at greater
risk of GI side effects. The incidence of adverse events was generally consistent between age
populations (see WARNINGS AND PRECAUTIONS; Gastrointestinal and Product Monograph,
CLINICAL TRIALS).
ADVERSE REACTIONS:
Adverse Drug Reaction Overview: Since VIMOVO contains both naproxen and
esomeprazole, the same pattern of undesirable effects reported for these individual
substances may occur. The most common adverse reactions seen with naproxen are
gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe.
Fatalities have occurred particularly in the elderly. Other common adverse reactions
include dyspepsia, stomach pain, nausea and vomiting. Common reactions seen with
esomeprazole in clinical trials include headache, diarrhea, flatulence, abdominal pain,
nausea, vomiting and dizziness, which are thought to be causally related. The most
commonly reported adverse reactions with VIMOVO are erosive gastritis, dyspepsia and
gastritis. No new safety findings were identified during VIMOVO treatment compared to
the established safety profile for the individual substances. To report a serious or
unexpected reaction to this drug, you may notify Health Canada by toll-free telephone:
866-234-2345 or toll-free fax: 866-678-6789.
Administration
Dosing considerations: VIMOVO must be swallowed whole with water, and not split,
chewed or crushed. VIMOVO should be taken at least 30 minutes before meals. VIMOVO does
not allow for administration of lower daily doses of naproxen or esomeprazole. If a lower daily
dose of either naproxen (i.e. ≤750 mg/day) or immediate-release (IR) esomeprazole (i.e.
≤40mg/day) is more appropriate, alternate therapy should be considered. Since VIMOVO is
a combination product, carefully consider the implications of any dosing schedule on both
components. Recommended dose and dose adjustment: For osteoarthritis/
rheumatoid arthritis/ankylosing spondylitis, the recommended daily dosage of VIMOVO is
375/20 mg (naproxen/esomeprazole) twice daily or 500/20 mg (naproxen/esomeprazole)
twice daily. Dosing Considerations in Special Populations: Geriatrics: See
WARNINGS AND PRECAUTIONS; Special Populations. Pediatrics (<18 years): VIMOVO is
not recommended for use in pediatric patients (see CONTRAINDICATIONS).
Dosage Forms and Packaging: VIMOVO contains an enteric-coated (EC) naproxen core
and immediate-release (IR) esomeprazole film coat. The formulation is designed to release the
active ingredients in a sequential fashion: esomeprazole is rapidly released in the stomach
followed by the delayed release of naproxen in the small intestine. VIMOVO (naproxen/
esomeprazole) 375/20 mg tablets are yellow, oval film coated tablets printed “375/20” in
black ink on one side; 500/20 mg tablets are yellow, oval film coated tablets printed “500/20”
in black ink on one side. VIMOVO tablets contain the following non-medicinal ingredients:
carnauba wax, croscarmellose sodium, glycerol monostearate, hypromellose, iron oxide black,
iron oxide yellow, macrogols, magnesium stearate, methacrylic acid-ethyl acrylate copolymer
(1:1) dispersion, methyl parahydroxybenzoate, polydextrose, polysorbate, povidone, propylene
glycol, propyl parahydroxybenzoate, silica colloidal anhydrous, titanium dioxide and triethyl
citrate. VIMOVO 375/20 mg or 500/20 mg tablets are supplied in HDPE bottles of 60 tablets.
Carcinogenesis and mutagenesis: There is no evidence from animal data that either naproxen or esomeprazole are
carcinogenic or mutagenic. In the long-term repeat-dose/carcinogenicity studies with omeprazole, gastric enterochromaffin-like
(ECL) cell carcinoids were noted in the rat, but not the mouse or dog. It has been demonstrated that this is a result of an indirect
mode of action, rather than being a direct effect of omeprazole on the ECL-cells; prolonged acid suppression leads to prolonged
hypergastrinemia, provoking ECL cell hyperplasia, which eventually progresses into ECL cell carcinoids (see Product Monograph,
TOXICOLOGY). Treatment with esomeprazole for up to 1 year in more than 800 patients has not resulted in any significant
pathological changes in the gastric oxyntic endocrine cells. Short-term treatment and long-term treatment with the racemate,
omeprazole, capsules in a limited number of patients for up to 11 years have not resulted in any significant pathological changes
in gastric oxyntic endocrine cells. Cardiovascular: Naproxen is a non-steroidal anti-inflammatory drug
(NSAID). Use of some NSAIDs is associated with an increased incidence of cardiovascular adverse events
(such as myocardial infarction, stroke or thrombotic events) which can be fatal. The risk may increase
with the duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease
may be at greater risk. Caution should be exercised in prescribing VIMOVO, which contains naproxen, to
patients with risk factors for cardiovascular disease, cerebrovascular disease or renal disease, such as
any of the following (NOT an exhaustive list): Hypertension, dyslipidemia/hyperlipidemia, diabetes
mellitus, congestive heart failure (NYHA I), coronary artery disease (atherosclerosis), peripheral
arterial disease, smoking, creatinine clearance <60 mL/min or 1 mL/sec. Use of NSAIDs such as naproxen, which
is a component of VIMOVO, can lead to new hypertension or can worsen pre-existing hypertension, either of which may increase
the risk of cardiovascular events as described above. Thus blood pressure should be monitored regularly. Consideration should be
given to discontinuing VIMOVO, should hypertension either develop or worsen with its use. Use of NSAIDs such as naproxen, which
is a component of VIMOVO, can induce fluid retention and edema, and may exacerbate congestive heart failure, through a renallymediated mechanism (see WARNINGS AND PRECAUTIONS; Renal, Fluid and Electrolyte Balance). For patients with a high risk of
developing an adverse CV event, other management strategies that do NOT include the use of NSAIDs should be considered first.
To minimize the potential risk for an adverse CV event, the lowest effective dose should be used for the
shortest possible duration. Endocrine and Metabolism: Corticosteroids: VIMOVO is NOT a substitute for
corticosteroids. It does NOT treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation
of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a
decision is made to discontinue corticosteroids (see DRUG INTERACTIONS; Drug-Drug Interactions, Glucocorticoids).
Gastrointestinal: Serious GI toxicity (sometimes fatal), such as ulceration, inflammation, perforation, obstruction and
gastrointestinal bleeding, can occur at any time, with or without warning symptoms, in patients treated with NSAIDs, such as
naproxen, which is a component of VIMOVO. While VIMOVO has been shown to significantly decrease the occurrence of gastric
ulcers compared to EC-naproxen alone, ulceration and associated complications can still occur. Minor upper GI problems, such as
dyspepsia, commonly occur at any time. Health care providers should remain alert for ulceration and bleeding in patients treated
with VIMOVO, even in the absence of previous GI tract symptoms. Most spontaneous reports of fatal GI events are in elderly or
debilitated patients and therefore special care should be taken in treating this population. To minimize the potential risk
for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. For
high risk patients, alternate therapies that do not involve NSAIDs should be considered (see WARNINGS AND PRECAUTIONS;
Special Populations, Geriatrics). Patients should be informed about the signs and/or symptoms of serious GI toxicity and
instructed to discontinue using VIMOVO and seek emergency medical attention if they experience any such symptoms. The utility
of periodic laboratory has NOT been demonstrated, nor has it been adequately assessed. Most patients who develop a serious
upper GI adverse event on NSAID therapy have no symptoms. Upper GI ulcers, gross bleeding or perforation, caused by NSAIDs,
appear to occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These
trends continue, thus increasing the likelihood of developing a serious GI event at some time during the course of therapy. Even
short-term therapy has its risks. Caution should be taken if prescribing VIMOVO to patients with a history of ulcer disease or
gastrointestinal bleeding. If GI bleeding or ulceration occurs, VIMOVO should be discontinued immediately and appropriate
treatment sought. Other risk factors for GI ulceration and bleeding include the following: Helicobacter pylori infection, increased
age, prolonged use of NSAID therapy, excess alcohol intake, smoking, poor general health status or concomitant therapy with any
of the following: Anti-coagulants (e.g. warfarin); anti-platelet agents (e.g. ASA, clopidogrel); oral corticosteroids (e.g.
prednisone); Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g. citalopram, fluoxetine, paroxetine, sertraline). In studies
comprising patients who were older than 50 years of age and/or had a prior history of peptic ulcer, VIMOVO was shown to
significantly lower gastric ulcer rates compared to EC-naproxen, regardless of concomitant therapy with low-dose ASA (see
Product Monograph, CLINICAL TRIALS). Gastrointestinal symptomatic response to therapy with VIMOVO does not preclude the
presence of gastric malignancy. Genitourinary: Some NSAIDs are associated with persistent urinary symptoms (bladder pain,
dysuria, urinary frequency), hematuria or cystitis. The onset of these symptoms may occur at any time after the initiation of
therapy with a NSAID. Should urinary symptoms occur, in the absence of an alternate explanation, treatment with VIMOVO should
be stopped to ascertain if symptoms disappear. This should be done before urological investigations or treatments are carried out.
Hematologic: NSAIDs inhibiting prostaglandin biosynthesis interfere with platelet function to varying degrees; patients who
may be adversely affected by such an action, such as those on anti-coagulants or suffering from hemophilia or platelet disorders
should be carefully observed when VIMOVO is administered. Anti-coagulants: Numerous studies have shown that the
concomitant use of NSAIDs and anti-coagulants increases the risk of bleeding. Concurrent therapy of VIMOVO, which contains the
NSAID naproxen, with warfarin requires close monitoring of the international normalized ratio (INR). Even with therapeutic INR
monitoring, increased bleeding may occur. Anti-platelet Effects: NSAIDs inhibit platelet aggregation and have been shown
to prolong bleeding time in some patients. Unlike acetylsalicylic acid (ASA), their effect on platelet function is quantitatively less,
or of shorter duration, and is reversible. NSAIDs have no proven efficacy as anti-platelet agents and should NOT be used as a
substitute for ASA or other anti-platelet agents for prophylaxis of cardiovascular thromboembolic diseases. Anti-platelet therapies
(e.g. ASA) should NOT be discontinued (see DRUG INTERACTIONS; Drug-Drug Interactions, Acetylsalicylic Acid (ASA) or other
NSAIDs). Blood dyscrasias: Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and
agranulocytosis) associated with the use of NSAIDs are rare, but could occur with severe consequences. Anemia is sometimes
seen in patients receiving NSAIDs. This may be due to fluid retention, GI blood loss, or an incompletely described effect upon
erythropoiesis. Patients on long-term treatment with NSAIDs, should have their hemoglobin or hematocrit checked if they exhibit
any signs or symptoms of anemia or blood loss. Hepatic/Biliary/Pancreatic: With NSAIDs, borderline elevations of one or
more liver enzyme tests (AST, ALT, alkaline phosphatase) may occur in up to 15% of patients. These abnormalities may progress,
may remain essentially unchanged, or may be transient with continued therapy. Chronic alcoholic liver disease and probably other
forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is
increased. The implication of this finding for naproxen dosing is unknown, but caution is advised when high doses are required. It
is prudent to use the lowest effective dose. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an
abnormal liver function test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction
while on therapy with this drug. Severe hepatic reactions including jaundice and cases of fatal hepatitis, liver necrosis and hepatic
failure, some of them with fatal outcomes, have been reported with NSAIDs. Although such reactions are rare, if abnormal liver
tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop (e.g. jaundice), or if systemic
manifestations occur (e.g. eosinophilia, associated with rash, etc.), this drug should be discontinued. If there is a need to
prescribe this drug in the presence of impaired liver function, it must be done under strict observation. Hypersensitivity
Reactions: Anaphylactoid Reactions: As with NSAIDs in general, anaphylactoid reactions have occurred in patients
without known prior exposure to naproxen, a component of VIMOVO. In post-marketing experience, rare cases of anaphylactic/
anaphylactoid reactions and angioedema have been reported in patients receiving naproxen. VIMOVO, which contains naproxen,
should NOT be given to patients with the ASA-triad. This symptom complex typically occurs in asthmatic patients who experience
rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking ASA or other NSAIDs (see
CONTRAINDICATIONS). ASA-Intolerance: VIMOVO, which contains naproxen, should NOT be given to patients with complete
or partial syndrome of ASA-intolerance (rhinosinusitis, urticaria/angioedema, nasal polyps, asthma) in whom asthma,
anaphylaxis, urticaria/angioedema, rhinitis or other allergic manifestations are precipitated by ASA or other NSAIDs. Fatal
anaphylactoid reactions have occurred in such individuals. As well, individuals with the above medical problems are at risk of a
severe reaction even if they have taken NSAIDs in the past without any adverse reaction (see CONTRAINDICATIONS). Crosssensitivity: Patients sensitive to one NSAID may be sensitive to any of the other NSAIDs as well. Serious skin reactions:
See WARNINGS AND PRECAUTIONS; Skin. Immune: See WARNINGS AND PRECAUTIONS; Infection, Aseptic Meningitis.
Infection: Naproxen, a component of VIMOVO, as with other NSAIDs, may mask signs and symptoms of an underlying infectious
disease. Aseptic Meningitis: Rarely, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches,
nausea and vomiting, fever or clouding of consciousness) have been observed. Patients with autoimmune disorders (systemic
lupus erythematosus, mixed connective tissue diseases, etc.) seem to be pre-disposed. Therefore, in such patients, the health
care provider must be vigilant to the development of this complication. Pseudomembranous colitis: Pseudomembranous
colitis has been reported with nearly all antibacterial agents, including clarithromycin and amoxicillin, and may range in severity
from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent
to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may
permit overgrowth of Clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibioticassociated colitis”. After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be
initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe
cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with
an antibacterial drug clinically effective against C. diff colitis. Decreased gastric acidity due to any means, including any proton
pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump
inhibitors may lead to a slightly increased risk of gastrointestinal infections such as Salmonella, Campylobacter and possibly
C. diff. Neurologic: Some patients may experience drowsiness, dizziness, blurred vision, vertigo, tinnitus, hearing loss,
insomnia or depression with the use of NSAIDs, such as naproxen, a component of VIMOVO. If patients experience such adverse
reaction(s), they should exercise caution in carrying out activities that require alertness. Ophthalmologic: Blurred and/or
diminished vision has been reported with the use of NSAIDs. If such symptoms develop, VIMOVO, which contains naproxen, should
be discontinued and an ophthalmologic examination performed. Ophthalmologic examination should be carried out at periodic
intervals in any patient receiving VIMOVO for an extended period of time. Peri-Operative Considerations: See
CONTRAINDICATIONS; Coronary Artery Bypass Graft Surgery. Psychiatric: See WARNINGS AND PRECAUTIONS; Neurologic.
Renal: Long term administration of NSAIDs to animals has resulted in renal papillary necrosis and other abnormal renal
pathology. In humans, there have been reports of acute interstitial nephritis, hematuria, low grade proteinuria and occasionally
nephrotic syndrome. Renal insufficiency due to NSAID use is seen in patients with pre-renal conditions leading to reduction in renal
blood flow or blood volume. Under these circumstances, renal prostaglandins help maintain renal perfusion and glomerular
filtration rate (GFR). In these patients, administration of a NSAID may cause a reduction in prostaglandin synthesis leading to
impaired renal function. Patients at greatest risk of this reaction are those with pre-existing renal insufficiency (GFR <60 mL/min
or 1 mL/s), dehydrated patients, patients on salt restricted diets, those with congestive heart failure, cirrhosis, liver dysfunction,
taking angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, cyclosporin, diuretics, and those who are
elderly. Serious or life-threatening renal failure has been reported in patients with normal or impaired renal function after short
term therapy with NSAIDs. Even patients at risk who demonstrate the ability to tolerate a NSAID under stable conditions may
decompensate during periods of added stress (e.g. dehydration due to gastroenteritis). Discontinuation of NSAIDs is usually
followed by recovery to the pre-treatment state. Caution should be used when initiating treatment with NSAIDs, such as naproxen,
a component of VIMOVO, in patients with considerable dehydration. Such patients should be rehydrated prior to initiation of
therapy. Caution is also recommended in patients with pre-existing kidney disease. Advanced Renal Disease: See
CONTRAINDICATIONS. Fluid and Electrolyte Balance: Use of NSAIDs such as naproxen, a component of VIMOVO, can
promote sodium retention in a dose-dependent manner, which can lead to fluid retention and edema, and consequences of
increased blood pressure and exacerbation of congestive heart failure. Thus, caution should be exercised in prescribing VIMOVO
in patients with a history of congestive heart failure, compromised cardiac function, hypertension, increased age or other
conditions predisposing to fluid retention (see WARNINGS AND PRECAUTIONS; Cardiovascular). Use of NSAIDs such as naproxen,
a component of VIMOVO, can increase the risk of hyperkalemia, especially in patients with diabetes mellitus, renal failure,
increased age, or those receiving concomitant therapy with adrenergic blockers, angiotensin-converting enzyme inhibitors,
angiotensin-II receptor antagonists, cyclosporin, or some diuretics. Electrolytes should be monitored periodically (see
CONTRAINDICATIONS). Respiratory: ASA-induced asthma is an uncommon but very important indication of ASA and NSAID
sensitivity. It occurs more frequently in patients with asthma who have nasal polyps. Sexual Function/Reproduction: The
use of naproxen as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not
recommended in women attempting to conceive. Therefore, in women who have difficulties conceiving, or who are undergoing
investigation of infertility, withdrawal of VIMOVO, which contains naproxen, should be considered. Skin: In rare cases, serious
skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis and erythema multiforme
have been associated with the use of some NSAIDs. Because the rate of these reactions is low, they have usually been noted
during post-marketing surveillance in patients taking other medications also associated with the potential development of these
serious skin reactions. Thus, causality is NOT clear. These reactions are potentially life threatening but may be reversible if the
causative agent is discontinued and appropriate treatment instituted. Patients should be advised that if they experience a skin
rash they should discontinue their NSAID and contact their physician for assessment and advice, including which additional
therapies to discontinue.
SPECIAL POPULATIONS:
Hepatic Insufficiency: VIMOVO is not recommended for use in patients with severe hepatic impairment due to increased risk
of NSAID associated bleeding and/or renal failure (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS; Hepatic/
Biliary/Pancreatic). In patients with mild to moderate hepatic impairment VIMOVO should be used with caution and hepatic
function closely monitored. Renal Insufficiency: VIMOVO is not recommended for use in patients with severe renal
impairment or deteriorating renal disease (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS; Renal). In patients
with mild to moderate renal impairment VIMOVO should be used with caution and renal function closely monitored. Poor
Metabolizers: The CYP 2C19 and CYP 3A4 isozymes are responsible for metabolism of esomeprazole. The CYP 2C19 isozyme,
which is involved in the metabolism of all available proton pump inhibitors, exhibits polymorphism. Some 3% of Caucasians and
15-20% of Asians lack CYP 2C19 and are termed “poor metabolizers”. At EC-esomeprazole steady state (40 mg for 5 days), the
ratio of AUC in poor metabolizers to AUC in the rest of the population is approximately 2. Dosage adjustment of VIMOVO based
on CYP 2C19 status is not necessary (see DOSAGE AND ADMINISTRATION and Product Monograph, ACTION AND CLINICAL
PHARMACOLOGY; Pharmacokinetics, Special Populations).
