1. 1 Lotronex ® (alosetron HCl) Tablets Risk-Benefit Issues Victor F. C. Raczkowski, M.D. Director, Division of Gastrointestinal and Coagulation Drug Products April 23, 2002

2. 2 Modifying the Benefit-Risk Balance Three principal approaches –Limit use to patients with most disabling IBS symptoms –Increase benefit –Decrease risk

3. 3 Limiting Lotronex Use to Patients With 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

4. 4 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

5. 5 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

6. 6 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

7. 7 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

8. 8 How Best to Describe Patients in Whom Benefits Exceed Risks? Approved Indication: February 2000 Revised Indication: August 2000 Proposed Indication: April 2002

9. 9 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.

10. 10 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.

11. 11 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.

12. 12 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

13. 13 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?

14. 14 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

15. 15 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

16. 16 Does the Proposed Plan Adequately Describe Appropriate Physicians? Knowledge Experience Specialty Other important characteristics

17. 17 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

18. 18 Potentially Serious Drug-Associated Adverse Events Constipation (dose-related) Ischemic colitis (idiosyncratic?) Small-bowel ischemia (idiosyncratic?)

19. 19 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)?

20. 20 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

21. 21 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

22. 22 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.

23. 23 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

24. 24 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

25. 25 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

26. 26 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

27. 27 Conclusions: Risk-Management Plan Success of the plan could be evaluated through: –Process controls –Evaluation of outcomes