Kwartaalbericht 4 kwartaal 2010 8 november 2010

Transcription

Kwartaalbericht 4 kwartaal 2010 8 november 2010
Kwartaalbericht
4e kwartaal 2010
8 november 2010
Contents
Voorwoord
3
1. Observations
4
1.1.
Bisphosphonates and depressive reactions
4
1.2.
Norfloxacin and hypoglycaemia
12
1.3.
Inhaled fluticasone and epistaxis
16
1.4.
Oxaliplatin and laryngospasm
20
2. Short notes
2.1.
24
Baclofen and constipation
24
3. Publications
25
2
Voorwoord
Op 22 september jl. heeft het Europees Parlement een aantal wijzigingen
aangenomen die van belang zijn voor de farmacovigilantie in Europa.
Sleutelbegrippen waren onder meer: transparantie en de positie van de patiënt.
Het is duidelijk dat de patiënt een centrale positie heeft: het gaat er om dat de
gebruiker van geneesmiddelen zo veilig mogelijke geneesmiddelen krijgt en
toegang heeft tot alle relevante informatie daarover. Vertrouwen is daarbij dus
een derde sleutelbegrip.
Het melden door patiënten zal in heel Europa gestimuleerd worden. Nederland
loopt daarin voorop, zowel in aantal meldingen als in het analyseren van de
bijdrage die deze meldingen leveren aan signaaldetectie. De bij dit
Kwartaalbericht gevoegde literatuur illustreert dat.
Ook voorzien de nieuwe regels erin dat op de bijsluiters wordt aangegeven dat
gebruikers bijwerkingen bij het nationale meldcentrum kunnen melden, iets waar
Lareb al jaren voor pleit.
Ook transparantie is een sleutelbegrip in de nieuwe regelgeving. De Nederlandse
meldingen zijn voor iedereen op de website van Lareb zichtbaar en we weten dat
zorgverleners daar ook gebruik van maken.
De signalen in dit Kwartaalbericht zullen ook op de website zichtbaar gemaakt
worden. Bij de verschillende bronnen die Lareb gebruikt bij de analyse van
mogelijke signalen ontbreekt het Risk Management Plan. Hoewel het formeel
openbaar schijnt te zijn, is het voor ons en anderen niet makkelijk toegankelijk.
Wellicht moet hier de transparantie nog verder geïmplementeerd worden, want
het is van groot belang dat bekend is welke risico’s van bijwerkingen er mogelijk
zijn.
Kees van Grootheest
directeur Lareb
3
1. Observations
1.1.
Bisphosphonates and depressive reactions
Introduction
Bisphosphonates are the most commonly prescribed medications for the
treatment of osteoporosis [1].
Alendronate (Fosamax®) is indicated for the treatment and prevention of
osteoporosis in postmenopausal women, treatment to increase bone mass in men
with osteoporosis, treatment of glucocorticoid-induced osteoporosis in men and
women receiving glucocorticoids in a daily dosage equivalent to 7.5 mg or greater
of prednisone and who have low bone mineral density, and treatment of Paget’s
disease of bone in men and women [2]. Alendronate with colecalciferol (vitamin
®
D3) (Fosavance ) is indicated for the treatment of postmenopausal osteoporosis
in patients at risk of vitamin D insufficiency [3].
Risedronate (Actonel®) is used for the same indications as alendronate [4].
®
Risedronate with calcium (Actokit ) is indicated for the treatment and prevention
of osteoporosis in postmenopausal women [5].
Etidronate with calciumcarbonate (Didrokit®) is indicated for the prevention and
treatment of osteoporosis in post-menopausal women and the prevention of
corticosteroid induced osteoporosis [6].
®
Ibandronate (Bonviva ) is indicated for the treatment of osteoporosis in
postmenopausal women at increased risk of fracture [7].
Pamidronate (Pamipro®) is used intravenously for a different indication than most
other bisphosphonates, namely tumour-induced hypercalcaemia, osteolytic
lesions in patients with breast cancer related bone metastasis and multiple
myeloma stage III [8]. Intravenous pamidronate is also used as APD infusion for
the indication osteoporosis.
®
Zoledronate (Zometa ) is indicated for prevention of skeletal related events in
patients with advanced malignancies involving bone or treatment of tumourinduced hypercalcaemia [9].
The most commonly used bisphosphonate in the Netherlands [10], alendronate
®
(Fosamax ), was granted marketing authorization in 1996 [2].
Lareb received several reports of depression, depressed state or mood with the
use of the bisphosphonates alendronate, etidronate and pamidronate. Although
no reports of depressive reactions were received for other bisphosphonates, we
included these in the overview of the literature.
According to the DSM-IV criteria [11] depressive disorders can be divided in
major depressive disorder, dysthymic disorder and depressive disorder not
otherwise specified. The essential feature of a major depressive episode is a
period of at least two weeks during which there is either depressed mood or the
lost of interest or pleasure in nearly all activities. The individual must also
experience four symptoms drawn from a list which includes changes in appetite or
weight, sleep, psychomotor activity, decreased energy, feelings of worthlessness
or guilt, difficulty thinking, concentrating or making decisions, or recurrent
thoughts of death or suicidal ideation or plans or attempts [11].
Depression or depressed mood is not described in the SmPC of alendronate
(Fosamax®) [2], alendronate with colecalciferol (Fosavance®) [3], risedronate
(Actonel®) [4], risedronate with calcium carbonate (Actokit®) [5], etidronate with
®
®
calcium carbonate (Didrokit ) [6], ibandronate (Bonviva ) [7], pamidronate
®
®
(Pamipro ) [8] or zoledronate (Zometa ) [9].
4
Reports
On July 22, 2010, the database of the Netherlands Pharmacovigilance Centre
Lareb contained 14 reports concerning depression with the use of alendronate,
etidronate or pamidronate.
