# Presentation: 489221

**Center for Drug Evaluation and Research**** **

**Non-Prescription Mevacor® 20 mg**
**Joint Advisory Committee Meeting**
**NDA 21-213**

**Mary H. Parks, MD**
**Deputy Division Director**
**Division of Metabolic and Endocrine Drug Products**
**January 13-14, 2005**
**Bethesda, MD**

## Outline:

**Regulatory history of Rx-to-OTC switch for lipid-lowering drugs**
**Overview of previously submitted applications for nonprescription lipid-lowering drugs**
**Initial Mevacor OTC proposal**
**Overview of current Mevacor application**
**Areas for consideration of the current program**

## HISTORICAL OVERVIEW

**Mid-1990s**
**bile acid resin binders proposed for OTC use**
**1997 Guidance on OTC Tx of Hypercholesterolemia**
**chronic, asymptomatic condition requiring accurate diagnosis and clinical testing under directed care of HCP**
**recommendation that drug treatments for such condition not be sold OTC**

## HISTORICAL OVERVIEW

**1999 two applications for statin Rx to OTC switch submitted to the FDA**
**July 2000**
**2 separate AC mtgs for lovastatin and pravastatin OTC**

## July 2000 Advisory Committee for Mevacor® 

**10 mg dose proposed**
**Target population**
**males > 40 yrs and postmenopausal females**
**no CVD, DM or significant HTN**
**not on prescription lipid-lowering drug**
**TC 200-240 mg/dL**
**LDL-C ******** 130 mg/dL**

## July 2000 Advisory Committee for Mevacor® 10 mg

**Efficacy Concerns**
**NCEP guidelines for initiation of tx and treatment goals not incorporated**
**clinical benefit could not be extrapolated from clinical outcomes data for proposed dose and target population**
**consumer comprehension of complexities of treatment not demonstrated**

## July 2000 Advisory Committee for Mevacor® 10 mg

**Safety Concerns**
**muscle**
**potential for drug-drug interactions**
**hepatic**
**recommendations for hepatic laboratory monitoring**
**safety in patients w/ undiagnosed liver disease**
**pregnancy category X**

## 2000-2005

**1997 FDA Guidance to Industry withdrawn in 2001**
**NCEP ATP III Guidelines published 2001**
**new risk categories**
**new goals of treatment **
**subsequent update July 2004**

## NCEP - ATP III GuidelinesNational Cholesterol Education Progam - Adult Treatment Panel

**Risk Categories (10-yr risk of developing CV event)**
**CHD or CHD risk equivalent (10-yr risk > 20%)**
**2+ risk factors (10-yr risk ******** 20%)**
**0-1 risk factor (10-yr risk < 10%)**
**DM, PAD, other clinical presentations of atherosclerosis ~ CHD risk equivalent**
**Initiation of drug therapy depends on risk category of individual but on background of lifestyle changes/modifications**

## CURRENT PROPOSAL FOR MEVACOR® OTC

**Target Population**
**“****A primary prevention population with ******** 20 % 10-yr risk of CHD w/o underlying chronic conditions that complicate consumer self-management”**
**males 45 yrs or older/females 55 yrs or older**
**LDL between 130 and 170 mg/dL**
**have at least one of (smoking, HDL 1-39, FH+, HTN)**
**Proposed Dose - fixed daily dose of 20 mg**

## CURRENT PROPOSAL FOR MEVACOR® OTC

**Treatment goal for target population is LDL < 130 mg/dL ( NCEP: if Tg > 200 then nonHDL < 160)**
**Consumers need to know cholesterol values before and while on therapy**
**Consumers need to know baseline risks and changes in health status that might alter risk/benefit of lovastatin 20 mg**

## EFFICACY

**Lovastatin 20 mg LDL-lowering**
**EXCEL and AFCAPS/TexCAPS clinical trials**
**Consumer Use study**
**mean LDL reduction ~ 24%**
**Clinical benefits of lovastatin 20 mg**
**extrapolation from AFCAPS/TexCAPS, 5 yr pbo controlled outcomes study evaluating lovastatin 20 to 40 mg daily (primary endpt:  unstable angina, nonfatal MI, CHD death)**

## SAFETY

**Re-evaluation of clinical trial database for EXCEL and AFCAPS/TexCAPS**
**6,582 patients exposed to lovastatin 20-80 mg daily in a 48 wk study (EXCEL)**
**3,304 patients exposed to lovastatin 20 to 40 mg daily in a 5 yr study (AFCAPS)**
**Evaluation of global postmarketing safety database from marketing until present (~17 yrs of postmarketing use; ~27 million patient-yrs exposure**

## SAFETY

**Conclusion for muscle and liver safety concerns:**
**risk of myopathy/rhabdomyolysis is extremely low that the 20 mg dose, if labeled adequately **_**and**_** understood by the consumer, is an acceptable dose for OTC use**
**there is little to no hepatic risk in patients with normal hepatic function**
**concerns of safety of lovastatin in patients with asymptomatic liver disease including viral hepatitis not addressed in prospective studies; however, abstract of a study in ~40 patients and a retrospective study to be presented by sponsor**

## SAFETY

**Pregnancy safety concerns:**
**preclinical studies conducted and reviewed under prescription NDA**
**FDA concludes pregnancy category X should be retained based on:**
**findings of preclinical studies**
**agreement b/w sponsor and FDA that risk exceeds benefit during pregnancy - retain contraindication in pregnancy**
**inadvertent exposure in first-trimester of pregnancy and adequacy of labeling/consumer comprehension**

## Areas for Consideration:  Efficacy

**Caveats of extrapolation from AFCAPS/TexCAPS**
**post-hoc analysis**
**nonrandomized comparisons**
**none of the subgroups selected by the sponsor fully reflects the OTC population as AFCAPS included patients who were titrated to 40 mg and were treated to a lower LDL-C goal**
**longterm benefit observed w/ AFCAPS assumes adherence to therapy in the OTC setting**
**changes in health status may dictate need for more aggressive tx**

## Areas for Consideration:  Safety

**Current program proposes safety issues addressed through labeling**
**effectiveness of labeling evaluated in CUSTOM**
**Impact of changes in health status and interacting meds on safety, particularly long-term**