# Presentation: 683191

## One Year Post Exclusivity Adverse Event Review:Fosinopril Pediatric Subcommittee of the Anti-infective Drugs Advisory Committee Meeting June 9, 2004

**Lawrence** **Grylack, MD****Medical Officer**
**Division of Pediatric Drug Development****Center for Drug Evaluation and Research **
**Food and Drug Administration**

## Background Drug Information

**Moiety: **Monopril® (fosinopril)
**Therapeutic Category: **Anti-hypertensive; ACE inhibitor
**Sponsor: **Bristol-Myers Squibb
**Indications:**
**Adults**
- Treatment of hypertension, used alone or in combination with thiazide diuretics. Management of heart failure as adjunctive therapy
**Pediatrics**
- There are NO approved pediatric indications
**Original Market Approval**:* *May 16, 1991
**Pediatric Exclusivity Granted: **January 27, 2003

## Drug Use Trends in Outpatient Settings:Fosinopril

- Prescriptions dispensed Mar 2001 – Feb 20041
- Renin angiotensin antagonist class of drugs: 20% increase from 164 million to 197 million.
- Fosinopril: 25% decrease from 6.8 million to 5.1 million.
- Fosinopril/Hydrochlorothiazide (HCTZ): 33% increase from 377,000 to 503,000.
- Less than 0.1% of prescription claims for fosinopril and fosinopril/HCTZ were for pediatrics (aged 1-16).2
- Overall, there were an estimated 5,100 pediatric prescriptions for fosinopril and 500 for fosinopril/HCTZ during the one year post exclusivity period.1,2*

- 1IMS Health, National Prescription Audit *Plus*TM, On-line, Source Year  Mar 2001 – Feb 2004, Data Extracted Mar 2004
- 2AdvancePCSTM, Dimension Rx, On-line, Mar 2001 to Feb 2004
- *Calculation based on application of proportions of pediatric fosinopril prescriptions in AdvancePCS  to IMS Health, National Prescription Audit *Plus* to  estimate number of fosinopril prescriptions dispensed nationwide to pediatric population

## Drug Use Trends in Inpatient Settings:Fosinopril

- CHCATM data demonstrated that from Oct  2001 to Sep 2003, 30 of 548,279 pediatric discharges were associated with fosinopril.1
- Actual discharge data from Premier’sTM inpatient database consisting of approximately 450 hospitals revealed pediatric use of fosinopril was associated  with less than 0.2% of discharges (164 of 102,000) between 1/01 -9/03.2

- 1Child Health Corporation of AmericaTM:  Pediatric Health Information System (PHIS), Oct 2001 - Sep 2003
- 2Premier PerspectiveTM, 1st Quarter 2001 -  3rd Quarter 2003

## Adverse Event Reports: Fosinopril01/27/03 - 02/27/04 

- Total number of reports, all ages:
- 191 reports (138 U.S.)
- Pediatric reports:
- No pediatric reports were submitted during this time period.

## Fosinopril

- Two studies done for exclusivity.
- Single-dose PK using oral solution of 0.3 mg/kg in 43 patients between one month and 16 years. An age-dependent increase in bioavailability was shown.
- An efficacy and safety dose-ranging trial was done in 253 patients between six and 16 years, using tablets. A dose-response relationship was not demonstrated.  No deaths or cases of angioedema were reported .

## Fosinopril

- PK parameters, efficacy and safety information for pediatric patients 6 – 16 years
- PK parameters similar to adults
- No dose response seen
- Adverse event profile similar to adults
- Dosing information is available for pediatric patients greater than 50kg
- The fosinopril formulations for children less than 50 kg  used in the exclusivity studies are not commercially available.

## Need for Age-Appropriate Formulations

- Many adult dosage forms such as tablets and capsules are inappropriate for infants and preschool children
- As part of their studies for pediatric exclusivity, all sponsors are encouraged to develop age-appropriate commercially marketable pediatric formulations

## Need for Age-Appropriate Formulations: Goal

- Commercially available (strongly preferred)
- Pharmacy compounded recipe in the label