Table 1. Reports of depression associated with the use of bisphosphonates
Patient,
Sex, Age
Drug
Indication for use
Concomitant
medication
Suspected adverse
drug reaction
Time to onset,
Action with drug
outcome
A 16425
F, 61 – 70
years
alendronate 10 mg
daily,
osteoporosis
spironolactone,
furosemide,
ipratropium,
budesonide
depressed state,
hoarseness,
drowsiness,
abdominal discomfort
6 weeks
discontinued
not reported
B 17110
F, 70
years and
older
alendronate 10 mg
daily,
unspecified
hydrophilic cream depressed state
(‘lanette’),
calcium carbonate
6 weeks
no change
not reported
beclomethasone
depressed state
3 weeks
discontinued
recovered after
one month
ranitidine,
isradipine,
triamterene/
epitizide
depressed state
4 years
discontinued
recovered
C 19211
etidronate cyclical use
M, 41 – 50 of 400 mg daily during
years
14 days followed by 72
days of calcium
carbonate,
osteoporosis
D* 19212
F, 51 – 60
years
etidronate cyclical use
of 400 mg daily during
14 days followed by 72
days of calcium
carbonate,
osteoporosis
D* 19212
F, 51 – 60
years
pamidronate 90 mg per
IV, osteoporosis
depressed state,
agitation
quickly after start
discontinued
recovered
E 22487
F, 31 – 40
years
alendronate 10 mg
daily,
osteoporosis
fluvoxamine 50 mg 3
times daily
drug level decreased,
depression
aggravated
not reported
discontinued
not reported
F 28069
F, 70
years and
older
alendronate 10 mg
daily,
osteoporosis
depressed state
not reported
discontinued
recovered
G 45315
F, 61 – 70
years
alendronate 70 mg
weekly,
osteoporosis
depression,
gastro-intestinal
disorder,
bone pain,
peripheral oedema,
fatigue
not reported
exactly, gradual
onset
discontinued
recovering
H 47307
F, 51 – 60
years
alendronate 70 mg
weekly,
osteoporosis
depression,
restlessness,
emotional lability
couple of days
discontinued,
recovered,
positive
rechallenge
ibuprofen,
temazepam
diazepam
5
Patient,
Sex, Age
Drug
Indication for use
Concomitant
medication
I 48815
alendronate 70 mg
M, 51 – 60 weekly,
years
unspecified
J 65558
F, 70
years and
older
alendronate with
colecalciferol 70
mg/2800 ie weekly,
osteopenia
K, 104474
F, 61 – 70
years
alendronate 70 mg
weekly,
osteoporosis
L 88028
F, 61 – 70
years
alendronate 70 mg
weekly,
osteoporosis
diazepam,
maprotiline,
nitrazepam,
vitamin C + garlic
pantoprazole,
salbutamol
M 101865 etidronate cyclical use
M, 41 – 50 of 400 mg daily during
years
14 days followed by 72
days of calcium
carbonate,
osteoporosis
N 70459
F, 31 – 40
years
anastrozole 1 mg,
breast cancer,
goserelin 3.6 mg in
injection,
breast cancer,
alendronate 70 mg
weekly, prevention
ibandronate
calcium
carbonate/
colecalciferol,
zolpidem
Suspected adverse
drug reaction
Time to onset,
Action with drug
outcome
depressed state,
bone pain,
oedema legs,
fatigue,
allergic reaction
not reported
discontinued
not reported
depressed state
5 hours
discontinued
recovered
depressed mood,
anxiety
not reported
discontinued
recovered
depressed mood
month
discontinued
recovered
depressed mood
within a day
discontinued and
replaced by
risedronate
recovered
depressed mood,
arthralgia,
cough,
insomnia,
nausea
2 weeks
discontinued,
recovered,
rechallenge only
for the
anastrozole and
goserelin
* Patient D appears twice in table 1. See the description of this case below.
Patient A uses budesonide as concomitant medication. For this drug depression
is listed in the SmPC as a rare adverse drug reaction (incidence 0.1 - 0.01%) [12].
The cases of patient C en D were previously published by Wolffenbuttel &.van der
Klauw [13] and also reported to Lareb.
Patiënt C is male aged 41 – 50 years who was treated with etidonate for
osteoporosis. He had a medical history of chronic obstructive pulmonary disease
and had been treated with corticosteroids for a prolonged period. The patient
suffered from fatigue, concentration impairment, irritation, spontaneous crying and
depressed feelings. The reaction occurred after each cycle of etidronate use and
recovered within weeks. Each following time etidronate was used again, the
reaction reoccurred. The blood calcium level was within the normal range in this
patient. Etidronate was withdrawn and the reaction did not occur again for the
following five years.
Patient D appears twice in table 1, this case had not been divided into two
separate case reports with their own ID-numbers at the time of reporting (1997).
Patient D had been treated for osteoporosis with etidronate since she was 50. At
the age of 54 changes in her mood, memory impairment and difficulties with
concentration occurred. She felt depressed and emotionally drained. The blood
calcium level was within the normal range in this patient. After withdrawal of
etidronate the patient recovered within two months. Her other medication had not
been changed during this period.
6
When the patient was 56 pamidronate 90 mg per IV was started to treat her
osteoporosis. Quickly after start of pamidronate the same reactions occurred
again and the patient became depressed and agitated. Pamidronate was
withdrawn and she recovered. Treatment with bisphosphonates was not started
again; the patient was treated with colecaliferol, vitamin D and calcium.
Patient E had a history of depression. Fluvoxamine had been used for years and
every time this drug was discontinued a relapse of the depression occurred. The
last six years the patient had been using fluvoxamine constantly and had not
suffered from a relapse of the depression. After alendronate was started, the
depression worsened again. In hospital the blood level of fluvoxamine was
determined; this had decreased without a known cause. A possible interaction
between alendronate and fluvoxamine was reported to the pharmacovigilance
centre. At the time of reporting (12-10-1998), alendronate was discontinued but
the patient had not recovered.
Patient J (consumer report) reported that the first couple of weeks after
alendronate with colecaliferol she only suffered from complaints a few hours after
intake. Gradually the depressed state prolonged and she also suffered from
fatigue. In her report the patient asked if there was a possibility for an interaction
between maprotiline and alendronate with colecalciferol. After withdrawal of the
suspect drug she recovered. The indication for the use of maprotiline, a tricyclic
antidepressant, is not given in this report.
Patient M only suffered from a depressed mood during the 14 days of etidronate
use during a cycle. During the following 72 days of calcium carbonate use the
reaction recovered.
Patient N (consumer report) reported that she thinks the combination between
anastrozole and goserelin was the main cause for her depressed mood. There
was a positive dechallenge for all suspected drugs (anastrozole, goserelin and
alendronate) but a positive rechallenge was only reported for anastrozole and
goserelin. The patients’ serious illness could also be a factor in the occurrence of
the depressed state.
Other sources of information
SmPC
Depressive reactions including depression or depressed state or mood are not
described in the Dutch SmPC’s of the various bisphosphonates [2-9]. The Dutch
SmPC of pamidronate [8] describes some psychiatric adverse drug reactions like
agitation and visual hallucinations. The Dutch SmPC of zoledronate mentions
anxiety, sleep disturbance and confusion as possible psychiatric reactions [9].
Depression is not described in the US SmPC of alendronate (Fosamax®) [14].
®
The US SmPC of etidronate (Didronel ) mentions neuropsychiatric events
including amnesia, confusion, depression and hallucination as events based on
worldwide postmarketing experience [15].
The US SmPC of risedronate (Actonel®) mentions that depression occurred with
an incidence of 6.8% compared to 6.1% with placebo in combined phase 3
postmenopausal osteoporosis treatment trials [16]. Four randomized, doubleblind, placebo-controlled multinational trials of 3232 women aged 38 to 85 years
with postmenopausal osteoporosis were combined. The duration of the trials was
up to three years, with 1619 patients exposed to placebo and 1613 patients
exposed to risedronate 5 mg. Based on the numbers on the SmPC, this
2
difference is not statistically significant (2-sided Χ -test p-value = 0.43)
7
During a study which compared risedronate 5 mg daily and 35 mg weekly for the
treatment of osteoporosis in postmenopausal women (n=965), the incidence of
depression was 2.3% for both groups [17].
®
The US SmPC of zoledronate (Zometa ) describes that in 3 randomized, doubleblind, active, and placebo-controlled clinical trials in patients with multiple
myeloma and bone metastases, the incidence of depression in patients receiving
zoledronic acid 4 mg (n=1,031) compared to pamidronate 90 mg (n=556) and to
placebo (n=455) was 14% versus 17% versus 11%, respectively [18].
