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SLIDES FORSLIDES FORNDA 21-213 ADVISORY NDA 21-213 ADVISORY
COMMITTEE COMMITTEE PRESENTATIONPRESENTATION
Joint Advisory Committee MeetingJoint Advisory Committee MeetingFDA PresentationsFDA Presentations
Clinical Efficacy and Safety ReviewClinical Efficacy and Safety Review Mary H. Parks, MD (DMEDP)Mary H. Parks, MD (DMEDP)
Review of Actual-Use TrialsReview of Actual-Use Trials Andrea Leonard-Segal, MD (DOTCDP)Andrea Leonard-Segal, MD (DOTCDP)
Drug-Drug and Drug-Food InteractionsDrug-Drug and Drug-Food Interactions Jim Wei, PhD (OCPB)Jim Wei, PhD (OCPB)
Label ComprehensionLabel Comprehension Karen Lechter, JD, PhD (DDMAC)Karen Lechter, JD, PhD (DDMAC)
Joint Advisory Committee Joint Advisory Committee Meeting on Nonprescription Meeting on Nonprescription
Availability of Lovastatin 10 mgAvailability of Lovastatin 10 mg
Thursday, July 13, 2000Thursday, July 13, 2000
Mary H. Parks, MDMary H. Parks, MD
Division of Metabolic and Endocrine Drug ProductsDivision of Metabolic and Endocrine Drug Products
Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research
NDA 21-213NDA 21-213
Sponsor’s rationale for nonprescription Sponsor’s rationale for nonprescription lovastatinlovastatin
Definition of the OTC-target populationDefinition of the OTC-target population Clinical studies reviewed in DMEDPClinical studies reviewed in DMEDP Efficacy of lovastatin 10 mgEfficacy of lovastatin 10 mg Safety of lovastatin Safety of lovastatin Conclusion: benefit-risk relationship of Conclusion: benefit-risk relationship of
nonprescription lovastatinnonprescription lovastatin
Total-C Levels and CHD Mortality
0
2
4
6
8
10
12
<180 182-202 203-220 221-244 >244
Total-C in mg/dL
CH
D M
ort
alit
y R
ate
Sponsor’s RationaleSponsor’s Rationale
MRFIT. JAMA. 1986;256:2823-2828.
NCEP RecommendationsNCEP Recommendations
Initial TreatmentInitial Treatment dietary modificationdietary modification exerciseexercise CHD risk factor reductionCHD risk factor reduction
Drug TreatmentDrug Treatment HDL-C level<35 mg/dL OR HDL-C level<35 mg/dL OR 2 risk 2 risk
factors factors LDL-C level of LDL-C level of 160 mg/dL 160 mg/dL
AFCAPS/TexCAPSAFCAPS/TexCAPS 5-year randomized, double-blinded, placebo-5-year randomized, double-blinded, placebo-
controlled trialcontrolled trial lovastatin 20-40 mglovastatin 20-40 mg eligibility criteria:eligibility criteria:
men > 45 yrs age and postmenopausal womenmen > 45 yrs age and postmenopausal women total-C 180-264 mg/dLtotal-C 180-264 mg/dL LDL-C 130-190 mg/dLLDL-C 130-190 mg/dL HDL-C < 45 mg/dL for men; < 47 mg/dL for womenHDL-C < 45 mg/dL for men; < 47 mg/dL for women
Two-thirds of cohort had Two-thirds of cohort had 2 CHD risk factors 2 CHD risk factors
Based on NCEP Guidelines, 17% of the 6,605 study Based on NCEP Guidelines, 17% of the 6,605 study cohort qualified for drug treatmentcohort qualified for drug treatment
AFCAPS/TexCAPSAFCAPS/TexCAPS
Primary composite endpointPrimary composite endpoint
Fatal or nonfatal MIFatal or nonfatal MI Unstable angina Unstable angina Sudden cardiac deathSudden cardiac death
AFCAPS/TexCAPSAFCAPS/TexCAPSPrimary Endpoint ResultsPrimary Endpoint Results
After 5 yrs with 70% completion rate:After 5 yrs with 70% completion rate:
LOVASTATIN 3.5%LOVASTATIN 3.5%
PLACEBO 5.5%PLACEBO 5.5%
P<.0001P<.0001
OTC-Target PopulationOTC-Target Population Sponsor’s Definition*Sponsor’s Definition*
Males > 40 years and postmenopausal females Males > 40 years and postmenopausal females No CVD, DM or significant HTN No CVD, DM or significant HTN Not on prescription lipid-lowering drug Not on prescription lipid-lowering drug Total-C 200 - 240 mg/dLTotal-C 200 - 240 mg/dL LDL-C LDL-C 130 mg/dL 130 mg/dL
*Does not include HDL-C*Does not include HDL-C
Based on NHANES III, the estimated OTC-Based on NHANES III, the estimated OTC-eligible population is 15.5 million.eligible population is 15.5 million.
