# Presentation: 097197

## Lotronex® (alosetron HCl) TabletsRisk-Benefit Issues

**Victor F. C.  Raczkowski, M.D. **
**Director, Division of Gastrointestinal and**
**Coagulation Drug Products**
**April 23, 2002**

## Modifying the Benefit-Risk Balance

**Three principal approaches**
**Limit use to patients with most disabling IBS symptoms**
**Increase benefit**
**Decrease risk**

## 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**

## 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**

## 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**

## 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**

## 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 **

## How Best to DescribePatients in Whom Benefits Exceed Risks?

**Approved Indication: February 2000**
**Revised Indication: August 2000**
**Proposed Indication: April 2002**

## 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.**

## 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.**

## 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.**

## 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**

## 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?**

## 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**

## 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**

## Does the Proposed Plan Adequately Describe Appropriate Physicians?

**Knowledge**
**Experience**
**Specialty**
**Other important characteristics**

## 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**

## Potentially SeriousDrug-Associated Adverse Events

**Constipation (dose-related)**
**Ischemic colitis (idiosyncratic?)**
**Small-bowel ischemia (idiosyncratic?)**

## 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)?**

## 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**

## 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**

## 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.**

## 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**

## 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**

## 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**

## 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**

## Conclusions:Risk-Management Plan

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