Based on the numbers in the SmPC, the difference between zoledronate and
2
placebo is not statistically significant (2-sided Χ -test p-value = 0.13). The
difference between pamidronate and placebo is statistically significant (2-sided
2
Χ -test p-value = 0.007)
Literature
In the article by Wolffenbuttel &.van der Klauw [13] a third patient is presented,
whose case was not reported to Lareb. This patient was a female, aged 67 who
also suffered from a depressed mood, agitation and impaired concentration with
cyclical use of etidronate. The blood calcium level was within the normal range in
this patient. Shortly after withdrawal of etidronate, she recovered. There were no
other emotional or psychosocial problems. Alendronate was started and the
depressed mood reoccurred together with insomnia, palpitations and rash.
Alendronate was withdrawn and the patient recovered. Three monthly intravenous
pamidronate was started without reoccurrence of the reactions.
To the best of our knowledge no other case reports about bisphosphonateinduced depressive reactions have been published.
Databases
Table 2. Reports of depressive reactions associated with bisphosphonates in the Lareb
database
Drug
Number of
reports
ROR (95% CI)
Alendronate
11
1.3 (0.7 - 2.5)
Etidronate
3
2.5 (0.8 – 7.9)
Bisphosphonates in
total
14
1.5 (0.9 - 2.6)
For the Lareb database the MedDRA Preferred terms depression and depressed
mood in association with bisphosphonates, with and without calcium or
colecalciferol were taken into account. One patient also suffered from depressed
feelings during the use of pamidronate, a reporting odds ratio was not calculated
for pamidronate.
Table 3. Reports of depressive reactions associated with bisphosphonates in the WHO
database
Drug
Number of
reports
ROR (95% CI)
Alendronate
638
2.3 (2.1 - 2.5)
Etidronate
18
0.7 (0.5 - 1.1)
Pamidronate
89
1.9 (1.5 – 2.3)
Bisphosphonates in
986
1.5 (1.4 - 1.6)
8
Drug
Number of
reports
ROR (95% CI)
total
For the WHO database the terms WHO-ART terms depression, depression
aggravated and depression psychotic in association with bisphosphonates, with
and without calcium or colecalciferol were taken into account.
On August 3rd the Eudravigilance database contained 753 reports of depression
associated with use of one of the bisphosphonates. Specified for individual
bisfosfonates results in the following number of reports of depression:
alendronate 636, risedronate 42, zoledronate 214, etidronate 1, clodronate,
ibandronate 46, pamidronate 116. Because in some reports, more than one
bisphosphonate was reported as a suspect drug the total number exceeds 777.
Prescription data
The number of patients using bisphosphonates in the Netherlands is shown in
table 4.
Table 4. Number of patients using bisphosponates in the Netherlands between 2006 and
2009* [10]
Drug
2006
2007
2008
2009
Etidronate
2
.
.
.
Etidronate with calcium
12,735
9,295
7,133
5,742
Alendronate
144,080
139,770
141,250
149,300
Aledronate with
colecalciferol
12,567
17,883
21,309
25,610
Ibandronate
4,855
8,481
10,756
12,083
Risedronate
59,033
61,755
66,077
72,343
Risedronate with
calcium
10,973
12,400
12,798
12,763
603
1,367
275
452
Zoledronate
* There are no data for pamidronate available
Mechanism
The mechanism through which bisphosphonates might induce depressive
symptoms is unknown. Bisphosphonates, including alendronate, can cause
hypocalcaemia. Acute hypocalcaemia is commonly associated with symptoms of
breathlessness, palpitations, tingling, and spasm. In comparison, chronic
hypocalcaemia is more commonly associated with fatigue, irritability, memory
loss, depression, confusion, delusions, and hallucinations. However, the decrease
in serum calcium is generally mild and occurs with the start of therapy and then
plateaus over time [19].
In the patients that were described by Wolffenbuttel &.van der Klauw [13], the
blood calcium levels were within the normal range.
The authors of a case report of hallucinations associated with alendronate
described the hypothesis that changing from the once-daily to the once-weekly
formulation of alendronate, although resulting in similar values for the area under
the concentration-time curve, yields a greater maximum serum concentration of
the drug, ultimately precipitating the adverse reaction their patient experienced.
However, this could not be confirmed in their patient since the poor bioavailability
9
with oral administration of alendronate results in serum concentrations below the
lower limit of quantification (5 ng/ml) [19].
There were two cases reported to Lareb where a possible drug interaction
between alendronate (with colecalciferol) and fluvoxamine (patient E) or
maprotiline (Patient J) was mentioned. An interaction between bisphosphonates
and antidepressant drugs such as SSRI’s or TCA’s is not described in Stockley’s
Drug interactions [20].
Discussion
Lareb received 14 reports concerning depressive reactions with the use of
alendronate or etidronate. In nine cases there was a positive dechallenge and in
one patient also a positive rechallenge. In the other four cases the outcome was
not reported. A close temporal relationship with the start of each cycle of use of
etidronate was reported in patient D and M.
In the literature information about this association is scarce, although the US
SmPCs of certain bisphosphonates mention the occurrence of depression as an
adverse drug event [15,17,18]. However, for risedronate and zoledronate the
occurrence of depression was similar in the placebo and the treated group [16].
Lareb has received only reports about three of the bisphosphonates available on
the Dutch market namely etidronate, pamidronate and alendronate. In the WHO
database there are also reports of depression with other bisphosphonates. This
association could possibly be a class-effect for all the bisphosphonates. However,
a possible class-effect is not fully supported by the cases Lareb received.
Depression is mentioned in the literature as one of the possible risk factors for
osteoporosis [21].
Conclusion
These cases illustrate a possible signal of depressive reactions occurring with
alendronate, pamidronate and etidronate. This association could possibly be a
class-effect for all the bisphosphonates.
• Possible new signal of
alendronate, pamidronate and
etidronate associated with
depressive reactions
References
1. Strampel W, Emkey R, Civitelli R. Safety considerations with bisphosphonates for the treatment of
osteoporosis. Drug Saf 2007;30(9):755-63.
2. Dutch SmPC Fosamax®. (version date: 12-9-2009, access date: 22-7-2010) http://db.cbgmeb.nl/IB-teksten/h18021.pdf.
3. Dutch SmPC Fosavance®. (version date: 8-7-2010, access date: 22-7-2010)
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000619/WC500024251.pdf.
4. Dutch SmPC Actonel®. (version date: 24-2-2010, access date: 22-7-2010) http://db.cbgmeb.nl/IB-teksten/h24990.pdf.
10
5. Dutch SmPC Actokit®. (version date: 11-3-2010, access date: 22-7-2010) http://db.cbg-meb.nl/IBteksten/h31634.pdf.
6. Dutch SmPC Didrokit®. (version date: 4-3-2009, access date: 22-7-2010) http://db.cbg-meb.nl/IBteksten/h13739.pdf.
7. Dutch SmPC Bonviva®. (version date: 7-7-2010, access date: 22-7-2010)
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000501/WC500052652.pdf.
8. Dutch SmPC Pamipro®. (version date: 5-6-2009, access date: 22-7-2010) http://db.cbg-meb.nl/IBteksten/h30331.pdf.
9. Dutch SmPC Zometa®. (version date: 5-6-2010, access date: 22-7-2010)
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000336/WC500051730.pdf.
10. College for Health Insurances. GIP database. (version date: 9-6-2009, access date: 10-2-2010)
http://www.gipdatabank.nl/index.asp?scherm=tabellenFrameSet&infoType=g&tabel=01basis&item=J01FF.
11. American Psychiatric Association. DSM-IV Diagnostic and Statistical Manual of Mental Disorders.
ed. Washington DC: American Psychiatric Association; 1994.