Clinical Studies ReviewedClinical Studies Reviewed
Protocol 075 (The Efficacy Study)Protocol 075 (The Efficacy Study)
Protocol 076 (The Pharmacy Study)Protocol 076 (The Pharmacy Study)
Protocol 079 (Restricted Access Study)Protocol 079 (Restricted Access Study)
AFCAPS OTC-eligible PopulationAFCAPS OTC-eligible Population
Issues AddressedIssues Addressed
EfficacyEfficacy LDL-C reductionLDL-C reduction Clinical cardiovascular benefitClinical cardiovascular benefit
SafetySafety Clinical trialsClinical trials PostmarketingPostmarketing
EfficacyEfficacy
LDL-C ReductionLDL-C Reduction
Clinical Studies ReviewedClinical Studies Reviewed Protocol 075Protocol 075
Blinded, Diet, Placebo-Controlled StudyBlinded, Diet, Placebo-Controlled Study 12-hour fasting serum lipids12-hour fasting serum lipids
Weeks 0, 6, 12Weeks 0, 6, 12
Protocol 076Protocol 076 Open-label, No diet, Uncontrolled StudyOpen-label, No diet, Uncontrolled Study 2-hour fasting fingerstick lipids2-hour fasting fingerstick lipids
Weeks 0, 8, 16, 24Weeks 0, 8, 16, 24
Protocol 079Protocol 079 Open-label, No diet, Uncontrolled StudyOpen-label, No diet, Uncontrolled Study 6-hour fasting fingerstick lipids6-hour fasting fingerstick lipids
Weeks 0, 8Weeks 0, 8
Study Adherence by WeekStudy Adherence by Week
0 6 12P075
0 8 16 24 0 8P076 P079
%
LDL % Change from BaselineLDL % Change from BaselineCompletersCompleters
12 wks 8 wks 8 wks
91% completersat wk 12
79% completersat wk 8
63% completersat wk 8
-25
-20
-15
-10
-5
0
5
P075 P076 P079
LDL-C ReductionLDL-C ReductionConclusionsConclusions
Compliant and adherent individualsCompliant and adherent individuals 18% reduction in LDL18% reduction in LDL
Actual nonprescription setting Actual nonprescription setting poor drug adherencepoor drug adherence >30% dropouts by Week 8 and 24 >30% dropouts by Week 8 and 24
in the actual-use studiesin the actual-use studies
EfficacyEfficacy
Clinical Cardiovascular Clinical Cardiovascular BenefitBenefit
Clinical Cardiovascular Benefit?Clinical Cardiovascular Benefit?
Does LDL-C lowering with Does LDL-C lowering with lovastatin 10 mg in the OTC-lovastatin 10 mg in the OTC-target population confer clinical target population confer clinical benefit?benefit?
No evidence from controlled No evidence from controlled clinical trials.clinical trials.
Clinical Cardiovascular Benefit?Clinical Cardiovascular Benefit?6,605 AFCAPS total cohort6,605 AFCAPS total cohort
Total-C 200-240 mg/dLLDL-C 130 mg/dL
no DM or significant HTN*
3,805 OTC-eligible*no HDL-C criterion is imposed
2,800 excluded
AFCAPS/TexCAPSAFCAPS/TexCAPS OTC-Eligible Subgroup OTC-Eligible Subgroup
Post-Hoc AnalysisPost-Hoc Analysis
LOVASTATIN LOVASTATIN (n=1,884)(n=1,884) 3.0% 3.0%
PLACEBO PLACEBO (n=1,921)(n=1,921) 5.3% 5.3%
AFCAPS = OTC-Target AFCAPS = OTC-Target Population?Population?
Different lovastatin doseDifferent lovastatin dose AFCAPS/TexCAPS 20-40mgAFCAPS/TexCAPS 20-40mg 51.5% of the AFCAPS subgroup 51.5% of the AFCAPS subgroup
required treatment with 40 mg required treatment with 40 mg per day to achieve an LDL-C < per day to achieve an LDL-C < 110 mg/dL 110 mg/dL
OTC-Target population 10 mgOTC-Target population 10 mg
AFCAPS = OTC-Target AFCAPS = OTC-Target Population?Population?
Mean Change in LDL-C after 12 weeks
-30
-25
-20
-15
-10
-5
0
5
AFCAPS20 mgn=1325
P07510 mgn=96
AFCAPS = OTC-Target Population?AFCAPS = OTC-Target Population?AFCAPS Subgroup Event Rates by AFCAPS Subgroup Event Rates by
Baseline HDL-CBaseline HDL-C
AFCAPS = OTC-Target Population?AFCAPS = OTC-Target Population?
