1. 1 Update to Post Exclusivity Pediatric Adverse Event Review: Atorvastatin 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

2. 2 Background Drug Information Drug: Lipitor ® (atorvastatin) Therapeutic Category: lipid-lowering agent Sponsor: Pfizer Original Market Approval: December 17, 1996 Pediatric Exclusivity Granted: February 22, 2002 Mechanism of action: inhibitor of HMG-CoA reductase

3. 3 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 20 mg daily

4. 4 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: 10-80 mg daily

5. 5 Atorvastatin: Pediatric Labeling Changes Patient Package Insert approved May, 2004; updated June, 2006 –Indicated for children over 10 years whose cholesterol does not come down enough with exercise and low fat diet alone –Keep out of reach of children

6. 6 Atorvastatin: Pediatric Drug Use Trends 1 Pediatric use is small (< 0.1% of total number of prescriptions dispensed in retail pharmacies) # of pediatric prescriptions dispensed by year: –in 2002: 36,668 prescriptions –in 2003: 36,894 –in 2004: 37,101 –in 2005: 32,381 1 Verispan, Vector One ® : National (VONA), data extracted Aug 2006

7. 7 Atorvastatin: Pediatric Adverse Events None during the one year post exclusivity (2/22/02-3/22/03) 12 (0.15% of total reports for all ages) during the subsequent three year period (3/22/03-8/22/06) –All serious, including one death –9 post-natal reports in children 2-16 years (3 accidental ingestions; 6 other reports) –3 in utero exposures (included 1 stillbirth); pregnancy category X

8. 8 Atorvastatin: Pediatric Other Post-Natal Adverse Events 6 other reports in patients aged 4-16 years –iron-deficiency anemia (16 year old female; anemia labeled) –pancreatitis (labeled) –muscle stiffness, chest pain and elevated CPK level (labeled) –bone marrow suppression (no details provided; unlabeled) –bronchospasm (positive rechallenge; unlabeled) –hemoptysis (diffuse pulmonary alveolar hemorrhage; unlabeled)

9. 9 Bronchospasm Case Report Foreign report 4 year old male Diagnosis: myocardial ischemia Medications: –simvastatin since 3/04; duration unknown –atorvastatin since 4/04; duration unknown –clopidogrel and aspirin Bronchospasm (reversible): noted 3/04; positive rechallenge x3 (no details provided); intervention not reported but resolved 5/04

10. 10 Hemoptysis Case Report Foreign report 16 year old male Diagnosis: familial hypercholesterolemia Medications: –atorvastatin: 6/04-1/05 –nicotinic acid: 6/04-12/04 Hemoptysis 12/04; bronchoscopy: diffuse pulmonary alveolar hemorrhage; echocardiogram: cardiomegaly; diagnosed with moderate heart failure

11. 11 Atorvastatin: Pediatric Other Post-Natal Adverse Events Above adverse events that are unlabeled are confounded by underlying illness, concomitant medications and/or insufficient information.

12. 12 Atorvastatin: In Utero Exposures Congenital blindness; atorvastatin during first 8 weeks of pregnancy. Congenital hepatomegaly, single functional kidney and stillbirth at 33 weeks gestational age; maternal diabetes mellitus; insulin, gliclazide, metformin and atorvastatin: unknown start date but last 3 drugs discontinued 2.5 months prior to delivery. “Born with myopathy”; paternal exposure to atorvastatin 2-3 months prior to conception.

13. 13 Summary: Atorvastatin Pediatric unlabeled post-natal adverse events: no new safety signal identified: few reports, single cases, confounded or insufficient information In utero exposures: Pregnancy category X The FDA recommends routine monitoring of atorvastatin for AEs in all populations Does the Advisory Committee concur?

14. 14 Acknowledgements OSE Jennie Chang David Moeny Jo Wyeth Rosemary Johann-Liang PMHS Lisa Mathis Kristin Phucas DMEP Eric Colman Eileen Craig