12. Dutch SmPC Pulmicort®. (version date: 18-9-2008, access date: 22-9-2010) http://db.cbgmeb.nl/IB-teksten/h13698.pdf.
13. Wolffenbuttel BH, van der Klauw MM. [Psychiatric side effects associated with diphosphonate
treatment]. Ned Tijdschr Geneeskd 2003;147(1):35-7.
14. US SmPC Fosamax®. (version date: 1-3-2010, access date: 23-7-2010)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020560s051s055s057,021575s012s0
16s018lbl.pdf.
15. US SmPC Didronel®. (version date: 31-12-2010, access date: 23-7-2010)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017831s055lbl.pdf.
16. US SmPC Actonel®. (version date: 31-12-2009, access date: 23-7-2010)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020835s036lbl.pdf.
17. US SmPC Actonel with calcium (Copacked)®. (version date: 22-8-2006, access date: 23-7-2010)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021823s004_LBL.pdf.
18. US SmPC Zometa®. (version date: 9-11-2009, access date: 23-7-2010)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021223s018lbl.pdf.
19. Coleman CI, Perkerson KA, Lewis A. Alendronate-induced auditory hallucinations and visual
disturbances. Pharmacotherapy 2004;24(6):799-802.
20. Baxter, K ed. Stockley's Drug Interactions [online]. (version date: 2010, access date: 26-7-2010)
http://www.medicinescomplete.com/.
21. Cizza G, Primma S, Coyle M, Gourgiotis L, Csako G. Depression and osteoporosis: a research
synthesis with meta-analysis. Horm.Metab.Res 2010;42(7):467-82.
11
1.2.
Norfloxacin and hypoglycaemia
Introduction
Norfloxacin is a fluoroquinolone antibiotic. It inhibits bacterial deoxyribonucleic
acid synthesis and can therefore be used as a wide spectrum antibiotic.
Norfloxacin is registered for therapeutic use in acute recurrent urinary tract
infections, prostatitis, bacterial gastroenteritis, gonorrhoeic urethritis, proctitis and
cervicitis as well for prophylactic use in neutropenic patients [1-5]. Norfloxacin has
been used internationally since 1983. Fluoroquinolones have both hypoglycemic
and hyperglycemic effects in diabetic as well as non-diabetic patients [7].
Although a class effect is suspected, some fluoroquinolones have a more
profound effect on glucose homeostasis, for example gatifloxacin [7-9] and
temafloxacin [8], which were withdrawn due to this effect. Levofloxacin is also
believed to have hypoglycemic effects [9]. Evidence of ciprofloxacin effects on
hypoglycemia is sparser and only based on case reports in patients using
sulfonylurea in a pre-existing diabetes mellitus [8]. Hypoglycaemia is not
mentioned in the SmPCs of norfloxacin [1-5]
Hypoglycaemia not related to diabetes treatment, salicylate intoxication or use of
alcohol occurs seldom. Besides endogenous hyperinsulinism or rare
malignancies or paraneoplastic effects, sepsis or starvation may induce
hypoglycaemia [10].
Five cases of norfloxacin and hypoglycamia associated with norfloxacin use,
including two cases of hypoglycaemia in non-diabetic subjects, are presented in
this report.
Reports
On July 7, 2010 the database of the Netherlands Pharmacovigilance Centre
Lareb contained five reports (Table 1) concerning hypoglycemia associated with
norfloxacin use.
Table 1. Reports of hypoglycemia associated with the use of norfloxacin.
Patient,
Number,
Sex, Age
Drug
Indication for use
Concomitant
medication
Suspected adverse
drug reaction
Time to onset,
Action with drug
Outcome
A 21494
F, 21 – 30
years
norfloxacin
urinary tract infection
OAC (Mercilon®),
ibuprofen
hypoglycaemia (2.9
mmol/l, postprandial
3.3 mmol/l)
two days;
withdrawn;
recovered
glucose 4.4
mmol/l and 5.9
mmol/l
prior
hypoglycaemia
during earlier
norfloxacin
treatment
betahistine
estriol
ibuprofen
magnesium hydroxide,
paracetamol,
haloperidole,
rosuvastatin,
omeprazole,
rivastigmine
hypoglycaemia
three days
withdrawn,
glucagon therapy,
recovered
B, 104591 norfloxacin 400mg bd
F, 70 years urinary tract infection
and older
12
Patient,
Number,
Sex, Age
Drug
Indication for use
C 73853
M, 31 – 40
years
Concomitant
medication
Suspected adverse
drug reaction
Time to onset,
Action with drug
Outcome
norfloxacin 400mg
not reported
urinary tract infection
insulin diabetes mellitus
type 1
hypoglycaemia
glucose blood levels
were not specified,
however
20 units reduction of
daily insulin need
one day;
norfloxacin
withdrawn;
recovered
D, 75154
F, 61 – 70
years
norfloxacin 400mg
cystitis
metformin 1000mg bd
insulin (lispro and
glargin)
ipratropium salbutamole
salmeterole/fluticasone
montelukast
prednisolone
hypoglycaemia
(2.7mmol/l
one day,
withdrawn,
outcome unclear
due to unstable
diabetes and
infections
unresponsive to
antibiotic
treatment,
weeks later
patient died due
to non-related
cause
(cerebrovascular
accident)
E 21415
F, 61 – 70
years
norfloxacin
urinary tract infection
400mg daily
glimepiride
type 2 diabetes mellitus
3mg
metoprolol, valsartan,
hydrochlorothiazide,
triamterene, pravastatin
hypoglycaemia (2.9
mmol/l
75 minutes
discontinued,
replaced by
nitrofurantoin
recovered despite
ongoing
glimepiride use
Lareb received five reports of norfloxacin associated hypoglycaemia, all reported
by health care professionals and objectified by glucose levels or need of insulin,
or given the administration of glucagon in patient B, most probably objectified. In
all five cases the reported reaction consisted of both subjective symptoms and a
measured low blood glucose. Three cases are particularly interesting due to short
latencies, (Case E), a positive rechallenge (Case A) and an objectified increase in
insulin need (Case C).
Three patients (C, D, E) have been diagnosed with type 2 diabetes, so other DMrelated factors cannot be excluded. No indication of other alternative causes like
excessive use of alcohol or salicylates was reported. Two patients involved had
no history of diagnosed diabetes mellitus (A and B). However in both patients,
glucose metabolism and counter balancing hepatic function may have been
altered. Patient B is diagnosed with a chronic liver disease. Patient B has been
shown to have an impaired glucose metabolism with a HbA1C slightly above
reference levels (4.0-5.9%) and increased glucose levels in both postprandial and
sober state.
Causality assessment in Case D is complex. Patient D was known with recurrent
urinary tract infections not responsive to several antibiotics, however without
indication of complications which may lead to hypoglycaemia. Norfloxacin has
been used in a prior antibiotic course without inducing hypoglycaemia. Since
blood glucose levels were fluctuating over a prolonged period, it is difficult to
assess the contribution of norfloxacin to decreased glucose levels. Weeks after
the event patient died unexpectedly due to a cerebrovascular accident. No blood
glucose levels after norfloxacin treatment were accessible to reporter.
13
Other sources of information
SmPC
Hypoglycaemia is not mentioned in the Dutch norfloxacin SmPCs. However in the
US SmPC, the warning is given to use norfloxacin with caution because of an
increased hypoglycaemic risk in patients using glibenclamide [11].