0
0.2
0.4
0.6
0.8
1Proportion of population with HDL > 40
AFCAPS P075 P076 P079 NHANES
3 months
AFCAPS = OTC-target populationAFCAPS = OTC-target populationAdherence to Drug?Adherence to Drug?
Clinical Cardiovascular BenefitClinical Cardiovascular BenefitConclusionsConclusions
AFCAPS not representative of OTC-AFCAPS not representative of OTC-target populationtarget population HDL-CHDL-C
Poor adherence to drug treatmentPoor adherence to drug treatment AFCAPS 5yr - 70% completersAFCAPS 5yr - 70% completers Actual use 3 mos - 40% completersActual use 3 mos - 40% completers
SafetySafety
Clinical TrialsClinical Trials
Safety of Lovastatin 10 mgSafety of Lovastatin 10 mgClinical TrialsClinical Trials
10 mg dose10 mg dose Comparable to placebo Comparable to placebo Incidence of myalgias < 2% in all studiesIncidence of myalgias < 2% in all studies No cases of rhabdomyolysis, No cases of rhabdomyolysis,
myoglobinuria, or hepatic toxicitymyoglobinuria, or hepatic toxicity Discontinuation of medication due to Discontinuation of medication due to
reported AEs higher in the actual-use reported AEs higher in the actual-use studies vs controlled, clinical trialsstudies vs controlled, clinical trials
Safety - Clinical Trials Safety - Clinical Trials 20-80 mg dose (AFCAPS and EXCEL)20-80 mg dose (AFCAPS and EXCEL)
consecutive 3x ULN liver enzyme elevationconsecutive 3x ULN liver enzyme elevation <1% 20-40 mg daily dose<1% 20-40 mg daily dose 1.5% 80 mg daily dose1.5% 80 mg daily dose
myopathy (symptoms and CPK > 10 ULN)myopathy (symptoms and CPK > 10 ULN) 0.1% 40 mg daily dose0.1% 40 mg daily dose 0.2% 80 mg daily dose0.2% 80 mg daily dose
one case of rhabdomyolysis for 20 mg doseone case of rhabdomyolysis for 20 mg dose
Limitations of Safety AssessmentsLimitations of Safety Assessments Clinical Trials Clinical Trials
exclusion of patients on interacting exclusion of patients on interacting drugsdrugs
exclusion of patients with co-exclusion of patients with co-morbid conditionsmorbid conditions
scheduled MD visits and scheduled MD visits and monitoringmonitoring
SafetySafety
Spontaneous ReportsSpontaneous Reports
Postmarketing Safety Postmarketing Safety ConcernsConcerns
Liver failureLiver failure
RhabdomyolysisRhabdomyolysis
- drug-drug interaction- drug-drug interaction
- drug-food interaction- drug-food interaction
Liver FailureLiver Failure
Case DefinitionCase Definition Unduplicated U.S. cases ofUnduplicated U.S. cases of
clinical diagnosis of liver failure clinical diagnosis of liver failure oror receipt of liver transplantreceipt of liver transplant
Time periodTime period From marketing 8/31/87 to 2/25/00From marketing 8/31/87 to 2/25/00
Background Rate vs. Reporting RateBackground Rate vs. Reporting Rate
Estimated background rate of Estimated background rate of
idiopathic liver failure is 1 per idiopathic liver failure is 1 per
million person-years million person-years Estimated four-year reporting rate Estimated four-year reporting rate
is 1.4 per million PYE for lovastatin-is 1.4 per million PYE for lovastatin-associated liver failure (1987-1990)associated liver failure (1987-1990)
RhabdomyolysisRhabdomyolysis
Case definitionCase definition Unduplicated U.S. cases Unduplicated U.S. cases
Clinical diagnosis of rhabdomyolysis Clinical diagnosis of rhabdomyolysis CPK > 10,000 IU/LCPK > 10,000 IU/L
Time periodTime period From marketing 8/31/87 to 4/4/00From marketing 8/31/87 to 4/4/00
Background rate for this AE unknownBackground rate for this AE unknown
191 Cases Rhabdomyolysis191 Cases RhabdomyolysisPercent of Cases Reported by DosePercent of Cases Reported by Dose
0
20
40
60
80
100
10m
g
20m
g
40m
g
60m
g
80m
g
100
mg
Unknow
n
Dispensed Prescriptions for Lovastatin in Dispensed Prescriptions for Lovastatin in U.S. 1999 (Total Rx = 3,177,000)U.S. 1999 (Total Rx = 3,177,000)
Rxs
4%
72%
24%
Source: IMS HEALTH National Prescription Audit TM
0
500000
1000000
1500000
2000000
2500000
10mg 20mg 40mg
4%
72%
24%
RhabdomyolysisRhabdomyolysisDrug-Drug InteractionsDrug-Drug Interactions
RhabdoCasesn=191
