The role of 5-ASA in Inflammatory Bowel Disease

Transcription

The role of 5-ASA in Inflammatory Bowel Disease
Crohn’s and Colitis Foundation of Canada - CCFC & You Education Symposium
Medications and IBD
Dr. Alan Low, BSc.(Pharm.), Pharm. D., RPh., FCSHP, CCD
Clinical Associate Professor,
Faculty of Pharmaceutical Sciences, UBC
Manager, Medical Affairs & Government Affairs, Servier
Inflammatory Bowel Disease
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Inflammatory Bowel Disease (IBD) refers to a
condition of chronic recurrent inflammation of the
gastrointestinal tract of unclear cause.
Clinical course of IBD is usually a course of active
disease, often referred to as flares or recurrences,
followed by periods of remission.
Two major types of IBD are:
– Ulcerative Colitis (UC)
– Crohn's Disease (CD)
Worldwide Incidence of IBD

9000 newly diagnosed cases annually
– About 2-3 in 10,000 people
– There are 200,000 people with IBD in Canada

Peak onset: 15 to 25 years of age
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Second peak incidence: 50 to 65 years of age

Clinical presentation varies widely for UC and CD
Pinchbeck ER, Kirdelkis J, Thompson, ABR : Inflammatory Bowel Disease in
North America. Clin Gastroenterology 10:505, 1988.
Podolsky DK. Inflammatory bowel disease. NEJM 2002;347:417
Hanauer S. Inflammatory Bowel Disease. N Engl J Med. 1996;334(13):841-8
CCFC The Burden of Inflammatory Bowel Disease in (IBD)Canada, 2008
Causes of IBD
Genetic
Susceptibility
Immune
System Issues
IBD
Intestinal
Microflora
Environmental
Triggers
(Infection)
Chronic Inflammation
Mediator Imbalance
Pro-inflammatory
TNF
IL-1β
IL-12 / IL-18
IFNγ
Anti-inflammatory
IL-4 / IL-13
IL-1Ra
TGFβ
IL-10
PGE2
Environmental Triggers
Antibiotics
Infections
IBD
NSAIDs
Diet
Smoking
Stress
Natural Courses of UC
Course
Only one disease
episode during study
In remission at any
given time
Intermittent disease
course
Patients were followed for up to 25 years.
Langholz E, et al. Gastroenterology. 1994;107:3-11
Patients (%)
23
40-50
77
Natural Courses of CD –The Facts
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Nearly 80% of patients require surgery
within 20 years of onset1
Recurrence within 6 years of surgery: 90%
endoscopic/radiologic, 58% symptomatic2
20% of patients treated with steroids fail
to respond after 1 year
36% of patients are unable to discontinue
steroids due to rapid recurrence3
1Mekhjian
HS, et al. Gastroenterology. 77;898: 1979
2McLeod RS, et al. Gastroenterology. 113:1823; 1997
3Munkholm P, et al. Gut. 35:360; 1994
Toxic Megacolon
 Complication
occurring in 1-2% of
patients with UC and Crohn’s colitis
– electrolyte imbalance, opiates,
anticholinergics, laxatives, low protein
intake leading to lumen edema
 Acute
dilatation of the colon with
associated infection
 Mortality rate up to 30%
(perforation, peritonitis)
Toxic Megacolon (con’t)
 Treatment
– Medicines (IV steroids, IV antibiotics)
– Surgery
– Fluid and electrolytes replacement
– Nutrition support
– Bowel rest
 Avoid
opiates, anticholinergics, and
stimulant laxatives (eg. cascara,
senna, bisacodyl, castor oil)
Goals in Treating IBD
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Prompt diagnosis and treatment to
manage symptoms of active disease
Induction of complete remission
Education on therapy and disease
Individualized treatment options –
treatment based on shared decisionmaking (minimize side-effects while
maintaining efficacy and adherence)
Improve quality of life
Maintenance of remission
Minimize steroid use
IBD Therapy
Therapeutic options for IBD
