1 One Year Post Exclusivity Adverse Event Review: Benazepril Pediatric Advisory Committee Meeting February 14, 2005 Lawrence Grylack, MD Medical Officer.

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1 One Year Post Exclusivity Adverse Event Review: Benazepril Pediatric Advisory Committee Meeting February 14, 2005 Lawrence Grylack, MD Medical Officer Division of Pediatric Drug Development Center for Drug Evaluation and Research Food and Drug Administration

2 Background Drug Information Drugs: Lotensin ® (benazepril HCL); Lotensin HCT ® (benazepril hydrochlorothiazide); Lotrel ® (benazepril/amlodipine) Therapeutic Category: anti-hypertensive (ACE inhibitor) Sponsor: Novartis Adult & Pediatric Indication: Treatment of hypertension, age ≥6 years Original Market Approval: June 25, 1991 (Lotensin ® ); May 19, 1992 (Lotensin HCT ® ); March 3, 1995 (Lotrel ® ) Pediatric Exclusivity Granted: July 2, 2003

3 Drug Use Trends in Outpatient Settings: Benazepril Decrease in prescriptions dispensed for single ingredient benazepril products from 8.8 million (8/01-7/02) to 7.2 million (8/03-7/04) for all ages 1 Less than 0.1% of benazepril and combination products prescribed for ages 1-16 years 2 Based on IMS Health, NDTI™, no pediatric use for benazepril or benazepril/hydrochlorothiazide (HCTZ) reported during past three years 3 Estimated 5,000 mentions of benazepril/amlodipine in y.o. group for Dx of “essential hypertension unspecified” during 8/03-7/ IMS Health, National Prescription Audit Plus , On-Line, Aug 2001 – Jul 2004, Data Extracted Sep Caremark Dimension Rx TM On-Line, Aug 2001 – Jul 2004, Data Extracted Sep IMS Health, National Disease and Therapeutic Index , CD-Rom, Aug Jul 2004, Data Extracted Sep 2004

4 Pediatric Exclusivity Studies: Benazepril Pharmacokinetics (PK) Efficacy and Safety - Forced Dose Titration - Randomized Withdrawal - Open Label

5 Pediatric Exclusivity Studies: PK (3 studies) Study 1: Bioavailability of extemporaneously compounded suspension compared to tablet in 30 healthy adults Bioequivalence demonstrated Study 2: PK of benazepril and benazeprilat studied after a single dose in 30 healthy children, aged 0.7 to 16.9 years Mean clearance (CL) values for benazepril in children were larger than in adults. Mean CL of benazeprilat in school age children was twice that of healthy adults, and mean CL in adolescents was 27% greater than in healthy adults.

6 Pediatric Exclusivity Studies: PK (3 studies) (cont.) Study 3: Open label, steady state PK study in 57 pediatric patients, aged 1 month to 16 years, given multiple daily doses for 5 days Mean CL of benazepril was higher in study patients compared to healthy children and adults. Mean CL of benazeprilat in children 6-12 years old was more than twice that of healthy adults; in adolescents, it was 27% higher than that of healthy adults. Terminal elimination half-life of benazeprilat in pediatric patients (6-16 years) was one-third that observed in adults.

7 Pediatric Exclusivity Studies: Efficacy and Safety 107 hypertensive patients, 7-16 years of age, were studied in forced dose titration phase for 4 weeks. Hypertension defined as mean systolic blood pressure (SBP) or mean diastolic blood pressure (DBP) > 95 th % for height, age, gender, off antihypertensive medications Doses ranged from mg/kg, maximum total dose 40 mg, in tablet form

8 Pediatric Exclusivity Studies: Efficacy and Safety (cont.) 85 patients who responded to therapy during the forced titration phase enrolled in a 2-week randomized, double- blind, withdrawal, placebo-controlled study. Primary efficacy endpoint: change from baseline trough SBP during drug withdrawal phase –Increases in mean changes of SBP and DBP in placebo group were greater than changes in all three benazepril dose groups (low, medium and high). –SBP and DBP in placebo group increased by 4 to 6 mm Hg more than in drug groups. –No dose-response observed

9 Pediatric Exclusivity Studies: Efficacy and Safety (cont.) 70 patients were enrolled in 26 week open- label extended phase with 64 completions. This study phase provided additional safety data.

10 Pediatric Exclusivity Studies: Safety (n=107) No deaths Serious Adverse Events (SAEs) (n=9) Renal failure and transplant rejection, urinary tract infections, increased creatinine with history of kidney transplant, hypertensive crisis, bowel obstruction, severe sleep apnea, severe depression Discontinuations due to AEs (n=9) Angioedema, abnormal liver function, abnormal blood creatinine, kidney transplant rejections, aggravated cough, rash, hypertensive crisis, hyperactivity/insomnia

11 Labeling Changes Resulting from Exclusivity Studies Clearance of benazeprilat (active metabolite) in y.o. twice that of healthy adults; clearance in y.o. is 27% higher than healthy adults No dose response observed among drug-treated patients Recommended starting daily dose 0.2 mg/kg; daily dose of >0.6 mg/kg not studied Treatment not recommended in pediatric patients <6 years or with glomerular filtration rate <30 mL/min

12 Labeling Changes Resulting from Exclusivity Studies (cont.) Pediatric AEs similar to adults Long-term effects of drug on growth and development have not been studied. Instructions for preparation of suspension available in label

13 Adverse Event Reports since Market Approval: Benazepril Monotherapy 06/25/ /02/04 Total number of reports, all ages †* : –1,842 reports (1,366 US) 973 serious (686 US) –97 deaths (30 US) Pediatric reports * : –5 reports (2 US) All serious –No deaths † Includes reports with unknown age * Counts may include duplicate reports

14 Most Common Adverse Events since Market Approval Pediatric * : anorexia, asthenia, gastroenteritis, hyperchloremia, hypoaldosteronism, metabolic acidosis, nausea, somnolence, vomiting Adult : angioneurotic edema, cough, lingual edema, facial edema, dizziness, dyspnea, headache, asthenia, hyperkalemia Underlined events = Unlabeled events *All underlined events on this slide are from one case

15 Adverse Event Reports during the One-Year Post-Exclusivity Period: Benazepril Monotherapy 07/02/ /02/04 Total number of reports, all ages †* : –111 reports (65 US) 97 serious (51 US) - 19 deaths (5 US) Pediatric reports * : –3 reports (1 US) All serious –No deaths † Includes reports with unknown age * Counts may include duplicate reports

16 Pediatric Adverse Events: Unduplicated Pediatric Reports (n=2) 1.Four y.o. male with hypertension due to nephrotic syndrome; hyperchloremic metabolic acidosis secondary to hypoaldosteronism found after 4 months of benazepril 0.3 mg/kg/d; improvement after reduction in dose to 0.2 mg/kg and complete recovery after drug discontinued 2.Two y.o male with resolving viral infection; possible accidental ingestion of benazepril, rosiglitazone and carisoprodol (doses of medications unknown), with choking, cough, crying followed by sleep; outcome unknown

17 Summary: Benazepril No pattern discernible in pediatric AEs for benazepril monotherapy No AEs found for combination products during exclusivity period This completes the one-year post-exclusivity AE monitoring as mandated by BPCA. FDA recommends routine monitoring of AEs for this drug in all populations. Does the Advisory Committee concur?

18 Acknowledgements ODS Mark Avigan Gerald Dal Pan Laura Governale Daniela Sanders Judy Staffa DCRDP Abraham Karkowsky Salma Lemtouni Elena Mishina Alisea Sermon ORP Roy Castle, Jr.