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Update to Post Exclusivity Pediatric Adverse Event Review:

Simvastatin

Pediatric Advisory Committee Meeting November 16, 2006

Jean Temeck, MD, Acting Medical Team LeaderPediatric and Maternal Health StaffOffice of New DrugsCenter for Drug Evaluation and Research Food and Drug Administration

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Background Drug Information

• Drug: Zocor® (simvastatin)

• Therapeutic Category: lipid-lowering agent

• Sponsor: Merck & Co., Inc.

• Original Market Approval: December 23, 1991

• Pediatric Exclusivity Granted: February 22, 2002

• Mechanism of action: inhibitor of HMG-CoA reductase

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Background Drug Information

• Pediatric Indication: adjunct to diet to reduce total-C, LDL-C, and Apo B levels in boys and post-menarchal girls, 10 to 17 years of age with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present– LDL-C remains >190 mg/dl or– LDL-C remains >160 mg/dl and there is a positive family

history of premature CVD or >2 CVD risk factors are present

• Pediatric Dosage:– initial dose 10 mg daily with maximum 40 mg daily

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Background Drug Information

• Pediatric Indication: to reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.

• Dosage: 40-80 mg daily

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Simvastatin: Pediatric Drug Use Trends1

• Pediatric use is small (<0.1% of total number of prescriptions dispensed in retail pharmacies)

• # of pediatric prescriptions dispensed by year:– in 2002: 13,498 prescriptions– in 2003: 12,397– in 2004: 11,427– in 2005: 10,466

1Verispan, Vector One®: National (VONA), data extracted Sep 2006

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Simvastatin: Pediatric Adverse Events

• 4 reports during the one year post exclusivity (2/22/02-3/22/03)– All serious, including one death– 2 post-natal (↑LDH: also on ibuprofen; ↑CPK and

neuroleptic malignant syndrome: also on zuclopenthixol)– 2 in utero exposures (fetal distress but healthy newborn;

pre-term birth (32 weeks), severe hypotrophy, IUGR, post-natal death (day 3 of “prematurity”), multiple maternal concomitant medications)

– Conclusion: reports confounded by concomitant medications and/or underlying illness

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Simvastatin: Pediatric Adverse Events

• 6 (0.13% of total reports for all ages) during the subsequent three year period (3/22/03-8/22/06)– All serious, including one death– 3 post-natal reports in children 6-14 years – 3 (?4) in utero exposures (included 1

spontaneous miscarriage); pregnancy category X

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Simvastatin: Pediatric Post-Natal Adverse Events (3/22/03-8/22/06)

• 3 reports in patients aged 6-14 years– 2 reports: ↑CPK; one also with muscle stiffness

and chest pain ; both with concomitant medications (one with cyclosporine) (labeled)

– 1 Thrombotic thrombocytopenic purpura (TTP) (unlabeled): confounded by underlying disease (systemic lupus erythematosis and Sjogren’s syndrome) and concomitant medications

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Simvastatin: In Utero Exposures (n=3, ?4)

(3/22/03-8/22/06)

– Spontaneous miscarriage; simvastatin during first 2 weeks of pregnancy

– Skin outgrowth fifth finger of left hand with anlage of a fingernail; simvastatin weeks 2-4 and salbutamol month 7 of pregnancy

– Lower limb deformity; 1st trimester exposure; multiple concomitant medications (aspirin, acteaminophen, codeine and propoxyphene)

– VACTERL association; first trimester exposure; concomitant medication (promegestone) a

a= Edison RJ and Muenke M. New England Journal of Medicine 2004;350(15):1579-1582 .

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Summary: Simvastatin• One pediatric unlabeled post-natal adverse

event, TTP, confounded by underlying illness and concomitant medications

• In utero exposures: Pregnancy category X

• The FDA recommends routine monitoring of simvastatin for AEs in all populations

• Does the Advisory Committee concur?

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Acknowledgements

OSEJennie ChangLaura GovernaleDavid MoenyJo WyethRosemary Johann-Liang

PMHSLisa MathisKristin Phucas

DMEPEric ColmanEileen Craig