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Update to Post Exclusivity Pediatric Adverse
Event ReviewSimvastatin Pediatric Advisory
Committee Meeting November 16, 2006
Jean Temeck, MD, Acting Medical Team
Leader Pediatric and Maternal Health Staff Office
of New Drugs Center 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 (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 Sjogrens
  syndrome) and concomitant medications

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Simvastatin In Utero Exposures (n3,
?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 2004350(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

• OSE
• Jennie Chang
• Laura Governale
• David Moeny
• Jo Wyeth
• Rosemary Johann-Liang
• PMHS
• Lisa Mathis
• Kristin Phucas

• DMEP
• Eric Colman
• Eileen Craig