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Lotronex® (alosetron HCl) Tablets

Risk-Benefit Issues

Victor F. C. Raczkowski, M.D.

Director, Division of Gastrointestinal and

Coagulation Drug Products

April 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