# Presentation: 688488

## DRAFT SLIDES FOR NDA 21-198 ADVISORY COMMITTEE PRESENTATIONS

## Joint Advisory Committee MeetingFDA Presentations

**Clinical Efficacy and Safety**
**Mary H. Parks, MD (DMEDP)**
**Actual-Use Trials**
**Daiva Shetty, MD (DOTCDP)**
**Label Comprehension Studies**
**Karen Lechter, JD, PhD (DDMAC)**

## Joint Advisory Committee Meeting on Nonprescription Availability of Pravastatin 10 mg

**Friday, July 14, 2000**
**Mary H. Parks, MD**
**Division of Metabolic and Endocrine Drug Products**
**Center for Drug Evaluation and Research**

## NDA 21-198

**Sponsor’s rationale for nonprescription Pravastatin**
**Definition of the OTC-target population**
**Clinical studies reviewed in DMEDP**
**Safety of Pravastatin **
**Conclusions:  benefit-risk relationship of nonprescription pravastatin**

## Sponsor’s Rationale

**MRFIT.  *****JAMA. *****1986;256:2823-2828.**

## Sponsor’s Rationale

**Clinical trials demonstrate reduction in cardiovascular events with lipid-lowering drugs**
**primary and secondary prevention **
**across a broad range of cholesterol levels**

## Sponsor’s Rationale

**Inadequate treatment of population to NCEP Goals**
**< 2 CHD risk factors present**
**treatment goal:  LDL-C<160 mg/dL**
****** ****2 CHD risk factors present**
**treatment goal:  LDL-C<130 mg/dL**
**established CHD**
**treatment goal:  LDL-C<100 mg/dL**

## Sponsor’s Rationale

**Consumer interest**
**low-fat, diet foods**
**dietary supplements                                                           **
**Unrestricted access to pravastatin provides an adjunct for lowering cholesterol**

## OTC-Target PopulationSponsor’s Definition

**Who should use:**
**told by MD to lower cholesterol but not on drug treatment**
**total-C 200-240 mg/dL, LDL-C > 130 mg/dL**
**Who should NOT use:**
**presence of CHD or DM**
**on prescription lipid-lowering drug**
**children and pregnant women**

## Clinical Studies Reviewed

**10 and 40 mg placebo-controlled studies**
**PREDICT  **
**(Pravachol Experience in a Documented Consumer-Use Trial)**
**24-wk, randomized, open-label**
**Rx vs OTC pravastatin groups**
**OPTIONS **
**(OTC Pravachol in an Observed Naturalistic Setting)**
**12-wk, open-label, uncontrolled**
**OTC pravastatin in HMO setting**

## Issues Addressed

**LDL-C reduction **
**Necessity of MD involvement**
**Adherence to drug treatment**
**Clinical cardiovascular benefit**
**Safety**
**Clinical trials**
**Postmarketing**

## LDL-C Reduction

## LDL-C Reduction

**18-22% LDL-C reduction **
**placebo-controlled studies**
**diet enforced**
**in non OTC-target population**

## PREDICTQualified and Treated

**Randomization to OTC or Rx group**

**Study Physician Consult**
**treatment guidelines applied**

**Qualified for Treatment**

**Qualified and Treated Subgroup**
**15% of OTC and 19% of Rx group**

## PREDICTTreatment Guidelines

## LDL-C ReductionPREDICT

**Qualified and treated subgroups**
**18% required dose titration to 20 or 40 mg to achieve NCEP goals **
**17-18% LDL reduction for both OTC and Rx patients**

## PREDICTQualified and Treated

**Randomization**

**499 treated**

**355 treated**

**Qualified and Treated**
**352 (99.2% of treated)**

**Qualified and Treated**
**253 (50.7% of treated)**

**OTC**
**n=1924**

**RX**
**n=1948**

## NECESSITY OF PHYSICIAN INVOLVEMENT

## PREDICTStudy Drug Discontinuation

## PREDICTMD Recommended Discontinuations

## Necessity of MD Involvement

**OTC self-selection**
**overtreatment**
**undertreatment**
**inappropriate treatment**

## Adherence to Therapy

## OPTIONSSubject Disposition

**n=2207**

**n=782**

**n=404**

**n=321**

**n=156**

## Clinical Cardiovascular Benefit

## Clinical Cardiovascular Benefit?

**not demonstrated:**
** ****in OTC target population**
** ****for OTC product and dose**
** ****in OTC setting **

## SafetyClinical Trials

## Safety - Clinical Trials	

**10 mg dose**
**No rhabdomyolysis, myoglobinuria, or hepatic toxicity**
**Incidence of myalgias < 2%**
**Incidence of hepatic enzyme elevation similar between pravastatin and placebo (< 2%)**
**Discontinuation of medication due to reported AEs higher in the OTC group vs Rx group (PREDICT)**

## Safety - Clinical Trials	

**40 mg dose**
**3 placebo-controlled trials of ~ 5yrs**
**consecutive 3x ULN liver enzyme rates < 1% for pravastatin; no significant difference to placebo**
**no cases of hepatic failure **
**1 case of reported rhabdomyolysis**

## Limitations of Safety Assessments

**Clinical Trials**
**exclusion of patients on interacting drugs**
**exclusion of patients with co-morbid conditions**
**scheduled MD visits and safety monitoring**

## Safety - Spontaneous Reports

**Liver Failure**
**Rhabdomyolysis**

## Liver Failure

**Case definition**
**clinical diagnosis of liver failure stated by reporter**
**liver transplant**
**Reporting time period**
**from marketing until 2/25/00**

## Liver Failure

**13 Cases**
**8 domestic, 5 foreign**
**dose**
**10 mg (3 cases), 20 mg (6), 40 mg (1), unknown (3)**
**10 unconfounded cases**

## Liver Failure

**No increase from background rate of idiopathic liver failure**

## Rhabdomyolysis

**Case definition**
**clinical diagnosis of rhabdomyolysis**
**CPK > 10,000 IU/L**
**Reporting time period**
**marketing until April-May 2000**
**Background rate unknown for this AE**

## Rhabdomyolysis35 Cases

## Dispensed Prescriptions for Pravastatin in U.S. 1999 (Total Rx = 12,871,000)

**Rxs**

**9%**

**64%**

**27%**

- Source: IMS HEALTH National Prescription Audit

## Rhabdomyolysis

**True incidence rate unknown but risk exists**
**Potential increased risk**
**concomitant use with certain medications**
**fibrates, cyclosporine, erythromycin**
**co-morbid medical conditions**
**Cases may increase with increase use of 10 mg dose in OTC setting**

## Safety of OTC Pravastatin

**Dependent upon:**
**Comprehension of label**
**Following label instructions**
**No self-titration**
**No use by high-risk individuals**** in the unrestricted, unsupervised OTC setting**
**drug-drug interactions **
**co-morbid medical conditions**

## Summary of Issues Addressed

**LDL-C reduction**
**Adherence to drug treatment**
** ****Necessity of MD involvement**
**Clinical cardiovascular benefit**
**Safety**

## Conclusion

**What is the balance of benefit versus risk of nonprescription pravastatin?**