MONITORING AND LABORATORY TESTS:
Patients on long-term treatment with VIMOVO should have their blood pressure monitored regularly and an ophthalmic
examination should be carried out at periodic intervals (see WARNINGS AND PRECAUTIONS; Cardiovascular and Ophthalmic).
Hemoglobin, hematocrit, red blood cells (RBCs), white blood cells (WBCs), and platelets should be checked in patients on longterm treatment with VIMOVO. Additionally, concurrent therapy with warfarin requires close monitoring of the international
normalized ratio (INR) (see WARNINGS AND PRECAUTIONS; Hematology). Serum transaminase and bilirubin should be monitored
regularly during VIMOVO therapy (see WARNINGS AND PRECAUTIONS; Hepatic, Biliary, Pancreatic). Serum creatinine, creatinine
clearance and serum urea should be checked in patients during VIMOVO therapy. Electrolytes including serum potassium should
be monitored periodically (see WARNINGS AND PRECAUTIONS; Renal). Monitoring of plasma lithium concentration is
recommended when stopping or starting VIMOVO therapy.
ADVERSE REACTIONS:
Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specific conditions the adverse
reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates
in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related
adverse events and for approximating rates. Adverse event data is provided from controlled studies using VIMOVO, involving
2317 patients ranging in duration from 3-12 months. Patients received either 500/20 mg of VIMOVO twice daily (n=1157),
500 mg of enteric-coated (EC) naproxen twice daily (n=426), 200 mg of celecoxib once daily (n=488), or placebo (n=246). All
adverse reactions, regardless of causality, occurring in ≥2% of patients from two 6-month randomized, double-blind, parallelgroup controlled clinical studies (Study 301 and 302) conducted in patients at risk of developing NSAID-associated ulcers
compared to EC-naproxen are presented in the below table.
Table 1: Adverse Reactions, regardless of causality, occurring ≥2% in arthritisa patients at risk of
NSAID-induced ulcers from Studies 301 and 302 (pooled, 6 months duration)
Preferred term (sorted by SOC)
Percentage of Subjects With Adverse Events
VIMOVO (500/20 mg) BID
(n=428)
EC-naproxen 500 mg BID
(n=426)
Gastritis erosive
19.4
38.0
Dyspepsia
18.0
26.8
Gastritis
17.1
14.1
Diarrhea
6.1
5.2
Gastric ulcer
5.6
23.7
5.6
8.7
Nausea
5.1
4.9
Hiatus hernia
4.2
5.9
Abdominal distension
3.7
3.8
Flatulence
3.7
3.1
Esophagitis
3.5
7.5
Constipation
2.6
2.8
Abdominal pain
2.3
1.6
Erosive duodenitis
2.1
11.7
Abdominal pain lower
2.1
2.6
Duodenitis
1.4
7.3
Gastritis hemorrhagic
1.2
2.1
Gastroesophageal reflux disease
0.9
3.5
THE MEDICAL POST | NewS
late start ‘least awful
option’ for Quebec
med students
l
aval University says pushing the start
date for first-year medical students
to Oct. 1 was the least painful way of
dealing with this year’s student strikes.
“Any solution we picked was going to
be a bad one,” said Dr. Jean-François Montreuil, Laval’s vice-dean of undergraduate
studies. “But we think we chose the least
awful option.”
Officials at both Laval and the University
of Montreal decided in early June to push
back the start date for first-year students, so
they would have time to complete delayed
courses.
According to Dr. Montreuil, only 14 of
Laval’s 229 first-year medical students were
affected.
Medical schools in Quebec are unique
because they accept some students without
a bachelor degree.
However, strikes affected college-level
CEGEP classes, meaning faculties were
faced with first-year students who had not
finished some key courses.
Some of those CEGEP classes were slated
to finish at the end of September, with students heading straight to medical school.
Meanwhile, returning students started
classes in early September.
Sherbrooke University took a staggered
approach, with the first cohort starting in
August and a second, smaller one starting
early this month.
At McGill University in Montreal, nine
students accepted straight out of CEGEP
will get three special science classes but will
have to catch up quickly.
“They will be carrying the same course
load as their classmates, come the winter
2013 semester,” said Charmaine Lyn, the
faculty admissions director. MP
(n=428)
EC-naproxen 500 mg BID
(n=426)
Duodenal ulcer
0.7
5.4
Erosive esophagitis
0.5
5.6
3.8
Infections and infestations
Upper respiratory tract infection
4.9
Bronchitis
2.3
1.9
Urinary tract infection
2.3
1.4
Sinusitis
1.9
2.1
Nasopharyngitis
0.9
2.3
1.2
2.3
Headache
2.6
1.4
Dysgeusia
2.1
1.4
2.3
2.6
Musculoskeletal and connective tissue disorders
Arthralgia
Respiratory, thoracic, and mediastinal disorders
Cough
a
Studies also included 23% patients with chronic musculoskeletal conditions requiring ongoing NSAID therapy
Patients taking VIMOVO had significantly fewer pre-specified NSAID-associated upper GI adverse events (including duodenal
ulcers) (53.3%) compared to patients taking EC-naproxen alone (70.4%). As well, patients taking VIMOVO had significantly less
discontinuations due to adverse reactions compared to patients taking EC-naproxen alone (7.9% vs. 12.5% respectively). The
most common reasons for discontinuations due to adverse events in the VIMOVO treatment group were upper abdominal pain
(1.2%, n=5), duodenal ulcer (0.7%, n=3) and erosive gastritis (0.7%, n=3). Among patients receiving naproxen alone, the most
common reasons for discontinuations due to adverse events were duodenal ulcer 5.4% (n=23), dyspepsia 2.8% (n=12) and
upper abdominal pain 1.2% (n=5). The proportion of patients discontinuing treatment due to pre-specified NSAID-associated
upper gastrointestinal adverse events (including duodenal ulcers) in patients treated with VIMOVO was 4.0% compared to 12.0%
for patients taking EC-naproxen (p<0.001).
Adverse reaction data for VIMOVO, regardless of causality, occurring in ≥2 % of patients, and greater than placebo from two
3-month randomized double-blind, placebo-controlled clinical studies conducted in patients with osteoarthritis of the knee are
presented below.
Table 2: Adverse Reactions, regardless of causality, occurring ≥2% in patients with osteoarthritis of
the knee from Studies 307 and 309 (3 months duration)
(n=490)
Celecoxib 200 mg QD
(n=488)
Placebo
(n=246)
12.2
Dyspepsia
8.4
10.7
Diarrhea
5.5
2.9
3.7
4.1
4.3
3.3
Constipation
3.5
2.0
1.2
Nausea
3.5
3.1
3.7
Dizziness
3.1
0.8
2.0
Headache
2.7
3.7
5.3
1.2
1.2
General disorders and administration site conditions
Peripheral edema
3.1
Musculoskeletal and connective tissue disorders
Arthralgia
1.4
2.9
1.6
Back pain
1.2
2.9
2.0
1.4
0.6
2.8
1.0
1.2
2.4
Respiratory, thoracic and mediastinal disorders
Cough
Infections and infestations
Sinusitis
Similar percentages of subjects receiving either VIMOVO or celecoxib withdrew from these studies due to treatment emergent
adverse events (6.9% and 7.8% respectively). There were no adverse reactions in which more than 1% of subjects withdrew from
any treatment group. The long-term safety of VIMOVO was evaluated in an open label clinical trial of 239 patients, of which
135 patients received 500/20 mg of VIMOVO for 12 months. There were no differences in frequency or types of adverse
reactions seen in the long-term safety study compared to shorter-term treatment in the randomized controlled studies above. In
the pooled data from all VIMOVO clinical trials in patients (n=2317), there were 4 reports of atrial fibrillation/flutter. All 4 events
occurred in patients assigned to VIMOVO but all were assessed as unrelated or unlikely to be related to study drug.
Other Adverse Events: Post-Market Adverse Drug Reactions: Because post-marketing events are reported
voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or clearly establish a
causal relationship to the product. The following post-marketing adverse events have been reported with NSAIDS including
naproxen and naproxen sodium, taken alone. Gastrointestinal: Peptic ulcers, perforation, or GI bleeding, sometimes fatal,
particularly in the elderly. Heartburn, nausea, esophagitis, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal
pain, nonpeptic gastrointestinal ulceration, melena, hematemesis, stomatitis, ulcerative stomatitis, exacerbation of ulcerative
colitis and Crohn’s disease, pancreatitis, gastritis. Infections: Aseptic meningitis. Blood and Lymphatic System
Disorders: Agranulocytosis, aplastic anemia, eosinophilia, hemolytic anemia, leucopenia, thrombocytopenia. Immune
System Disorders: Anaphylactoid reactions. Metabolic and Nutrition Disorders: Hyperkalemia. Psychiatric
57
Biking for humanity
Marc Robitaille
By mark cardwell
Quebec City
OCTOBeR 9, 2012
Second-year
medical
Student
Quinn Thomas
says he wanted
to do something to
help people even
before he becomes
a doctor. So the
21-year-old Laval
University student
decided to spend
the summer cycling
across Canada in
an effort to raise
awareness about
the need for organ
and tissue donation.
He is seen here
in August during
a stop in Sault Ste.
Marie, Ont., where he met with organ donor recipients, one
of more than a dozen such events he has attended since he
started his cross-country trek in June.
Disorders: Depression, dream abnormalities, insomnia. Nervous System Disorders: Dizziness, drowsiness, headache,
lightheadedness, retrobulbar optic neuritis, convulsions, cognitive dysfunction, inability to concentrate. Eye Disorders: Visual
disturbances, corneal opacity, papillitis, papilledema. Ear and Labyrinth Disorders: Hearing impairment, hearing
disturbances, tinnitus, vertigo. Cardiac Disorders: Palpitations, cardiac failure has been reported in association with NSAID
treatment, congestive heart failure. Vascular Disorders: Hypertension, vasculitis. Respiratory, Thoracic and
Mediastinal Disorders: Dyspnea, pulmonary edema, asthma, eosinophilic pneumonitis. Hepatobiliary Disorders:
Hepatitis (some cases of hepatitis have been fatal), jaundice. Skin and Subcutaneous Tissue Disorders: Ecchymoses,
itching (pruritus), purpura, skin eruptions, sweating, alopecia, epidermal necrolysis, very rarely toxic epidermal necrolysis,
erythema multiforme, bullous reactions, including Stevens-Johnson syndrome, erythema nodosum, fixed drug eruption, lichen
planus, pustular reaction, skin rashes, SLE, urticaria, photosensitivity reactions, including rare cases resembling porphyria
cutanea tarda (“pseudoporphyria”) or epidermolysis bullosa and angioneurotic edema. If skin fragility, blistering or other
symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored. Musculoskeletal
and Connective Tissue Disorders: Myalgia, muscle weakness. Renal and Urinary Disorders: Hematuria, interstitial
nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis. Reproductive System and Breast
Disorders: Female infertility. General Disorders and Administration Site Conditions: Edema, thirst, pyrexia (chills
and fever), malaise. Investigations: Abnormal liver function tests, raised serum creatinine. From esomeprazole post-marketing
experience there have been uncommon reports (<1%) of peripheral edema, insomnia, paresthesia, somnolence, vertigo and
increased liver enzymes. There have also been rare reports (<0.1%) of blurred vision, hypersensitivity reactions
(e.g. angioedema, anaphylactic reaction/shock), myalgia, leukopenia, thrombocytopenia, depression, alopecia, hepatitis with or
without jaundice, hyponatremia, agitation, confusion, taste disturbance, bronchospasm, stomatitis, GI candidiasis, rash, dermatitis,
photosensitivity, arthralgia, malaise, and hyperhidrosis. Very rarely (<0.01%) agranulocytosis, erythema multiforme, StevensJohnson syndrome, toxic epidermal necrolysis, pancytopenia, aggression, hallucination, hepatic failure, hepatic encephalopathy,
interstitial nephritis, muscular weakness, gynecomastia, hypomagnesaemia and microscopic colitis have been reported.
DRUG INTERACTIONS:
Overview: Drug-Drug Interactions: Studies conducted with VIMOVO have shown no interactions between its two
components, naproxen and esomeprazole. Interaction studies have not been conducted with VIMOVO and other drugs.
Interactions for VIMOVO would be expected to reflect those of the monocomponents, taken separately, which are detailed below.
NSAID related drug-drug interactions: Acetylsalicylic acid (ASA) or other NSAIDs: The use of VIMOVO in addition to an
NSAID, including over-the-counter ones (such as ASA and ibuprofen) for analgesic and/or anti-inflammatory effects is NOT
recommended because of the absence of any evidence demonstrating synergistic benefits and the potential for additive adverse
reactions. The exception is the use of low-dose ASA for cardiovascular protection, when another NSAID containing product, such
as VIMOVO is being used for its analgesic/anti-inflammatory effect, keeping in mind that combination NSAID therapy is
associated with additive adverse reactions. However, in clinical trials, patients taking VIMOVO in combination with low-dose ASA
did not have an increased occurrence of gastric ulcers compared to patients taking VIMOVO alone. Ulcer complications such as
bleeding, perforation and obstruction were not studied in VIMOVO trials. Some NSAIDs (e.g. ibuprofen) may interfere with the
anti-platelet effects of low-dose ASA, possibly by competing with ASA for access to the active site of cyclooxygenase-1. Albumin
Bound Drugs: The naproxen anion may displace from their binding sites other drugs which are also albumin-bound and may lead
to drug interactions. For example, in patients receiving bishydroxycoumarin or warfarin, the addition of VIMOVO, which contains
naproxen, could prolong the prothrombin time. These patients should, therefore, be under careful observation. Similarly, patients
receiving VIMOVO and a hydantoin, sulfonamide or sulfonylurea should be observed for adjustment of dose if required. Antacids:
The rate of absorption of naproxen is altered by concomitant administration of antacids but is not adversely influenced by the
presence of food. Anti-coagulants: See WARNINGS AND PRECAUTIONS; Hematologic, Anti-coagulants. Anti-hypertensives: NSAIDs
may diminish the anti-hypertensive effect of Angiotensin Converting Enzyme (ACE) inhibitors. Combinations of ACE inhibitors,
angiotensin-II antagonists, or diuretics with NSAIDs might have an increased risk for acute renal failure and hyperkalemia. Blood
pressure and renal function (including electrolytes) should be monitored more closely in this situation, as occasionally there can
be a substantial increase in blood pressure. Naproxen and other NSAIDs can reduce the antihypertensive effect of propranolol and
other beta blockers as well as other antihypertensive agents. Anti-platelet Agents (including ASA): There is an increased risk of
bleeding, via inhibition of platelet function, when anti-platelet agents are combined with NSAIDs, such as naproxen, a component
of VIMOVO (see WARNINGS AND PRECAUTIONS; Hematologic, Anti-platelet Effects). Cyclosporin: Inhibition of renal prostaglandin
activity by NSAIDs may increase the plasma concentration of cyclosporine and/or the risk of cyclosporine induced nephrotoxicity.
Patients should be carefully monitored during concurrent use. Cholestyramine: Concomitant administration of cholestyramine can
delay the absorption of naproxen, but does not affect its extent. Digoxin: Concomitant administration of an NSAID with digoxin
can result in an increase in digoxin concentrations which may result in digitalis toxicity. Increased monitoring and dosage
adjustments of digitalis glycosides may be necessary during and following concurrent NSAID therapy. Diuretics: Clinical studies as
well as post-marketing observations have shown that NSAIDs can reduce the effect of diuretics. Glucocorticoids: Some studies
have shown that the concomitant use of NSAIDs and oral glucocorticoids increases the risk of GI adverse events such as ulceration
and bleeding. This is especially the case in older (>65 years of age) individuals. Lithium: Monitoring of plasma lithium
concentrations is advised when stopping or starting a NSAID, as increased lithium concentrations can occur. Methotrexate: Caution
is advised in the concomitant administration of naproxen and methotrexate since naproxen and other NSAIDs have been reported
to reduce the tubular secretion of methotrexate in an animal model, thereby possibly enhancing its toxicity. When given together
with proton pump inhibitors, methotrexate levels have been reported to increase in some patients. This may indicate that both
naproxen and esomeprazole could enhance the toxicity of methotrexate. The clinical relevance is likely to be greater in patients
receiving high doses of methotrexate and in patients with renal dysfunction. Caution should be used when VIMOVO is
administered concomitantly with methotrexate. In patients administered high doses of methotrexate a temporary withdrawal of
VIMOVO is recommended (see WARNINGS AND PRECAUTIONS; Renal). Probenecid: Probenecid given concurrently increases
naproxen anion plasma levels and extends its plasma half-life significantly. Caution is advised when probenecid is administered
concurrently. Selective Serotonin Reuptake Inhibitors (SSRIs): Concomitant administration of NSAIDs and SSRIs may increase the
risk of gastrointestinal ulceration and bleeding (see WARNINGS AND PRECAUTIONS; Gastrointestinal). Tacrolimus: As with all
NSAIDs caution is advised when tacrolimus is co-administered because of the increased risk of nephrotoxicity. Esomeprazole
related drug-drug interactions: Esomeprazole magnesium is metabolized by the cytochrome P-450 system (CYP), mainly
in the liver, through CYP 2C19 and CYP 3A4. There are no clinically significant interactions between esomeprazole and diazepam,
phenytoin, quinidine or cisapride (cisapride not marketed in Canada). Drugs known to inhibit CYP 2C19 or CYP 3A4 or both (such
as clarythromycin and voriconazole) may lead to increased esomeprazole serum levels by decreasing the rate of esomeprazole’s
metabolism. Drugs known to induce CYP 2C19 or CYP 3A4 or both (such as rifampin and St. John’s Wort) may lead to decreased
esomeprazole serum levels by increasing the esomeprazole metabolism (see DRUG-HERB INTERACTIONS). Diazepam:
Concomitant administration of EC-esomeprazole (30 mg once daily for 5 days) resulted in a 45% decrease in the clearance of
diazepam in healthy male volunteers. Studies in females have not been conducted. Increased levels of diazepam were seen some
12 hours after dosing and later when the plasma levels of diazepam were below its therapeutic range. Therefore, this interaction
is unlikely to be of clinical significance. Warfarin: Concomitant administration of 40 mg EC-esomeprazole (once daily for 3 weeks)
to male and female patients on stable anticoagulation therapy with warfarin, resulted in a 13% increase in trough plasma levels
of R-warfarin (the less potent enantiomer) while that of S-warfarin was unchanged. Coagulation times were stable throughout
the entire study period. No clinically significant interaction was observed. However, from post marketed use, cases of elevated
international normalized ratio (INR) of clinical significance have been reported during concomitant treatment with warfarin. Close
monitoring is recommended when initiating and ending treatment with warfarin or other coumarin derivatives (refer to approved
Product Monograph for warfarin or relevant coumarin derivative). Cilostazol (not marketed in Canada): Omeprazole as well as
esomeprazole act as inhibitors of CYP 2C19. Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study,
increased Cmax and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites, 3,4-dihydrocilostazol, by
29% and 69% respectively. Phenytoin: Concomitant administration of 40 mg EC-esomeprazole (once daily for 2 weeks) to male
and female epileptic patients stabilized on phenytoin, resulted in a 13% increase in trough plasma levels of phenytoin. This minor
interaction is unlikely to be of clinical relevance as dose reduction was not required in any patient nor was the profile and
frequency of adverse events affected. Results from a range of interaction studies with EC-esomeprazole versus other drugs
indicate that daily doses of 40 mg EC-esomeprazole, given for 5 to 21 days in male and/or female subjects, has no clinically
relevant interactions with CYP 1A2 (caffeine), CYP 2C9 (S-warfarin), and CYP 3A (quinidine, estradiol and cisapride [cisapride
not marketed in Canada]). Antiretroviral Drugs: Omeprazole, the racemate of esomeprazole, like other acid-reducing agents, has
been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions
are not always known. A change in gastric pH may change the absorption of the antiretroviral drug. Other possible interaction
mechanisms are via CYP 2C19. Reports indicate that omeprazole has a significant impact on atazanavir exposure, decreasing
AUC, Cmax and Cmin. This interaction is only partially overcome by the addition of ritonavir to the atazanavir treatment regimen.
