1. 1 One Year Post-Exclusivity Adverse Event Review: Sirolimus Pediatric 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. 2 Background Drug Information Drug: Rapamune ® (sirolimus) Therapeutic Category: immune suppressant Sponsor: Wyeth Pharmaceuticals Indications: Prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants Original Market Approval: September 15, 1999 Pediatric Exclusivity Granted: November 17, 2004

3. 3 Drug Use Trends in Outpatient Settings: Sirolimus Pediatric patients (0-16 years) accounted for 4.3% (7,100) of the 165,000 Rapamune ® prescriptions dispensed in the U.S. (Dec 2004 to Nov 2005) 1 The pediatric use of Rapamune ® increased from 4,900 prescriptions in the year prior to exclusivity (Dec 2003 to Nov 2004 ) to 7,100 prescriptions in the year following exclusivity (Dec 2004 to Nov 2005) 1 Patients in the 12-16 year old subgroup accounted for the majority of prescriptions dispensed to pediatrics in the post- exclusivity period, with almost 60% of the annual Rapamune ® prescriptions dispensed to this group of pediatric patients 1 1 Verispan, LLC, December 2002 – November 2005, Data Extracted 1/06

4. 4 Pediatric Exclusivity Studies: Sirolimus Study 1: Randomized study in high immunologic risk pediatric renal allograft recipients that compared the following regimens for safety and efficacy: –Sirolimus plus calcineurin inhibitor (cyclosporine or tacrolimus) and corticosteroids –Double therapy: calcineurin inhibitor and corticosteroids –Triple therapy: calcineurin inhibitor plus azathioprine or mycophenolate mofetil and corticosteroids Study 2: A Double-Blind Randomized Trial of Steroid Withdrawal in Sirolimus and Cyclosporine-Treated Primary Transplant Recipients Pharmacokinetic data collected from both studies

5. 5 Efficacy failure in the intention-to-treat (ITT) population (n=102) was numerically more frequent in patients randomly assigned to receive the combination of sirolimus and a calcineurin inhibitor than in the subjects allocated to standard therapy (29/65, 44.6% versus 12/37, 32.4%, respectively) When comparing only patients 18 years old or younger (24/53, 45.3% versus 11/25, 44.0%, respectively) efficacy failure rates were similar Results of Pediatric Exclusivity Studies

6. 6 Results of Pediatric Exclusivity Studies (cont.) Adverse events such as abdominal pain, fever, abnormal renal function, and urinary tract infection (UTI) were significantly more common in the sirolimus treatment cohort compared with standard therapy –UTI rates were 15% versus 1% in the sirolimus combination group versus the control group, respectively

7. 7 Results of Pediatric Exclusivity Studies (cont.) Pharmacokinetics of Sirolimus and Cyclosporine Regimen –Younger children had overall lower sirolimus dose normalized to exposure apparently due to higher clearance –A strong correlation at steady-state between whole blood sirolimus pharmacokinetic values were observed for all treatments and regimens –Sirolimus trough concentrations were adequate surrogates for sirolimus exposure

8. 8 Resultant Labeling from Exclusivity Studies Information on pharmacokinetic parameters Safety and efficacy of sirolimus established in children 13 years or older judged to be at low to moderate immunologic risk In pediatric (<18 years of age) renal transplant recipients considered high immunologic risk the use of sirolimus in combination with calcineurin inhibitors and corticosteroids was associated with: – an increased risk of deterioration of renal function –lipid abnormalities –urinary tract infections  Safety and efficacy have not been established in pediatric patients less than 13 years old or in pediatric renal transplant recipients considered at high immunologic risk

9. 9 Adverse Event Reports since Market Approval (December 2005): Sirolimus Raw counts*All reports (US)Serious (US)Death (US) All Ages3712 (1415)2981 (1231)375 (160) Adults (> 17)2254 (1011)2471 (931)322 (133) Pediatrics (0-16)88 (57)82 (51)6 (5) *may include duplicates and unknown ages

10. 10 Adverse Event Reports 1 Year Post Exclusivity Period: Sirolimus Raw counts*All reports (US)Serious (US)Death (US) All ages862 (342)845 (325)86 (36) Adults (> 17)713 (273)706 (266)66 (26) Pediatrics (0-16)19 (10) 0 * may include duplicates and unknown ages

11. 11 Pediatric Deaths in Post-Marketing Period (n=6) 15 year old recurrence of hepatoblastoma with fatal complications following liver transplant  This is a high risk of cancer recurrence in transplanted hepatoblastoma patients 10 year old renal transplant patient with subsequent renal vein thrombosis and infarction of donor kidney –Developed respiratory failure and cardiac arrest  Known transplant complication of renal vein thrombosis versus sirolimus related thrombosis

12. 12 Pediatric Deaths in Post-Marketing Period (n=6) (cont.) 9 year old with renal and cardiac transplant –Developed severe thrombocytopenia and leukopenia three weeks after transplant –Died three weeks later  Sirolimus associated with bone marrow suppression 2.5 year old study patient with congenital genitourinary abnormalities status post renal transplant –Died of complications of aspergillus pneumonia and gastrointestinal bleeding  Aspergillus pneumonitis and CMV colitis known complication of immunosuppression

