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

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

• Moiety Allegra (fexofenadine hydrochloride)
• Therapeutic Category Anti-histamine
• Sponsor Aventis Pharmaceuticals Inc.
• Indications
• Seasonal allergic rhinitis dosage for adults and
  children 12 years of age 60 mg twice daily, or
  180 mg once daily
• children 6-11 years of age 30 mg twice daily
• Chronic idiopathic urticaria dosage for adults
  and children 12 years of age 60 mg twice daily
  
• children 6-11 years of age 30 mg twice daily
• Original Market Approval July 25, 1996
• Pediatric Exclusivity Granted January 27, 2003

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Clinical Studies for Exclusivity

• A total of 415 children 6months and lt 6 years
  of age with allergic rhinitis were given
  fexofenadine in three pivotal studies.
• Phase 1 PK study characterizing the dose for
  children 6 months to 2 years of age.
• Phase 3 study assessing safety and tolerability
  in two groups
• 6 months to 2 years of age and 10.5kg
• 6 months to 2 years of age and 10.5 kg
• A previous safety and tolerability study on
  children 2 to lt6 years of age was also
  submitted.
• Adverse events for fexofenadine occurred at
  similar frequencies as placebo and there was no
  evidence of a new safety signal.

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Clinical Studies for Exclusivity

• Efficacy was extrapolated from adult data as the
  disease course and pathophysiology of allergic
  rhinitis and chronic idiopathic urticaria as well
  as the drugs effect are similar in children and
  in adult patients.
• The studies conducted on children 6 months and
  lt2 years of age, and 2 years to lt 6 years of age
  utilized fexofenadine powder mixed with
  applesauce or rice cereal. There is no marketable
  age appropriate formulation for children 6
  months to lt 6 years of age.

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Drug Use Trends in Outpatient Settings
Fexofenadine

• Fexofenadine is the leading prescription
  non-sedating anti-histamine in the market since
  loratadine became OTC in 2002.1
• The total number of fexofenadine products
  dispensed increased from approximately 20.8
  million in 2000 to 29.6 million in 2003.1
• Pediatric patients (age 1 16 years) accounted
  for approximately 8.3 of total U.S.
  prescriptions of fexofenadine dispensed in 2003
  (2.5 million).1, 3
• The most common diagnoses associated with use in
  pediatric patients (age 0-16 yrs) in 2003 were
  allergic rhinitis (approx 37) and allergic
  disorder (approx 11).2
• 1IMS Health, National Prescription Audit Plus?,
  Jan 2000 Dec 2003, Data Extracted Apr 2004
• 2IMS Health, National Disease and Therapeutic
  Index?, CD-Rom, 6 Year Jan 2000 Dec 2003 ,
  Data Extracted Apr 2004
• 3AdvancePCS? Dimension Rx, Data Extracted Apr
  2004
• Calculation based on application of
  proportions of pediatric fexofenadine
  prescriptions in AdvancePCS? to IMS Health,
  National Prescription Audit Plus? to estimate
  number of fexofenadine prescriptions dispensed
  nationwide to pediatric population.

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Adverse Events From Pediatric Clinical Trials
Included in the Label

• Greater than 2
• Headache
• Accidental injury
• Coughing
• Fever
• Pain
• Otitis media
• Upper resp. infection

• Less than lt1
• Insomnia
• Nervousness
• Sleep disorders
• Rare rash
• Urticaria
• Pruritus
• Hypersensitivity reactions

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Adverse Event Reports Fexofenadine1/27/03
2/27/04

• Total number of reports, all ages
• 158 reports (84 U.S.)
• Pediatric reports
• 8 unduplicated reports including 2 with serious
  outcomes
• one hospitalization
• one life threatening
• No pediatric deaths

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Unlabeled Pediatric Adverse Events
Fexofenadine1/27/03 2/27/04

• Psychosis exacerbation, suicidal ideation,
  depression
• Seizure
• Visual disturbances
• Abnormal liver function
• Urinary tract infection/fungal
• Non-accidental overdose of multiple drugs and
  prolonged QT
• Prematurity
• Maternal exposure
• Medication error

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Individual Pediatric Adverse Event Reports

• A 15 year old with schizoaffective disorder and
  attention deficit disorder experienced life
  threatening exacerbation of psychosis, suicidal
  ideation, and depression. Patient also on
  Geodon, Effexor, Concerta. Symptoms resolved in
  4-5 days after discontinuation of fexofenadine.

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Individual Pediatric Adverse Event Reports (cont.)

• Seizure in a 13 year old on concomitant
  medications including sertraline, olanzapine,
  minocycline and bupropion (has warning about the
  potential to cause seizures) .
• A 7 year old patient reported seeing black dots,
  white foam, and bubbles, and loss of color
  vision after one day on fexofenadine. Symptoms
  improved 3 days after discontinuation of drug.

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Individual Pediatric Adverse Event Reports
(cont.)

• A 10 year old patient developed a bacterial
  urinary tract infection and abnormal liver
  function tests after receiving fexofenadine for 1
  week. The child had received another drug that is
  labeled for hepatic function impairment before
  the event. The child recovered after
  fexofenadine was discontinued.
• A 16 year old patient developed a fungal urinary
  tract infection and pyelonephritis. The patient
  was taking multiple medications for depression
  and gastritis. The patient was hospitalized.

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Individual Pediatric Adverse Event Reports
(cont.)

• A 13 year old attempted suicide with intentional
  overdose of fexofenadine acetaminophen,
  metoclopramide, and tramadol. QT prolongation
  to 441 msec was observed but normalized the
  following day.

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Individual Pediatric Adverse Event Reports (cont.)

• Baby born preterm at 27 weeks of gestation, small
  for gestational age with abnormal
  alpha-1-fetoprotein born by cesarean section to a
  mother with pre-eclampsia. Mother also on
  concomitant medications during pregnancy (allergy
  shots, vitamins, Augmentin).
• Refill of prescription for Allegra-D filled with
  Zyrtec-D. No adverse event reported.

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Closing Observations Fexofenadine

• There were few pediatric adverse event reports
  during the one-year post pediatric exclusivity
  period.
• FDA will continue its routine monitoring of
  adverse event reports in all populations.