Similarly, decreased serum levels of nelfinavir have also been reported when given together with omeprazole. Concomitant
administration of omeprazole with atazanavir and nelfinavir is not recommended. For other antiretroviral drugs, such as
saquinavir, increased serum levels have been reported. There are also some antiretroviral drugs where unchanged serum levels
have been reported when given with omeprazole. Due to the similar pharmacodynamic effects and pharmacokinetic properties
of omeprazole and esomeprazole, concomitant administration of EC-esomeprazole and antiretroviral drugs such as atazanavir and
nelfinavir is not recommended (see WARNINGS AND PRECAUTIONS). Methotrexate: When given together with proton pump
inhibitors, methotrexate levels have been reported to increase in some patients. This may indicate that esomeprazole
could enhance the toxicity of methotrexate. Caution should be used when VIMOVO is administered concomitantly with
methotrexate. In patients administered high doses of methotrexate, a temporary withdrawal of VIMOVO is recommended.
Voriconazole: Concomitant administration of EC-esomeprazole with a combined inhibitor of CYP 2C19 and CYP 3A4 may result
in more than double the levels of esomeprazole exposure. As with all drugs that reduce gastric acidity, changes in plasma levels
of other drugs whose absorption is pH dependent (e.g. ketoconazole, itraconazole or erlotinib) must be taken into account when
they are co-administered with esomeprazole. The absorption of ketoconazole, itraconazole or erlotinib can decrease during
treatment with esomeprazole. Digoxin: The absorption of digoxin can increase during treatment with esomeprazole and other
drugs that reduce gastric acidity. Concomitant treatment with omeprazole (20 mg daily) and digoxin in ten healthy subjects
increased the bioavailability of digoxin by an average of 10% (up to 30% in two out of ten subjects). Other interactions: As
demonstrated with other PPIs, prolonged use may impair the absorption of protein-bound Vitamin B12 and may contribute to the
development of Vitamin B12 deficiency. Drug-Food Interactions: Concomitant administration of food can delay the
absorption of the naproxen component of VIMOVO, but does not affect its extent of absorption. Concomitant administration of
food however, does not delay the absorption of the esomeprazole component of VIMOVO, but significantly reduces its extent of
absorption (see DOSAGE AND ADMINISTRATION; Dosing Considerations and Product Monograph, ACTIONS AND CLINICAL
PHARMACOLOGY; Pharmacokinetics, Absorption, Food Effect). Drug-Herb Interactions: Use of St. John’s Wort may lead to
decreased esomeprazole serum levels by increasing the esomeprazole metabolism (see DRUG INTERACTIONS, Esomeprazole
related Drug-Drug Interactions). Drug-Laboratory Interactions: During treatment with antisecretory drugs,
chromogranin A (CgA) increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for
neuroendocrine tumours. To avoid this interference esomeprazole treatment should be temporarily stopped five days before CgA
measurements. (See also WARNINGS AND PRECAUTIONS; Special Populations, Monitoring and Laboratory Tests).
Drug-Lifestyle Interactions: There are no specific studies about effects on the ability to drive vehicles and to use machinery.
It should be taken into account that some of the adverse effects (e.g. dizziness) reported following the use of VIMOVO may
reduce the ability to react. Patients who experience visual disturbances or other central nervous system disturbances should
refrain from these activities. Concurrent use of alcohol with an NSAID may increase the risk of gastrointestinal side effects,
including ulceration and hemorrhage.
DOSAGE AND ADMINISTRATION:
Missed Dose: The missed dose should be taken as soon as remembered, and then the regular dosing schedule should be
continued. Two doses of VIMOVO should not be taken at the same time. Special Populations: Hepatic Insufficiency: VIMOVO
is not recommended for use in patients with severe hepatic impairment (see CONTRAINDICATIONS, WARNINGS AND
PRECAUTIONS; Hepatic/Biliary/Pancreatic and WARNINGS AND PRECAUTIONS; Special Populations). Renal Insufficiency:
VIMOVO is not recommended for use in patients with severe renal impairment or deteriorating renal disease (see
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS; Renal and WARNINGS AND PRECAUTIONS; Special Populations). Poor
Metabolizers: Dosage adjustment based on CYP 2C19 status is not necessary (see WARNINGS AND PRECAUTIONS; Special
Populations and Product Monograph, ACTION AND CLINICAL PHARMACOLOGY; Pharmacokinetics, Special Populations).
OVERDOSAGE:
For management of suspected drug overdose, contact your regional Poison Control Centre.
There is no clinical data on overdosage with VIMOVO. Any effects of an overdose with VIMOVO would be expected to reflect those
of the monocomponents of naproxen and esomeprazole, taken separately. Naproxen: Significant overdosage may be
characterized by drowsiness, dizziness, disorientation, heartburn, indigestion, epigastric pain, abdominal discomfort, nausea,
vomiting, transient alterations in liver function, hypoprothrombinemia, renal dysfunction, metabolic acidosis and apnea. A few
patients have experienced convulsions, but it is not clear whether or not these were naproxen related. Gastrointestinal bleeding
may occur. Hypertension, acute renal failure, respiratory depression and coma may occur after the ingestion of NSAIDs but are
rare. Anaphylactoid reactions have been repeated with therapeutic ingestion of NSAIDs, and may occur following an overdose.
Patients should be managed by symptomatic and supportive care following NSAIDs overdose. There are no specific antidotes.
Prevention of further absorption (e.g. activated charcoal) may be indicated in patients seen within 4 hours of ingestion with
symptoms or following a large overdose. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be
useful due to high protein binding. Esomeprazole: Limited information is available on the effects of higher doses in man, and
specific recommendations for treatment cannot be given. Experience from a patient who deliberately ingested an overdose of
EC-esomeprazole (280 mg), demonstrated symptoms that were transient, and included weakness, loose stools and nausea.
Single doses of 80 mg EC-esomeprazole have been shown to be uneventful. No specific antidote is known. Esomeprazole is
extensively protein-bound and is therefore not readily dialyzable. Treatment should be symptomatic and general supportive
measures should be utilized.
Product Monograph is available upon request from AstraZeneca Canada Inc.
Revision date: November 17, 2011.
VIM171E
AstraZeneca Canada Inc.
1004 Middlegate Road, Mississauga, Ontario L4Y 1M4
www.astrazeneca.ca
T 1-800-668-6000 F 1-800-250-1909
VIMOVO® and the AstraZeneca logo are registered trademarks of the AstraZeneca group of companies. © AstraZeneca 2012
2.5 mg tablets
PRESCRIBING SUMMARY
PATIENT SELECTION CRITERIA
THERAPEUTIC CLASSIFICATION
Anti-coagulant (direct Factor Xa inhibitor)
ELIQUIS (apixaban) is indicated for the prevention of venous
thromboembolic events (VTE) in adult patients who have undergone
elective knee or hip replacement surgery.
Pregnant Women: There are no data from the use of apixaban in
pregnant women. Animal studies do not indicate direct or indirect
harmful effects with respect to reproductive toxicity. Apixaban is not
recommended during pregnancy.
Nursing Women: It is unknown whether apixaban or its metabolites are
excreted in human milk. Available data in animals have shown excretion
of apixaban in milk. In rats, this resulted in high milk-to-maternal plasma
ratios (apixaban AUC ~ 30, Cmax~ 8). A risk to newborns and infants
cannot be excluded. A decision must be made to either discontinue
breast-feeding or to discontinue/abstain from ELIQUIS therapy.
Hip Fracture Surgery Patients: Apixaban has not been studied in clinical
trials in patients undergoing hip fracture surgery to evaluate efficacy and
safety in these patients. Therefore, ELIQUIS is not recommended in these
patients.
Pediatrics (<18 years of age): The safety and efficacy of ELIQUIS in
children below age 18 have not yet been established. No data are available.
Geriatrics (≥65 years of age): No dose adjustment is necessary
in elderly patients. Of the total number of subjects in clinical studies
of apixaban in VTE prevention following major orthopedic surgery
(N=5924), 50 percent were 65 and older, while 16 percent were 75
and older. No clinically significant differences in safety or effectiveness
were observed when comparing subjects in different age groups (see
WARNINGS AND PRECAUTIONS, Renal; DOSAGE AND ADMINISTRATION,
Renal Impairment and Geriatrics).
Patients on Dual Antiplatelet Therapy: In high-risk post-acute coronary
syndrome patients, apixaban 5 mg BID as an adjunct to standard
antiplatelet treatment has lead to significantly increased bleeding.
CONTRAINDICATIONS
ELIQUIS is contraindicated in patients with clinically significant active
bleeding; lesions at increased risk of clinically significant bleeding:
cerebral infarct (ischemic or hemorrhaghic) in the previous 6 months,
patients with spontaneous impairment of hemostasis; hepatic
disease associated with coagulopathy and clinically relevant bleeding
risk; concomitant systemic treatment with strong inhibitors of both
CYP3A4 and P-gp; and hypersensitivity to apixaban or any of the
ingredients of the formulation.
SAFETY INFORMATION
General: Interaction With Inhibitors of Both Cytochrome P450 3A4
(CYP3A4) and P-glycoprotein (P-gp): Co-administration of apixaban with
ketoconazole (400 mg o.d.), a strong inhibitor of CYP3A4 and P-gp, led
to a 2-fold increase in mean apixaban AUC and a 1.6-fold increase in
apixaban Cmax. Therefore, the use of ELIQUIS is contraindicated in patients
receiving concomitant systemic treatment with strong inhibitors of both
CYP3A4 and P-gp, such as azole-antimycotics (e.g., ketoconazole,
itraconazole, voriconazole and posaconazole), and HIV protease inhibitors
(e.g., ritonavir). These medicinal products may increase apixaban
exposure by 2-fold (see Drug-Drug Interactions). No dose adjustment for
apixaban is required when co-administered with less potent inhibitors of
CYP3A4 and/or P-gp.
Interaction With Inducers of Both CYP3A4 and P-gp: The concomitant
use of ELIQUIS with strong CYP3A4 and P-gp inducers (e.g., rifampin,
phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may
lead to a ~50% reduction in apixaban exposure. Use caution when
co-administering ELIQUIS with strong inducers of both CYP3A4 and P-gp
(see Drug-Drug Interactions).
Interaction With Other Medicinal Products Affecting Hemostasis: Care is
to be taken if patients are treated concomitantly with medicinal products
affecting hemostasis such as non-steroidal anti-inflammatory drugs
(NSAIDs), acetylsalicylic acid, or other platelet aggregation inhibitors or
antithrombotic agents (see Drug-Drug Interactions).
Hematologic: Hemorrhage Risk: As with other anticoagulants, patients
taking ELIQUIS are to be carefully observed for signs of bleeding. ELIQUIS
is recommended to be used with caution in conditions with increased
risk of hemorrhage, such as: congenital or acquired bleeding disorders;
active ulcerative gastrointestinal disease; bacterial endocarditis;
thrombocytopenia; platelet disorders; history of hemorrhagic stroke;
severe uncontrolled hypertension; and recent brain, spinal, or
ophthalmological bleeding or surgeries. ELIQUIS administration should
be discontinued if severe hemorrhage occurs (see OVERDOSAGE). In
the event of hemorrhagic complications, treatment must be discontinued
and the source of bleeding investigated. The initiation of appropriate
treatment, e.g., surgical hemostasis or the transfusion of fresh frozen
plasma, should be considered. If life-threatening bleeding cannot be
controlled by the above measures, administration of recombinant factor
VIIa may be considered. However, there is currently no experience with
the use of recombinant factor VIIa in individuals receiving apixaban.
Re-dosing of recombinant factor VIIa could be considered and titrated
depending on improvement of bleeding.
Hepatic/Biliary/Pancreatic: Hepatic Impairment: ELIQUIS is
contraindicated in patients with hepatic disease associated with coagulopathy
and clinically relevant bleeding risk (see CONTRAINDICATIONS). ELIQUIS
is not recommended in patients with severe hepatic impairment. ELIQUIS
should be used with caution in patients with mild or moderate hepatic
impairment (Child Pugh A or B) (see DOSAGE AND ADMINISTRATION,
Special Populations, Hepatic Impairment).
Patients with elevated liver enzymes (ALT/AST > 2 x ULN, or total bilirubin
≥1.5 x ULN) were excluded in the clinical trials in patients with major
orthopedic surgery. Therefore, ELIQUIS should be used with caution in this
population.
Peri-Operative Considerations: Spinal/Epidural Anesthesia or Puncture:
When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural
puncture is employed, patients treated with antithrombotic agents for
prevention of thromboembolic complications are at risk of developing an
epidural or spinal hematoma which can result in long-term or permanent
paralysis. The risk of these events may be increased by the post-operative
use of indwelling epidural catheters or the concomitant use of medicinal
products affecting hemostasis. Indwelling epidural or intrathecal catheters
must be removed at least 5 hours prior to the first dose of ELIQUIS. The risk
of transient or permanent paralysis may also be increased by traumatic or
repeated epidural or spinal puncture. Patients are to be frequently monitored
for signs and symptoms of neurological impairment (e.g., numbness
or weakness of the legs, bowel or bladder dysfunction). If neurological
compromise is noted, urgent diagnosis and treatment is necessary. Prior
to neuraxial intervention, the physician should consider the potential benefit
versus the risk in anticoagulated patients or in patients to be anticoagulated
for thromboprophylaxis. An epidural catheter should not be withdrawn within
24 hours (~ 2 x T½) of the last administration of ELIQUIS. ELIQUIS should be
administered no sooner than 5 hours after the removal of the catheter.
Renal: Renal Impairment: No dose adjustment is necessary in patients with
mild or moderate renal impairment (creatinine clearance ≥30 mL/min). Limited
clinical data in patients with severe renal impairment (creatinine clearance
15-29 mL/min) indicate that apixaban plasma concentrations are increased;
therefore, apixaban is to be used with caution in these patients because of a
potentially higher bleeding risk. Because there is very limited clinical experience
in patients with creatinine clearance <15 mL/min and there are no data in
patients undergoing dialysis, apixaban is not recommended in these patients
(see DOSAGE AND ADMINISTRATION, Special Populations, Renal Impairment).
Pregnant Women: There are no data from the use of apixaban in
pregnant women. Animal studies do not indicate direct or indirect
harmful effects with respect to reproductive toxicity. Apixaban is not
recommended during pregnancy.
Nursing Women: It is unknown whether apixaban or its metabolites are
excreted in human milk. Available data in animals have shown excretion
of apixaban in milk. In rats, this resulted in high milk-to-maternal plasma
ratios (apixaban AUC ~ 30, Cmax ~ 8). A risk to newborns and infants
cannot be excluded. A decision must be made to either discontinue
breast-feeding or to discontinue/abstain from ELIQUIS therapy.
Hip Fracture Surgery Patients: Apixaban has not been studied in clinical
trials in patients undergoing hip fracture surgery to evaluate efficacy and
safety in these patients. Therefore, ELIQUIS is not recommended in these
patients.
Pediatrics (<18 years of age): The efficacy and safety of ELIQUIS in
children below age 18 have not yet been established. No data are available.
Geriatrics (≥65 years of age): No dose adjustment is necessary in elderly
patients. Of the total number of subjects in clinical studies of apixaban in
VTE prevention following major orthopedic surgery (N=5924), 50 percent
were 65 and older, while 16 percent were 75 and older. No clinically
significant differences in safety or effectiveness were observed when
comparing subjects in different age groups.
Patients on Dual Antiplatelet Therapy: In high-risk post-acute coronary
syndrome patients, apixaban 5 mg BID as an adjunct to standard
antiplatelet treatment has lead to significantly increased bleeding.
Monitoring and Laboratory Tests: The pharmacodynamic effects
of apixaban are reflective of the mechanism of action (FXa inhibition).
As a result of FXa inhibition, apixaban prolongs clotting tests such
as prothrombin time (PT), INR and activated partial thromboplastin
time (aPTT). Changes observed in these clotting tests at the expected
therapeutic dose are small and subject to a high degree of variability.
They are not recommended to assess the pharmacodynamic effects
of apixaban. Apixaban also demonstrates anti-FXa activity as evident
by reduction in Factor Xa enzyme activity in the Rotachrom Heparin
chromogenic assay. Anti-FXa activity exhibits a close direct linear
relationship with apixaban plasma concentration, reaching maximum
values at the time of apixaban peak plasma concentrations. The
relationship between apixaban plasma concentration and anti-FXa
activity is linear over a wide dose range of apixaban, and precision of
the Rotachrom assay is well within acceptable limits for use in a clinical
laboratory. The dose- and concentration-related changes observed
following apixaban administration are more pronounced, and less variable,
with anti-FXa activity compared with clotting tests. Predicted steadystate peak and trough anti-FXa activity with apixaban 2.5 mg BID dosing
are 1.3 IU/mL (5th/95th percentile 0.67-2.4 IU/mL) and 0.84 IU/mL
(5th/95th percentile 0.37-1.8 IU/mL), respectively, demonstrating less
than a 1.6-fold fluctuation in peak-to-trough anti-FXa activity over the
dosing interval.
Although treatment with apixaban does not require routine monitoring
of exposure, the Rotachrom anti-FXa assay may be useful in situations
where knowledge of apixaban exposure may help to inform clinical
decisions.
ADVERSE REACTIONS
(see Supplemental Product Information and Product Monograph for
full listing)
The safety of apixaban 2.5 mg twice daily has been evaluated
in one Phase II and three Phase III studies (ADVANCE 1, 2 and 3)
including 5,924 patients exposed to apixaban after undergoing major
orthopedic surgery of the lower limbs (elective hip replacement or
elective knee replacement) and treated for up to 38 days. Common
adverse reactions (occurring at a rate of ≥1%) were nausea, anemia,
contusion and hemorrhage.