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Pharmacologic agents
Anti-inflammatory
Immunosuppressive
Antimicrobial
Biologics
Psychological
IBD
Nutritional
Surgery
The Medications
Drug Category
Drugs
Anti-inflammatory
• Mesalamine (5-ASA)
• Corticosteroids (prednisone, budesonide)
Immunosuppressive
•
•
•
•
•
Antibicrobial
• Metronidazole
• Clarithromycin
• Ciprofloxacin
Probiotic
• Many yogurts, supplements, milks, other
Biologic
• Infliximab
• Adalimumab
• Certolizumab
Azathioprine
6-mercaptopurine,
Methotrexate
Cyclosporin
Tacrolimus
Therapeutic Options – Mild to
Moderate Disease (acute therapy)
Ulcerative Colitis (UC)* Crohn’s Disease (CD)*
Pancolitis
• Oral 5-ASA agents
• Oral 5-ASA agents
• Oral corticosteroids
• Oral corticosteroids
• Antibiotics for perianal
disease/ fistulas
Proctitis/distal colitis
• Azathioprine for perianal
disease/ fistulas
• Oral and/or topical 5-ASA
agents
• Oral or topical steroid therapy
*Therapies for UC and CD depend on disease severity and location; it is common to use more than one medication
simultaneously to achieve the best clinical response.
Patients in Endoscopic Remission at
6 Months Intention-to-Treat Analysis
80
70.1
% in Remission
70
60
48.3
50
40
30
20
10
0
5-ASA (Asacol) 1.6 g/d
Placebo
The Mesalamine Study Group. An Oral Preparation of Mesalamine as Long-Term
Maintenance Therapy for Ulcerative Colitis. Ann Intern Med 1996:124:204-211.
Adverse Events
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Most frequent
–
–
–
–
–
–
Nausea
Headache
Vomiting
Diarrhea
Abdominal pain
Flatulence (passing of gas)
The Mesalamine Study Group. An Oral Preparation of Mesalamine as Long-Term
Maintenance Therapy for Ulcerative Colitis. Ann Intern Med 1996:124:204-211.
Therapeutic Options – Moderate to
Severe Disease (acute therapy)
Ulcerative Colitis (UC)*
Crohn’s Disease (CD)*
• IV corticosteroids or
oral corticosteroids
• Cyclosporine
• IV corticosteroids or
oral corticosteroids
• Colectomy
• Infliximab
• Infliximab (for lumenal and
fistulizing disease)
• Adalimumab (for lumenal
and fistulizing disease)
• Certolizumab (for lumenal
and fistulizing disease)
• Tacrolimus
*Therapies for UC and CD depend on disease severity and location; it is common to use more than one medication
simultaneously to achieve the best clinical response.
Dose Response to Mesalamine
in Active Ulcerative Colitis
% Patients in Remission/Improved
*
80
70
60
50
*
40
*
*
30
20
10
0
Placebo
1.6 gm
2.0 gm
Mesalamine
* Significantly different from placebo (two trials combined)
4.0 gm
4.8 gm
Mechanism for Antibody Neutralization of
TNF-α
Macrophage
or activated
T-cell
TNF
TNF
receptor
Anti-TNF
van Deventer S. Gut. 1997; 40:443-46
Scalion BJ. Cytokine. 1995: 7:251-59
Feldman M, et al. Advances in Immunology. 1997: 64:283-350
Target Cell
Clinical Response and Remission
in All Infliximab-treated Patients
Response (%)
100
P<0.001
Placebo
(n=25)
75
P<0.005
65
50
25
33
17
4
0
4-Week
Clinical Response
4-Week
Clinical Remission
Clinical response defined as a  70-point decrease in CDAI score from baseline.
Clinical remission defined as a CDAI score < 150.
Targan, N Engl J Med, 1997
Infliximab 5, 10,
and 20 mg/kg
(n=83)
Therapeutic Options – Maintenance
Ulcerative Colitis (UC)*
Crohn’s Disease (CD)*
• Oral/topical 5-ASA agents
• Oral 5-ASA agents
• Immunomodulators
• Immunomodulators
oral azathioprine or mercaptopurine (steroiddependent or refractory patients)
oral azathioprine or mercaptopurine (steroiddependent or refractory patients)
• Methotrexate (if intolerant or not
responding to immunomodulators)
• Antibiotics
