NDA 21-242 Rectal Artesunate

1. NDA 21-242Rectal Artesunate Integrated Safety Rosemary Johann-Liang, M.D. Division of Special Pathogen and Immunological Drug Products

2. 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”

3. Implications of the Indication • In the “field” • Empiric Therapy (other severe febrile illnesses included) • Severe disease (unable to take PO) • Mainly very young children

4. SAFETY SUBMISSIONS • WHO-Sponsored Studies • Safety Review of published and unpublished safety information on studies of Artemisinin Derivatives • Summary of the data presented to the Chinese Authorities in 1989 • Neurotoxicity (WHO-sponsored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)

5. WHO-sponsored Studies

6. WHO-sponsored Studies

7. WHO-sponsored Studies: Clinical

8. WHO-sponsored Studies: AE

9. WHO-sponsored studies: Deaths

10. 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

11. 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)

12. WHO-sponsored Studies: Special Populations • < 2 years: only 8 of 166 children • > 50 years: only 6 of 153 adults with malaria • Renal & Hepatic impairment: not specifically studied • Pregnant: not included in studies • preclinical: consistent findings of impaired fetal survival; no evidence of teratogenicity • clinical from literature: no evidence of fetal injury or impairment of maternal health

13. WHO-sponsored Studies: Safety Summary • Very small safety database, all open-labeled • Studies mainly non-comparative • Safety assessment not available for special populations, in particular very young children • Dose exposure: mainly 1 rectal dose at 10 mg/kg • Overall, no unusual or serious pattern of adverse events; but minimal numbers for comparison • Overall, no unusual or serious laboratory abnormalities; but monitoring was sparse • Deaths on study few but not all with clear etiology

14. Safety Review of Published and Unpublished Clinical Studies on Artemisinin Derivatives

15. WHO- Safety Review: Types of Clinical Studies

16. Artesunate N = 6158 WHO-Safety Review: Disease Population Artemisinins N = 13,520

17. WHO-Safety Review: Adverse Events

18. Laboratory abnormalities in the order of 1% neutropenia reticulocytopenia eosinophilia anemia transaminitis culture-negative pyuria hemoglobinuria Few cases of elevated bilirubin ECG abnormalities in the order of 1% bradycardia prolongation of QT interval Few cases of 1st degree AV block, atrial extra-systoles and T-wave abnormalities WHO-Safety Review: Laboratory and ECG Abnormalities

19. WHO-Safety Review: Neurological Assessments • Majority: no neurological assessments • Dizziness most common • *Price R et al. Adverse Effects in Patients with acute falciparum malaria treated with artemisinin derivatives. Am J Trop Hyg. 1999:60; 547-55 • Patients with uncomplicated malaria • “ Neurologic examination could be performed reliably only in patients >5 years old” • Human Histopathology ( Hien et al 1999, artemether: n=6)

20. WHO-Safety Review: reassurance • comprehensive effort • relatively few side effects reported • lack of evidence: an association between artemisinin derivatives and increased neurological AE/ sequelae (in people with malaria)

21. WHO-Safety Review: problems • Methodological deficiences • drug vs. disease effects • uncertainty of pooling AEs •  #s for moderate/severe disease •  # for neurological assessment especially in young children • No raw data for FDA to review • Not GMP: sub-potent content of active ingredient Newton P et al. Fake Artesunate in Southeast Asia. Lancet 2001 Jun 16; 357 (9272):1904

22. Artemisinin Neurotoxicity Class effect: Artemisinin (QHS, qinghaosu), Artemether (AM), Arteether (AE) , Dihydroartemisinin (DHA) Symptomatic: apathy, unsteadiness, collapse, coma, death Neuropathological: chromatolysis, unique pattern of neuronal necrosis in brainstem nuclei (vestibular, cochlear, olivary, red and others)

23. Preclinical evidence: neurotoxicity margin of safety • WHO-sponsored expert consultation: Conclusions about AS • Limited Information for AS • No neuronal necrosis at 420 mg/kg IM x 1 or 200 mg/kg/day PO x 5-7d • WHO: Briefing Package regarding WHO-sponsored toxicology • total 210-300 mg/kg via IV / PO • 21 to 30 fold greater than total proposed human dose • FDA: BSA conversion to Human Equivalent Dose (HED) • 35-50 mg/kg (only 3-5 times)

24. Preclinical evidence: margin of safety

25. WHO-sponsored studies Neurological assessments performed for studies 5, 6, 7 only (should give 164 rectal AS recipients tested / 501 total, but missing data common) Young patients: assessments not reliable No pattern of neurological abnormalities was identified Literature/actual usage Main argument for the safety of artesunate Large body of experience No evidence of neuro toxicity with AS used in patients with malaria Minority were moderate/severe dz Main Ref. to Price et al study but children <5 did not get neurological assessments Adults Highest Dose: 45.7 mg/kg (n<30) Children Highest Dose: 57 mg/kg (n<30) Neurotoxicity: clinical experience

26. Neurotoxicity: What do we know • Neurotoxicity: dose-dependent • Lipid soluble derivatives: AE, AM • Water soluble derivatives: AS, AL • Most Neurotoxic: DHA > AE, AM >>AS, AL • Conversion to DHA: AS > AE, AM >> AL • Faster Elimination: AS >> AE, AM • Lipid soluble agents produce much longer periods of DHA activity. • Critical factor leading to neurotoxicity: Sustained level rather than peak level

27. Neurotoxicity: What we don’t know • Safety margin from preclinical clinical not determined yet and may not be as “wide”. HED: one rectal dose OK but unclear with repeated dosing. • AS elimination faster: IV > PO > Rectal; With repeated dosing, could rectal formulation also act as “depot” , causing sustained levels? • Brainstem nuclei affected: species specific? Humans? • DHA Tissue Distribution to parasitized cells, a buffer? • Empiric Use in febrile children (especially if repeated dosing and no buffer of parasitized cells): Sustained CNS DHA levels be possible?

28. Lack of information: populationsCan we make the link?

29. WHO Statements highly favorable safety profile number of AE small no consistent pattern of toxicity identified Uncertainties Neurotoxicity, safety margin Population for proposed indication Safety Summary: Benefit / Risk

30. Safety Summary: Benefit/Risk • Impact of the disease malaria to individual human suffering and global public health • Proposed rectal dose (10 mg/kg x1) within safety limits of collective current knowledge • Uncertainties and concerns expand if higher doses or repeated dosing becomes an issue