Bleeding In Hip or Knee Replacement Surgery Studies: As with
other anticoagulants, bleeding may occur during apixaban therapy in the
presence of associated risk factors such as organic lesions liable to bleed.
And, as with any anticoagulant, the use of ELIQUIS may be associated with
an increased risk of occult or overt bleeding from any tissue or organ, which
may result in posthemorrhagic anemia. The signs, symptoms, and severity
will vary according to the location and degree or extent of the bleeding (see
WARNINGS AND PRECAUTIONS, Hematologic, Hemorrhage Risk).
Major bleeding, the composite of major and clinically relevant non-major
(CRNM) bleeding, and all bleeding occurred with similar frequency
in patients treated with apixaban 2.5 mg twice daily or enoxaparin
40 mg once daily and lower frequency with apixaban 2.5 mg twice daily
compared with enoxaparin 30 mg every 12 hours (see Table 1 in the
Supplemental Information). All the bleeding criteria included surgical site
bleeding.
In all Phase III studies, bleeding was assessed beginning with the first
dose of double-blind study drug. In studies that compared apixaban to the
40 mg once daily dose of enoxaparin, the first dose of either enoxaparin
or injectable placebo was given 9 to 15 hours before surgery. Bleeding
during the treatment period for these studies includes events that
occurred before the first dose of apixaban, which was given 12-24 hours
after surgery. Bleeding during the post-surgery treatment period only
included events occurring after the first dose of study drug after surgery.
Over half the occurrences of major bleeding in the apixaban group in these
two studies occurred prior to the first dose of apixaban. For the study that
compared apixaban with enoxaparin given every 12 hours, the first dose
of both oral and injectable study drugs was 12-24 hours after surgery.
For this study, the treatment period and post-surgery treatment period
are identical. Table 1 in the Supplemental Information shows the bleeding
results from the treatment period and the post-surgery treatment period.
In total, 11% of the patients treated with apixaban 2.5 mg twice daily
experienced adverse reactions. Adverse reactions occurring in ≥1%
of patients undergoing hip or knee replacement surgery in the one
Phase II study and the three Phase III studies are listed in Table 2 in the
Supplemental Information.
Reporting Suspected Side Effects
To monitor drug safety, Health Canada through the Canada Vigilance
Program collects information on serious and unexpected effects of
drugs. If you suspect you have had a serious or unexpected reaction
to this drug you may notify Canada Vigilance by:
Toll-free telephone: 866-234-2345
Toll-free fax: 866-678-6789
Online: www.healthcanada.gc.ca/medeffect
By email: [email protected]
DRUG INTERACTIONS
(see Table 3 in the Supplemental Product Information and Product
Monograph for full listing).
Overview: CYP Inhibition: ELIQUIS does not inhibit CYP3A4 or any other
major CYP isoenzymes. In vitro apixaban studies showed no inhibitory
effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9,
CYP2D6 or CYP3A4 (IC50 >45 µM) and weak inhibitory effect on the
activity of CYP2C19 (IC50 >20 µM) at concentrations that are significantly
greater than peak plasma concentrations observed in patients.
CYP Induction: ELIQUIS does not induce CYP3A4 or any other major CYP
isoenzymes. Apixaban did not induce CYP1A2, CYP2B6, CYP3A4/5 at a
concentration up to 20 µM.
P-gp Inhibition: ELIQUIS does not inhibit P-gp based on in vitro data.
Drug-Drug Interactions: Apixaban is metabolized mainly via CYP3A4/5
with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2.
Apixaban is a substrate of transport proteins, P-gp and breast cancer
resistance protein (BCRP).
Interaction With Inhibitors of Both Cytochrome P450 3A4 (CYP3A4) and
P-gp: Co-administration of apixaban with ketoconazole 400 mg q.d.,
a strong inhibitor of both CYP3A4 and P-gp, led to a 2-fold increase in
apixaban mean AUC and a 1.6-fold increase in apixaban Cmax. The use
of ELIQUIS is contraindicated in patients receiving concomitant systemic
treatment with strong inhibitors of both CYP3A4 and P-gp, such as
azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole,
or posaconazole) and HIV protease inhibitors (e.g., ritonavir) (see
CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS – General).
Active substances moderately inhibiting the apixaban elimination
pathways, CYP3A4 and/or P-gp, are expected to increase apixaban
plasma concentrations to a lesser extent. Diltiazem 360 mg q.d. led to
a 1.4 and 1.3 fold increase in mean apixaban AUC and Cmax, respectively.
Naproxen (500 mg), an inhibitor of P-gp, led to a 1.5 fold and 1.6 fold
increase in mean apixaban AUC and Cmax, respectively. No dose adjustment
for apixaban is required when co-administered with less potent inhibitors of
CYP3A4 and/or P-gp.
Interaction With Inducers of Both CYP3A4 and P-gp: Co-administration of
apixaban with rifampicin 600 mg q.d., a strong inducer of both CYP3A4
and P-gp, led to an approximate 54% and 42% decrease in mean apixaban
AUC and Cmax, respectively. The concomitant use of apixaban with other
strong CYP3A4 and P-gp inducers (e.g., phenytoin, carbamazepine,
phenobarbital or St. John’s Wort) may also lead to reduced apixaban
plasma concentrations. Strong CYP3A4 inducers should be administered
with caution in combination with ELIQUIS.
Interaction With Other Medicinal Products Affecting Hemostasis: Care is
to be taken if patients are treated concomitantly with medicinal products
affecting hemostasis such as non-steroidal anti-inflammatory drugs
(NSAIDs), including acetylsalicylic acid. Concomitant use of other platelet
aggregation inhibitors or other antithrombotic agents with ELIQUIS is not
recommended because these medicinal products typically increase the
bleeding risk.
Drug-Food Interactions: ELIQUIS can be taken with or without food (see
DOSAGE AND ADMINISTRATION).
Drug-Herb Interactions: The concomitant use of ELIQUIS with strong
CYP3A4 and P-gp inducers (e.g., St. John’s Wort) may lead to reduced
apixaban plasma concentrations. Use caution when co-administering
ELIQUIS with strong inducers of both CYP3A4 and P-gp.
Drug-Laboratory Interactions: Clotting tests (e.g., PT, INR, and aPTT) are
affected as expected by the mechanism of action of apixaban. Changes
observed in these clotting tests at the expected therapeutic dose are small
and subject to a high degree of variability.
ADMINISTRATION
The recommended dose of ELIQUIS for VTE prevention in patients
following elective hip and knee replacement surgery is 2.5 mg twice
daily. ELIQUIS can be taken with or without food. The initial dose
should be taken 12 to 24 hours after surgery. In patients undergoing
hip replacement surgery, the recommended duration of treatment
is 32 to 38 days. In patients undergoing knee replacement surgery,
the recommended duration of treatment is 10 to 14 days.
SPECIAL POPULATIONS
Renal Impairment: No dose adjustment is necessary in patients with mild
or moderate renal impairment (creatinine clearance ≥30 mL/min). Limited
clinical data in patients with severe renal impairment (creatinine clearance
15-29 mL/min) indicate that apixaban plasma concentrations are increased;
therefore, apixaban is to be used with caution in these patients because
of a potentially higher bleeding risk. Because there is very limited clinical
experience in patients with creatinine clearance <15 mL/min and there are
no data in patients undergoing dialysis, apixaban is not recommended in
these patients (see WARNINGS AND PRECAUTIONS).
Hepatic Impairment: ELIQUIS is contraindicated in patients with hepatic
disease associated with coagulopathy and clinically relevant bleeding risk
(see CONTRAINDICATIONS). ELIQUIS is not recommended in patients
with severe hepatic impairment (see WARNINGS AND PRECAUTIONS).
ELIQUIS should be used with caution in patients with mild or moderate
hepatic impairment (Child Pugh A or B). No dose adjustment is required in
patients with mild or moderate hepatic impairment (see WARNINGS AND
PRECAUTIONS). Patients with elevated liver enzymes (ALT/AST > 2 x ULN,
or total bilirubin ≥1.5 x ULN) were excluded in the clinical trials in patients
with major orthopedic surgery. Therefore, ELIQUIS should be used with
caution in this population.
Body Weight: No dose adjustment required.
Gender: No dose adjustment required.
Ethnicity: No dose adjustment required.
Pediatrics (<18 years of age): The efficacy and safety of ELIQUIS
in children below age 18 have not yet been established. No data are
available.
Geriatrics (≥65 years of age): No dose adjustment required (see
WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics).
Missed Dose: If a dose is missed, the patient should take ELIQUIS
immediately and then continue with twice daily intake as before.
OVERDOSAGE
For management of a suspected drug overdose, contact your
regional Poison Control Centre.
There is no antidote to ELIQUIS. Overdose of ELIQUIS may result in
hemorrhagic complications, due to its pharmacologic properties. In the
event of hemorrhagic complications, treatment must be discontinued,
and the source of bleeding investigated. Appropriate treatment, e.g.,
surgical hemostasis or the transfusion of fresh frozen plasma, should be
considered.
In controlled clinical trials, orally-administered apixaban in healthy
subjects at doses up to 50 mg daily for 3 to 7 days (25 mg BID for 7 days
or 50 mg QD for 3 days) [10 times the daily maximum recommended
human dose] had no clinically relevant adverse effects. A preclinical study
in dogs demonstrated that oral administration of activated charcoal up
to 3 hours after apixaban administration reduced apixaban exposure;
therefore, activated charcoal may be considered in the management of
apixaban overdose.
ADVERSE REACTIONS
Table 1 - Bleeding in Patients Undergoing Elective Hip or Knee Replacement Surgery
Bleeding endpoint a
ADVANCE-3
Hip replacement surgery
ADVANCE-2
Knee replacement surgery
ADVANCE-1
Knee replacement surgery
Apixaban
Enoxaparin
Apixaban
Enoxaparin
Apixaban
Enoxaparin
2.5 mg po bid
40 mg sc qd
2.5 mg po bid
40 mg sc qd
2.5 mg po bid
30 mg sc q12h
35±3 days
35±3 days
12±2 days
12±2 days
12±2 days
12±2 days
First dose
First dose
First dose
First dose
First dose
First dose
12 to 24 hours post-surgery
9 to 15 hours prior to surgery
9 to 15 hours prior to surgery
n = 2673
n = 2659
n = 1501
n = 1508
n = 1596
n = 1588
All treated
Treatment Periodb
Major
22 (0.8%)
18 (0.7%)
9 (0.6%)
14 (0.9%)
11 (0.7%)
22 (1.4%)
Fatal
0
0
0
0
0
1 (<0.1%)
Major
129 (4.8%)
134 (5.0%)
53 (3.5%)
72 (4.8%)
46 (2.9%)
68 (4.3%)
313 (11.7%)
334 (12.6%)
104 (6.9%)
126 (8.4%)
85 (5.3%)
108 (6.8%)
+CRNM
All
Post-surgery Treatment Period
Major
9 (0.3%)
11 (0.4%)
4 (0.3%)
9 (0.6%)
11 (0.7%)
22 (1.4%)
Fatal
0
0
0
0
0
1 (<0.1%)
Major
96 (3.6%)
115 (4.3%)
41 (2.7%)
56 (3.7%)
46 (2.9%)
68 (4.3%)
261 (9.8%)
293 (11.0%)
89 (5.9%)
103 (6.8%)
85 (5.3%)
108 (6.8%)
+CRNM
All
a
b
All bleeding criteria included surgical site bleeding.
Includes bleeding events which occurred before the first dose of apixaban.
Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be
compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Table 2: Adverse Reactions Occurring in ≥1% of Patients in Either Group Undergoing Hip or Knee Replacement Surgery
Apixaban
2.5 mg BID PO
n= 5924
(%)
Enoxaparin
40 mg SC OD or 30 mg SC q12h
n= 5904
(%)
153 (2.6)
159 (2.7)
153 (2.6)
178 (3.0)
GASTROINTESTINAL DISORDERS
Nausea
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia (including post-operative and hemorrhagic anemia, and respective laboratory parameters)
VASCULAR DISORDERS
Hemorrhage (including hematoma, and vaginal and urethral hemorrhage)
67 (1.1)
81 (1.4)
INJURY, POISONING AND PROCEDURAL COMPLICATIONS
Contusion
83 (1.4)
115 (1.9)
Post-procedural hemorrhage (including post-procedural hematoma, wound hemorrhage, vessel puncture
54 (0.9)
60 (1.0)
site hematoma and catheter site hemorrhage)
HEPATOBILIARY DISORDERS
Transaminases increased (including alanine aminotransferase increased and alanine aminotransferase
50 (0.8)
71 (1.2)
Aspartate aminotransferase increased
47 (0.8)
69 (1.2)
Gamma-glutamyltransferase increased
38 (0.6)
65 (1.1)
abnormal)
Less common Clinical Trial adverse reactions in apixaban-treated patients undergoing hip or knee replacement surgery occurring at a frequency of ≥0.1% to <1%:
Blood and lymphatic system disorders: thrombocytopenia (including platelet count decreases)
Gastrointestinal disorders: gastrointestinal hemorrhage (including hematemesis and melena), hematochezia
Hepatobiliary disorders: liver function test abnormal, blood alkaline phosphatase increased, blood bilirubin increased
Injury, poisoning and procedural complications: wound secretion, incision site hemorrhage (including incision site hematoma), operative hemorrhage
Renal and urinary disorders: hematuria (including respective laboratory parameters)
Respiratory, thoracic and mediastinal disorders: epistaxis
Vascular disorders: hypotension (including procedural hypotension)
Less common Clinical Trial adverse reactions in apixaban-treated patients undergoing hip or knee replacement surgery occurring at a frequency of <0.1%:
Gingival bleeding, hemoptysis, hypersensitivity, muscle hemorrhage, ocular hemorrhage (including conjunctival hemorrhage), rectal hemorrhage
DRUG INTERACTIONS
Table 3 - Summary of Drug-Drug Interactions
Proper Name
Reference
Effect
Clinical Comment
Ketoconazole
CT
Co-administration of apixaban with ketoconazole (400 mg once a day) a strong inhibitor of both CYP3A4 and P-gp led to a
2-fold increase in mean apixaban AUC and a 1.6 fold increase in mean apixaban Cmax.
The use of ELIQUIS is contraindicated in patients receiving systemic treatment with strong inhibitors of both CYP3A4 and
P-gp (such as ketoconazole, itraconazole, voriconazole, posaconazole and ritonavir).
Diltiazem
CT
Diltiazem (360 mg once a day), considered as moderate CYP3A4 and a weak P-gp inhibitor, led to a 1.4 fold increase in
mean apixaban AUC and a 1.3 fold increase in Cmax.
No dose adjustment for apixaban is required.
Naproxen
CT
Apixaban had no effect on naproxen AUC or Cmax. Naproxen (500 mg, single dose) an inhibitor of P-gp but not an inhibitor of
CYP3A4, led to a 1.5-fold and 1.6-fold increase in mean apixaban AUC and Cmax, respectively.
Corresponding increases in clotting tests were observed for apixaban. No changes were observed in the effect of naproxen
on arachidonic acid-induced platelet aggregation and no clinically relevant prolongation of bleeding time was observed after
concomitant administration of apixaban and naproxen.
No dose adjustment for either agent is required.
Rifampin
CT
Co-administration of apixaban with rifampin, a strong inducer of both CYP3A4 and P-gp, rifampin, led to an approximate
54% and 42% decrease in mean apixaban AUC and Cmax, respectively.
Strong inducers of both CYP3A4 and P-gp should be co-administered with caution.
Enoxaparin
CT
Enoxaparin had no effect on the pharmacokinetics of apixaban. After combined administration of enoxaparin (40 mg single
dose) with apixaban (5 mg single dose), an additive effect on anti-Factor Xa activity was observed.
Due to an increased bleeding risk, care is to be taken if patients are treated concomitantly with any other anticoagulants.
Acetylsalicyclic acid (ASA)
CT
Pharmacokinetic or pharmacodynamic interactions were not evident when apixaban was co-administered with acetylsalicylic
acid 325 mg once a day.
Clopidogrel
CT
Pharmacokinetic or pharmacodynamic interactions were not evident when apixaban was co-administered with clopidogrel
75 OD or with the combination of clopidogrel 75 mg and acetylsalic acid 162 mg OD. However, an increased bleeding risk
on dual antiplatelet therapy was found in a clinical trial in ACS.
In a clinical trial of high-risk post-acute coronary syndrome patients, characterized by multiple cardiac and noncardiac
comorbidities, who received ASA or the combination of ASA and clopidogrel, a significant increase by 2-fold in bleeding risk
was reported for apixaban compared to placebo.
Atenolol
CT
Co-administration of a single dose of apixaban (10 mg) and atenolol (100 mg), a common beta-blocker, did not alter the
pharmacokinetics of atenolol or have a clinically relevant effect on apixaban pharmacokinetics. Following administration of
the two drugs together, mean apixaban AUC and Cmax were 15% and 18% lower than when administered alone.
Famotidine
CT
The administration of apixaban 10 mg with famotidine 40 mg had no effect on apixaban AUC or Cmax.
No dose adjustment for apixaban is required when co-administered with famotidine. These data indicate that apixaban
pharmacokinetics are not likely to be altered by changes in gastric pH or co-administration with other organic cation
transport inhibitors.
Digoxin
CT
Co-administration of apixaban (20 mg once a day) and digoxin (0.25 mg once a day), a P-gp substrate, did not affect
digoxin AUC or Cmax.
No dose adjustment for digoxin is required. Apixaban does not inhibit P-gp mediated substrate transport.
CT = clinical trial
Complete Product Monograph available on request.
Product Monograph version: December 13, 2011
60
OCTOBER 9, 2012
Inside Dr. Brian Day’s
B.C. Charter challenge
Suit echoes 2005
Quebec ruling
on wait times
BY DavID GoDkIn
Vancouver

T
he head of two privately
run surgical clinics in
Vancouver says he will
continue to challenge the
constitutionality of provincial
medicare legislation if the
Supreme Court of British
Columbia grants an injunction
preventing him from extrabilling patients.
This follows the release of
NOR_78044_PI_MedPost_Pad_E:NOR_78044_PI_Pad_E_R4
6/27/12
We treat thousands of
patients a year that are
removed from the (public)
wait lists.—Dr. Brian Day
a six-month audit in June that
found the Cambie Surgical
Centre and the Specialist
11:07 AM
Prescribing Summary
THERAPEUTIC CLASSIFICATION: Antihypertensive-antianginal agent
INDICATIONS AND CLINICAL USE: Hypertension: PrNORVASC® (amlodipine besylate)
is indicated in the treatment of mild to moderate essential hypertension. Combination
of NORVASC with a diuretic, a beta-blocking agent, or an angiotensin converting
enzyme inhibitor has been found to be compatible and showed additive
antihypertensive effect.
