Lotronex

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Lotronex (alosetron HCl) TabletsRisk-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
  lt2/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 PlanInforming 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 patients 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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ConclusionsPatient 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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ConclusionsSafety 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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ConclusionsIschemic 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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ConclusionsConstipation

• 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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ConclusionsRisk-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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ConclusionsRisk-Management Plan

• Success of the plan could be evaluated through
• Process controls
• Evaluation of outcomes