1 / 48

SLIDES FOR NDA 21-213 ADVISORY COMMITTEE PRESENTATION

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)

daria
Download Presentation

SLIDES FOR NDA 21-213 ADVISORY COMMITTEE PRESENTATION

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. SLIDES FORNDA 21-213 ADVISORY COMMITTEE PRESENTATION

  2. Joint Advisory Committee MeetingFDA 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)

  3. 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

  4. 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

  5. Sponsor’s Rationale MRFIT. JAMA. 1986;256:2823-2828.

  6. 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

  7. 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

  8. AFCAPS/TexCAPS Primary composite endpoint • Fatal or nonfatal MI • Unstable angina • Sudden cardiac death

  9. AFCAPS/TexCAPSPrimary Endpoint Results After 5 yrs with 70% completion rate: LOVASTATIN 3.5% PLACEBO 5.5% P<.0001

  10. OTC-Target PopulationSponsor’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.

  11. Clinical Studies Reviewed • Protocol 075 (The Efficacy Study) • Protocol 076 (The Pharmacy Study) • Protocol 079 (Restricted Access Study) • AFCAPS OTC-eligible Population

  12. Issues Addressed • Efficacy • LDL-C reduction • Clinical cardiovascular benefit • Safety • Clinical trials • Postmarketing

  13. EfficacyLDL-C Reduction

  14. 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

  15. Study Adherence by Week % 0 6 12 0 8 16 24 0 8 P075 P076 P079

  16. LDL % Change from BaselineCompleters 8 wks 8 wks 12 wks 91% completers at wk 12 79% completers at wk 8 63% completers at wk 8

  17. LDL-C ReductionConclusions • 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

  18. EfficacyClinical Cardiovascular Benefit

  19. 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.

  20. Clinical Cardiovascular Benefit? 6,605 AFCAPS total cohort Total-C 200-240 mg/dL LDL-C  130 mg/dL no DM or significant HTN* 2,800 excluded 3,805 OTC-eligible *no HDL-C criterion is imposed

  21. AFCAPS/TexCAPS OTC-Eligible Subgroup Post-Hoc Analysis LOVASTATIN (n=1,884) 3.0% PLACEBO (n=1,921) 5.3%

  22. 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

  23. AFCAPS = OTC-Target Population?

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

  25. AFCAPS = OTC-Target Population? Proportion of population with HDL > 40 NHANES P075 P076 P079 AFCAPS

  26. AFCAPS = OTC-target populationAdherence to Drug? 3 months

  27. Clinical Cardiovascular BenefitConclusions • AFCAPS not representative of OTC-target population • HDL-C • Poor adherence to drug treatment • AFCAPS 5yr - 70% completers • Actual use 3 mos - 40% completers

  28. SafetyClinical Trials

  29. Safety of Lovastatin 10 mgClinical 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

  30. 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

  31. Limitations of Safety Assessments • Clinical Trials • exclusion of patients on interacting drugs • exclusion of patients with co-morbid conditions • scheduled MD visits and monitoring

  32. SafetySpontaneous Reports

  33. Postmarketing Safety Concerns • Liver failure • Rhabdomyolysis - drug-drug interaction - drug-food interaction

  34. 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

  35. 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)

  36. 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

  37. 191 Cases RhabdomyolysisPercent of Cases Reported by Dose

  38. Dispensed Prescriptions for Lovastatin in U.S. 1999 (Total Rx = 3,177,000) 72% 72% Rxs 24% 24% 4% 4% Source: IMS HEALTH National Prescription Audit TM

  39. RhabdomyolysisDrug-Drug Interactions

  40. Erythromycin† Clarithromycin† Nefazodone† Danazol† Cyclosporine† †Metabolized through the CYP3A4 isoenzyme Itraconazole† Ketoconazole† Mibefradil† (‘98 withdrawal) Gemfibrozil Niacin Reported Drug-Drug Interactions With Lovastatin

  41. Reported Drug-Food InteractionGrapefruit Juice • One case report • lovastatin 80 mg and gemfibrozil 1200 mg > 5 years • baseline renal impairment • onset 2 wks after initiating grapefruit juice

  42. RhabdomyolysisConclusions • Most reported cases associated with drug-drug interactions • Many interactions are due to competition for CYP3A4 metabolic pathway

  43. 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

  44. Drugs Withdrawn from U.S. Market Due to CYP3A4 • Seldane (terfenadine) -1997 • Posicor (mibefradil) -1998 • Hismanal (astemizole) -1999 • Propulsid (cisapride) - 2000

  45. CYP3A4 Drug Withdrawals • Withdrawn despite • Changes to the label warnings • Dear Healthcare Professional letters • Black box warnings

  46. Safety of OTC LovastatinConclusions • 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

  47. 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

  48. Conclusion What is the balance of benefit versus risk of nonprescription lovastatin?

More Related