Lovastatin-fibrate interactionLovastatin-non fibrate drugs interactionLovastatin-GF juice interactionLovastatin Alone
7640174
Total No. Cases Involving DrugInteractions
116 (61%)
Reported Drug-Drug Reported Drug-Drug Interactions With LovastatinInteractions With Lovastatin
Erythromycin†Erythromycin† Clarithromycin†Clarithromycin† Nefazodone†Nefazodone† Danazol†Danazol† Cyclosporine†Cyclosporine†
††Metabolized through the CYP3A4 isoenzymeMetabolized through the CYP3A4 isoenzyme
Itraconazole†Itraconazole† Ketoconazole†Ketoconazole† Mibefradil†Mibefradil†
(‘98 withdrawal)(‘98 withdrawal) GemfibrozilGemfibrozil NiacinNiacin
Reported Drug-Food InteractionReported Drug-Food InteractionGrapefruit JuiceGrapefruit Juice
One case reportOne case report lovastatin 80 mg and gemfibrozil 1200 lovastatin 80 mg and gemfibrozil 1200
mg > 5 yearsmg > 5 years baseline renal impairmentbaseline renal impairment onset 2 wks after initiating grapefruit onset 2 wks after initiating grapefruit
juicejuice
RhabdomyolysisRhabdomyolysisConclusionsConclusions
Most reported cases associated with Most reported cases associated with
drug-drug interactions drug-drug interactions
Many interactions are due to Many interactions are due to
competition for CYP3A4 metabolic competition for CYP3A4 metabolic
pathwaypathway
Product Label - Interacting DrugsProduct Label - Interacting Drugs Do not use product if also on:Do not use product if also on:
erythromycin or clarithromycinerythromycin or clarithromycin ketoconazole or itraconazoleketoconazole or itraconazole nefazodonenefazodone cyclosporinecyclosporine protease inhibitorsprotease inhibitors niacin or gemfibrozilniacin or gemfibrozil Rx statin drugs (simvastatin,pravastatin, Rx statin drugs (simvastatin,pravastatin,
fluvastatin, atorvastatin, cerivastatin, lovastatin)fluvastatin, atorvastatin, cerivastatin, lovastatin) List not complete and likely to increaseList not complete and likely to increase Challenging to consumersChallenging to consumers
Drugs Withdrawn from U.S. Drugs Withdrawn from U.S. Market Due to CYP3A4Market Due to CYP3A4
Seldane (terfenadine) -1997 Seldane (terfenadine) -1997 Posicor (mibefradil) -1998Posicor (mibefradil) -1998 Hismanal (astemizole) -1999Hismanal (astemizole) -1999 Propulsid (cisapride) - 2000Propulsid (cisapride) - 2000
CYP3A4 Drug WithdrawalsCYP3A4 Drug Withdrawals
Withdrawn despiteWithdrawn despite Changes to the label Changes to the label
warnings warnings Dear Healthcare Dear Healthcare
Professional lettersProfessional letters Black box warningsBlack box warnings
Safety of OTC LovastatinSafety of OTC LovastatinConclusionsConclusions
Dependent upon:Dependent upon: Consumer comprehension of labelConsumer comprehension of label Use of product according to label instructionsUse of product according to label instructions
No self-titration to higher dosesNo self-titration to higher doses No use by individuals at risk for drug-related No use by individuals at risk for drug-related
toxicity in unrestricted OTC settingtoxicity in unrestricted OTC setting–drug-drug interactionsdrug-drug interactions–drug-food interactionsdrug-food interactions–co-morbid medical conditionsco-morbid medical conditions
Summary of Issues AddressedSummary of Issues Addressed LDL-C reductionLDL-C reduction
lowers LDL-C but effectiveness in OTC-lowers LDL-C but effectiveness in OTC-population diminished by poor drug adherencepopulation diminished by poor drug adherence
Clinical Cardiovascular BenefitClinical Cardiovascular Benefit no established benefit of drug treatment in no established benefit of drug treatment in
OTC-Target populationOTC-Target population any benefit offset by poor drug adherenceany benefit offset by poor drug adherence
SafetySafety drug-drug/drug-food interactionsdrug-drug/drug-food interactions unrestricted/unsupervised OTC environmentunrestricted/unsupervised OTC environment
ConclusionConclusion
What is the balance of benefit versus What is the balance of benefit versus risk of nonprescription lovastatin?risk of nonprescription lovastatin?