# Presentation: 350667

## 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**

## 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

## 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

## 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

## 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

## Atorvastatin: 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:  36,668 prescriptions
- in 2003:  36,894
- in 2004:  37,101
- in 2005:  32,381
- 1Verispan, Vector One®: National (VONA), data extracted Aug 2006

## 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

## 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)

## 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

## 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

## Atorvastatin: Pediatric Other Post-Natal Adverse Events

- Above adverse events that are unlabeled are confounded by underlying illness, concomitant medications and/or insufficient information.

## 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.

## 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?

## Acknowledgements

- _OSE_
- Jennie Chang
- David Moeny
- Jo Wyeth
- Rosemary Johann-Liang
- _PMHS_
- Lisa Mathis
- Kristin Phucas

- _DMEP_
- Eric Colman
- Eileen Craig