# Presentation: 748672

## SLIDES FORNDA 21-213 ADVISORY COMMITTEE PRESENTATION

## Joint Advisory Committee MeetingFDA Presentations

**Clinical Efficacy and Safety Review**
**Mary H. Parks, MD (DMEDP)**
**Review of Actual-Use Trials**
**Andrea Leonard-Segal, MD (DOTCDP)**
**Drug-Drug and Drug-Food Interactions**
**Jim Wei, PhD (OCPB)**
**Label Comprehension**
**Karen Lechter, JD, PhD (DDMAC)**

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

**Thursday, July 13, 2000**
**Mary H. Parks, MD**
**Division of Metabolic and Endocrine Drug Products**
**Center for Drug Evaluation and Research**

## NDA 21-213

**Sponsor’s rationale for nonprescription lovastatin**
**Definition of the OTC-target population**
**Clinical studies reviewed in DMEDP**
**Efficacy of lovastatin 10 mg**
**Safety of lovastatin **
**Conclusion:  benefit-risk relationship of nonprescription lovastatin**

## Sponsor’s Rationale

**Sponsor’s Rationale**

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

## NCEP Recommendations

**Initial Treatment**_** **_
**dietary modification**
**exercise**
**CHD risk factor reduction**
**Drug Treatment**
**HDL-C level<35 mg/dL OR  ******** 2 risk factors **
**LDL-C level of ******** 160 mg/dL**

## AFCAPS/TexCAPS

**5-year randomized, double-blinded, placebo-controlled trial**
**lovastatin 20-40 mg**
**eligibility criteria:**
**men > 45 yrs age and postmenopausal women**
**total-C 180-264 mg/dL**
**LDL-C 130-190 mg/dL**
**HDL-C < 45 mg/dL for men; < 47 mg/dL for women**
**Two-thirds of cohort had ******** 2 CHD risk factors**
***Based on NCEP Guidelines, 17% of the 6,605 study cohort qualified for drug treatment***

## AFCAPS/TexCAPS

**Primary composite endpoint**
**Fatal or nonfatal MI**
**Unstable angina  **
**Sudden cardiac death**

## AFCAPS/TexCAPSPrimary Endpoint Results

**After 5 yrs with 70% completion rate:**
**LOVASTATIN      3.5%**
**PLACEBO           5.5%**
**P<.0001**

## OTC-Target Population Sponsor’s Definition*

**Males > 40 years and postmenopausal females **
**No CVD, DM or significant HTN **
**Not on prescription lipid-lowering drug **
**Total-C 200 - 240 mg/dL**
**LDL-C ******** 130 mg/dL**
****Does not include HDL-C***
***Based on NHANES III, the estimated OTC-eligible population is 15.5 million.***

## Clinical Studies Reviewed

**Protocol 075 (The Efficacy Study)**
**Protocol 076 (The Pharmacy Study)**
**Protocol 079 (Restricted Access Study)**
**AFCAPS OTC-eligible Population**

## Issues Addressed

**Efficacy**
**LDL-C reduction**
**Clinical cardiovascular benefit**
**Safety**
**Clinical trials**
**Postmarketing**

## EfficacyLDL-C Reduction

## Clinical Studies Reviewed

**Protocol 075**** **
**Blinded, Diet, Placebo-Controlled Study**
**12-hour fasting serum lipids**
**Weeks 0, 6, 12**
**Protocol 076**** **
**Open-label, No diet, Uncontrolled Study**
******2-hour fasting fingerstick lipids**
**Weeks 0, 8, 16, 24**
**Protocol 079**
** ****Open-label, No diet, Uncontrolled Study**
******6-hour fasting fingerstick lipids**
**Weeks 0, 8**

##      Study Adherence by Week

**0**

**6**

**12**

**P075**

**0**

**8**

**16**

**24**

**0**

**8**

**P076**

**P079**

**%**

## LDL % Change from BaselineCompleters

**12 wks**

**8 wks**

**8 wks**

**91% completers**
**at wk 12**

**79% completers**
**at wk 8**

**63% completers**
**at wk 8**

## LDL-C ReductionConclusions

**Compliant and adherent individuals**
**18% reduction in LDL**
**Actual nonprescription setting **
**poor drug adherence**
**>30% dropouts by Week 8 and 24 in the actual-use studies**

## EfficacyClinical Cardiovascular Benefit

## Clinical Cardiovascular Benefit?

**Does LDL-C lowering with lovastatin 10 mg in the OTC-target population confer clinical benefit?**
**No evidence from controlled clinical trials.**

## Clinical Cardiovascular Benefit?

**6,605 AFCAPS total cohort**

**Total-C 200-240 mg/dL**
**LDL-C ******** 130 mg/dL**
**no DM or significant HTN***

**3,805 OTC-eligible**

****no HDL-C criterion is imposed***

**2,800 excluded**

## AFCAPS/TexCAPS OTC-Eligible Subgroup Post-Hoc Analysis

**LOVASTATIN ****(n=1,884)****     3.0%**
**PLACEBO       ****(n=1,921)****     5.3%**

## AFCAPS = OTC-Target Population?

**Different lovastatin dose**
**AFCAPS/TexCAPS 20-40mg**
**51.5% of the AFCAPS subgroup required treatment with 40 mg per day to achieve an LDL-C < 110 mg/dL **
**OTC-Target population 10 mg**