Chronic Stable Angina: NORVASC is indicated for the management of chronic stable
angina (effort-associated angina) in patients who remain symptomatic despite
adequate doses of beta-blockers and/or organic nitrates or who cannot tolerate those
agents. NORVASC may be tried in combination with beta-blockers in chronic stable
angina in patients with normal ventricular function. When such concomitant therapy is
introduced, care must be taken to monitor blood pressure closely since hypotension
can occur from the combined effects of the drugs.
CONTRAINDICATIONS: NORVASC is contraindicated in patients with severe
hypotension (less than 90 mmHg systolic).
Use in Pregnancy: There is no clinical experience with NORVASC in pregnant women.
NORVASC should be used during pregnancy only if the potential benefit outweighs the
potential risk to the mother and fetus.
Nursing Mothers: It is not known whether amlodipine is excreted in human milk. Since
amlodipine safety in newborns has not been established, NORVASC should not be
given to nursing mothers.
Use in Children: The use of NORVASC is not recommended in patients less than
6 years of age since safety and efficacy have not been established in that population.
Use in Elderly: NORVASC should be used cautiously in elderly patients. Dosage
adjustment is advisable.
Safety Information
WARNINGS: Outflow Obstruction (Aortic Stenosis): NORVASC should be used with
caution in a presence of fixed left ventricular outflow obstruction (aortic stenosis).
Use in Patients with Impaired Hepatic Function: NORVASC should be administered
with caution in these patients and careful monitoring should be performed. A lower
starting dose may be required (see Supplemental Product Information for dosing
recommendations in this patient population).
Beta-blocker Withdrawal: NORVASC gives no protection against the dangers of
abrupt beta-blocker withdrawal and such withdrawal should be done by the gradual
reduction of the dose of beta-blocker.
PRECAUTIONS: Hypotension: NORVASC may occasionally precipitate symptomatic
hypotension. Careful monitoring of blood pressure is recommended, especially in
patients with a history of cerebrovascular insufficiency, and those taking medications
known to lower blood pressure.
Use in Patients with Congestive Heart Failure: Although generally calcium channel
blockers should only be used with caution in patients with heart failure, it has been
observed that NORVASC had no overall deleterious effect on survival and
cardiovascular morbidity in both short-term and long-term clinical trials in these
patients. While a significant proportion of the patients in these studies had a history of
ischemic heart disease, angina or hypertension, the studies were not designed to
evaluate the treatment of angina or hypertension in patients with concomitant heart
failure.
Peripheral Edema: Mild to moderate peripheral edema was the most common
adverse event in the clinical trials. The incidence of peripheral edema was dosedependent and ranged in frequency from 3.0 to 10.8% in 5 to 10 mg dose range. Care
should be taken to differentiate this peripheral edema from the effects of increasing left
ventricular dysfunction (see Supplemental Product Information for more general
precaution and drug interaction information).
ADVERSE REACTIONS: NORVASC has been administered to 1,714 patients (805
hypertensive and 909 angina patients) in controlled clinical trials (vs. placebo alone and
with active comparative agents). Most adverse reactions reported during therapy were
of mild to moderate severity.
Hypertension: In the 805 hypertensive patients treated with NORVASC in controlled
clinical trials, adverse effects were reported in 29.9% of patients and required
discontinuation of therapy due to side effects in 1.9% of patients. The most common
adverse reactions in controlled clinical trials were: edema (8.9%), and headache
(8.3%).
Angina: In the controlled clinical trials in 909 angina patients treated with NORVASC,
adverse effects were reported in 30.5% of patients and required discontinuation of
therapy due to side effects in 0.6% of patients. The most common adverse reactions
reported in controlled clinical trials were: edema (9.9%) and headache (7.8%).

Referral Clinic charged more
than 200 patients fees beyond
what is allowed under the prov-
Page 1
Administration
Dosage should be individualized depending on patient’s tolerance and responsiveness.
For both hypertension and angina, the recommended initial dose of NORVASC is 5 mg
once daily. If necessary, dose can be increased after 1-2 weeks to a maximum dose of
10 mg once daily.
Use in the Elderly or in Patients with Impaired Renal Function: The recommended
initial dose in patients over 65 years of age or patients with impaired renal function is
5 mg once daily. If required, increasing the dose should be done gradually and with
caution.
Use in Patients with Impaired Hepatic Function: Dosage requirements have not
been established in patients with impaired hepatic function. When NORVASC is used in
these patients, the dosage should be carefully and gradually adjusted depending on
patient’s tolerance and response. A lower starting dose of 2.5 mg once daily should be
considered.
Use in Children: The effective antihypertensive oral dose in pediatric patients ages
6-17 years is 2.5 mg to 5 mg once daily. Doses in excess of 5 mg daily have not been
studied; the pediatric administration of NORVASC should be based on careful
risk/benefit assessment (see Supplemental Product Information for more information
on use in children).
WARNINGS: Increased Angina and/or Myocardial Infarction: Rarely, patients, particularly those with severe
obstructive coronary artery disease, have developed documented increased frequency, duration and/or severity of angina
or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The
mechanism of this effect has not been elucidated.
SPECIAL POPULATIONS
Use in Children: Pediatric safety and efficacy studies beyond 8 weeks of duration have not been conducted.
The effect of NORVASC on blood pressure in patients less than 6 years of age is not known. The pediatric
administration should be based on a careful risk/benefit assessment of the limited available information. The
risk/benefit assessment should be conducted by a qualified physician.
DRUG INTERACTIONS: As with all drugs, care should be exercised when treating patients with multiple medications.
Dihydropyridine calcium channel blockers undergo biotransformation by the cytochrome P450 system, mainly via CYP 3A4
isoenzyme. Coadministration of amlodipine with other drugs which follow the same route of biotransformation may result
in altered bioavailability of amlodipine or these drugs. Dosages of similarly metabolized drugs, particularly those of low
therapeutic ratio, and especially in patients with renal and/or hepatic impairment, may require adjustment when starting or
stopping concomitantly administered amlodipine to maintain optimum therapeutic blood levels.
Amlodipine has a low (rate of first-pass) hepatic clearance and consequent high bioavailability, and thus, may be expected
to have a low potential for clinically relevant effects associated with elevation of amlodipine plasma levels when used
concomitantly with drugs that compete for or inhibit the cytochrome P450 system.
Beta-blockers: When beta-adrenergic receptor blocking drugs are administered concomitantly with NORVASC, patients
should be carefully monitored since blood pressure lowering effect of beta-blockers may be augmented by amlodipine's
reduction in peripheral vascular resistance.
Sildenafil: A single 100 mg dose of sildenafil (VIAGRA) in subjects with essential hypertension had no effect on AUCt or
Cmax of amlodipine. When sildenafil (100 mg) was coadministered with amlodipine, 5 or 10 mg in hypertensive patients, the
mean additional reduction of supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic.
Atorvastatin: In healthy volunteers, coadministration of multiple 10 mg doses of NORVASC with 80 mg of atorvastatin
resulted in no significant change in the AUCt or Cmax or Tmax of atorvastatin.
Interaction with Grapefruit Juice: Following oral administration of 10 mg amlodipine to 20 male volunteers,
pharmacokinetics of amlodipine were similar when amlodipine was administered with and without grapefruit juice. For
further information on drug interactions, refer to the complete Product Monograph.
SYMPTOMS AND TREATMENT OF OVERDOSAGE: Symptoms: Overdosage can cause excessive peripheral
vasodilation with marked and probably prolonged hypotension and possibly a reflex tachycardia. In humans, experience with
overdosage of NORVASC is limited. When amlodipine was ingested at doses of 105-250 mg some patients remained
normotensive with or without gastric lavage while another patient experienced hypotension (90/50 mmHg) which
normalized following plasma expansion. A patient who took 70 mg of amlodipine with benzodiazepine developed shock
which was refractory to treatment and died. In a 19 month old child who ingested 30 mg of amlodipine (about 2 mg/kg)
there was no evidence of hypotension but tachycardia (180 bpm) was observed. Ipecac was administered 3.5 hrs after
ingestion and on subsequent observation (overnight) no sequelae were noted.
Treatment: Clinically significant hypotension due to overdosage requires active cardiovascular support including frequent
monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine
output. A vasoconstrictor (such as norepinephrine) may be helpful in restoring vascular tone and blood pressure, provided
that there is no contraindication to its use. As NORVASC is highly protein bound, hemodialysis is not likely to be of benefit.
Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Clearance of
amlodipine is prolonged in elderly patients and in patients with impaired liver function. Since amlodipine absorption is slow,
gastric lavage may be worthwhile in some cases.
To report an adverse event, please contact: 1-866-234-2345.
Product Monograph available on request. Contact 1-800-463-6001 or refer to www.pfizer.ca.
© 2007
Pfizer Canada Inc.
Kirkland, Quebec
H9J 2M5
NORVASC Pfizer Products Inc., owner/ Pfizer Canada Inc., Licensee
TM
Pfizer Inc., owner/ Pfizer Canada Inc., Licensee
®
CA0108NV001E
NORVASC PI
ince’s Medicare Protection Act.
Dr. Brian Day said the
injunction, if granted, will
result in layoffs at his clinics,
but more importantly, will
result in suffering for patients.
“We treat thousands
of patients a year that are
removed from the (public)
wait lists. These are often
desperate patients, so we will
present the constitutional
arguments at the injunction
hearing, (with) evidence that
there will be dramatic harm
that results if an injunction is
passed,” he said.
He added the same argument about wait times persuaded the Supreme Court of
Canada in 2005 to rule that
Quebec laws prohibiting
private medical insurance
violated the province’s Charter
of Human Rights and Freedoms. While the so-called
Chaoulli ruling (named after
the Quebec physician who
brought the suit against the
province) applied solely to
Quebec, Dr. Day said it raises a
key question for B.C. courts.
“Should a B.C. resident
suffering and potentially dying
on a wait list have the same
protection under the Charter
that the Supreme Court of
Canada granted to a Quebec
resident in the same position?”
Eighteen-year battle
Dr. Day said the squabble over
private clinics “has been dragging on for 18 years” and that
the courts, rather than politicians, should resolve the matter. In 2009, he challenged the
Medical Service Commission’s
authority to conduct audits at
privately owned and operated
medical clinics.
After a B.C. appeals court
upheld the commission’s audit
authority, Dr. Day agreed to
co-operate with the government investigation, provided it
was limited to his clinics’ B.C.
patients. Those audits began in
January 2012.
It’s not clear whether Dr.
Day and his clinic colleagues
will be prevented from practising medicine in the province if
the injunction is granted.
Medical Services Commission chairman Tom Vincent
said his objective in applying
for an injunction was not only
to halt extra billing, but also to
prevent federal penalties if the
OCTOBeR 9, 2012
61
Diagnostic Decision
province didn’t aim to stop the
practice. “There’s the potential
that the federal government
may withhold funds from
the province if we fail to take
action to halt extra billing,”
Vincent said.
But Dr. Day said the government’s use of the term “extrabilling” is deceptive because
it suggests doctors are billing
medicare above their normal
medical fees, or even billing
twice for a single service.
Patients part of suit
Physicians at his clinics are
merely charging patients for
things that would otherwise be
paid for under block hospital
grants in the public system,
such as medical tools, nursing
costs and time in the operation
room. To press his case, Dr. Day
has also borrowed a page from
the Chaoulli case by including
four patients―two children
and two cancer patients―in
the suit.
“We will argue that for the
B.C. government to subject
a 79-year-old patient with
terminal lung cancer to house
arrest for the rest of her life
is cruel punishment, and
unacceptable.”
Dr. Day said his clinics
will obey an injunction if it is
granted after Oct. 19, the last
day of hearings. But he added
this won’t prevent him from
challenging the constitutional
legitimacy of the B.C. Medicare Protection Act before the
provincial appeals court, or the
Supreme Court of Canada, if
necessary. MP
Pharmaceutical
ad with PI
Index
October 9, 2012
P.I.*
Product
Page(s)
Page
Accupril ------ 11 ------- 61
Advair ------- 16 ------- 49
BuTrans ------ 30 ------- 54
effexor ------ 22 ------- 40
eliquis ------- 14 ------- 58
Norvasc ----- 34 ------- 60
Omnaris - 19,21 ------- 42
Targin ------- 38 ------- 44
Vimovo --------2 ------- 56
Xarelto ------- 24 ------- 46
*Prescribing information; may
continue on subsequent pages
Test your knowledge with the Medical Post’s Diagnostic quiz!
History: A patient in her 30s presents at the ER for abdominal pain, mostly
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®
(quinapril hydrochloride)
®
(quinapril hydrochloride and hydrochlorothiazide)
Prescribing Summary
THERAPEUTIC CLASSIFICATION:
ACCUPRIL: Angiotensin Converting Enzyme (ACE) Inhibitor
ACCURETIC: ACE Inhibitor/Diuretic
INDICATION:
ACCUPRIL: For the treatment of essential hypertension, and for the treatment of
congestive heart failure as adjunctive therapy when added to diuretics and/or digitalis
glycosides.
ACCURETIC: For the treatment of essential hypertension in patients for whom
combination therapy is appropriate.
CONTRAINDICATIONS:
ACCUPRIL and ACCURETIC are contraindicated in patients who are hypersensitive to
these products; in patients with a history of angioedema related to previous treatment
with an ACE inhibitor; and in women who are pregnant, intend to become pregnant,
or are of childbearing potential and not using adequate contraceptive measures.
ACCUPRIL and ACCURETIC should be administered to women of childbearing age only
when such patients are highly unlikely to conceive and have been informed of the
potential hazards to the fetus. Because of the hydrochlorothiazide component,
ACCURETIC is contraindicated in patients with anuria or hypersensitivity to other
sulfonamide-derived drugs
Safety Information
When used in pregnancy, ACE inhibitors can cause injury or even death of the
developing fetus. When pregnancy is detected, ACCUPRIL and ACCURETEC
should be discontinued as soon as possible.
Angioedema (including intestinal angioedema) has been reported in patients
treated with ACCUPRIL and ACCURETIC, with higher risk in black than non-black
patients and in patients with a history of angioedema unrelated to ACE inhibitor
therapy. Angioedema can be fatal when there is laryngeal involvement so if laryngeal
stridor or angioedema of the face, tongue, or glottis occurs, discontinue ACCUPRIL or
ACCURETIC immediately, treat the patient appropriately, and observe carefully until
swelling disappears. Intestinal angioedema should be included in the differential
diagnosis of patients on ACE inhibitors presenting with abdominal pain, even without
facial angioedema and normal C-1 esterase levels.
Symptomatic hypotension can occur after administration of quinapril, (usually after
the first or second dose or when the dose was increased, and especially in volume
depleted patients), and could result in a myocardial infarction or cerebrovascular
accident in patients with ischemic heart or cerebrovascular disease, therefore start
treatment under close medical supervision.
Agranulocytosis and bone marrow depression have been caused by ACE inhibitors.
Periodic monitoring of white blood cell counts should be considered, especially in
patients with collagen vascular disease and/or renal disease.
Because the presence of concentrations of ACE inhibitor have been reported in
human milk, and because thiazides appear in human milk,ACCUPRIL and ACCURETIC
are not recommended in nursing women. Also, because their safety and
effectiveness in children have not been established, use in this age group is not
recommended.
For more information on warnings and precautions, including appropriate courses of
treatment and when to discontinue ACCUPRIL and ACCURETIC, refer to the complete
Product Monograph.
ADVERSE REACTIONS
ACCUPRIL has been evaluated for long-term safety in over 1100 hypertensive patients
treated for ≥1 year. In controlled clinical hypertension trials, the most frequent adverse
events (usually mild and transient in nature) were headache (8.1%), dizziness (4.1%),
cough (3.2%), fatigue (3.2%), rhinitis (3.2%), nausea and/or vomiting (2.3%), and
abdominal pain (2.0%). The most serious were angioedema (0.1%), renal
insufficiency (1 case), agranulocytosis (1 case) and mild azotemia (2 cases in
congestive heart failure patients). Myocardial infarction and cerebrovascular accident
occurred, possibly secondary to excessive hypotension in high-risk patients.
ACCUPRIL safety was also studied in 525 patients with congestive heart failure in
controlled clinical trials. Adverse event frequency was similar for both sexes and all
ages (i.e., older or younger than 65 years). Most frequent adverse events were
dizziness (11.2%), cough (7.6%), chest pain (6.5%), dyspnea (5.5%), fatigue (5.1%),
and nausea/vomiting (5.0%); most serious were angioedema (0.1%), chest pain of
unknown origin (0.8%), angina pectoris (0.4%), hypotension (0.1%), and impaired
renal function; and most common reasons for withdrawal were hypotension (0.8%)
and cough (0.8%). Myocardial infarct, and cerebrovascular accident occurred. Rare
cases of eosinophilic pneumonitis have been reported but hepatitis/hepatic failure
have rarely been observed with other ACE inhibitors.
ACCURETIC has been evaluated for safety in 1571 patients with essential
hypertension for at least one year. The most frequent adverse experiences in
controlled trials were headache (6.7%), dizziness (4.8%), cough (3.2%), and fatigue
(2.9%). Adverse reactions have been limited to those reported previously with
quinapril or hydrochlorothiazide when used separately for the treatment of
hypertension.Therapy was discontinued in 2.1% of patients due to an adverse event,
and headache (0.5%) and dizziness (0.3%) were the most frequent reasons for
withdrawal. Serious or clinically significant adverse reactions observed in less than
0.2% of patients treated with quinapril and hydrochlorothiazide were: hematemesis,
gout, syncope and angioedema.
To report suspected side effects, contact Health Canada at: 866-234-2345.
Administration
Dosage of both ACCUPRIL and ACCURETIC must be individualized.
ACCUPRIL for hypertension: Recommended initial dose (in patients not on diuretics)
is 10 mg daily. Adjust according to blood pressure response, generally every 2-4
weeks. Maximum dose: 40 mg daily.
ACCUPRIL for congestive heart failure: Recommended starting dose is 5 mg daily
administered under close medical supervision. After the initial dose, observe patient
for ≥2 hours or until blood pressure has stabilized for at least an additional hour. Once
medication is tolerated, increase dose gradually to 10 mg daily, then 20 mg daily,
then 40 mg daily in 2 equally divided doses, depending on patient response.
Maximum daily dose: 40 mg.
ACCURETIC: Fixed combination is not for initial therapy. Determine dose by titration
of the individual components. Some patients may require twice-daily administration;
most patients do not require more than 50 mg of the hydrochlorothiazide component
daily, particularly when combined with other antihypertensive agents.
See the complete Product Monograph for full dosing information in specific special
populations.
References
REFERENCES: 1. ACCUPRIL Product Monograph. Pfizer Canada Inc., September 2009. 2. ACCURETIC Product
Monograph. Pfizer Canada Inc., September 2009. 3. Pfizer Canada Pharmaceutical Group. Price List. January 2009.
PRECAUTIONS
The Product Monograph issues precautions regarding: patients with renal impairment (e.g., patients with
bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart
failure); patients dialysed with high-flux membranes and treated concomitantly with an ACE inhibitor;
patients receiving ACE inhibitors during low density lipoprotein apheresis with dextran sulphate; patients
receiving ACE inhibitors during desensitizing treatment with hymenoptera venom; the potential for
hyperkalemia; hypoglycemia in diabetic patients on insulin or oral hypoglycemic agents; patients with aortic
stenosis (theoretical risk only); patients undergoing major surgery or during anaesthesia with agents that
produce hypotension. See the Product Monograph for more information.
