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?