Safety of Artemisinin Derivatives in treatment of malaria

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Safety of Artemisinin Derivatives in treatment of
malaria
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History

• Preclinical data AS, AM provided to WHO, 1989
• Neurotoxicity, 1997 (8000 patients)
• Systematic reviews, 1998
• uncomplicated malaria
• severe malaria
• 2002
• Pharmacovigilance protocol
• Review of preclinical/clinical reproductive
  safety data
• Developed protocols to assess safety in pregnancy

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Pharmacovigilance -opportunity

• Safety data reports - regulatory requirement
• Spontaneous reporting - numerators not
  denominators
• Limited public sector involvement

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General pharmacovigilance

• Overall SAEs
• neurotoxicity
• other unpredicted reactions
• Safety in specific populations
• pregnancy
• paediatric
• Safety of Artemisinin combinations
• versus monotherapy

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AEFI - Vaccine programme

• Guinea-Bissau (2001) DTP and negative survival
  impact
• System
• 47 countries
• 133 trainees
• AFRO, EMRO, EURO, SEARO, WPRO
• Pool of facilitators
• Pharmacovigilance with artemisinins -- build on
  vaccine system

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Countries trained since 11/99

• AFRO
• Algeria
• Benin
• Burkina Faso
• Botswana
• Cote dIvoire
• Cameroon
• Ghana
• Guinea
• Kenya
• Mali
• Mauritius
• Niger
• Nigeria
• Senegal
• South Africa
• The Gambia
• Uganda
• Zimbabwe

• EMRO
• Egypt
• Morocco
• Tunisia
• Syria
• Jordan
• SEARO
• Bangladesh
• Bhutan
• India
• Indonesia
• Myanmar
• Nepal
• Maldives
• Sri Lanka
• Thailand

• WPRO
• Philippines
• Vietnam
• China

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Serious Adverse Reactions/Events
Centralised Function Coordinator Data
Analysis Confirmation
NRA

• SAEs
• Assessment
• Frequency
• Consistency
• Strength of association
• Specificity
• Temporal relationship
• Causality

Hospital / Referred medical facility
Evaluates report Takes action Notifies Procureme
nt agencies Manufacturer MOH Media
Patient
HW physician
Responds Assesses Screens Manages data
WHO Drug Safety Monitoring Centre, Uppsala
Treats Reports
Recognizes SAEs Refers
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Malaria in Pregnancy

• Pregnant women have higher densities and
  prevalences of parasitemia
• Stable transmission
• Women in 1st 2nd pregnancies most affected
• Parasitemia prevalence highest 20-36 weeks
• Clinical malaria higher in 2nd and 3rd trimesters

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HIV and Malaria in Pregnant Women

• HIV-positive women have higher prevalences and
  densities of peripheral and placental parasitemia
• Effect seen in HIV-positive women of all
  gravidities

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Cost-effective tools to fightmalaria during
pregnancy

• Treatment
• Case management
• Prevention
• Intermittent preventive treatment (IPT)
• Insecticide-treated nets

UNICEF/C-55-10/Watson
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• Intermittent Preventive Therapy

Benefit Mothers less malaria less
anaemia Infants fewer LBWs lower IMR
Rx
Rx
Quickening
20
30
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Birth
Conception
Weeks of pregnancy
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Two major issues for use of antimalarials in IPT
during pregnancy

• Is the drug toxic to the woman or the foetus
  during 2nd or 3rd trimesters, or to the infant
  during lactation?
• Is the drug use strategy and its implementation
  likely to have a benefit--to reduce the burden of
  malaria during pregnancy?
• What are the risks?

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Safety in Pregnancy

• Systematic review of all data in pregnancy
• Preclinical Informal Consultation- 29-30 May 2002
• Clinical - 22-23 July 2002
• Pharmacovigilance - 6 Sept 2002 - review of draft
  position statement

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Preclinical work

• Preclinical recommendations
• to repeat the embryotoxicity experiments in the
  rat and rabbit with pharmacokinetic information
  about the exposure of the dams and fetuses.
• To understand mechanism of toxicity to the fetus,
  to provide clues to the site and mechanism of the
  toxicity - of value in extrapolating results to
  humans.
• Clinical recommendations see position statement
• Drugs can be used for treatment, including IPT
• not 1st trimester
• Onus on public health to monitor safety, and
  increase understanding of risks in pregnancy

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Objectives

• Estimate the magnitude of risk associated with
  the use of ATMs vs other antimalarials in
  pregnancy
• Identify and quantify immediate and long term
  effects of exposure to ATMs in pregnancy

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Prospective surveillance - Registry

• Active prospective surveillance
• Multi-centre registry
• Enrollment of all exposed women
• Bangladesh, Zanzibar, Senegal, other countries
  introducing ATM where prospective monitoring in
  pregnancy is possible, likely to be complete
• Links to general Pharmacovigilance
• Links to Making Pregnancy Safer

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Active, prospective surveillance
Follow up during pregnancy after delivery

• Assessment
• Fetal viability
• spontaneous abortions
• interuterine deaths/stillbirths
• anomalies in live borns,
• stillborns, late fetal deaths (ATM vs
  antimalarials) - by exposure interval, dose
• determination of maternal mortality (ATM vs
  antimalarials)
• determination of neonatal mortality

Hospital
Pregnant woman exposed - ATM or not
Antenatal Clinic

• Determine proportion of LBW (ATM vs. other
  antimalarials)
• Assess developmental delays (ATM vs. other
  antimalarials)

Health Centre
Dispensary
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Next steps

• Pharmacovigilance
• Pharmacovigilance training - selected early use
  countries - January 2003
• Validation Data Collection Forms
• Pregnancy
• Identification of Safety Monitor/Coordinator -
  July 2002
• Site visit (Bangladesh/ South Africa) -
  validation Data Collection Forms
• Template database with WHO Drug Safety
  Monitoring, Uppsala
• Application to early use countries

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Program opportunity In most countries of Africa
gt70 of pregnant women attend antenatal clinics
Demographic and Health Surveys
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Knowledge gaps

• What is the risk-benefit of IPT in malaria
• For antimalarials given as mono-therapy (eg SP)
• Is there an added benefit from ATMs in IPT?
• There are research studies planned for IPT
• Where? What drugs, comparators, endpoints
• Can planned endpoints can be pooled to strengthen
  power, understanding of benefit
• Can planned studies include detailed safety
  monitoring of outcomes

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Episodes of malaria treated in pregnant women,
Thailand
Drug treatment Primary Re-treatment _____________
___________________________ Quinine 113 91 MF
Q 267 41 Artemisinin derivative 229 310 ___
____________________________________ TOTAL 609
442
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Artemisinin-based Combination Therapy (ACT) early
use countries
Changing national drug policy Burundi, Peru,
Zanzibar, Zambia Implementation studies Brazil,
Mozambique, Senegal, S.Africa, Tanzania
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