DOSING – SPECIAL POPULATIONS
Patients with renal impairment: For treatment of hypertension, starting doses should be reduced according
to creatinine clearance (see Product Monograph for specific guidelines). For use in hemodialysis patients,
quinapril should be administered on days when dialysis is not performed (see Product Monograph for more
information). ACCURETIC is not recommended in patients with severe renal dysfunction.
Elderly patients (≥65 years old): For treatment of hypertension, recommended initial dosage of ACCUPRIL is
10 mg daily (depending on renal function), followed by titration to the optimal response.
DRUG INTERACTIONS
The Product Monograph discusses drug-interactions for patients concomitantly taking ACE inhibitors and
diuretics, patients taking agents increasing serum potassium (e.g., spironolactone, triamterene or amiloride,
or potassium supplements), lithium, other antihypertensive agents and other agents. For further information,
refer to complete Product Monograph. In single dose pharmacokinetic studies, no important changes in
pharmacokinetic parameters were observed when ACCUPRIL was used concomitantly with propranolol,
hydrochlorothiazide, digoxin, or cimetidine. No change in prothrombin time occurred when ACCUPRIL and
warfarin were given together.
SYMPTOMS AND TREATMENT OF OVERDOSAGE
There is no information on overdosage with ACCUPRIL or ACCURETIC in humans. The most likely clinical
manifestation would be symptoms attributable to severe hypotension, which should be normally treated by
intravenous volume expansion with 0.9% sodium chloride. Hemodialysis and peritoneal dialysis have little
effect on the elimination of quinapril and quinaprilat.
The most common signs and symptoms observed for hydrochlorothiazide monotherapy overdosage are
those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration
resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate
cardiac arrhythmias.
Product monograph available on request. Contact 1-800-463-6001, or www.pfizer.ca.
© 2011, Pfizer Canada Inc., Kirkland, Quebec H9J 2M5
ACCUPRIL® and ACCURETIC® Parke, Davis & Company LLC, owner
TM
Pfizer Inc, owner/ Pfizer Canada Inc., Licensee
D000041116
PRESCRIBING INFO
62
OCTOBER 9, 2012
Renal failure less likely
to be treated in the elderly
Kidney disease
rates may also
be underestimated
in this population,
Alberta research
suggests
BY DEIRDRE MACLEAN
Calgary
O
lder adults with
kidney failure are less
likely to receive
treatment than are younger
patients with a similar level of
renal dysfunction. And
progressive kidney disease in
older adults is more common
than previously thought, a
community-based cohort study
in Alberta has shown.
Dr. Brenda Hemmelgarn, an
associate professor in the division of nephrology at the Uni-
versity of Calgary, and her colleagues at the Alberta Kidney
Disease Network conducted a
retrospective cohort study of
laboratory and administrative
data to find out whether age is
associated with treatment for
kidney failure.
More than 1.8 million Albertans ages 18 years and older
who had at least one serum
creatinine measure recorded
between May 2002 and March
2008 were included.
Kidney failure was defined
as two measures of estimated
glomerular filtration rate
(eGFR) below 15 ml/min/1.73m2.
The cohort was stratified by age
and kidney function and followed for a median of 4.4 years.
The outcome measures were
treated kidney failure (receipt
of long-term dialysis or transplant), untreated kidney failure
(progression to eGFR below
15 ml/min/1.73m2 without
dialysis or transplant) and allcause mortality.
Rate of treated kidney
failure higher in young
Although treatment for kidney
failure increased in all age
groups as eGFR declined, the
rate of treated kidney failure
was consistently higher among
the youngest age group (18 to
44 years).
For example, among participants with a baseline eGFR
of 15 to 29 ml/min/1.73 m2, the
rate of treated kidney failure
was 24.00 per 1,000 personyears for those ages 18 to 44
years, compared with 1.53 for
those ages 85 years and older.
Furthermore, the percentage of study participants who
had untreated kidney failure
(and the composite endpoint of
treated and untreated kidney
failure) increased progressively
with age.
“We had anticipated that
the rates of progressive kidney disease or kidney failure
would be higher in the older
adults but didn’t anticipate the
graded increase. I wouldn’t call
it surprising, but it was a bit
unexpected,” Dr. Hemmelgarn
said in an interview.
The authors noted the most
important finding of their
study is that the incidence of
advanced kidney disease in the
elderly may be “substantially
underestimated.”
Documenting dialysis
Previous studies that have
relied on initiation of dialysis
to gauge the incidence of
kidney failure provide infor-
mation only about treated
kidney failure.
In contrast, the Alberta
study yields information about
both treated and untreated
kidney failure, including the
estimate that untreated kidney
failure is two- to 10-fold higher
among adults older than 75
years compared with those
ages 18 to 44 years.
Dr. Hemmelgarn said she
expects the picture would be
similar across Canada. “We
looked at the rate of dialysis in
our province compared with
other provinces and it was
pretty similar; the way that care
and services are provided is
similar, so I’d anticipate, based
on other studies, that these
data would be similar as well.”
The study appeared in the
Journal of the American Medical Association (June 20). MP
Classifieds
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DOWNTOWN TORONTO
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(647)887-8001 after 5 PM
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Please call Ms. Nolan at 416-944-9393
Classified Advertising
1-800-668-8151
Classifieds
OCTOBeR 9, 2012
63
C-10 Positions Vacant
Emergency Physician (2)
Low Acuity Emergency Department
Are you interested in practicing with a core group of young committed physicians in one of
the most desirable towns in southern Ontario? Practicing in Petrolia will give you the perfect
balance of practice and quality of life.
Practice Opportunity:
• Well suited for a family doctor with interest or training in ER
• ACLS & ATLS required
• 10-hour day shift and 14 hour overnight shift, few patients after 23:00
• Patient volume 45-55 patients per 24 hours, most between 0800 & 2300
• Compensation under Alternate Payment Plan
• Community physicians provide back up
• Specialist support available in Sarnia
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• Warm weather, close proximity to large cities & international airports
• Friendly people, appreciative patients
The Charlotte Eleanor Englehart Hospital site of Bluewater Health in Petrolia is a 23 bed acute
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To inquire about this physician opportunity,
please contact: Dr. Mark Taylor,
Interim Chief of Professional Staff,
Bluewater Health
519-464-4400 ext 4534 or e-mail
[email protected]
My family and I enjoy everything that
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Dr.Clark(OrthopedicSurgeon)
ThunderBayRegionalHealthSciencesCentre
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We’ll show you how you can substantially increase your current family practice
income. We are a medically supervised weight loss organization with a stellar 30-year
record. Our patients achieve consistent, healthy, rapid weight loss (average four to
five lbs. per week). Our team of physicians find their work rewarding – professionally,
personally, and financially. Full and part-time opportunities are available in
Mississauga, Oakville, and Ottawa.
For more information,
please contact: Robyn Yack
•Natureinyourbackyard
We’ve got the best of all worlds
Physician Recruiter
phone: (416) 447-3438 ext. 229
e-mail: [email protected]
fax: (416) 447-0702
www.immigrationnorthwesternontario.ca
www.drbdiet.com
EAST YORK MEDICAL and THE TORONTO HEALTHCARE CENTRE
45 Overlea Blvd. Suite A6/27E
Sherwood Park Alberta
Family Physicians (FT/PT) needed in
our established and well
equipped clinic. Wonderful
community, EMR, competitive split.
Exceptional income potential.
Contact: Mel Snihurowych
780-400-3303 or at
[email protected]
www.synergymedicalclinic.ca
A busy multi-disciplinary Medical Centre, also a Family Health Group located in a mall, is
looking for General Practitioners interested in building a part-time or full time practice.
On-site X-ray, Ultrasound, Rehab and Lab
Also looking for Specialists in:
ENT, Psychiatry, Orthopedic Surgeon, Optometrist.
Competitive split and incentives.
Hours of operation:
Mon-Fri 9am-9pm, Sat 10am-6pm & Sun 11am-5pm
We will try to accommodate to best suit your schedule!
Need EVENING and WEEKEND coverage.
Interested? Call Safina at (647) 728-4508 or e-mail at [email protected]
Great Opportunity for Specialist or Family Physician
Sherwood Park
Synergy Wellness Centre
Seeking part-time or full-time physician(s) to share beautiful ready to use
space in brand new medical facility with EMR system included.
Please contact Dr. Mohammad Badawi at [email protected]
Physician Owner/Partner required
to work in Toronto walk-in clinic and
share administrative responsibilities
and financial opportunities.
Contact Dr. Ian Cohen at
[email protected]
or 647-282-0678
Busy growing Medical clinic in
Whitby/Bowmanville seeking
full or part-time family doctors
for walk-in clinic also FHG.
Please call: 905-435-5430 or
email: [email protected]
WALK-IN CLINIC / FAMILY PRACTICE
• Family Physicians required
• Busy shifts - now available
• Great split. Full-time / Part-time.
• Re-locate your practice or start a
new practice.
• Brampton + Etobicoke
[email protected]
or call : 416-725-5858
Downtown Mississauga
Busy clinic has available shifts for a
Walk-in/Family Physician and room
for a specialist. Attractive split.
For more information contact:
416-725-5406 or 905-275-4895
Needed Urgently for
Churchil Meadows Medical Center
Female FD to start her own practice and
share with WI shifts. Well established
clinic in excellent location in Mississauga.
Very well equipped paperless, spacious
6 exam rooms plus a procedure room and
2 offices. We are using Abelmed EMR.
Cost sharing or generous percentage.
Contact Dr. Fahmy cell: (905)-601-8607
Brampton ON. Full/Part time
Family Physician(s) required for
busy family practice/walk-in
clinic. High fee for service split.
Excellent easy to use EMR tablet with pen. Please call
Tel: 416-949-3830 or email:
[email protected]
Kingston, Ontario: Hospitalists
and Long Term Care Positions
We are looking to fill two part time Hospitalist
positions and one part time Long Term Care
position (with an option, if interested for LTC
Directorship). Hopefully one person will be
interested in the Hospitalist combined with
LTC (+/- LTC Director). This is a rewarding
clinical experience with abundant support,
light call and excellent leave.
Phone: 613-540-4912
$250.00/hr
Pediatrician, Internist,
Surgeon, sub-specialist. In busy
outpatient clinic in Mississauga.
Dr. Stein (416) 464-0238
St. Catharines, ON
Walk-In Clinic
• Busy Clinic
• Competitive Fee Split
• Flexible hours
Contact: Tony Saturno
[email protected]
416-523-2993
64
ClassifiEds
OCTOBER 9, 2012
Opportunities for
Family Doctors at a
new clinic in Manotick
Attractive Overhead rates &
Flexible Hours. Walk-ins/Family
Practice/FHG/EMR Available.
tel: 613-816-9968
web: www.caremedicsgroup.com
Richmond Hill, Ontario
Physician required for walk-in & family
practice in Richmond Hill clinic. Full
or part time available due to principal
physician sudden illness. Requires urgent
replacement for short term. Option to
extend to full time or part time associate.
Call: Charles 647-882-2903 or
AJAX, ONTARIO
PT/FT Walk-In/Family physician
Packages for new grads and student
loan repayment
Brand new modern state of the art
Clinic Fully EMR
Competitive split & very flexible hours
Call (905) 449-7980
Etobicoke, ON.
Busy Walk-in/Family Practice
Clinic immediately seeks FT/PT
Associate Family Physicians to replace
out-going incumbents. Part of a FHG.
Joining bonus and attractive split.
Call Kuljit Baweja
905-826-0899 or Cell 416-953-8775
SURGICAL POSITION
North York & Scarborough
clinics located inside LOBLAWS
An opportunity is now available for a general surgeon to join the
team of specialists at Shouldice Hospital.
and very busy shopping centre.
Very busy walk-in clinics/family practice
seeking family physicians, and specialists.
Physicians required for walk-in shifts as
well as opportunity to relocate an existing
practice or build a new practice.
Flexible hours and very attractive split.
The opportunity includes:
• Competitive compensation
• Dental and medical package for you and your family
• One day in ten on call
• Full administrative support
• Paid vacations without the need for locum
• Regular business working hours
• A strong focus on patient care with daily surgical rotation
Enjoy weekends and evenings with your family and join a busy,
world-renowned surgical practice in a unique, supportive environment.
Contact Mr. Urquhart at 905-889-1125 or by forwarding your
letter of introduction and CV by fax to: 905-889-4216, or
Email to [email protected].
80-100 PATIENTS
PER SHIFT GUARANTEED
In busy Mississauga Clinic.
Central Etobicoke,
Walk-in, Family Medicine, shifts
available, competitive split.
Dr. Meola
(416) 464-0238
Contact Annette
416-347-8186 or
[email protected]
WALK-IN SHIFTS
Brampton. Full-time, part-time
physicians and specialists required
Easy / friendly EMR
Burlington, ON
Please send query and C.V. to:
[email protected]
Dixon Walk In Clinic, a busy walk in clinic
is looking for a full-time family
physician. Great opportunity, overhead
20% & full support. Located in
Newmarket, ON in the Dixon Medical
Centre. For more info contact:
[email protected]
for a very busy family practice/walk-in
clinic. Very Modern and computerized
exam rooms, paperless, $200/hour
billing guarantee available.
Tel 647 627-4170 (William), email
[email protected]
Walk-In Shifts or
Family Practice Opportunity
for new Walmart Clinic in
Brampton Ontario.
Call 416-505-1711 or email:
[email protected]
Tel: 647-206-0790
BC CALLING
VANCOUVER AND NORTH SHORE
HEALTHWISE MEDICAL SERVICES
•
•
•
•
•
DOCTORS WANTED
FAMILY PRACTICE
URGENT CARE
FULL-TIME & PART-TIME
A BETTER LIFESTYLE
Contact: 604-671-8099
Fax: 604-926-1530
Toronto Poly Clinic
a group of two pain clinics is looking
for physicians with experience in
pain management, due to high
referral load. 30% overhead split
with third party work opportunity.
Full interventional pain clinic support
in CPSO PASSED facilities.
Please fax CV to attention of
Dr. Kevin ROD: 416-250-0323
FUSION CARE CLINIC
Beautiful new clinic in Richmond Hill,
fully EMR, seeking GP or specialist, FT/
PT, for walk-in or practice, flexible hours,
attractive split, to relocate or start a new
practice. tel : 647-961-6992 or
416-893-9732 or email
[email protected]
www.fusioncareclinic.ca
PSYCHIATRIST / MD PSYCHOTHERAPIST
Private practice available in association with Psychiatrists and Medical
Psychotherapists. Full or Part-time. Referrals available. Complete
office management. Ideal for relocators. Overhead 10%-20%
SHEPPARD ASSOCIATES
649 Sheppard Avenue West, Toronto, Ontario M3H 2S4
Phone: (416) 630-0610
Fax: (416) 398-5712
Etobicoke & Thornhill - 2 Locations
Looking for established practice to move-in. Guaranteed lower overhead than existing rent.
Complete turn-key relocation service, including calling/mailing to all patients and physical
relocation, with a proven patient retention rate of 95%...available at no charge.
Also available full/part-time WI & FP positions. Great location, brand new facility.
EMR, billing manager, allied health and clinical assistant on-site. Attractive split.
Billing & practice orientation for new grads.
Email [email protected] or call 647-238-8356
Toronto Memory Program is presently looking for additional physicians from the
following disciplines to join our expanding memory clinic: neurology, geriatrics, internal
medicine, geriatric and general psychiatry, family medicine and those with a care of the
elderly fellowship. Toronto Memory Program is a multidisciplinary, community based, OHIP
funded, medical facility specializing in the diagnosis and treatment of Alzheimer’s disease
and related disorders. Physicians provide consultations and ongoing care for patients
and are supported by trained clinical assistants. For further information please contact
Dr. Ian Cohen at 647-282-0678or [email protected].
Classified Advertising
1-800-668-8151
Classifieds
OCTOBeR 9, 2012
65
For over two decades, MCI Medical Clinics Inc. has offered complete
professional practice management solutions to Family Physicians in
Ontario, Alberta and B.C.
35 locations across Canada providing:
• Trained professional staff
• Superior facilities
• Practice flexibility
• Lifestyle options
• Retirement transition
IN
25
G
CEL
MCI Doctors say...
B R AT
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19 8 6-2 0
11
YEARS
To learn more contact:
Margaret Gillies T 1-866-624-8222 x433
E [email protected]
“Being a physician is challenging enough without the added stress of managing a medical practice.
MCI’s talented team of professionals and support staff takes the stress out of the office and allows
me to focus my energy on what I love most, the practice of medicine.” ~ Dr. Wendy Proctor
Etobicoke, ON: Exciting opportunity
for family doctors. Street level access at
a nice upscale neighborhood at Dundas
and Islington in heavy residential area.
for walk-in/family practice. busy patient
flow. F/T or P/T. Relocate or start a new
practice. EMR or paper. Contact:
[email protected] or phone:
416-882-9265 for more details
Busy, Growing Medical Clinic
in Downtown Toronto
seeking full or part-time Family
Doctors for walk-in clinic (FHG).
Call Lucio at 416-823-0615
C-12 Practices
for sale
C-18 Miscellaneous
Ottawa, Ontario - Fabulous Family
Practice Available Immediately
Auction for IHF License in GTA
A rare multi-modality IHF license in Pickering, Ontario is to be auctioned.
The IHF license has the following modalities:
• Nuclear Medicine
• In Vivo – General and SPECT
• Diagnostic Ultrasound
• General Ultrasound
• Vascular Ultrasound
•
•
•
•
•
Diagnostic Radiology
Fluoroscopy
Bone Mineral DXA
Mammography
Radiography
No other assets or liabilities to be sold with this. This is strictly a license only sale.
Non-conditional sealed bids must be received by end of business hours on Thursday
Nov 1, 2012. Closing of the above transaction will take place no later than Dec 31, 2012.
A Minimum reserve bid is in place.
Only serious principals please send inquiry to [email protected]
C-21 Medical services
Retiring? Relocating? Closing? Estate?
RSRS is the #1 medical records company. Since 1997.
• FREE compliant storage for your patient records
• FREE notification to your patients
• FREE digital copy of all patient records
• FREE boxes and shipping
• RSRS will sell or donate your medical equipment.
• Physician-managed and fully compliant.
Contact: Elan Eisen at 1-888-563-3732 Ext. 221 Email: [email protected]
Retiring, Moving, Closing your Practice?
DOCUdavit Solutions provides the most comprehensive
record storage services across Canada
• Free secure storage of ALL your paper patient records
(active & inactive)
• Free secure storage of your Patient EMR records
• Free mailing to all of your patients
• Free electronic copy of all your patient’s records
(On-line or CD/DVD)
• Free boxes and pickup of your patient records
• Capped fees and Family Discounts for your patient’s copies
and transfers (on-line, electronic or paper format)
CONTACT SID SOIL
1-888-781-9083, ext 105
[email protected]
www.docudavit.com
Physician Relocating. In FHO. Gross over
400,000. Awesome clientelle and staff.