13. 13 Pediatric Deaths in Post-Marketing Period (n=6) (cont.) 6 year old with short bowel syndrome status post intestinal transplant –Developed progressive encephalitis with elevated liver enzymes due to Hepatitis A along with primary EBV and HHV-6 infection –Graft removed and immunosupression discontinued –Subsequently developed erythroderma with severe edema and adenopathy followed by cytolytic hepatitis and eosinophillia –Died of multi-organ failure  Exacerbations of EBV and HHV-6 infections are known complications of immunosuppression

14. 14 Pediatric Deaths in Post- Marketing Period (n=6) (cont.) 12 year old with end-stage renal disease, post-transplant diabetes mellitus, hypertension and renal hyperplasia status post renal transplant –5 months after transplant hospitalized with viral lower respiratory infection with subglottic edema –Died following discharge –Death thought to be due to laryngeal inflammation and airway obstruction  Likely exacerbation of viral infection due to immune suppression

15. 15 Serious Pediatric Adverse Events 19 unduplicated pediatric reports in patients on sirolimus during the One-Year Post-Exclusivity Period –Transplant Complications/Rejection (n=8) –Gastrointestinal Events (n=3) * –Drug Interactions / Drug Level Fluctuations (n=3) ** Possible Interaction with Azithromycin (n=2) –Cardiac Events (n=2) –Infection (n=1) –Panniculitis (n=1) –Intracranial bleeding (n=1) Underlined events = Unlabeled events *paralytic ileus and haematochezia are not specifically mentioned, but the related events of ileus, rectal disorder and hemorrhage are mentioned ** Some drug interactions are labeled, others are not

16. 16 Pediatric Adverse Event: Possible Drug Interactions with Azithromycin (n=2) 6 year old renal transplant patient on sirolimus, tacrolimus, prednisone, and co-trimoxazole –On azithromycin for pneumonia –Overdose of tacrolimus due to a medication error increased tacrolimus and sirolimus levels and neurological side-effects –Sirolimus levels continued to be elevated even though tacrolimus stopped –Only when azithromycin was stopped, did the sirolimus level decrease

17. 17 Pediatric Adverse Event: Possible Drug Interactions with Azithromycin (n=2) (cont.) 5 year old renal transplant patient on sirolimus, tacrolimus, atorvastatin, ferrous sulfate –On azithromycin for pneumonia –Developed increased sirolimus and tacrolimus levels with neurotoxicity despite having the sirolimus dose reduced  These 2 cases are confounded by tacrolimus overexposure  Sirolimus label does not have any warnings about interactions with azithromycin  Compared to other drugs including but not limited to ketoconazole and erythromycin, azithromycin is a weak CYP3A inhibitor which are labeled

18. 18 Pediatric Adverse Event: Possible Drug Cardiac Adverse Events (n=2) 3 year old renal transplant patient on tacrolimus and sirolimus with iron deficiency –Fever and 3 month history of cough –X-ray showed massive cardiomegally and lung infiltrate –Echo showed moderate to large pericardial effusion –Viral work-up only revealed Adenovirus type 2 in stool –Had pericardiocentesis and the effusion stabilized and did not recur

19. 19 Pediatric Adverse Event: Drug Cardiac Adverse Events (n=2) (cont.) 2 year old renal transplant patient with hypertension and a prior history of pericardial effusion on tacrolimus, prednisone and sirolimus –Subsequent development of persistent pericardial effusion –Pericardial effusion increased in size despite decrease in sirolimus dose and was hospitalized twice for this condition –During second hospitalization, noted to have upper respiratory infection associated with fever, nausea and emesis –Following the second hospitalization, the pericardial effusion resolved on its own while on the reduced sirolimus dose  Office of Safety and Epidemiology is currently evaluating the association of sirolimus use with pericardial effusion

20. 20 Pediatric Adverse Event: Panniculitis (n=1) (foreign report) 14 year old renal transplant patient on azathioprine, prednisolone, sirolimus, nitrofurantoin and enalapril –Developed lower limb panniculitis 2 months after starting sirolimus and was hospitalized –Continued sirolimus for another 7 months –Recovered following the discontinuation of sirolimus therapy  Not enough information to make any conclusions about this AE

21. 21 Pediatric Adverse Event: Intracranial Bleed (n=1) (foreign report) 2 year old liver transplant patient with concurrent short- bowel syndrome on tacrolimus, prednisolone, sirolimus, loperamide and gentamicin –Treated with 2mg of sirolimus for 28 days –Day after stopping sirolimus developed intracranial hemorrhage –One and two weeks after the event, brain scan still indicated “new bleeding” –Patient recovered from event –Interval between transplant and intracranial hemorrhage not known  Hemorrhage is a labeled AE  Not clear if bleeding related to sirolimus since it occurred after it was discontinued

22. 22 Summary: Sirolimus OSE and the DSPTP are evaluating the association of sirolimus with pericardial effusion DSPTP is in discussions with the Sponsor about potential labeling changes This completes the one-year post-exclusivity AE reporting as mandated by BPCA FDA recommends routine monitoring of sirolimus for AEs in all populations Does the Advisory Committee concur?

23. 23 Acknowledgements OSE Evelyn Farinas Rosemary Johann-Liang Mark Avigan Laura Governale Toni Piazza-Hepp OND Hui-Hsing Wong Marc Cavaille Coll Hyun Son OCP Gerlie Gieser