Literature
Despite extensive coverage of hypoglycaemia related to other fluoroquinolones,
no publications on norfloxacin-induced hypoglycaemia are accessible through
Medline.
Databases
Hypoglycaemia associated with norfloxacin use is disproportionally present in the
rd
Netherlands Pharmacovigilance Centre database on August 3 2010. The World
Health Organization (WHO) pharmacovigilance database however did not support
causality on November 4th 2010. Results are shown in Table 2.
Table 2. Reporting odds ratios of norfloxacin and hypoglycaemia in the Netherlands’ and
WHO Pharmacovigilance database.
Drug and ADR
Number of reports
ROR (95% CI)
Lareb database
5
5.3 (2.2-13.0)
WHO database
18
0.6 (0.4-1.0)
On August 3rd the Eudravigilance database contained two serious reports of
hypoglycaemia associated with norfloxacin use and one of a hypoglycaemic
coma. One case was deemed life threatening but causality was blurred by the
presence of an insulinoma. The second case lead to decease of an eighty-year
old female with an insulin dependent form of diabetes. An additional twelve
preparations including insulin, pioglitazone and glibenclamide were also
suspected. The case of a hypoglycaemic coma occurred in an 81-year old female,
also known with insulin dependent diabetes. Insulin and pioglitazone were listed
under the additional suspect medications.
Prescription data
The number of patients using norfloxacin in the Netherlands is shown in table 3.
Table 3. Number of norfloxacin users in the Netherlands between 2005 and 2008 [6]
Drug
2005
2006
2007
2008
Norfloxacin
125,220
130,220
123,080
118,890
Mechanism
Serum glucose regulation is a complex process in which insulin secretion and
counteracting balances lead to a tight regulation of serum glucose levels. Both in
in-vitro and in animal studies, fluoroquinolones had inhibitory effects on the ATPsensitive K+ channels in pancreatic β cells, which regulate insulin secretion. This
effect is similar to the acting mechanism of sulfonylurea antidiabetics and leads
eventually to increased insulin secretion [8]. Quinine which contains a quinolone
group is believed to have similar effects exerted through its quinolone component.
Normally, hypoglycaemia due to increased insulin secretion, is counterbalanced
by molecules acting opposite to insulin like glucagon, however in people with an
altered glucose homoeostasis, as in type 2 diabetes or hepatic disease,
14
symptomatic hypoglycaemia may develop due to an impaired compensatory
function [7].
Discussion and Conclusion
Norfloxacin-induced hypoglycaemia is supported by five reports and is
disproportionally present in the Netherlands Pharmacovigilance Centre Lareb’s
database. Two patients involved had no history of diagnosed diabetes mellitus.
Conversely, this association is not disproportionally present in the database of the
World Health Organisation (WHO), where the reported numbers indicate a
‘protective effect’.
Hypoglycemia due to some fluoroquinolones is well established in literature and is
supported by a plausible mechanism. In addition to the reports about norfloxacin,
Lareb has received reports of hypoglycaemia in association with moxifloxacin (1
report), ciprofloxacin (1 report) and levofloxacin (1 report). The potential to induce
hypoglycaemia differs between fluoroquinolones and due to the absence of
reports in literature, norfloxacin is likely to be one of the fluoroquinolones with a
lesser potential to induce hypoglycaemia. Attention of norfloxacin-induced
hypoglycaemia is warranted, including mentioning of glucose lowering effects in
the SmPC.
• Attention of norfloxacin-induced
hypoglycaemia is warranted
References
1. Dutch SmPC norfloxacine 400 PCH. (version date: 15-5-2008, access date: 15-7-2010)
http://db.cbg-meb.nl/IB-teksten/h22824.pdf.
2. Dutch SmPC Norfloxacine ratiopharm 400 mg. (version date: 6-1-2008, access date: 15-7-2010)
http://db.cbg-meb.nl/IB-teksten/h23358.pdf.
3. Dutch SmPC Norfloxacine CF 400 mg. (version date: 23-6-2008, access date: 15-7-2010)
http://db.cbg-meb.nl/IB-teksten/h24265.pdf.
4. Dutch SmPC Norfloxacine Sandoz tablet 400 mg. (version date: 24-11-2009, access date: 15-72010) http://db.cbg-meb.nl/IB-teksten/h26800.pdf.
5. Dutch SmPC Norfloxacine Mylan 400 mg. (version date: 16-4-2010, access date: 15-7-2010)
http://db.cbg-meb.nl/IB-teksten/h29846.pdf.
6. GIP/college voor zorgverzekeringen. www.gipdatabank.nl. 2007(access date: 15-7-2010)
7. Lewis RJ, Mohr JF, III. Dysglycaemias and fluoroquinolones. Drug Saf 2008;31(4):283-92.
8. Saraya A, Yokokura M, Gonoi T, Seino S. Effects of fluoroquinolones on insulin secretion and
beta-cell ATP-sensitive K+ channels. Eur J Pharmacol 2004;497(1):111-7.
9. Aspinall SL, Good CB, Jiang R, McCarren M, Dong D, Cunningham FE. Severe dysglycemia with
the fluoroquinolones: a class effect? Clin Infect Dis 2009;49(3):402-8.
10. Cryer PE. Kaspar DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL,
editors.Harrison's Principles of Internal Medicine. 16th ed. New York: McGraw-Hill; 2005; 324,
Hypoglycemia. p. 2180-5.
11. FDA SmPC Noroxin®. (version date: 27-4-2009, access date: 30-7-2010)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019384s054lbl.pdf.
12. Smith, KM and Lomaestro, BM. What role do fluoroquinolone antimicrobial agents play in cardiac
dysfunction and altered glycemic control? (version date: 2010, access date: Journal of Pharmacy
Practice 5.
13. Menzies DJ, Dorsainvil PA, Cunha BA, Johnson DH. Severe and persistent hypoglycemia due to
gatifloxacin interaction with oral hypoglycemic agents. Am J Med 2002;113(3):232-4.
14. LeBlanc M, Belanger C, Cossette P. Severe and resistant hypoglycemia associated with
concomitant gatifloxacin and glyburide therapy. Pharmacotherapy 2004;24(7):926-31.
15
1.3.
Inhaled fluticasone and epistaxis
Introduction
Fluticasone is a locally acting potent corticosteroid and is registered in the
Netherlands since 1990. It is marketed as nasal drops and nasal spray
®
®
(Flixonase , Avamys ) for the indications vasomotor and allergic rhinitis, nasal
polyps, and as inhalation corticosteroid (ICS) (Flixotide®) in both an inhalation
dosisaerosol and a powder inhalation form for indications asthma and chronic
obstructive pulmonary disease (COPD).
Epistaxis, or nose bleed, is estimated to occur in 60% of persons during their
lifetime with a higher incidence during the winter months. The prevalence is
increased for children less than 10 years of age, is lower for adolescents and
young adults and then rises again after the age of 35 years. Nose bleeds are
more common in older patients; a mean age of 64 is mentioned [1]. Among
hospitalized patient with nose bleeds, male patient are more presented in the age
of 20-49 years. From the age of 50, no sex differences were found [2].
Approximately 6% of the patients with nosebleeds seek medical treatment. More
than 90% of episodes of epistaxis occur along the anterior nasal septum, at a site
called Kiesselbach’s area [1].
