Lotronex ® (alosetron HCl) Tablets Risk-Benefit Issues
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Lotronex® (alosetron HCl) Tablets
Risk-Benefit Issues
Victor F. C. Raczkowski, M.D. Director, Division of Gastrointestinal and
Coagulation Drug ProductsApril 23, 2002
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Modifying the Benefit-Risk Balance
• Three principal approaches– Limit use to patients with most disabling IBS
symptoms
– Increase benefit
– Decrease risk
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Limiting Lotronex Use to PatientsWith the Most Disabling Symptoms
• Burden of illness is variable in patients with IBS
• Symptoms: relatively minor disabling• Patients with most disabling symptoms:
– Stand to benefit the most– May accept greater risk
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Increase Benefit
• Lotronex has effects on several symptoms of IBS (e.g., diarrhea, urgency, abdominal pain and discomfort)
• Some patients with severe symptoms (e.g., urgency) have large benefit
• Patients with harder stools and stool frequency <2/day appear to have less benefit
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Increase Benefit• Quality-of-life assessments suggest
Lotronex may improve functional performance
• But marked improvements in functional performance could be better assessed in a randomized withdrawal study of IBS patients with disabling symptoms
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Decrease Risk
• Avoid adverse events, if possible– Appropriate patient selection and education– Appropriate physician selection and
education– Modify drug exposure– Consider relevant IBS factors
• Manage adverse events
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Two Goals of Patient Selection
• Prescribe only to patients in whom the benefits exceed the risks– Appropriate inclusion criteria– Appropriate exclusion criteria– Adequate disclaimers
• Prescribe only to adequately informed patients
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How Best to DescribePatients in Whom Benefits Exceed Risks?
• Approved Indication: February 2000
• Revised Indication: August 2000
• Proposed Indication: April 2002
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Approved Indication (February 2000)
• Lotronex is indicated for the treatment of irritable bowel syndrome (IBS) in women whose predominant bowel symptom is diarrhea.
• The safety and effectiveness of Lotronex in men have not been established.
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Revised Indication (August 2000)
• Lotronex is indicated for the treatment of women with diarrhea-predominant irritable bowel syndrome (IBS). Diarrhea-predominant IBS is characterized by at least 3 months of recurrent or continuous symptoms of abdominal pain or discomfort with either urgency, an increase in frequency of stool, or diarrhea not attributable to organic disease (see Appendix).
• Use in men: similar to original labeling.
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Proposed Indication (April 2002)
• Lotronex is indicated only for women with diarrhea-predominant irritable bowel syndrome (IBS) who have failed to respond to conventional therapy and who have signed the Patient-Physician Agreement (see BOXED WARNING, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS).
• Use in men: similar to original labeling.
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Does the Proposed Plan Adequately Describe Appropriate Patients?
• Appropriate Inclusion Criteria?– Severity of IBS symptoms
– Degree of disability from IBS
– Chronicity of IBS
– Failure of conventional IBS therapies
– Other important characteristics
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Does the Proposed Plan Adequately Describe Appropriate Patients?
• Appropriate Exclusion Criteria?– Contraindications
– Patients less likely to benefit
– Patients with risk factors (if known)
• Special populations (e.g., men)?
• Should the Patient-Physician Agreement include these elements for self-attestation?
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Proposed Risk-Management Plan:Informing Patients
• Sign Patient-Physician Agreement
• Agreement filed in medical record
• Receive Medication Guide
• Professional labeling: Physicians instructed to counsel patients on risks and benefits
• Slone-Eckerd survey will assess patient knowledge
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Goals of Physician Selection
• Lotronex prescribed only by physicians:– knowledgeable and experienced in diagnosis
and treatment of IBS
– able to diagnose and manage ischemic colitis and complications of constipation
– knowledgeable about Lotronex
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Does the Proposed Plan Adequately Describe Appropriate Physicians?
• Knowledge
• Experience
• Specialty
• Other important characteristics
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Does the Proposed Labeling Adequately Describe Appropriate Physicians?
• Physicians self attest to qualifications
• Sign Patient-Physician Agreement
• Agreement filed in patient’s medical record• Physicians’ agreements are not audited• Utilization study of UnitedHealthcare to
assess physician-prescribing behavior
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Potentially SeriousDrug-Associated Adverse Events
• Constipation (dose-related)
• Ischemic colitis (idiosyncratic?)
• Small-bowel ischemia (idiosyncratic?)
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Modify Drug Exposure• Limit dosage to decrease dosage-related side
effects:– Starting therapy (titrate upward)
– Adjust dose during maintenance therapy?
– Drug holidays?
• Discontinue therapy in non-responders
• Continue therapy only in true responders (versus apparent responders)?
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Consider Relevant IBS Factors
• IBS waxes and wanes
• Greater risk of adverse events during
particular phases of condition?
• Lotronex should not be used in patients
with constipation
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Manage Adverse Events
• Identify and act on early warning signs– Patient education
• Patient-Physician Agreement• Medication Guide
– Physician education• Professional labeling• Patient-Physician Agreement
– Monitoring of patients
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Conclusions:Patient Selection
• Burden of illness is variable in patients with IBS
• Lotronex has beneficial effects on several symptoms of IBS
• Patients with most disabling symptoms stand to benefit the most from Lotronex
• Risk-benefit balance is most favorable in patients with most disabling symptoms.
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Conclusions:Safety Outcomes
• Lotronex is associated with serious, or potentially serious, adverse events such as complications of constipation, ischemic colitis, mesenteric ischemia, and death
• Outcomes of ischemic colitis and constipation vary in seriousness
• Presenting symptoms do not necessarily predict severity of outcome
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Conclusions:Ischemic Colitis
• Risk factors for ischemic colitis or mesenteric ischemia have not been identified
• Cumulative risk of ischemic colitis increases over time (~2-5/1000 at 3 months)
• Risk may decrease after 1 month, little information after 6 months
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Conclusions:Constipation
• Constipation is a frequent, dose-related side effect associated with Lotronex
• ~25-30% experience constipation with Lotronex at 1 mg twice daily
• ~10% withdrew from clinical trials because of constipation at 1 mg twice daily
• Some adverse outcomes of constipation are serious
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Conclusions:Risk-Management Plan
• Full range of drug access options should be considered
• Could begin with a more restrictive plan• Program monitoring should occur at
– level of the patient– level of the physician– level of the pharmacist
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Conclusions:Risk-Management Plan
• Success of the plan could be evaluated through:– Process controls– Evaluation of outcomes