One Year Post Exclusivity Adverse Event Review: Topotecan Pediatric Subcommittee of the Anti-infective Drugs Advisory C

1. One Year Post Exclusivity Adverse Event Review:TopotecanPediatric Subcommittee of the Anti-infective Drugs Advisory Committee Meeting June 9, 2004 Susan McCune, MD, MA EdMedical Officer Division of Pediatric Drug DevelopmentCenter for Drug Evaluation and Research Food and Drug Administration

2. Background Drug Information • Moiety: Hycamtin® (topotecan) • Therapeutic Category: Anti-tumor oncologic agent • Sponsor: GlaxoSmithKline • Indications: • Adults • Metastatic carcinoma of the ovary after failure of initial or subsequent chemotherapy • Small cell cancer sensitive disease after failure of first-line chemotherapy • Pediatrics • There are NO approved pediatric indications • Original Market Approval: May 28, 1996 • Pediatric Exclusivity Granted: November 20, 2002

3. Clinical Studies for Exclusivity - Efficacy • Summaries of studies previously performed by the Pediatric Oncology Group that were initiated in 1992 and 1993. • Phase 2 study in pediatric solid tumors enrolled 108 patients less than 16 years of age. • Tumor types were Ewing’s sarcoma/Peripheral Neuroectodermal tumor, Neuroblastoma, Osteoblastoma, and Rhabdomyosarcoma. • Study endpoint was tumor response rate. • 86% of patients died with 10% dying within 30 days of the last dose of topotecan. • Overall response rate was 8% but the response rates for patients with neuroblastoma was 18% (alternative regimen using combinations of available drugs in patients with relapsed neuroblastoma are 35-50%). • No patients less than 2 years of age had a response.

4. Clinical Studies for Exclusivity – Safety and Dosing • Eight of the 11 patients that died within 30 days of the last dose of topotecan had progressive disease and 3 died with infection, a known complication. • 44% of patients were hospitalized with adverse events, primarily febrile neutropenia, fever or sepsis. • Pediatric Phase 2 dose was determined to be different from adults • Daily infusion for 5 consecutive days every 21 days • 1.4mg/m2/d without Granulocyte-Colony Stimulating Factor (G-CSF) • 2mg/m2/d with G-CSF • Adult dose 1.5mg/m2/d

5. Drug Use Trends in Inpatient Settings: Topotecan • Nationally projected hospital discharge data from Premier’s™ network of approximately 450 hospitals revealed pediatric use accounted for approximately 10.6% of discharges (425 of 4,001) between 7/01 and 6/03.1 • Pediatric topotecan use increased annually between 7/01 and 6/03 (6.3% to 18.6% of projected discharges).1 • Topotecan accounted for 407 discharges from 29 CHCA™ freestanding pediatric hospitals.2 • Most frequent diagnosis was chemotherapy encounter followed by malignant neoplasm of the adrenal gland • A significant limitation of our analysis is that FDA does not currently access data to capture use in the outpatient hospital clinic setting where most chemotherapy is administered 1Premier Perspective™, Jul 2001 - Jun 2003 2Child Health Corporation of America™: Pediatric Health Information System (PHIS) Jul 2001 - June 2003

6. Adverse Event Reports: Topotecan 11/20/02 - 12/20/03 • Total number of reports, all ages: • 29 reports (18 U.S.) • Pediatric reports: • No pediatric reports were submitted during this time period. • Unlabeled pediatric reports from 5/96 to 11/02 • Convulsion, hypotension, edema, speech disorder, arachnoiditis, ascites, Budd Chiari Syndrome, caecitis, confusional state

7. Comments • The FDA will continue its routine monitoring of adverse events in all populations.

8. One Year Post Exclusivity Adverse Event Review:TemozolomidePediatric Subcommittee of the Anti-infective Drugs Advisory Committee Meeting June 9, 2004 Susan McCune, MD, MA EdMedical Officer Division of Pediatric Drug DevelopmentCenter for Drug Evaluation and Research Food and Drug Administration

