One Year Post-Exclusivity Adverse Event Review: Ritonavir Pediatric Advisory Committee Meeting November 16, 2006

1. One Year Post-Exclusivity Adverse Event Review:RitonavirPediatric Advisory Committee Meeting November 16, 2006 Alan M. Shapiro, MD, PhD, FAAP Medical Officer Pediatric and Maternal Health Staff Office of New Drugs Center for Drug Evaluation and Research Food and Drug Administration

2. Background Drug Information • Drug: Norvir® (Ritonavir) • Therapeutic Category: HIV protease inhibitor • Sponsor: Abbott Laboratories • Indication: Treatment of HIV-infection in combination with other antiretroviral agents patients ≥ 2 years of age (prior to exclusivity) • Original Market Approval: March 1, 1996 • Pediatric Exclusivity Granted: June 14, 2005

3. Boosting Regimens • Resistance has been reported with all protease inhibitors (PIs) when used as monotherapy, and can develop rapidly even with combination therapy in which drug levels are subtherapeutic1 • inadequate dosing, poor drug absorption, rapid drug clearance and inadequate adherence • Ritonavir is mainly used now to increase the serum concentrations and decrease the dosage frequency of other PIs2 1 Excerpted from Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection; National Resource Center (NRC), HRSA, NIH November 3, 2005 2 Treatment Guidelines: Drugs for HIV Infection TheMedical Letter 4(50) October 2006

4. Boosting Regimens (cont.) • “Boosted” therapeutic regimens consisting of two PIs (e.g., low dose ritonavir plus saquinavir or lopinavir/ritonavir (LPV/RTV, Kaletra™) and combined with one or two Nucleoside Reverse Transcriptase Inhibitors (NRTIs) 1 • With the exception of LPV/RTV • limited data on safety and dosing of combination PI regimens in children1 1 Excerpted from Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection; National Resource Center (NRC), HRSA, NIH November 3, 2005

5. Ritonavir Pediatric Exclusivity Trials • Phase I/II, dose-finding, open-label study [pivotal] of two different doses of ritonavir used alone and in combination with lamivudine (3TC) and zidovudine (ZDV) in HIV-1 infected infants and children (n=50) • Safety and tolerance • Pharmacokinetics • Activity of ritonavir • Phase I/II, open-label, management study in HIV patients 6 months to 21 years of age with rapidly progressive/advanced disease failing current therapy (n=164 )

6. Exclusivity Trials Results • No statistically significant differences were noted in this small non-randomized study between the 350mg/ m2 and the 450mg/m2 twice daily doses during the first 104 weeks of follow-up with respect to HIV-1 RNA levels, CD4 cell count or CD4 percentage • Overall, the toxicity profile of ritonavir seen during the clinical trial appeared similar to that observed in adults • Ritonavir was a part of combination antiretroviral therapy • Therefore difficult to determine the exact contribution of ritonavir to any clinical or laboratory toxicities • Many of the approved antiretroviral drugs have overlapping toxicities

7. Labeling Changes Resulting from Exclusivity Studies: Ritonavir • Indication: extended age range from 2 years down to 1 month • Safety: AE profile in the pediatric population was similar to that for adults • PK / Dosing: Information was added for pediatric patients less than 2 years of age

8. Adverse Event Reports since Market Approval (March 1996): Ritonavir *may include duplicates and unknown ages

9. Adverse Event Reports 13 Month Post Exclusivity Period: Ritonavir * may include duplicates and unknown ages ** 3 unduplicated pediatric deaths

10. Adverse Events by Types of Ritonavir Exposure • Direct: Treatment of HIV-infected pediatric patients • Used in combination with other anti-retroviral agents for HIV treatment, so difficult to assign causality to reported adverse events • Indirect: Used during pregnancy by HIV+ mothers for maternal health and prevention of perinatal HIV • Exposed infants may or may not be HIV infected • Possible association of combination antiretroviral (ARV) therapy and premature delivery • Newborns receive ARV therapy postpartum, which may complicate interpretation of adverse events associated with in utero exposure

