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

Non-Prescription Mevacor ™ 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.

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

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  1. Non-Prescription Mevacor™20 mgMerck & 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

  2. Outline • Overview of NCEP ATP III Guidelines • Current proposal for Mevacor™ Daily (LDL label) • Current proposal for Mevacor™ Daily (TC label)

  3. Estimating the 10-year CHD Risk • Framingham Risk Score • Age • Total Cholesterol • Smoking status • HDL • Blood Pressure

  4. 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

  5. NCEP-ATP III GuidelinesNational 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

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

  7. CURRENT PROPOSAL FOR MEVACOR™ 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)]

  8. CURRENT PROPOSAL FOR MEVACOR™ 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

  9. TARGET POPULATION FOR MEVACOR™ 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%

  10. TREATMENT GOAL FOR MEVACOR™ 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

  11. TREATMENT GOAL FOR MEVACOR™ 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

  12. 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%

  13. 10-Year Risks for Both LDL and TC Labels

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

  15. 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?

  16. 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??

  17. 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.

  18. 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.

  19. 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.

  20. BACK-UP SLIDES

  21. Participants Taking Cholesterol/Lipid-Lowering Medicines: LDL-C ParadigmBy Self Assessment and Purchase Decision

  22. 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)

  23. 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.

  24. 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

  25. 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.

  26. 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.

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

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

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

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