(metronidazole, ciprofloxacin)
• Infliximab / Adalimumab
/Certolizumab
• Methotrexate (if intolerant or not
responding to
immunomodulators)
*Therapies for UC and CD depend on disease severity and location; it is common to use more than one medication
simultaneously to achieve the best clinical response.
Distal UC: Oral and Topical
Mesalamine Therapy
% of Patients Reporting
No Rectal Bleeding
Oral (2.4 g/d)
90
80
70
60
50
40
30
20
10
0
Rectal (4 g/d)
Combined
90
90*
70
65
56
33
44
40
14
1 Week
33
36
27
18
2 Weeks
*p < .002 vs oral alone, P=.04 vs topical alone
Safdi M, et al. Am J Gastroenterol. 1997;92:1867-1871.
3 Weeks
6 Weeks
Aminosalicylates in UC
Summary of Maintenance Therapy
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Sulfasalazine 2 to 4 g or other 5–ASAs 1.6 to 4.8g/d
– Study showed 4.8g/day better than 2.4g/day
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No comparative clinical data exist that show greater
efficacy as a primary endpoint for any of the 5-ASAs
for site-specific disease.
6MP/Azathioprine in corticosteroid-dependent
patients but may need 4 to 6 months to take effect
Steroids are not effective as maintenance therapy
and should be avoided due to side effects
Which 5-ASAs in IBD
Indications for Aminosalicylates in IBD
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mildly to moderately active disease (induce
remission)
prevention of relapse (flares)
How do physicians choose a 5-ASA:
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site of disease
severity of attacks
route of administration
patient response
frequency of relapse
dose-related side effects
compliance and cost issues
dose-response effect
5-ASAs in IBD
Mechanism of action
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topical not systemic
anti-inflammatory effect
Methods of delivery
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Azo bond
–
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pH-dependent
–
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two molecules split by colonic bacteria (e.g.,
sulfasalazine, Dipentum)
resin-coated 5-ASA delays release until exposure to
specific pH level (e.g., Asacol, mesalamine,
sulfasalazine)
Controlled-release
–
–
encapsulated, ethylcellulose-coated 5-ASA microsphere
released in small and large intestine (e.g., Pentasa)
rectal suspensions and suppositories formulation
stabilized with antioxidants
5-ASA Drug Delivery Systems
Azulfidine®
(sulfasalazine)
Dipentum®
(olsalazine)
COOH
NHSO2
N
N
N=N
5-ASA
CH
5-ASA
N=N
5-ASA
Sulfapyridine
Pentasa®
(mesalamine)
Asacol®
(mesalamine)
Rowasa®
(mesalamine)
Additional
Formulations
COOH
5-ASA
5-ASA
5-ASA
Microspheres
Eudragit S
Inert
carrier
OH
Ligumsky, et al. Gastroenterology. 1981;81:443.
Stenson, et al. J Clin Invest. 1982;69:494.
5-ASAs in IBD
Sulfasalazine
Active compound (5-ASA) has local anti-inflammatory
effects:
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Inhibits prostaglandins
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Inhibits leukotriene synthesis
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Acts as superoxide free radical scavenger
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Inactive carrier (sulfapyridine), linked by azo bond:
delivers 5-ASA to colon
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associated with more adverse effects than 5-ASA
5-ASAs in IBD
Sulfasalazine
Adverse effects:
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primarily sulfa-related (e.g., impairs folic acid,
headache, dizziness, nausea, fatigue, vomiting,
arthralgia) (30% have difficulties)