9. Background Drug Information • Moiety: Temodar® (temozolomide) • Therapeutic Category: Anti-tumor oncologic agent • Sponsor: Schering-Plough Research Institute • Indication: • Adults: Temozolomide capsules are indicated for the treatment of adult patients with refractory anaplastic astrocytoma, ie., patients at first relapse who have experienced disease progression on a drug regimen containing a nitrosourea and procarbazine. • Pediatrics: There are NO approved pediatric indications • Original Market Approval:August 11, 1999 • Pediatric Exclusivity Granted: November 20, 2002

10. Clinical Studies for Exclusivity • One Phase 1 and two Phase 2 open-label multicenter studies • Phase 1 dose escalation study in 27 pediatric patients with advanced non-CNS and CNS cancers • Phase 2 study in 63 pediatric patients with recurrent brain stem glioma and high grade astrocytoma • Phase 2 study (Cooperative Group Sponsored Study) in 122 pediatric patients with various recurrent CNS tumors • Patients ranged in age from 1 to 23 years of age with the majority of patients between 3 and 17 years of age

11. Results of the Clinical Studies for Exclusivity - Efficacy • The primary endpoint was tumor response rate • In the first study, there was 1 complete response (CR) and 3 partial responses (PR) among 27 patients • In the second study, there were no CR or PR in the brain stem glioma patients, and no CR and 12%PR in the high grade astrocytoma patients • In the third study, the overall response rate (CR+PR) was 5%. Only 1 patient achieved CR and 5 patients had PRs.

12. Results of the Clinical Studies for Exclusivity - Safety • Safety was assessed in 204 patients at doses of 100-240mg/m2 daily for 5 days every 28 days • Toxicity profile was similar to adults • Most common adverse events • Dizziness • Neuropathy • Paresthesia • Nausea/vomiting • Constipation • Myelosuppression

13. Drug Use Trends in Outpatient Settings: Temozolomide • The total number of prescriptions dispensed for temozolomide in the U.S. has nearly doubled over the past 3 years, from 50,000 prescriptions dispensed in 2001 to 93,000 in 2003.1 • The top prescribers for temozolomide in 2003 were oncology/neoplastic, neurology, and hematology. Only 1% of temozolomide prescriptions were written by pediatricians.1 1 IMS Health, National Prescription Audit Plus™, On-line, Source Year 2001 – 2003, Data Extracted Jan 2004

14. Drug Use Trends in Outpatient Settings: Temozolomide • The pediatric population (1-16 years of age) accounted for approximately 2,223 temozolomide prescriptions (3.1%) in 2002 and approximately 3,649 prescriptions (3.9%) in 2003.1,2* • The most frequent diagnosis associated with temozolomide use in both the adult and pediatric populations was “malignant neoplasm of the brain (unspecified sites).”3 1IMS Health, National Prescription Audit Plus™, On-line, Source Year 2001 – 2003, Data Extracted Jan 2004 2AdvancePCS™, Dimension Rx, January 2002 to Dec 2003 3IMS Health, National Disease and Therapeutic Index™, CD-ROM 3-Year Jan 2001 – Dec 2003, Data Extracted Jan 2004 *Calculation based on application of proportions of pediatric temozolomide prescriptions in AdvancePCSto IMS Health, National Prescription Audit Plus to estimate number of temozolomideprescriptions dispensed nationwide to pediatric population

15. Drug Use Trends in Outpatient Settings (Sales): Temozolomide • Sales in the U.S. have been on the rise, increasing from an estimated 1.8 million capsules sold in 2002 to over 2.2 million capsules sold in 2003.1 • The majority sales in the U.S. were to retail channels (80%), including chain and independent pharmacies, food stores with pharmacies, mail service, and long-term care pharmacies.1 1IMS Health, National Sales Perspectives™, On-line, Source Year 2001 – 2003, Data Extracted Jan 2004

