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

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One Year Post Exclusivity Adverse Event
ReviewFosinopril Pediatric Subcommittee of
the Anti-infective Drugs Advisory Committee
Meeting June 9, 2004
Lawrence Grylack, MDMedical Officer Division of
Pediatric Drug DevelopmentCenter for Drug
Evaluation and Research Food and Drug
Administration
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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

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Drug Use Trends in Outpatient SettingsFosinopril

• 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,
On-line, Source Year Mar 2001 Feb 2004, Data
Extracted Mar 2004 2AdvancePCS, 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
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Drug Use Trends in Inpatient SettingsFosinopril

• CHCA data demonstrated that from Oct 2001 to
  Sep 2003, 30 of 548,279 pediatric discharges were
  associated with fosinopril.1
• Actual discharge data from Premiers 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 Perspective, 1st
Quarter 2001 - 3rd Quarter 2003
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Adverse Event Reports Fosinopril01/27/03 -
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.

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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 .

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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.

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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

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Need for Age-Appropriate Formulations Goal

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