FDA AIDAC 7/10/02 1

NDA 21-242

Rectal Artesunate

Integrated Safety

Rosemary Johann-Liang, M.D.

Division of Special Pathogen and Immunological Drug Products

FDA AIDAC 7/10/02 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”

FDA AIDAC 7/10/02 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

FDA AIDAC 7/10/02 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• WHO-Sponsored Studies • Safety Review of published and unpublished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)

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WHO-sponsored Studies

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WHO-sponsored StudiesAll hospitalized patients

M alaysia, Thailand, Ghana, M alaw i, South Africa, Kenya, Brazil

2 Bioavailability2 Bioequivalency

3 "pivotal" clinical studies(2 pediatric, 1 adult)

3 publishedre-analysis studies

3 other clinical studies( 1 pediatric, 2 adult)

healthy volunteersn=66

childrenn=166 total, n=8 less than 2 years

m oderately severen=344

severe m alarian=91, n=5 from clinical

Safety Database: 13 study reportsn=501, n=435 w / m alaria, n=319 in clinical studies

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WHO-sponsored Studies: Clinical

Rectal Artesunate ComparatorAdults N=153 pts

148: Mod Severe Dz5: Severe Dz

N = 14 ptsAll: Severe DzAll: IV quinine

Children (<15 yrs)

N=166 ptsAll: Mod Severe Dz

N=8 for < 2 years old

N = 39 ptsAll: Mod Severe Dz17: PO Artesunate22: IV quinine

FDA AIDAC 7/10/02 8

WHO-sponsored Studies: AE

Children RectalArtesunate

Comparator(17 PO AS; 22 QN)

Overall AE 33 AE / 166 pts(20%)

10 AE / 39 pts(26%)

GI AE(nausea, vomiting,abdominal pain)

14 AE / 166 (8%) 5 AE / 39 (12%)

CNS AE(H/A, impairedconsciousness,convulsions)

10 AE / 166 (6%) 2 AE / 39 (5%)

FDA AIDAC 7/10/02 9

WHO-sponsored studies: Deaths

DHA level2 hrs: 2002 ng/m l (652+/-353.2)4 hrs: 977 ng/m l (396.8+/-545.2)

1 Pediatric Death3 y/o boy: 11.5 m g/kg x 1probable cause of death

W HO: "iatrogenic water intoxication"

3 Add. Deaths in P ivotal TrialsAll 3 w ith severe m alaria

1 death in AS; 2 IV quinine armW HO: Due to underlying m alarial dz

3 deaths in re-analysis studiespatients w ith severe m alaria

cause not determ inedall 3 had cleared their parasitem ia

In to ta l: 7 /501 (1 .4% )1/275 (.36% ) Modera te Severe D z

6/91 (6% ) Severe Ma la ria

FDA AIDAC 7/10/02 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

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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)

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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

FDA AIDAC 7/10/02 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

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Safety Review of Published and Unpublished Clinical Studies on

Artemisinin Derivatives

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WHO- Safety Review: Types of Clinical Studies

Artem isinin Derivatives

Phase In=8

129 patients

N oncom parativen=33

4186 patients

C om parative, N Rn=11

1476 patients

C om parative, Rn=78

7848 patients

safety Inform ationn=130

13,639 patients

Clinical S tudiesn=169

151 pub; 18 unpub15,498 patients

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WHO-Safety Review: Disease Population

Artesunate N = 6158

56%

1%

15%

28%

uncompmoderatesevereother

ArtemisininsN = 13,520

20%

7%

0%

73%

uncompmoderatesevereother

FDA AIDAC 7/10/02 17

WHO-Safety Review: Adverse Events

Pooling of adverse events across studies: problem aticNo Raw data: Data not review ed by FDA

Safety Review states

Severe M alaria"Few er incidence of hypoglycem ia,skin reactions, tinnitus, d izziness

than quinine"

Uncom plicated m alaria"Less pruritis than chloroquine

Less nausea, d izziness, tinnitus than quinineLess vom iting than m efloquine"

Com parative Studiesm ost com m on AE (in the order of <1%)

to be m ild G I events(nausea, vom iting, d iarrhea, Abd pain)

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WHO-Safety Review: Laboratory and ECG Abnormalities

Laboratory abnormalities in the order of 1%• neutropenia• reticulocytopenia• eosinophilia• anemia• transaminitis• culture-negative pyuria• hemoglobinuriaFew 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

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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)

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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)

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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

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Artemisinin Neurotoxicity

Class effect: Artemisinin (QHS, qinghaosu), Artemether (AM),

Arteether (AE) , Dihydroartemisinin (DHA)

Symptomatic: apathy, unsteadiness, collapse, coma, deathNeuropathological: chromatolysis, unique pattern of neuronal necrosis in brainstem nuclei (vestibular, cochlear, olivary, red and others)

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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)

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Preclinical evidence: margin of safety

BSA conversionof Rat 45-75 m g/kg

HED: 7.5 - 12.5 m g/kg IM

NOAELrat: 45-75 m g/kg IM x 1 or over 7d

dog: 3 - 6.25 m g/kg/day x 7dm onkeys: 100 m g/kg IM x 1 or over 7d

1998 W HO sponsoredexpert review of path m aterial

all available info. for AM, AE

BSA conversionof Rat 75 or 150 m g/kg

HED: 12 and 25 m g/kg PO

Not specific Neurotox studyUnexplained rat deaths

1/16 rat on day 4: 75m g/kg 2/16 rat on day 3: 150 m g/kg

preclinicalW HO-sponsored

toxicology studies for AS

Artem isinin N europathology

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Neurotoxicity: clinical experience

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)

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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

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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?

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Lack of information: populationsCan we make the link?

W HO conclusionshighly favorable safety profile

num ber of AE sm allno consistent pattern of toxicity identified

All hospitalized patientsAll w ith proven m alaria

m ainly m oderately-severe diseaseonly 8 patients < 2 years of age

NDA application

little inform ation availableeven in the large body of clinical experience

none in the W HO-specific studies of this NDA...to draw upon for safety evaluation for proposed indication

In the "field"em piric therapy

severe disease, unable to take POm ainly very young children

Proposed Indication

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Safety Summary: Benefit / Risk

WHO Statements

• highly favorable safety profile

• number of AE small• no consistent pattern

of toxicity identified

Uncertainties

• Neurotoxicity, safety margin

• Population for proposed indication

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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