# Presentation: 167374

## Non-Prescription MevacorTM 20 mgMerck & Co., Inc.New Drug Application 21-213 

**Nonprescription Drugs and Endocrinologic and Metabolic Drugs Advisory Committee Meeting**
**Silver Spring, Maryland**
**December 13, 2007**
**Eileen Craig, MD**
**Division of Metabolism and Endocrinology Products**

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

## Outline

**Overview of NCEP ATP III Guidelines**
**Current proposal for Mevacor****TM Daily (LDL label)****  **
**Current proposal for Mevacor****TM Daily (TC label)**** **

## Estimating the 10-year CHD Risk

**Framingham Risk Score**
**Age****	****	**
**Total Cholesterol**
**Smoking status**
**HDL**
**Blood Pressure**

## Major Risk Factors that Modify LDL Goals

**CHD RF other than LDL-C**
**+FH of premature CHD**
**HTN**
**Cigarette smoking**
**Low HDL (< 40 mg/dL)**
**Age (men ****≥45 yrs; women ≥55 yrs)**
***DM is a CHD risk equivalent**

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

**Risk Categories (10-yr risk of developing CV event)**
**	****	****- CHD or CHD risk equivalents (10-yr risk > 20%)**
**	****	****- 2+ risk factors for heart disease (10-yr risk 10-20%)**
**	****	****- 2+ risk factors for heart disease (10-yr risk < 10%)**
**	****	****- 0 to 1 risk factor for heart disease (10-yr risk < 10%)**
**DM, sym CAD, AAA, PVD ~ CHD risk equivalent**
**Initiation of drug therapy depends on the risk category of the individual **

## ATP III LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC) and Drug Therapy in Different Risk Categories

## CURRENT PROPOSAL FOR MEVACORTM DAILY (LDL label)

**Target Population**
**“****primary prevention of CHD by consumers who are at moderately high risk of CHD, consistent with the NCEP ATP III Guidelines”**
**LDL-C Label**
**Males 45 yrs or older/females 55 yrs or older**
**LDL between 130 and 170 mg/dL**
**Have at least one additional risk factor [smoking, HTN, FH+, low HDL (1-39)]**

## CURRENT PROPOSAL FOR MEVACORTM DAILY (TC label)

**Target Population**
**“****primary prevention of CHD by consumers who are at moderately high risk of CHD, consistent with the NCEP ATP III Guidelines”**
**Total Cholesterol Label**
**Males 45 yrs or older/females 55 yrs or older**
**TC between 200 and 240 mg/dL**
**Women only: Have at least one additional risk factor [smoking, HTN, FH+, low HDL (1-39)]**
**Women only: HDL between 1 and 59**

## TARGET POPULATION FOR MEVACORTM DAILY (TC label)

**Low CHD Risk**
**45-yr old man, no cardiac RF**
**TC=200, TG=100, HDL=50, LDL=130**
**10-yr risk for CHD= 4%**
**High CHD Risk**
**50-yr old man, smokes, HTN, FH+**
**TC=240, TG=100, HDL=20, LDL=200**
**10-yr risk for CHD****≥**** 30%**

## TREATMENT GOAL FOR MEVACORTM DAILY (LDL label)

**Proposed Dose: fixed daily dose of 20 mg**
**Treatment Goal for LDL label**
**LDL < 130 mg/dL**
**NCEP: moderately high risk persons (2+ RF and 10-yr risk 10-20%), optional LDL goal < 100 mg/dL**
**NCEP: LDL at goal but Triglycerides >200 then non-HDL goal = LDL goal + 30 mg/dL**

## TREATMENT GOAL FOR MEVACORTM DAILY (TC label)

**Proposed Dose: fixed daily dose of 20 mg**
**Treatment Goal for TC label**
**TC < 200 mg/dL**
**NCEP: based on LDL rather than TC goals**

## SELECT Study Consumer

**Demographics: 50 yr-old man**
**Risk Factors: **
**Low HDL, Smoker, + FH of Heart Disease**
**Cholesterol #s from test site**
**TC= 242,  LDL=190, HDL=38**
**Framingham Risk Score:  ****	****	****25%**

## 10-Year Risks for Both LDL and TC Labels

## Calculated 10-yr CHD Risk for Self-Selection=Yes, in LDL-C and TC arms

## Consumers on Lipid-Lowering Medications

**>30% of the participants taking lipid lowering medication stated that they were appropriate to use OTC lovastatin. **
**55% would take Mevacor Daily “in place of” their lipid-lowering medication which included atorvastatin, simvastatin, and rosuvastatin.**
**Should we be concerned that some individuals switch from more potent to less potent fixed-dose statin therapy? **

## Consumers on Lipid-Lowering Medications

**>30% of the participants taking lipid lowering medication stated that they were appropriate to use OTC lovastatin. **
**28% would take Mevacor Daily along with their lipid-lowering medication**
**Should we be concerned that some individuals will be at increased risk for side effects?**
**Myopathy, rhabdomyolysis**
**Hemorrhagic stroke??**

## SUMMARY: LDL & TC LABEL

**LDL label criteria are similar to, but not precisely the same as, the NCEP ATP III guidelines. **
**TC label criteria neither parallels the Guidelines in selecting consumers at moderate to moderately-high risk of CHD nor reflects the Guidelines for treatment goals--which are based on LDL goals.**