Systemic adverse drug reactions can occur during nasal and inhaled
administration of fluticasone. Epistaxis is a well known ADR during nasal use of
fluticasone [3], but it is not mentioned in the Dutch SmPCs of orally inhaled
fluticasone products [4-6].
Reports
On July 29, 2010, the database of the Netherlands Pharmacovigilance Centre
Lareb contained eight reports of epistaxis associated with the use of orally inhaled
fluticasone. These reports concerned male as well as female patients in varying
ages. The reports are listed in Table 1.
Table 1. Reports of epistaxis associated with the use of fluticasone
Patient,
Number,
Sex, Age
Drug (daily dose)
Indication for use
Concomitant
medication
Suspected adverse
drug reaction
Time to onset,
Action with drug
outcome
A 19187
F, 8 – 10
years
fluticasone
dose unknown
asthma
salbutamol
epistaxis
several hours
discontinued
recovered,
positive de- and
rechallenge
B 23740
fluticasone
F, 70 years 2 dd 500 mcg
and older
asthma
ipratropium,
salmeterol,
nifedipine,
nedocromil,
ranitidine
epistaxis
unknown
discontinued
recovered,
positive de- and
rechallenge
C 24936
M, 70
years and
older
fluticasone
2 dd 500 mcg
ipratropium,
famotidine,
captopril,
salbutamol
epistaxis
(3 to 4 times a day)
7 days
discontinued
recovered
D 26684
M, 5 – 7
years
fluticasone
2 dd 250 mcg
loratadine,
salbutamol,
salmeterol
epistaxis
unknown
continued
not recovered
16
Patient,
Number,
Sex, Age
Drug (daily dose)
Indication for use
Concomitant
medication
Suspected adverse
drug reaction
Time to onset,
Action with drug
outcome
E 48448
M, 61 – 70
years
fluticasone
chronic bronchitis
2 dd 250 mcg
losartan
epistaxis (one sided)
several hours
unknown
unknown
similar symptoms
during nasal use
of fluticasone
F 82593
F, 31 – 40
years
fluticasone
dose unknown
respiratory disorder
-
epistaxis
several days
continued
recovered
G 82930
M, 41 – 50
years
fluticasone
asthma
2 dd 250 mcg
-
epistaxis
several days
continued
recovering
H 107529
M, 11 – 20
years
fluticasone
2 dd 250 mcg
asthma
-
epistaxis;
blood in snot after
noose blowing
1 day
discontinued
recovered,
positive de- and
rechallenge
Time to onset varied from several hours to several days. In four cases a positive
dechallenge was reported, two of them with positive rechallenge as well.
In five cases the nose bleeds occurred in the winter (B, D-G).
Other sources of information
Literature
Epistaxis is mentioned as a possible adverse reaction of orally inhaled fluticasone
®
in the US SmPC of Flovent discus [7]. To the best of our knowledge, there are
no other publications on a possible association between orally inhaled fluticasone
and epistaxis.
In Micromedex [8] and Pubmed publications epistaxis is only described in
association with the use of nasal administration of fluticasone.
The relationship between skin bruising and inhaled corticosteroid (ICS) therapy is
described in several studies. In a large double-blind, randomized, placebocontrolled clinical trial with 1116 participants (544 ICS, 542 placebo) it was found
that a significantly higher proportion of ICS than placebo participants reported
easy bruising (11.2% vs 3.5%, respectively) and the slow healing of skin cuts or
sores (2.4% vs 0.5%, respectively) [9].
Lareb previously described the association between inhaled fluticasone and
haematoma in a quarterly report [10] and a publication [11]. By now, bruising is
mentioned as a possible adverse drug reaction in the SmPCs of inhaled
fluticasone, but epistaxis is not described.
Databases
The eight Lareb reports of epistaxis during use of orally inhaled fluticasone lead to
a reporting odds ratio (ROR) of 6.3 (95% CI 3.1-12.9). It should be noted that this
ROR includes the cases that occurred during the winter.
On July 29, 2010, the WHO database of the Uppsala Monitoring Centre contained
573 reports of epistaxis and orally inhaled fluticasone. This resulted in a
disproportional ROR of 26.2 (95% CI 24.1-28.6). This ROR also includes the
cases that occurred during the winter.
17
On August 3rd the Eudravigilance database contained six reports of epistaxis
associated with use of inhaled fluticasone. All six cases were rated serious (one
report of a life threatening event due to a combined nose and throat bleeding,
three additional reports of hospital admission, other in two cases). There are three
Portuguese cases which all concern 65-year old women. However, the reported
clinical event differs in each three cases, which most plausibly implies that these
cases concern separate events.
Prescription data
The number of patients using inhaled fluticasone in the Netherlands is shown in
Table 2.
Table 2. Number of users of inhaled fluticasone in the Netherlands between 2005 and
2008 [12]
Drug
Fluticasone
2006
302,320
2007
295,140
2008
276,110
2009
281,660
Mechanism
Thinning and bruising of the skin may occur while taking inhaled corticosteroids,
with evidence of a dose-response effect [13]. The presence of skin bruising can
be considered a visible marker of the adverse effects of corticosteroids on
collagen turnover in connective tissue, and serial skin examinations therefore can
be used to monitor potential systemic adverse effects in patients taking high-dose
therapy [14].
Inhaled corticosteroids most probably repress skin collagen synthesis. In a small
study with 18 asthma patients, both types I and III procollagen propeptide
concentrations decreased significantly after 6 weeks of even a low dose of
inhaled corticosteroids [15].
Epistaxis caused by inhaled corticosteroids may well be caused by the same
mechanism; repressed skin collagen synthesis, resulting in an increased
vulnerability of the skin and the cutaneous blood vessels.
Discussion and conclusion
Epistaxis is associated with several factors, including rhino-sinusitis, systemic
conditions associated with coagulopathy, septal perforations, dry mucosa, OslerWeber-Rendu syndrome and neoplasm [1]. The eight Lareb cases may all be
more susceptible to epistaxis due to their asthmatic condition, which is often
attended with or induced by (allergic) rhinitis [16]. Furthermore, the concomitant
medication of three patients (B, C and E) is most probably indicated for
hypertension. Hypertension may also contribute to epistaxis, although this theory
is controversial [1]. It should also be considered that there is an increased
incidence of nose bleeds during the winter months, probable due to
dehumidification of the nasal mucosa [1]. Since five of the eight case reports
occurred during the winter months (December to March), the contribution of this
factor cannot be excluded.
However, the positive de- (and re-)challenge in four cases - including cases B and
C - strongly supports the causal relation with use of fluticason.
The association between inhaled fluticasone and epistaxis is supported by the
disproportional number of reports both in the Lareb and WHO database, the
18
known effects of inhaled corticosteroids on skin haematoma, and the fact that
epistaxis is a known adverse drug reaction for nasal administration of fluticasone.
• Possible signal of epistaxis in
association with orally inhaled
fluticasone
References
1. Schlosser RJ. Clinical practice. Epistaxis. N Engl J Med 2009;360(8):784-9.
2. Tomkinson A, Roblin DG, Flanagan P, Quine SM, Backhouse S. Patterns of hospital attendance
with epistaxis. Rhinology. 1997;35(3):129-31.
3. Dutch SmPC Flixonase neusspray. (version date: 29-2-2008, access date: 5-8-2010) http://db.cbgmeb.nl/IB-teksten/h14424.pdf.