Great location. Location can be
purchased or leased.
Contact Tim Rourke M.D. 613-614-1793
or email: [email protected]
Interested in earning
money outside of OHIP?
Lucrative cosmetic medi-spa for sale in
Simcoe County. Ideal for new dermatologists, or family physicians looking to branch
outside of OHIP given the current situation.
SERIOUS enquires only to:
[email protected]
Practice for Sale
Well established fully equipped
paper based G.P. practice next to
Broadway Skytrain station for sale.
Inquiries Fax: 604-874-0034 or
write to: 403-1750 East 10th Ave.
Vancouver BC V5N 5K4
Family Practice for Sale Brantford, ON.
Excellent opportunity for new grad. 1500
well culled FHO rostered patients, 100%
EMR. Turn-key shared office/overhead
facility. Six weeks covered vacation.
1/25 call. 10 min from Ancaster.
Available January 1/2013.
phone: (519) 771-6500
C-21 Medical
services
Going EMR?
NEED TO SCAN YOUR
PATIENT RECORDS?
FIND OUT HOW WE CAN DO IT
FOR LESS!
Contact DOCUdavit Solutions
1-888-781-9083 ext. 105
[email protected]
www.docudavit.com
Richmond Hill, ON
Opportunity for GP (FT/PT)
in a busy family practice/Walk-in.
Best split in the industry. Flexible hours.
Beautiful new office, close to hospital.
Contact: (905) 251-8234
or email: [email protected]
Scarborough – Walk-in Clinic
Physicians needed for locum or P/T
shifts at established clinic. M-F 4-8pm.
Sat 10-2pm. Very competitive 15/85
split. Flexible hours. Space also available
for full-time GP. Contact: 416.315.6282
Email: [email protected]
FULL-TIME or PART-TIME
FAMILY PHYSICIAN
needed for busy, established
walk-in clinic in Mississauga.
Opportunity to build a Family
Practice or relocate an existing
practice. Please Call:
(416) 678-5588
Parliament/Gerrard Clinic
411 Parliament Street
• Part/Full-time Doctor needed
• Family/Walk-in avaialble
• Percentage or partner or total ownership
Please call: Mr. King
416-938-1176
Full-Time/Part-Time Doctor
Required In Etobicoke
Q FREE RENT Q
Well established clinic in prime
location. Call Wael at 416-720-5943
or email [email protected]
Classi¿ed
Advertising
1-800-668-8151
Barth Syndrome Foundation 2012
Request for Research Proposals
The Barth Syndrome Foundation, Inc. (BSF) and its international affiliates are
pleased to announce the availability of funding for basic science and clinical
research on the natural history, biochemical basis, and treatment of Barth
syndrome. BSF’s Research Grant Program allows young, non-tenured
investigators to include in their submitted budget up to 75% of the total grant
amount as Principal Investigator (PI) salary. In addition, for those clinical
applications where volunteers must travel to a clinical research site, these
travel expenses will be handled separately and not included in the application
budget limitation. We encourage all investigators at every professional level
to submit their best ideas for advancing the state of knowledge about Barth
syndrome so that progress can be made in finding a specific treatment or
cure for this unusual mitochondrial disease. There are no geographical
limitations to this funding.
For more information, please visit BSF’s Research Grant Program
webpage at www.barthsyndrome.org/english/View.asp?x=1635
66
oCToBer 9, 2012
THE MEDICAL POST
Diversion
“Dr. Lifestyle” is the alter-ego of Halifax psychiatrist Dr. Lara Hazelton.
Dave Whamond is a Calgary illustrator.
By Dr. Lara Hazelton
and Dave Whamond
Clinical
Challenge
Te challenges below present clinical issues from three of the upcoming UPDATES on the Complex
Patient with Diabetes Fall 2012 CME programs. Advance your learning and prepare for the sessions
by reviewing and refecting on these current patient-care topics.
UPDATES on the
COMPLEX PATIENT
The 5As Framework
for
Obesity Management
Do your patients look to you for help
with obesity?
In a 2010 survey of Canadians, only 5% of respondents
reported that they had asked their family physician about
weight loss, 19% had been advised to lose weight without
specifically asking, and only 14% reported that their waist
circumference had been measured – yet 96% said their
blood pressure had been measured and 56% had been
screened for diabetes.
What are the fundamental principles
of obesity management?
Using health care practitioner and expert interviews as a
foundation, a Canadian primary practice working group
agreed on five core principles of obesity management,
which were presented at the 2011 National Obesity
Summit Workshop. The five principles recommended to
guide primary physicians in obesity management include:
1) obesity is a chronic condition; 2) obesity management is
about improving health and well being and not simply
reducing the numbers on the scale; 3) early intervention
means addressing root causes and removing roadblocks;
4) success is different for every individual; 5) a patient’s
best weight may never be an ideal weight.
What are the key elements of obesity
assessment and patient counselling?
The 5As of obesity management in primary care are:
1) Ask for permission to discuss the patient’s weight;
2) Assess obesity-related risks to health and well being,
the potential root causes of weight gain, the patient’s
readiness to change, complications and barriers to weigh
loss, and clinical measures of weight (BMI, waist
circumference, staging of obesity); 3) Advise on the need
for a long-term strategy, the benefits of modest weight
loss, the risks of obesity, and available treatment options;
4) Agree on realistic weight loss expectations, health
outcomes, and a treatment plan, with a focus on
behaviour change using SMART goals; 5) Assist the
patient in identifying and addressing barriers to weight
loss and accessing resources and programs, as well as
arrange follow-up/referrals.
NEW! UPDATES on the Complex Patient with Diabetes is now ofering you the convenience of
some programs online. Extend your learning experience and earn extra credits. Go to
www.myCMEUPDATES.ca and select online UPDATES – no charge, fast, convenient and secure!
“Mock Clinic”: Incorporating
New Treatment Options into Your
Type 2 Diabetes Practice
What is the rationale for early and
aggressive treatment to reach
established A1c targets in type 2
diabetes mellitus?
When A1c levels are increased, glycemic control
deteriorates, requiring active treatment intensification. A
1% reduction in A1c has been associated with a 37%
reduction in microvascular endpoints, a 21% reduction in
diabetes-related endpoints, a 21% reduction in
diabetes-related deaths, and a 14% reduction in
myocardial infarction.
What are the consequences of
hypoglycemia for patients with type 2
diabetes mellitus?
Hypoglycemia is associated with reduced quality of life,
reduced treatment satisfaction, poorer treatment
adherence, and an increase in mortality rates. It should be
noted that even patients who are well controlled on
conventional regimens may experience recurrent,
unrecognized hypoglycemia.
Aside from insulin, what are the
current treatment options for type 2
diabetes mellitus and where does
each exert its effects?
Each drug class has a unique mechanism of action,
working to regulate glucose production, glucagon
secretion, insulin secretion, insulin resistance, and/or
effects of incretin. Metformin exerts its effects in the liver
and in muscle tissue, alpha glucosidase inhibitors in the
stomach (preventing digestion of carbohydrates),
sulphonylureas and meglitinides in the pancreas,
thiazolidinediones in the liver, fat and muscle tissue, and
incretin agents (GLP-1 receptor agonists, DPP-4
inhibitors) in the pancreas and liver; GLP-1 receptor
agonists also slow gastric emptying.
Which type of patient is more likely
to benefit from incretin therapies?
http://www.obesitynetwork.ca/join
In general, incretin therapy is recommended for the
patient who is not achieving glycemic targets on
metformin and for whom hypoglycemia is a concern. In
particular, DPP-4 inhibitors may benefit the patient who
requires modest A1c reductions and weight neutrality,
while the patient who requires larger A1C reductions and
weight loss may benefit from GLP-1 receptor agonists.
Incretin therapies are not recommended for patients with
a history of pancreatitis.
Developed by
Supported by an educational grant from
Join the Canadian Obesity Network for access to a
network of 8,000 health practitioners and researchers
dedicated to the prevention and treatment of obesity.
Membership is free and signing up takes less than
5 minutes.
Managing Type 2 Diabetes
Mellitus:
4 Hot Questions
Should patients with type 2 diabetes
mellitus take acetylsalicylic acid
(ASA)?
A critical review of recently published evidence revealed
that ASA had no benefit for primary prevention of
cardiovascular disease, i.e., for those patients with type 2
diabetes who did not have pre-existing cardiovascular
disease. Taking low-dose ASA regularly may have some
benefit for those who have existing cardiovascular
disease (secondary prevention).
How should resistant hypertension be
treated in people with type 2 diabetes
mellitus?
The American Heart Association defines resistant
hypertension as blood pressure that remains above goal
despite concurrent use of three optimally dosed
antihypertensive agents of different classes. People with
type 2 diabetes are at greater risk of treatment-resistant
hypertension because blood pressure targets are lower for
these patients (<130/80 mmHg) vs. the general
population. Physicians should review potential causes of
resistant hypertension (e.g., non-adherence, drug
interactions, sleep apnea, etc.). If another medication is
indicated, consider prescribing spironolactone (12.5–
50 mg daily) or possibly doxazosin or amiloride.
How and when should insulin be
added to the treatment regimen of a
patient with type 2 diabetes mellitus?
A critical review of recently published evidence and
Canadian Diabetes Association guidelines revealed that
physicians should consider starting a long-acting insulin
analogue (insulin glargine or detemir) if a patient taking
metformin alone or metformin plus a sulphonylurea is not
achieving a target of HbA1c ≤7%. For the patient taking
metformin alone who is not achieving this target, consider
adding insulin as a second agent to reduce the risk of side
effects (e.g., hypoglycemia, weight gain).
Is it necessary or safe to treat to a
target of HbA1c <6%?
A critical appraisal of evidence demonstrated that the
main benefit of intensive therapy vs. conventional therapy
was a reduction in microvascular complications. Intensive
therapy did not affect rates of mortality, myocardial
infarction, or stroke in patients with type 2 diabetes.
Developed by
UPDATES on the Complex Patient with Diabetes – Fall 2012 CME Program
Quality CME for Family Medicine and General Practice
For program details, accreditation status for each study program and locations go to www.myCMEUPDATES.ca
Register Now!
Register Online – Fast, convenient, secure!
Please register early as seating for some venues is limited.
(use code CC4)
Actinic Keratosis is a precancerous condition1
FIELD
OF
Over 40% of all squamous cell carcinomas arise from Actinic Keratoses2
CERISATION
CAN
Non-visible AK lesions are also present in the area of visible lesions, and are
estimated to occur 10 times more often than visible lesions.3 This is known
as feld cancerisation. Treatment should therefore include the feld of sun
damage beyond visible lesions.
I’ve been
playing
with ¼re
for 58 years
When I was a kid, sunburns
were a part of summer.
We bragged about them.
Honestly, I still sometimes
forget to use sunscreen.
Give sun-damaged skin the vigilance it requires
1. Cohen JL. Actinic keratosis treatment as a key component of preventive strategies for nonmelanoma skin cancer. J Clin Aesthet Dermatol 2010; 3(6):
39-44. 2. Feldman SR, Fleischer AB, Jr. Progression of actinic keratosis to squamous cell carcinoma revisited: clinical and treatment implications. Cutis
2011; 87(4):201-207. 3. Berman B, Amini S, Valins W, Block S. Pharmacotherapy of actinic keratosis. Expert Opinion on Pharmacotherapy 2009; 10(18):1-17.
®Registered trademark of LEO Pharma A/S used under license and distributed by LEO Pharma Inc., 123 Commerce Valley Dr. E., Suite 400, Thornhill, Ontario L3T 7W8
www.leo-pharma.com
T y p e 2 D i a b e T es
coNTribUTors
specialisT overview
Harpreet S. Bajaj, MD, MpH,
ecNU, DabiM
associate endocrinologist
lMc endocrinology centre
brampton, ont.
priMary care review
Alan Kaplan MD, ccFp(eM), FcFp
chairperson
Family physician airways Group of
canada
richmond Hill, ont.
coNTeNTs
Background .................... 2
Benefits and usage ........ 2
Clinical outcomes
from trials ...................... 2
Incretins in clinical
practice .......................... 4
Future outlook ................ 4
Primary Care Review
........................................ 3
Case Study ..................... 4
Clinical Focus™ is a regular sponsored
feature designed to provide Canadian
physicians with the latest in clinical
thinking and therapeutic practice. Before
prescribing any mentioned medication,
please refer to the appropriate product
monograph. The information and opinions
contained herein reflect the views and
experience of the authors and not necessarily those of the sponsor.
The Role of
IncReTIn TheRapy
Type 2 diaBeTes is a meTaBoliC disorder resulTing from impairmenT of
the body’s ability to use insulin effectively. Over time, this biochemical dysregulation leads to a
progressive failure of beta cells to meet insulin production demands and a concomitant decline
in glycemic control. A number of agents are available to treat the condition, including metformin,
sulfonylureas, glinides, thiazolinediones (TZDs), alpha-glucosidase inhibitors, insulin – and most
recently, a group of drugs known as incretin-based therapies or incretin agents.
Incretin agents represent a significant advance in diabetes management in that they minimize – and in some cases, reverse – two of the biggest challenges associated with diabetes
management: weight gain and hypoglycemia. As a result of these benefits, these medications
have become increasingly prominent in clinical practice and are now endorsed in most treatment
guidelines for type 2 diabetes, including the 2008 Canadian Diabetes Association (CDA) clinical
practice guidelines.1
This Clinical Focus explains the mechanisms behind incretin-based therapies, the differences
between the two sub-classes within this group of drugs, and the patients who stand to benefit
most from these agents.
MAde poSSiBle tHrougH tHe finAnciAl Support of novo nordiSK cAnAdA
◆ 1
Type 2 DiabeTes
Table 1 Incretin agents overview
incretin agents approved in canada
DPP-4 inhibitors (oral)
GlP-1 receptor agonists (injected)
• Saxagliptin (Onglyza)
• Sitagliptin (Januvia)
• Linagliptin (Trajenta)
• Exenatide (Byetta)
• Liraglutide (Victoza)
distinguishing features
DPP-4 inhibitors (oral)
GlP-1 receptor agonists (injected)
• Increase levels of GLP-1 to
physiologic range
• Limited by endogenous incretin
secretion
• Moderate efficacy
• Well tolerated
• No weight change
• Pharmacological levels
of GLP-1
• Not limited by endogenous
secretion
• Enhanced efficacy
• Some nausea
• Associated with weight loss
Background
Standard anti-diabetic medications
are quite effective at lowering blood
glucose, but they all come with sideeffects and risks. Metformin is an
excellent first-line drug, but up to
30% of users experience gastrointestinal side-effects. The sulfonylurea glyburide is associated with a
39% excess risk of hypoglycemia.
The risk of hypoglycemia is similar
with the newer sulfonylureas and
glinides, though not as pronounced.
Thiazolidinediones (TZDs) are very
effective glucose-lowering agents
and do not cause hypoglycemia, but
they have been implicated with an
increased risk of heart failure and of
fractures. Recent concerns about the
potential link with cardiovascular
disease (for rosiglitazone) and bladder cancer (for pioglitazone) have led
to a marked decrease in the use of
this class.
Diabetes itself is associated with
weight gain, and many anti-diabetic
drugs (notably sulfonylureas, TZDs
and insulin) exacerbate this tendency.
Weight gain promotes insulin resistance, which in turn may lead to
treatment-resistant hypertension and
worsening of dyslipidemia, together
with progression of type 2 diabetes.
Incretin-based therapies address the
double challenge of hypoglycemia
and weight gain while offering a glucose-lowering capacity comparable to
that of most other agents.
The importance of
postprandial glucose
In type 2 diabetes, the pancreatic
beta cells lose their ability to secrete
enough insulin to maintain a glycemic balance. The first-phase insulin
spike, secreted in response to a meal,
is the most markedly attenuated, and
the second-phase insulin surge is
also abnormal. Type 2 diabetes also
counteracts the normal drop in glucagon secretion after meals. These
combined processes lead to postprandial hyperglycemia.
And why is this important? Both
fasting plasma glucose (FPG) and
postprandial glucose (PPG) contribute to hemoglobin HbA1c (a
measure of long-term glucose con-
2
trol and marker of diabetes complication risk). As a patient’s HbA1c
gets closer to target, the relative
contribution of postprandial glucose
to the HbA1c level becomes greater.
If HbA1c falls between 7.0% and
8.0%, targeting PPG as well as FPG
is more likely to bring HbA1c down
to target than reducing FPG alone.
We know that oral glucose produces a greater insulin response
t han intravenous glucose. This
occurs because ingesting glucose
(e.g., in a meal) releases two major
gut hormones into the circulation:
glucose-dependent insulinotropic
polypeptide (GIP) and glucagonlike polypeptide 1 (GLP-1). These
compounds, called incretins, help
lower postprandial glucose by stimulating the release of insulin from
pancreatic beta cells and reducing
the amount of glucagon secreted by
pancreatic alpha cells. These properties, along with a delay in gastric
emptying, are known as the incretin
effect. Incretin-based therapies capitalize on this phenomenon.
Mechanism of action
In people with t y pe 2 diabetes,
endogenous incretins are less effective at stimulating insulin secretion
and glucagon suppression following
meals. Incretin-based therapies help
correct this impairment by increasing postprandial serum incretin
levels. This group of drugs falls into
two categories:
• DPP-4 inhibitors: Endogenous
GLP-1 is rapidly cleaved and deactivated by an enzyme called DPP-4 (dipeptidyl peptidase-4). DPP-4 inhibitors
deactivate the DPP-4 enzyme, thus
enabling GLP-1 and GIP to remain in
the circulation for a longer time. These
drugs are given orally.
• GLP-1 receptor agonists: These
agents are modified forms of GLP-1
that have the same biological activity as the endogenous variety but are
not recognized or metabolized by the
DPP-4 enzyme, thus allowing a longer duration of action. Administered
by subcutaneous injection, GLP-1
receptor agonists have the added benefit of curbing appetite and delaying
gastric emptying.
DPP-4 inhibitors raise blood levels
of GLP-1 to about two to three times
the normal range, whereas GLP-1
receptor agonists raise it nine- to
tenfold. (Raising the dose of DPP-4
agents does not significantly increase
their effect, because currently used
doses already inhibit more than 95%
of the DPP-4 enzyme.)
Benefits and usage
Benefits
Both subclasses of incretin agents
lower PPG (preferentially compared
to FPG) and HbA1c. This glucoselowering effect is more pronounced
with GLP-1 receptor agonists, which
may approach insulin in their antihyperglycemic capacity in patients with
moderate hyperglycemia.
Incretin agents minimize the risk
of hypoglycemia because they only
stimulate insulin secretion when
blood glucose is high, as is the case
after a meal. When blood glucose
levels are low-normal, incretins do
not cause them to drop further into
the hypoglycemic range. In contrast,
drugs such as sulfonylureas continue
to stimulate the pancreas to release
insulin even if blood glucose is already
low, hence leading to a significant risk
for hypoglycemia and a need for constant carbohydrate consumption.