## AFCAPS = OTC-Target Population?

## AFCAPS = OTC-Target Population?AFCAPS Subgroup Event Rates by Baseline HDL-C

## AFCAPS = OTC-Target Population?

**Proportion of population with HDL > 40**** **

**AFCAPS**

**P075**

**P076**

**P079**

**NHANES**

## AFCAPS = OTC-target populationAdherence to Drug?

**3 months**

**AFCAPS = OTC-target population****Adherence to Drug?**

## Clinical Cardiovascular BenefitConclusions

**AFCAPS not representative of OTC-target population**
**HDL-C**
**Poor adherence to drug treatment**
**AFCAPS 5yr - 70% completers**
**Actual use 3 mos - 40% completers**

## SafetyClinical Trials

## Safety of Lovastatin 10 mgClinical Trials

**10 mg dose**
**Comparable to placebo **
**Incidence of myalgias < 2% in all studies**
**No cases of rhabdomyolysis, myoglobinuria, or hepatic toxicity**
**Discontinuation of medication due to reported AEs higher in the actual-use studies vs controlled, clinical trials**

## Safety - Clinical Trials 

**20-80 mg dose (AFCAPS and EXCEL)**
**consecutive 3x ULN liver enzyme elevation**
**<1% 20-40 mg daily dose**
**1.5% 80 mg daily dose**
**myopathy (symptoms and CPK > 10 ULN)**
**0.1% 40 mg daily dose**
**0.2% 80 mg daily dose**
**one case of rhabdomyolysis for 20 mg dose**

## Limitations of Safety Assessments

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

## SafetySpontaneous Reports

## Postmarketing Safety Concerns

**Liver failure**
**Rhabdomyolysis**
**	****	****- drug-drug interaction**
**	****	****- drug-food interaction**

## Liver Failure

**Case Definition**
**Unduplicated U.S. cases of**
**clinical diagnosis of liver failure ****	****or**
**receipt of liver transplant**
**Time period**
**From marketing 8/31/87 to 2/25/00**

## Background Rate vs. Reporting Rate

**Estimated background rate of idiopathic liver failure is 1 per million person-years **
**Estimated four-year reporting rate is 1.4 per million PYE for lovastatin-associated liver failure (1987-1990)**

## Rhabdomyolysis

**Case definition**
**Unduplicated U.S. cases **
**Clinical diagnosis of rhabdomyolysis **
**CPK > 10,000 IU/L**
**Time period**
**From marketing 8/31/87 to 4/4/00**
**Background rate for this AE unknown**

## 191 Cases RhabdomyolysisPercent of Cases Reported by Dose

## Dispensed Prescriptions for Lovastatin in U.S. 1999 (Total Rx = 3,177,000)

**Rxs**

- 4%

- 72%

- 24%

**Source: IMS HEALTH National Prescription Audit TM**

**4%**

**72%**

**24%**

## RhabdomyolysisDrug-Drug Interactions

## Reported Drug-Drug Interactions With Lovastatin

**Erythromycin†**
**Clarithromycin†**
**Nefazodone†**
**Danazol†**
**Cyclosporine†**
**†****Metabolized through the CYP3A4 isoenzyme**** **

**Itraconazole†**
**Ketoconazole†**
**Mibefradil†**
**	****(‘98 withdrawal)**
**Gemfibrozil**
**Niacin**

## Reported Drug-Food InteractionGrapefruit Juice

**One case report**
**lovastatin 80 mg and gemfibrozil 1200 mg > 5 years**
**baseline renal impairment**
**onset 2 wks after initiating grapefruit juice**

## RhabdomyolysisConclusions

**Most reported cases associated with  drug-drug interactions **
**Many interactions are due to competition for CYP3A4 metabolic pathway**

## Product Label - Interacting Drugs

**Do not use product if also on:**
**erythromycin or clarithromycin****	**
**ketoconazole or itraconazole****	**
**nefazodone**
**cyclosporine**
**protease inhibitors**
**niacin or gemfibrozil**
**Rx statin drugs (simvastatin,pravastatin, fluvastatin, atorvastatin, cerivastatin, lovastatin)**
**List not complete and likely to increase**
**Challenging to consumers**

## Drugs Withdrawn from U.S. Market Due to CYP3A4

** ****Seldane (terfenadine) -1997  **
** ****Posicor (mibefradil) -1998**
** ****Hismanal (astemizole) -1999**
** ****Propulsid (cisapride) - 2000**

## CYP3A4 Drug Withdrawals

**Withdrawn despite**
**Changes to the label warnings **
**Dear Healthcare Professional letters**
**Black box warnings**

## Safety of OTC LovastatinConclusions

**Dependent upon:**
**Consumer comprehension of label**
**Use of product according to label instructions**
**No self-titration to higher doses**
**No use by individuals at risk for drug-related toxicity in unrestricted OTC setting**
**drug-drug interactions**
**drug-food interactions**
**co-morbid medical conditions**

## Summary of Issues Addressed

**LDL-C reduction**
**lowers LDL-C but effectiveness in OTC-population diminished by poor drug adherence**
**Clinical Cardiovascular Benefit**
**no established benefit of drug treatment in OTC-Target population**
**any benefit offset by poor drug adherence**
**Safety**
**drug-drug/drug-food interactions**
**unrestricted/unsupervised OTC environment**

## Conclusion

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