11. AEs from Direct Exposure during the One-Year Post-Exclusivity Period (n=33)** • Deaths (n=3) • Hepatic Events (n=7) • Drug Interaction with fluticasone propionate: • Cushing Syndrome (n=5) • Pancreatitis (n=2) • Gastrointestinal (GI) symptoms (n=2) • Drug Ineffective (n=3) • Skin reactions (n=3) • Miscellaneous (n=8) • anemia, Pseudomonas aeruginosa sepsis, epistaxis, arthropathy, convulsion associated with pyrexia, alopecia, nystagmus with photophobia and strabismus and spontaneous abortion Underlined events = Unlabeled events ** 4 reports due to use of lopinavir /ritonavir

12. Pediatric Deaths- Direct Exposure during the One-Year Post-Exclusivity Period (n=3) • 16-year old HIV infected female on lopinavir/ritonavir, stavudine, and lamivudine died of cryptococcal meningitis • 21-month old HIV infected patient on lopinavir/ritonavir, lamivudine, stavudine died of cardio-respiratory complications secondary to disseminated cytomegalovirus infection • A 2-year-old male patient died due to hemorrhagic pneumonia, ruptured porencephalic cyst, medication error, bronchospasm and deterioration of renal function while enrolled in a clinical trial of atazanavir, stavudine, lamivudine and ritonavir therapies

13. In Utero Exposure Adverse Events (n=17)* • Most commonly reported AEs • Fetal / Intrauterine growth retardation (n=3) • Neutropenia (n=3) • Anemia (n=2) • Hypertriglyceridemia (n=2) • Blood lactate or lactic acid increased (n=3)** • CPK increased (n=2) * Most patients had more than one listed adverse event ** All three patients exposed to nucleoside reverse transcriptase inhibitors both in utero and post-partum known to be associated with lactic acidosis Underlined = unlabeled event

14. In Utero Exposure Adverse Events (cont.) • Congenital anomalies (n=7) • Ventricular septal defect • Micrognathia and cardiac murmur • DiGeorge syndrome, • Hypospadias • Congenital pyelocaliectasis • Polydactyly • Trisomy 15 • The interpretation of congenital anomalies in ritonavir exposed patients complicated by the health of the mother (HIV) and the use of multiple antiretrovirals during pregnancy • One intrauterine death at 34 weeks gestation in a 35 year old female on saquinavir, ritonavir, zidovidine and lamivudine with severe endometriosis. Fetus delivered following demise and nuchal cord noted but no apparent birth defects Underlined = unlabeled event

15. Ritonavir Drug Use1 • Pediatric patients accounted for approximately 0.8% of Norvir® (ritonavir) prescriptions. • Number of patients receiving Norvir® over the pre to post-exclusivity years increased 20% for adults and decreased 31% for pediatric patients aged 0-16 years. • In the post exclusivity year, an estimated 765 pediatric patients and over 94,000 adult patients received a Norvir® prescription. • Projected number of unique pediatric patients (aged 0 through 16 years) who received a dispensed prescription for Kaletra® (lopinavir/ritonavir) decreased by 8% from 2,600 in the pre-exclusivity year to 2,383 in the post-exclusivity year. 1Verispan, LLC, Vector One National (VONA) Data extracted 8-8-2006

16. Summary • There are no concerning safety signals • HIV is a serious frequently fatal disease and antiretroviral therapy has many known serious adverse events • Causality interpretation also confounded by concomitant medications • This completes the one-year post-exclusivity AE reporting as mandated by BPCA • The FDA recommends routine monitoring of ritonavir for AEs in all populations • Does the Advisory Committee concur?

17. Acknowledgements OSE • Melissa Truffa • Mark Avigan • Kendra Worthy • Andrea Feight • Solomon Iyasu • DAVP • Andreas Pikis • Kim Struble