DPP- 4 i n h ibitors have been
found to be weight neutral – a distinct advantage over agents such as
sulfonylureas or TZDs, which are
associated with weight gain. GLP-1
receptor agonists are the first-ever
group of drugs to consistently show
the benefit of weight loss in patients
with type 2 diabetes. In research trials, subjects taking these drugs for
six months lost an average of two
to three kilograms. In my clinical
experience, many patients lose double this amount of weight within the
initial six months of GLP-1 therapy,
probably because I select overweight
or obese patients when prescribing
these drugs, while the trials included
patients of all baseline weights. It is
known that weight loss with GLP-1
receptor agonists correlates with
baseline BMI (i.e., obese patients
lose more weight with the drug than
normal-weight patients).
Several trials have found incretins
to increase pancreatic beta cell function in patients with type 2 diabetes.
In a one-year study comparing the
GLP-1 receptor agonist exenatide
with insulin glargine, exenatide significantly improved several measures
of beta cell function, including firstand second-phase glucose-stimulated
C-peptide secretion. 2 In another
study, treatment with the GLP-1
agent liraglutide for 14 weeks resulted
in similar dose-dependent improvements in first- and second-phase insulin secretion.3
Usage
DPP-4 inhibitors are indicated as
Made possible through the financial support of novo nordisk canada
combination therapy with metformin and/or sulfonylureas or as
monotherapy in metformin-intolerant patients. Both GLP-1 receptor
agonists are approved for use with
metformin (exenatide is also indicated for use with a sulfonylurea)
and in triple therapy with metformin and a sulfonylurea. Recently,
sitagliptin, saxagliptin and exenatide
were approved for use in combination with insulin.
The CDA guidelines recommend
educating patients about lifestyle
modification at each clinic visit,
initiating drug therapy if a patient
has not reached target within three
months, and adding another drug
in patients who fail to reach target
within six months. Incretin therapies complement metformin, which
exerts most of its action on fasting
blood glucose. As such, incretins
are a valuable add-on at any point
after initiation of metformin and
are gaining wider acceptance as
preferred second-line agents after
failure of metformin monotherapy.
The increasingly popular practice
of prescribing incretins with metformin reflects a general paradigm shift
toward the greater use of combination therapy. In the UK Prospective
Diabetes Study, 50% of patients
achieved an HbA1c of 7% after three
years of monotherapy with sulfonylurea, metformin or insulin, but only
25% maintained this level of glycemic control after nine years.4 These
figures underscore the progressive
nature of type 2 diabetes and the
challenge of substantially impacting
this progression with monotherapy.
Clinical outcomes
from trials
Efficacy
Studies have found that adding an
incretin agent to a diabetes management regimen has a significant glucose-lowering effect. When added to
other agents in Phase 3 clinical trials:
• Sitagliptin has lowered HbA1c by
an extra 0.6% to 0.7%.
• Saxagliptin has lowered HbA1c by
• Linagliptin has lowered HbA1c by
Reductions in HbA1c with GLP-1
receptor agonists have been more
robust, with the added benefit of
weight loss. When added to other
agents in Phase 3 clinical trials:
• Exenatide has lowered HbA1c by
an extra 0.4% to 0.9%
• Liraglutide has lowered HbA1c by
In the head-to-head LEAD-6 trial
between the two available GLP-1
receptor agonists, liraglutide 1.8
mg QD reduced HbA1c by 1.12%
and exenatide 10 μg BID by 0.79%
at 26 weeks (p < 0.001), when added
to metformin and/or sulfonylurea
therapy.5 Both drugs induced a robust
weight loss (3.24 kg for liraglutide vs.
Type 2 DiabeTes
FIGuRE 1. Composite endpoint at week 26
50
45
Patients reaching target (%)
2.87 kg for exenatide), leading to
speculative consideration of these
agents as weight loss medications in
individuals without diabetes.
In a head-to-head trial comparing a DPP-4 inhibitor (sitagliptin)
with a GLP-1 receptor agonist (liraglutide), patients randomized to
liraglutide had significantly greater
HbA1c reductions (1.29% with 1.2
mg/day and 1.51% with 1.8 mg/day)
and weight loss (2.78 kg with 1.2 mg/
day and 3.68 kg with 1.8 mg/day)
than sitagliptin (0.88% and 1.16 kg,
respectively) at 52 weeks of therapy.6
A recent meta-analysis of seven
trials (see Figure 1) found GLP-1
receptor agonists (exenatide and
liraglutide) to be more successful
than insulin glargine, the sulfonylurea glimepiride, or the TZD rosiglitazone at bringing about the combined endpoint of HBA1c under 7%,
absence of hypoglycemia, and lack of
weight gain.7 Incretin therapies and
insulin were the only medications
that performed better than placebo
in achieving this composite endpoint.
40
40%
HbA1c<7%, no hypoglycemia, no weight gain
35
32%*
30
25%*
25
20
15%**
15
11%**,††
10
8%**,††
6%**,††
8%**,††
5
0
Liraglutide
1.8 mg
(n=1513)
Liraglutide
1.2 mg
(n=1077)
Exenatide
(n=186)
Sitagliptin
(n=210)
Glargine
(n=225)
SU
(n=447)
TZD
(n=226)
Placebo
(n=505)
Vs. liraglutide 1.8 mg (*p<0.001; **p<0.0001). Vs. liraglutide 1.2 mg (†† p<0.0001)
Adapted from Zinman et al. Diab Obes Metab 2012;14(1):77-82.
PRIMARY CARE REVIEW
perspective
Medical management
Diabetes has been increasing in prevalence
in most parts of the world. Part of this trend
can be traced to rising obesity rates, another
part to more inclusive diagnostic criteria. This
broader “diagnostic net” came into being
because we know that early intervention can
help. If mild diabetes is treated as “a bit of a
sugar problem” rather than an important condition, people tend not to make changes.
FPG testing has become part of the routine
medical workup. Physicians need to be extravigilant about ordering these tests in people
from higher-risk ethnic groups (e.g., South
Asian), overweight/obese people, and people
with risk factors for the metabolic syndrome.
Diet and exercise can delay the need for
medication, but the great majority of patients
eventually require drug therapy. Current clinical guidelines have not quite caught up with
current practice surrounding the available antidiabetic drugs.
We used to rely on the sulfonylurea drug
class to help patients manage their blood glucose levels, but this practice has changed.
Sulfonylureas essentially “squeeze” the pancreas to make more insulin, which can accelerate beta cell failure, and do not improve insulin resistance. They are also associated with
weight gain and may induce hypoglycemia,
which can become recalcitrant.
Metformin has stood the test of time, which
is why we still use it first-line. It improves
insulin resistance in the liver, does not cause
weight gain, and is only rarely associated with
hypoglycemia. The maximum dose is 2,500
mg/day, but if the drug does not work at 2,000
mg, raising the dose will likely not yield an
improvement. Patients with elevated creatinine
should avoid metformin because of the small
but real risk of lactic acidosis in this group. The
drug can also cause significant gastrointestinal
upset and/or nausea in a not insignificant number of people.
TZDs improve insulin sensitivity and preserve
beta cell function, while yielding significant
reductions in HbA1c. However, the increased
risk of heart failure, cardiovascular events and
bladder cancer linked to TZDs in some studies
has dramatically curtailed their use.
The advent of basal insulin has markedly
improved our ability to deal with insulin deficiency. It removes the need for frequent testing and keeps hypoglycemia in check. On the
negative side, it tends to increase appetite, and
many patients resist moving to this “next step”
in management intensity.
after the diagnosis
When patients learn they have type 2 diabetes,
they sometimes react with fear that they will
need to take insulin right away. Physicians can
allay these fears by informing patients about
the steps involved in diabetes management,
starting with diet and exercise. It is also very
helpful to refer patients to a diabetes education
clinic at this stage.
When I first make a diagnosis of type 2 diabetes and discuss nutrition with patients, I try
to cover the following points:
• Weight optimization
• Reduction of carbohydrates to facilitate
weight loss
• The principle of glycemic index
• Replacing juices and soft drinks with water to
help reduce sugar intake and induce satiety.
Diabetes arises from insulin deficiency and/
or insulin resistance, the latter being a more
significant factor in heavier people. A change in
diet can often mitigate insulin deficiency, while
weight loss and exercise can help reverse insulin
resistance. In my experience, however, exercise
presents a significant barrier for many patients.
Incretin-based therapies represent one of
the most significant advances in diabetes management because they address many of the
problems outlined above (notably weight gain
and hypoglycemia). To help patients understand their mechanism of action without overcomplicating the explanation, I tell them that
incretins “keep the insulin effect around a little
longer after meals.”
DPP-4 inhibitors can decrease HbA1c by up
to 1%, are well tolerated, and are weight neutral. I recommend using these agents sooner
rather than later in type 2 diabetes management. Linagliptin can be used in people with
poor renal function, which makes it unique in
the DPP-4 class.
GLP-1 receptor agonists reduce HbA1c to
a greater extent than DPP-4 inhibitors and are
associated with weight loss. Injection is the
biggest patient barrier to their acceptance by
patients, followed by gastrointestinal sideeffects. To minimize the latter issue, I often
start patients on half-doses and gradually
titrate the dose upward. My patients generally
report very good satisfaction with these drugs
once they get past their fears about injection.
Both oral and injected incretin agents have
an additive benefit when used with metformin.
I often move patients quickly to DPP-4 inhibitors
after a short period on metformin monotherapy,
because these drugs are so well tolerated. I don’t
usually start with GLP-1 receptor agonists without trying DPP-4 inhibitors first, but I may move
more quickly to the GLP-1 subclass in overweight
or obese patients who want to lose weight.
While family doctors may hesitate to modify their management strategies to include a
newer class of drugs, research to date suggests that incretin-based therapies have a
robust risk/benefit profile and an important role
to play in type 2 diabetes management.
◆ 3
Type 2 DiabeTes
GLP-1 receptor agonists have
also been studied as combination
therapy with insulin. In one study,
adding exenatide to ongoing insulin
glargine treatment resulted in a placebo-adjusted HbA1C reduction of
0.7% after 30 weeks (p < 0.001).8 The
addition of exenatide also mitigated
increases in insulin dose. Further, the
exenatide group lost an average of 1.8
kg, while average weight increased
by 1 kg in the placebo group. In a
similar study, the addition of insulin
detemir to background treatment
with metformin and liraglutide yielded an additive reduction of -0.5% in
HbA1C after 26 weeks (p<0.0001).
Weight loss, an average of 3.5 kg with
metformin and liraglutide, was maintained when insulin was added.9
Safety
Since the launch of the first incretin agent seven years ago, clinical
experience has revealed these drugs
to have a promising safety profile.
DPP-4 inhibitors have few to no sideeffects. Nausea, the most common
adverse effect with GLP-1 receptor
agonists, is reported initially by about
10% to 15% of subjects and typically
becomes less pronounced within days
to weeks with continued use (returning to placebo levels after 10 to 12
weeks in the case of liraglutide).
In my experience, patients on
GLP-1 receptor agonists who eat
large portion sizes or high-fat meals
tend to experience more nausea.
Some of these patients may need
“hand holding” from physicians and
health educators to get through the
initial adjustment period. I have found
it helpful to counsel patients that nausea may occur but will likely be transient, as well as to slowly titrate the
dose depending on tolerability.
Some reported cases of acute pancreatitis in patients taking these drugs
have led the U.S. Food and Drug
Administration to add a warning to
the exenatide and sitagliptin labels.
However, diabetes itself is associated
with an increased risk of pancreatitis, and research to date suggests that
patients initiating treatment with these
agents are no more likely to develop
acute pancreatitis than those taking
other anti-diabetic medications.10
Incretins in clinical
practice
Incretin agents are most appropriate for obese or overweight patients
whose HbA1c falls between 7% and
9%. If HbA1c levels exceed 9%, the
patient may need to be on insulin. I
am less inclined to use these agents
in lean patients with type 2 diabetes,
as this profile is more often associated with insulin deficiency than
resistance, so insulin therapy may
be the preferred option.
Choosing between subclasses
If a patient has a small elevation in
4
HbA1c and the FPG is close to normal, it is reasonable to target PPG
with the goal of lowering HbA1c to
7% or less. DPP-4 inhibitors are a
reasonable choice in such a scenario. I
also favour DPP-4 inhibitors in older
patients, who tend to experience
more nausea with a GLP-1 receptor
agonist and who often don’t require
the additional benefit of weight loss.
In a patient with HbA1c of 8% or
higher, a GLP-1 agent would have
a greater chance of bringing the
patient down to target than a DPP-4
inhibitor.
GLP-1 receptor agonists are generally not warranted in patients starting out at a normal weight. However,
most people with type 2 diabetes are
either overweight or have central
adiposity (as determined by waist circumference), making GLP-1 receptor
agonists a good choice for them.
The injectable administration of
GLP-1 receptor agonists acts as a
deterrent for some patients, but this
barrier often breaks down when they
are shown how easy it is to self-inject.
I remind patients that it is less painful to inject insulin or GLP-1 agents
than to prick fingertips, which most
of them do regularly for glucose testing. In my experience, patients are
unlikely to discontinue treatment
with these agents if forewarned about
potential initial transient side-effects,
especially those patients who lose a
significant amount of weight.
Cost and coverage
W hile incretin agents have significant benefits as outlined above,
practical issues of high cost and
limited insurance coverage act as an
impediment to wider clinical usage.
Most private insurance companies
cover both DPP-4 inhibitors and
GLP-1 receptor agonists, whereas
public coverage may be more limited
depending on the province/territory.
Future outlook
GLP-1 agonists with a longer duration of action (and a more convenient weekly injection schedule) are
in current development, and a onceweekly formulation of exenatide has
recently become available in the
U.S. and Europe.
Studies to date show some encouraging signals for cardiovascular benefits from incretin agents. Several
ongoing trials, collectively involving
over 100,000 patients worldwide,
are evaluating the long-term cardiovascular effects of incretin therapy.
These trials should help establish
the utility of these agents in preventing microvascular and macrovascular
complications of diabetes, in addition
to clarifying their role in maintaining
durability of glycemic control.
CASE STUDY
L awrence is a farm equipment
regional sales manager who frequently travels for work. Diagnosed
with type 2 diabetes three years ago,
he started metformin 1,000 mg BID
two months after his initial diagnosis.
His weight loss efforts stalled after
an initial loss of 4 kg and he now weighs 93 kg, which puts him in
the Class I obese category. He is not happy with his body image and
tries to select “healthier” foods, but has trouble keeping portions
under control.
Lawrence has not been able to achieve target glucose and HbA1c
levels on metformin alone. His most recent lab results were FPG 9.8
mmol/L and HbA1c 8.2%.
You schedule a visit with him to discuss lifestyle and pharmacologic strategies for more effectively managing his diabetes. When
you bring up the future consideration of insulin therapy (if his glucose levels remain uncontrolled despite lifestyle modification and
oral agents), he expresses extreme anxiety about this possibility due
to fear of needles.
As a young, obese patient with poor glycemic control, Lawrence
is a good candidate for incretin agents. In his case, either a DPP-4
inhibitor or GLP-1 receptor agonist would be a suitable choice.
scenario 1
Given Lawrence’s aversion to injections, you prescribe a DPP-4 inhibitor. After three months on the drug, his HbA1c has dropped to 7.4%
and his FPG is 8.1 mmol/L. You let Lawrence know that these figures,
while representing a significant improvement, still fall short of target
and you bring up the option of insulin once again. When he still balks
at this possibility, you present a further alternative: continue with the
metformin + oral incretin therapy and add a longer-acting sulfonylurea
in a triple therapy combination. You inform him that this regimen will
require constant vigilance about hypoglycemia. Lawrence agrees to
try it. Three months later his HbA1c has finally fallen below 7%, but
he experienced mild hypoglycemia on two occasions. He has gained
2 kg of weight during this six-month period.
scenario 2
You help Lawrence overcome his resistance to injections by giving him a demonstration and discussing the potential benefits and
adverse effects of a GLP-1 receptor agonist added to metformin.
Three months later his HbA1c has fallen to 6.9%, his FPG is 6.7,
and his weight has dropped by 3 kg, even though he hasn’t made a
conscious effort to lose weight.
2. Bunck MC et al. One-year treatment with
exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial. Diabetes Care 2009;32(5):762-768.
3. Vilsbøll T et al. Liraglutide, a once-daily
human GLP-1 analogue, improves pancreatic
B-cell function and arginine-stimulated insulin
secretion during hyperglycaemia in patients
with Type 2 diabetes mellitus. Diabet Med
2008;25(2):152-156.
4. Turner RC et al. Glycemic control with diet,
sulfonylurea, metformin, or insulin in patients
with type 2 diabetes mellitus: progressive
requirement for multiple therapies (UKPDS
49). UK Prospective Diabetes Study (UKPDS)
Group. JAMA 1999;281(21):2005-2012.
5. Buse JB et al. Liraglutide once a day versus
exenatide twice a day for type 2 diabetes: a
26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet
2009;374(9683):39-47.
6. Pratley R et al. One year of liraglutide treatment offers sustained and more effective
glycaemic control and weight reduction com-
publisher Janet Smith
senior account Manager Norm Cook
editor Deirdre Maclean
project editor Gabrielle Bauer
art direction Lima Kim
REFERENCES
1. Canadian Diabetes Association 2008 Clinical
Practice Guidelines. Canadian Journal of
Diabetes 2008;32:Suppl 1
pared with sitagliptin, both in combination
with metformin, in patients with type 2 diabetes: a randomised, parallel-group, open-label
trial. International Journal of Clinical Practice
2011;65(4):397-407.
7. Zinman B et al. Achieving a clinically relevant
composite outcome of an HbA1c of <7%
without weight gain or hypoglycaemia in type
2 diabetes: a meta-analysis of the liraglutide
clinical trial programme. Diabetes Obesity &
Metabolism 2012;14(1):77-82.
8. Rosenstock J et al. Baseline factors associated with glycemic control and weight loss when
exenatide twice daily is added to optimized
insulin glargine in patients with type 2 diabetes.
Diabetes Care 2012;35:955-958.
9. DeVries JH, Bain S, Thomsen A, et al.
Sequential intensification of metformin treatment in type 2 diabetes with liraglutide followed by randomized addition of basal insulin
prompted by A1C targets. Diabetes Care 2012
Jul;35(7):1446-54.
10. Drucker DJ et al. The safety of incretin-based
therapies—review of the scientific evidence. J
Clin Endocrinol Metab 2011;96:2027–2031.
This supplement is published by Rogers
Healthcare Group, One Mount pleasant Road,
Toronto, Ontario M4y 2y5. Telephone: (416)
764-2000, Fax: (416) 764-3931. Clinical Focus is
a trademark of Rogers publishing. No part of
this publication may be reproduced, in whole
or in part, without the written permission of
the publisher. Copyright © 2012.

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