1. 1 One Year Post Exclusivity Adverse Event Review: Fexofenadine Pediatric Subcommittee of the Anti-infective Drugs Advisory Committee Meeting June 9, 2004 Jane Filie, MD Medical Officer Division of Pediatric Drug Development Center for Drug Evaluation and Research Food and Drug Administration

2. 2 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

3. 3 Clinical Studies for Exclusivity A total of 415 children ≥ 6months and < 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 <6 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.

4. 4 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 drug’s effect are similar in children and in adult patients. The studies conducted on children ≥ 6 months and <2 years of age, and 2 years to < 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 < 6 years of age.

5. 5 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 1 IMS Health, National Prescription Audit Plus , Jan 2000 – Dec 2003, Data Extracted Apr 2004 2 IMS Health, National Disease and Therapeutic Index , CD-Rom, 6 Year Jan 2000 – Dec 2003, Data Extracted Apr 2004 3 AdvancePCS  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.

6. 6 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 <1%: Insomnia Nervousness Sleep disorders Rare rash Urticaria Pruritus Hypersensitivity reactions

7. 7 Adverse Event Reports: Fexofenadine 1/27/03 – 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

8. 8 Unlabeled Pediatric Adverse Events: Fexofenadine 1/27/03 – 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

9. 9 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.

10. 10 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.

11. 11 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.

12. 12 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.

13. 13 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.

14. 14 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.