## SUMMARY: LDL & TC LABEL

**The majority of consumers, using either label, were not in the correct target population of 5 to 20% CHD risk.**
**~1/3 of consumers taking lipid-lowering medication stated that OTC lovastatin was appropriate to use**
**> 1/2 would replace their Rx med with OTC lovastatin**
**> 1/4 would take OTC lovastatin with their Rx med**
**Whether a consumer self-selecting for treatment based on the TC label can appropriately assess his or her treatment goal, which is based on an LDL target, was not explored in this submission.**

## Acknowledgements

**DMEP Clinical Review Team **
**Eric Colman, M.D. **
**Mary Parks, M.D. **
**Division of Drug Risk Evaluation **
**Jo Wyeth, Pharm.D. **
**Shewit Bezabeh, M.D., M.P.H. **
**DMEP Project Management **
**Margaret Simoneau M.S., R.Ph. **

## BACK-UP SLIDES

## Participants Taking Cholesterol/Lipid-Lowering Medicines: LDL-C ParadigmBy Self Assessment and Purchase Decision

## Hemorrhagic stroke incidence: Relative risk meta-analysis plot

**Henyan NN, Riche DM, East HE, Gann PN. Impact of Statins on Risk of Stroke: A Meta-Analysis. *****The Annals of Pharmacotherapy *****Dec 2007; 41:1937-1945 (Figure 4)**

## References on Statin Therapy and Hemorrhagic Stroke

**Asia Pacific Cohort Studies Collaboration. Joint effects of systolic blood pressure and serum cholesterol on cardiovascular disease in the Asia Pacific region. *****Circulation *****2005; 112: 3384–90.**
**Bang OY, Saver JL, Liesbeskind DS, et al. Cholesterol level and symptomatic hemorrhagic transformation after ischemic stroke thrombolysis. Neurology 2007; 68:737-42. Epub 20 Dec 2006.**
**Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. *****Lancet *****2005; 366: 1267–78.**
**Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomized placebo controlled trial. Lancet 2004; 364:685-96.**
**Ebrahim S, Sung J, Song YM, Ferrer R, Lawlor D, Davey Smith G. Serum cholesterol, haemorrhagic stroke, ischaemic stroke, and myocardial infarction: Korean national health system prospective cohort study. *****BMJ *****2006; 333: 22–28.**

## References on Statin Therapy and Hemorrhagic Stroke

**Henyan NN, Riche DM, East HE, Gann PN. Impact of Statins on Risk of Stroke: A Meta-Analysis. *****The Annals of Pharmacotherapy *****Dec 2007; 41:1937-1945**
**Iso H, Naito Y and Kitamura A *****et al.*****, Serum total cholesterol and mortality in a Japanese population, *****J Clin Epidemiol***** 1994; 47: 961–969.**
**Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the Multiple Risk Factor Intervention Trial. N Engl J Med 1989; 320:904-10.**
**Kent DM. Stroke—an equal opportunity for the initiation of statin therapy. N Engl J Med 2006;355:613-5.**
**Law, MR, Thompson SG, Wald NJ. Assessing possible hazards of reducing serum cholesterol. *****BMJ *****1994; 308: 373–79.**
**Lee S-H, Bae H-J, Yoon B-W, Kim H, Kim D-E, Roh J-K. Low concentration of serum total cholesterol is associated with multifocal signal loss lesions on gradient-echo magnetic resonance imaging: analysis of risk factors for multifocal signal loss lesions. Stroke 2002; 33:2845-2849**

## References on Statin Therapy and Hemorrhagic Stroke

**Lin CH, Shimizu Y, Kato H, et al. Cerebrovascular disease in a fixed population of Hiroshima and Nagasaki, with special reference to relationship between type and risk factors. Stroke 1984;15:653-60.**
**Lindenstrom E, Boysen G, Nyboe J. Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: the Copenhagen City Heart Study. *****BMJ***** 1994; 309: 11–15.**
**The Long Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339:1349-57.**
**Menotti A, Blackburn H, Kromhout D, et al. The inverse relation of average population blood pressure and stroke mortality rates in the Seven Countries Study: a paradox. Eur J Epidemiol 1997; 13:379-86.**
**Nakamura H, Arakawa K, Itakura H, et al. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomized controlled trial. Lancet 2006; 368:1155-63.**

## References on Statin Therapy and Hemorrhagic Stroke

**Neaton JD, H. Blackburn H, Jacobs D et al., Serum cholesterol level and mortality findings for men screened in the Multiple Risk Factor Intervention Trial. Multiple Risk Factor Intervention Trial Research Group, *****Arch Intern Med***** 152 (1992), pp. 1490–1500.**
**Prospective Studies Collaboration. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Lancet 1995;346:1647-53.**
**Prospective Studies Collaboration. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths *****Lancet *****2007; 370: 1829–39**
**The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355:549-59.**
**Stemmermann GN, Chyou PH, Kagan A, Nomura AM, Yano K. Serum cholesterol and mortality among Japanese-American men. The Honolulu (Hawaii) Heart Program, *****Arch Intern Med***** 151 (1991), pp. 969–972. **
**Yano K, Reed DM, MacLean CJ. Serum cholesterol and hemorrhagic stroke in the Honolulu Heart Program. Stroke 1989;20:1460-1465.**

## AFCAPS/TEXCAPS Event rates and NNT as reported by the Applicant in NDAs submitted in 1999 and 2004

## Applicant’s Kaplan-Meier Event Rates for Each Subgroup By Treatment Over 5 Years

## Applicant’s Kaplan-Meier Event Rates for Each Subgroup By Treatment Over 6 Years