4. Dutch SmPC Flixotide Inhalator / Flixotide Volumatic. (version date: 22-7-2009, access date: 5-82010) http://db.cbg-meb.nl/IB-teksten/h16212.pdf.
5. Dutch SmPC Flixotide Diskus. (version date: 1-4-2009, access date: 5-8-2010) http://db.cbgmeb.nl/IB-teksten/h18192.pdf.
6. Dutch SmPC Flixotide Nebules. (version date: 23-2-2010, access date: 5-8-2010) http://db.cbgmeb.nl/IB-teksten/h21834.pdf.
7. US SmPC Flovent Diskus. (version date: 2010, access date: 5-8-2010)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020833s021lbl.pdf.
8. Thomson Micromedex, Greenwood Village Colorado USA. Micromedex® Healthcare Series,
(electronic version). (version date: 2010, access date: 5-8-2010) http://www.thomsonhc.com.
9. Tashkin DP, Murray HE, Skeans M, Murray RP. Skin manifestations of inhaled corticosteroids in
COPD patients: results from Lung Health Study II. Chest 2004;126(4):1123-33.
10. Inhaled and intranasal fluticasone propionate and haematoma. (version date: 2007, access date:
5-8-2010) http://www.lareb.nl/documents/kwb_2007_4_flut.pdf.
11. Gerritsen RF, Borgsteede SD, Harmark L. Hematoom als bijwerkingen fluticason. Pharmaceutisch
Weekblad 2008;143(36):38-9.
12. College for health insurances. GIP database. (version date: 9-6-2009, access date: 6-8-2010)
http://www.gipdatabank.nl/.
13. Capewell S, Reynolds S, Shuttleworth D, Edwards C, Finlay AY. Purpura and dermal thinning
associated with high dose inhaled corticosteroids. BMJ 1990;300(6739):1548-51.
14. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: A systematic review and
meta-analysis. Arch Intern Med 1999;159(9):941-55.
15. Autio P, Karjalainen J, Risteli L, Risteli J, Kiistala U, Oikarinen A. Effects of an inhaled steroid
(budesonide) on skin collagen synthesis of asthma patients in vivo. Am J Respir Crit.Care Med
1996;153(3):1172-5.
16. Shaaban R, Zureik M, Soussan D, Neukirch C, Heinrich J, Sunyer J, Wjst M, Cerveri I, Pin I,
Bousquet J, et al. Rhinitis and onset of asthma: a longitudinal population-based study. Lancet
2008;372(9643):1049-57.
19
1.4.
Oxaliplatin and laryngospasm
Introduction
Oxaliplatin (Eloxatin®) is a platinum compound with antineoplasmatic properties
and is registered in the Netherlands since 2005. Oxaliplatin is used in
combination with 5-fluorouracil and folinic acid in the treatment of metastatic
colorectal cancer. It is also indicated as adjuvant therapy in the treatment of colon
carcinoma (stage III) after a complete resection of the primary tumor [1]. The
platinum compound in oxaliplatin forms a complex with 1,2-diaminocyclohexane
and an oxalate group [1] which interferes with DNA synthesis [2]. The complex is
more hydrophobic than the complex formed by cisplatin and carboplatin, other
platinum compounds and is therefore less nephro-ototoxic than cisplatin and less
myelotoxic than carboplatin [3].
Laryngospasm is characterized as a brief episode of uncontrolled muscular
contraction of the laryngeal cords [4,5]. This can lead to episodes of complete
upper-airway occlusion [5]. Risk factors for laryngospasm are laryngopharyngeal
reflux [6] (sleep-related [7]) and as post-surgery complication, especially in
pediatrics [8].
Reports
On August 10, 2010 the database of the Netherlands Pharmacovigilance Centre
Lareb contained four reports concerning laryngospasm in association with the use
of oxaliplatin. Of these four reports, report A is reported by a health professional
and the other three are reported by the Marketing Authorization Holder (MAH).
Table 1. Reports of laryngospasm associated with the use of oxaliplatin.
Patient,
Number,
Sex, Age,
Reporter
Drug
Indication for use
Concomitant
medication
Suspected adverse
drug reaction
Time to onset,
number of cycle,
action with drug
outcome
A 106930 oxaliplatin 200 mg
F, 70 years metastatic colon
and older
carcinoma
thiamazole,
levothyroxin,
sotalol,
dorzolamide,
candesartan,
enalapril
laryngospasm
1 minute
45 days after first
cycle
drug withdrawn
recovered
B 56403
F, 51 – 60
years
clemastine,
diazepam,
ondansetron,
dexamethasone
laryngospasm
muscle spasm
few hours after
oxaliplatin
infusion
second cycle drug
withdrawn
outcome unknown
estrogen with
levonorgestrel,
fentanyl
laryngospasm
nausea
vomiting
immediately after
oxaliplatin
infusion
second cycle
action and
outcome unknown
oxaliplatin 270 mg once
per 3 weeks
colorectal carcinoma
cetuximab
capecitabine
bevacizumab
C 54749 =
54751
F, 41 – 50
years
oxaliplatin 178 mg once
per 3 weeks
unknown
capecitabin
irinotecan
20
Patient,
Number,
Sex, Age,
Reporter
Drug
Indication for use
Concomitant
medication
Suspected adverse
drug reaction
Time to onset,
number of cycle,
action with drug
outcome
D 82048
F, 61 – 70
years
oxaliplatin
unknown
diazepam,
ondansetron,
metformin,
imipramine,
paracetamol with
codein,
dexamethasone,
bevacizumab,
glimepiride.
laryngeal spasm,
wheezing, pale,
clammy
within 1 day
third cycle
administration
time enlarged to 6
hours
recovered
Case A was reported by a medical specialist. The laryngeal spasm occurred 45
days after the first infusion of the drug and 1 minute after the last infusion. The
patient recovered after treatment with adrenaline, clemastine, ranitidine,
hydrocortisone, intubation and admission to the intensive care.
Case B was reported by the Marketing Authorization Holder. The therapy date,
route of administration and daily dose are unknown for the concomitant
medication diazepam. There is no further information about the reported muscle
spasms.
Latency time was in all cases within a day of the last oxaliplatin infusion. All
patients experienced laryngospasm after administration of oxaliplatin.
Other sources of information
SmPC
The Dutch SmPC of oxaliplatin [1] does mention subjective feelings of dysphagia
and dyspnoea and/ or feeling to choke, without any objective evidence with
problems to breathe or laryngospasm or bronchospasm (no stridor or wheezing).
Laryngospasm with objective evidence is not mentioned in the Dutch SmPC of
oxaliplatin [1].
The US SmPC [9] mentions an acute syndrome of pharyngolaryngeal dysesthesia
in 1-2% of patients. This syndrome is characterized by subjective sensations of
dysphagia or dyspnea, without any laryngospasm or bronchospasm (no stridor or
wheezing).
Laryngospasm is mentioned as a clinical symptom when an overdosage of
oxaliplatin is given [9].
Literature
Brandi et al [3] described hypersensitivity reactions related to oxaliplatin.
Laryngospasm is mentioned as severe form of a hypersensitivity reaction. A total
of 17 patients with hypersensitivity reactions were described, two of them
experienced laryngospasm after their second and third infusion number. The
infusion of oxaliplatin was stopped and replaced by a saline infusion.
