《NDA 21-242Rectal Artesunate》.pptVIP

FDA AIDAC 7/10/02 NDA 21-242Rectal Artesunate Integrated Safety Rosemary Johann-Liang, M.D. Division of Special Pathogen and Immunological Drug Products Proposed Indication “Single 10 mg/kg dose of artesunate rectal capsules in the initial management of acute malaria in patients who cannot take medication by mouth and for whom parenteral treatment is not available” Implications of the Indication In the “field” Empiric Therapy (other severe febrile illnesses included) Severe disease (unable to take PO) Mainly very young children SAFETY SUBMISSIONS WHO-Sponsored Studies Safety Review of published and unpublished safety information on studies of Artemisinin Derivatives Summary of the data presented to the Chinese Authorities in 1989 Neurotoxicity (WHO-sponsored consultation) WHO-sponsored Studies WHO-sponsored Studies WHO-sponsored Studies: Clinical WHO-sponsored Studies: AE WHO-sponsored studies: Deaths WHO-sponsored Studies: Labs Laboratory monitoring was limited. Only one clinical study had comprehensive labs recorded (CBC, Chem, LFTs) HCT ( n= 250) Overall, transient decrease at 12-24 hours with rise to baseline by day 7, to normal by day 28 SGOT / SGPT (n= 48) Only monitored in 1 study. 3 patients with rise over 3X UL after normal baseline, peaking day 7-14, falling by day 21 ECG (n=48) Only monitored in 1 study. No significant abnormalities noted WHO-sponsored studies : Dose PK and clinical studies: one rectal dose majority receiving 10 mg/kg (6.8 to 22.2 mg/kg) Re-analysis studies: repeated rectal dosing over 3-4 days with mean doses between 25-32 mg/kg total dose (11.3 to 45.7 mg/kg) Maximum dose exposure for Adults 45.7 mg/kg total dose given over 4 days in 8 divided doses Maximum dose exposure for Children 21.4 mg/kg with the longest duration of exposure of 7 days (rectal dose x 1 followed by oral dosing: study 5) WHO-sponsored Studies: Special Populations 2 years: only 8 of 166 children 50 years: only 6 of 153 adult