16. Drug Use Trends in Inpatient Settings: Temozolomide • CHCA™ data demonstrated that from July 2002 to June 2003, there were 17 pediatric discharges associated with temozolomide.1 1Child Health Corporation of AmericaTM:  Pediatric Health Information System (PHIS), Jul 2002 - Jun 2003

17. Limitations to Drug Use Data in Outpatient Settings: • Currently, outpatient data sources available to FDA do not capture drug use data in outpatient hospital clinics where considerable chemotherapy treatments are provided. • However, the sales data do capture products sold to outpatient clinic settings through number of temozolomide capsules sold to the various sales distribution channels. • These data suggest that approximately 20% of temozolomide is purchased by hospitals and clinics. The number of chemotherapy treatment centers in the sales audit is unknown at this time.1 • Therefore, it appears that the majority of temozolomide use is captured through this assessment of outpatient use. 1IMS Health, National Sales Perspectives™, On-line, Source Year 2001 – 2003, Data Extracted Jan 2004

18. Adverse Event Reports: Temozolomide11/20/02 - 12/20/03 • Total number of reports, all ages: • 250 reports (160 U.S.) • Pediatric reports: • 5 unduplicated pediatric reports (2 U.S.) • All with serious outcomes and one death • Gender: Female (4), Male (1) • Age: 2-5 years (3), 6-11 years (2) • Diagnosis: Blastoma (1), Adrenal metastatic neuroblastoma (1), Anaplastic astrocytoma (1), Medulloblastoma (1), Brain stem tumor (1)

19. Adverse Event Reports: Temozolomide11/20/02 - 12/20/03 • Brain edema • Concomitant radiation therapy • Death • Potentially due to underlying condition • Hemangioma acquired • Potentially related to underlying condition, concomitant medications or radiation therapy • ITP • Potentially labeled event or secondary to underlying condition • Myelodysplastic syndrome • Potentially labeled event or secondary to underlying condition Clinically Significant Unlabeled Adverse Events Although not specifically delineated in the label, these are all potentially related to a labeled process or the underlying disease state.

20. Adverse Events: Temozolomiden=5 • A three year old started temozolomide to treat pineal blastoma and subsequently (unknown relation to drug treatment) died of an unspecified cause. The event was reported by the patient’s father. • A six year old was treated with temozolomide (90mg/m2/d) for recurrent anaplastic astrocytoma. Concomitant medications included a flu vaccine, Bactrim, and radiation therapy. Following temozolomide use, a cavernous hemangioma was noted on MRI (not previously seen on MRI). Following temozolomide treatment, the patient was admitted with thrombocytopenia requiring platelet transfusions, IVIG infusions, prednisone and monitoring of the hemangioma. This was diagnosed as ITP and subsequent bone marrow analysis revealed a myelodysplastic syndrome. The patient was discharged with an improved clinical status 18 days after admission.

21. Adverse Events: Temozolomide(cont.) • A four year old started temozolomide for treatment of medulloblastoma. An infection (disseminated Fusariosis) was reported but there was no outcome of the event documented. • A four year old was treated with temozolomide (120mg/m2/d) for adrenal metastatic neuroblastoma. She developed thrombocytopenia, anemia and fever which were managed with blood transfusions and antibiotics. One month after temozolomide treatment, she recovered without sequelae and was given a second cycle of temozolomide without recurrence. • An eight year old was treated with temozolomide (140mg reduced to 60mg) for a brainstem tumor. Concomitant therapy included radiation therapy. A routine MRI revealed “radiation-induced cerebellum edema” requiring hospitalization for intracranial drainage. She was subsequently discharged in stable condition.

22. Comments • Labeled and unlabeled adverse events reported • The unlabeled events have also been reported in adults and are not unique to pediatrics • The FDA will continue its routine monitoring of adverse events in all populations.