Antihistaminics and 100 -1000 mg hydrocortisone was administered. In this
article, no difference was made between subjective or objective evidence for
laryngospasm.
21
Databases
On August 10, 2010 the Lareb database contained four reports on oxaliplatin and
laryngospasm. In respect to the other reports in the database this association is
disproportionally reported (ROR 56.2, 95% CI 18.4- 171).
Lareb also received reports of symptoms that can be part of laryngospams.
Dyspnoea (10 reports), bronchospams (1 report) and the feeling to choke (1
report) was reported with the use of oxaliplatin. These events were also reported
with the use of carboplatin or cisplatin, other cytostatic drugs with a platinum
compound. Laryngospasm is not reported before in associations with the use of
carboplatin or cisplatin.
On August 10, 2010 the WHO Collaborating Centre had received 85 reports of
oxaliplatin and laryngospasm which was disproportionally present in the database
(ROR 13.6, 95% CI 10.5-16.2).
On August 3rd the Eudravigilance database contained 155 reports of
laryngospasm associated with oxaliplatin use. All cases but four were rated
serious. In three cases the reported reaction lead to the death of the patient
involved. In 29 cases life-threatening aspects were indicated. Ages when
specified ranged from 28 to 77 years. Fifty male patients were involved, 99
women. In the remaining six cases no sex was specified.
Prescription data
The prescription data for oxaliplatin are not available through the GIP database of
the College for health insurances.
Mechanism
Laryngospasm can be part of a hypersensitivity reaction [3]. Because patients
developed laryngospasm after multiple infusions of oxaliplatin, sensitization is
likely [3]. The reactions occurred fast after the infusion. Therefore a type I
hypersensitivity Ig-E mediated reaction is suggested [3].
There are also different hypothesis for hypersensitivity with the use of oxaliplatin
suggesting the platinum salt can induce a cascade of reactions leading to
cytokines of forming a major histocompatibility complex (MHC) [3].
Discussion
The four cases reported to the Netherlands Pharmacovigilance Centre Lareb
suggest oxaliplatin can induce laryngospasm. This is also mentioned in the SmPC
but without any objective evidence. In at least one report (patient A) objective
evidence (intubation) was present. In addition three cases of laryngospasm were
reported.
In reports B and C, there were also other suspected drugs. However,
laryngospasm started within a few hours after oxaliplatin infusion so oxaliplatin is
most likely for the events.
Although other factors for laryngospasm can not be excluded, risk factors like
laryngopharyngeal reflux were not mentioned in the reports. The reported latency
times also supports a causal relationship.
Conclusion
Lareb received four reports of laryngospasm associated with the use of
oxaliplatin. Subjective feeling of laryngospasm is described in the SmPC.
However, in at least one report there was also intubation and therefore objective
22
evidence for laryngospasm. Therefore, laryngospasm should not only be
mentioned as a subjective event in the SmPC of oxaliplatin.
• Laryngospasm should be
mentioned as an objective event in
the SmPC of oxaliplatin
References
1. Dutch SmPC Eloxatin®. (version date: 16-4-2010, access date: 9-8-2010) http://db.cbg-meb.nl/IBteksten/h32774.pdf.
2. CVZ. Farmacotherapeutisch Kompas. (version date: 1-7-2009, access date: 14-9-2009)
www.fk.cvz.nl.
3. Brandi G, Pantaleo MA, Galli C, Falcone A, Antonuzzo A, Mordenti P, Di Marco MC, Biasco G.
Hypersensitivity reactions related to oxaliplatin (OHP). Br J Cancer. 2003;89(3):477-81.
4. Jochems AAF; Joosten FWMG. Coelho. Zakwoordenboek der Geneeskunde. 29 ed. 2009. 497p.
5. Gdynia HJ, Kassubek J, Sperfeld AD. Laryngospasm in neurological diseases. Neurocrit.Care
2006;4(2):163-7.
6. Obholzer RJ, Nouraei SA, Ahmed J, Kadhim MR, Sandhu GS. An approach to the management of
paroxysmal laryngospasm. J Laryngol.Otol. 2008;122(1):57-60.
7. Roland MM, Baran AS, Richert AC. Sleep-related laryngospasm caused by gastroesophageal
reflux. Sleep Med 2008;9(4):451-3.
8. Flick RP, Wilder RT, Pieper SF, van KK, Ellison KM, Marienau ME, Hanson AC, Schroeder DR,
Sprung J. Risk factors for laryngospasm in children during general anesthesia. Paediatr.Anaesth
2008;18(4):289-96.
9. American SmPC Eloxatin®. (version date: 13-3-2009, access date: 10-8-2010)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021492s011,021759s009lbl.pdf.
23
2. Short notes
2.1.
Baclofen and constipation
On August 10, 2010, the Netherlands Pharmacovigilance Centre Lareb had
received four reports of constipation in association with baclofen. The Dutch
SmPCs of baclofen are inconsistent with regard to mentioning constipation as
adverse drug reaction. Some SmPCs [1,2] do mention constipation, while others
[3] do not mention this adverse reaction.
Constipation should be mentioned in the SmPCs of all baclofen containing
products.
References
1. Dutch SmPC baclofen Actavis. (version date: 29-11-2006, access date: 10-8-2010) http://db.cbgmeb.nl/IB-teksten/h21618.pdf.
2. Dutch SmPC Lioresal®. (version date: 16-10-2007, access date: 10-8-2010) http://db.cbgmeb.nl/IB-teksten/h06347.pdf.
3. Dutch SmPC baclofen Ratiopharm, PCH, Sandoz and Mylan. (version date: 29-10-2004, access
date: 10-8-2010) http://db.cbg-meb.nl/IB-teksten/h12153.pdf.
24
3. Publications
1. Mannesse CK, Van Puijenbroek EP, Jansen PA, van Marum RJ, Souverein
PC, Egberts TC. Hyponatraemia as an adverse drug reaction of antipsychotic
drugs: a case-control study in VigiBase. Drug Saf 2010;33(7):569-78.
2. Plouvier A. Selectieve serotonine-heropnameremmers en hypoglykemie bij
patiënten met diabetes mellitus. Gebu 2010;44(6):67-8.
3. Passier JL, Van Puijenbroek EP, Jonkers GJ, van Grootheest AC.
Pancreatitis associated with the use of itraconazole. Neth J Med
2010;68(6):285-9.
4. Blokpoel RGT, Broos N, de Jong-van den Berg LTW, de Vries TW. Waarde
omeprazol bij huilende zuigelingen beperkt. Ned Tijdschr Geneeskd
2010;154(A1850):1-4.
5. Tengstrand M, Star K, Van Puijenbroek EP, Hill R. Alopecia in association
with lamotrigine use: an analysis of individual case safety reports in a global
database. Drug Saf 2010;33(8):653-8.
6. van Hunsel F, van der Welle C, Passier A, van Puijenbroek E, van Grootheest
K. Motives for reporting adverse drug reactions by patient-reporters in the
Netherlands. Eur J Clin Pharmacol 2010; Nov;66(11):1143-50.
7. Broos N, Van Puijenbroek EP. Interaction between topical miconazole and
coumarins. Eur J Clin Pharmacol 2010; 2010 Nov;66(11):1171-2
8. Oosterhuis I, Puijenbroek EP. Lareb Intensive Monitoring onder de loep.
Pharmaceutisch Weekblad 2010;35:24-5.
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