hematologic - blood related abnormalities
unpredictable (e.g., skin rash, aplastic anemia,
hemolytic anemia, agranulocytosis, altered sperm
motility, bone marrow suppression,
bronchospasm, nephrotic syndrome, etc.)
5-ASAs in IBD
Benefits of pH-dependent 5-ASAs
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maximize release of mesalamine (5-ASA) at
inflammation site
Results in decreased systemic availability
limit absorption in upper GI tract (depending
upon pH release)
fewer sulfa-related side effects (e.g., headache,
fatigue, dizziness, diarrhea, abdominal pain,
nausea, etc.)
no reports of sperm abnormalities or infertility
tolerated by 80-90% of sulfasalazine-intolerant
or hypersensitive patients
5-ASAs in IBD
Importance of Gastrointestinal pH levels:
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Drug release can be targeted for greater topical
efficacy at disease site, e.g., 5-ASA release at pH
7.0 is roughly equivalent to terminal ileum
pH is increasingly more alkaline (higher) in lower
gut
pH levels differ slightly among individuals
pH levels of GI tract are affected by:
– stress
– diet
– activity
– concomitant drugs
– concurrent medical conditions
– disease severity
– fluctuations by individual
Location of Oral 5-ASA Release
Stomach
Jejunum
Ileum
Colon
sulfasalazine
Dipentum®
(olsalazine)
Asacol® (mesalamine)
delayed-release tablets
Pentasa® (mesalamine) controlled-release capsules
Interchangeability of Products
 If
need arises to interchange 5-ASA
products
– Discuss valid reason with patient
– Inform patient, caregiver(s), physician(s)
– Monitor for changes in response
(ie. Change in disease activity, flare, etc)
Osteoporosis in IBD
 Incidence 20% to 30%
– Corticosteroid use, dose, and duration important
– Other factors can increase risk (age, smoking,
amenorrhea, exercise status, calcium, Vit D, etc.)
 Corticosteroid-associated bone loss occurs quickly
(3 months of therapy or more)
 All people with IBD should considered risk assessment
 If high risk, consider calcium, vitamin D, and
bisphosphonates [risedronate, alendronate, zoledronic
acid], teriparatide, denosumab, raloxifene, hormone
therapy
Keep Up Your Bone Health
Exercise:
Weight-bearing, 4
times per week as
deemed appropriate
Calcium:
1000mg-1200mg daily
(maximum of 500mg at
once) from diet and
supplement
Vitamin D:
1000-2000 IU daily
Fall Prevention:
Balance, muscle
strengthening, fix loose
carpets
Some Points to Consider
Take medications at regular intervals as
prescribed
 Recognize side effects and look at strategies
to minimize
 Discuss issues and concerns with
pharmacist, nurse or doctor
 Consult with a dietician

– dietary advice
– individualize food choices
– nutritional supplements
Other Considerations

Watchouts:
– Watch for signs of stress (consider relaxation
techniques)
– Keep a diary of symptoms and flares as well as
any side effects (if side effects occur from
sulfasalazine discuss 5-ASA with your doctor)
– Avoid or minimize use of bowel active agents
(eg. laxatives and antidiarrheals or Gravol)
– Avoid drugs such as NSAIDs and triggers
– Stop smoking (especially with Crohn’s)
Other Considerations
 Watchouts:
– Pay attention to chronic or long-term use
of corticosteroids (eg. Prednisone).
(Reduce or eliminate corticosteroids in
consultation with doctor or
gastroenterologist)
 Minimize
use of corticosteroids (lowest dose,
shortest time)
– Maximize the potential of one treatment
before moving on escalating to another
treatment, optimize the dose
Crohn’s and Colitis Foundation of Canada - CCFC & You Education Symposium
Questions
Dr. Alan Low