Evidence-based review of malaria chemoprophylactic drugs

1. Evidence-based review of malaria chemoprophylactic drugs

2. Rationale CDC malaria prophylaxis recommendations made by Malaria Epidemiology Branch with input from Division of Global Migration and Quarantine Informally have sought external input – e.g. ASTMH; phone and email communications from providers Expert meeting on Malaria Chemoprophylaxis held at CDC in January 2003: a more formal mechanism to elicit expert opinion/input on policies and recommendations

3. Preparation for meeting Extensive literature review Creation of evidence-based documents Main points summarized in 2-3 page “Guidelines” documents Points that are potentially unclear or controversial were raised as Discussion Points at the meeting

4. Evidence-based documents (I) Recommended dosing Efficacy and effectiveness Data from various studies listed in table format Pharmacokinetics Adherence Safety Information also in table format Severe and mild/moderate ADRs*

5. Evidence-based documents (II) Contraindications Duration of use Therapeutic index/overdosage Drug interactions Special populations – children, pregnant women, persons with pre-existing medical conditions Cost

6. Topics discussed (I) Overall recommendations: Areas with CQ (chloroquine)-sensitive Plasmodium falciparum: CQ is drug of choice (hydroxy-CQ alternative) Areas with CQ-resistant P. falciparum - 3 options: Mefloquine Doxycycline Atovaquone/proguanil

7. Topics discussed (II) 6 drugs recommended for prophylaxis, including terminal prophylaxis, were covered in individual sessions: CQ Hydroxychloroquine Doxycycline Atovaquone/proguanil Mefloquine Primaquine

8. Topics discussed (III) Additional sessions: Health communications Self-treatment and the low risk traveler

9. Example of discussion points raised: Mefloquine (I) Indication Dosing How much time to start before travel? Loading dose? Split dose? (twice weekly) Efficacy ADRs How can we better communicate? What about long term neuropsychiatric ADRs? Are there gender differences? Interaction with alcohol? Need to monitor LFTs* or ophthalmologic exam?

10. Example of discussion points raised: Mefloquine (II) Contraindications Use in persons with history febrile seizures? Precautions Cardiovascular disease? Pilots? Divers? Drug interactions Use during pregnancy Concerns about spontaneous abortions/stillbirths? Use during breastfeeding Use in children

11. Overall recommendations (I) Confirmed drug choices in both areas with chloroquine (CQ)–sensitive and CQ-resistant P. falciparum Areas with CRPF Alphabetize by generic name No drug of choice Primaquine (PQ) at 30 mg/day added as 2nd-line choice

12. Overall recommendations (II) Elimination of CQ/proguanil as option in areas of CRPF Explicitly state that in areas with CSPF* if cannot tolerate CQ (or hydroxy-CQ) use one of the drugs for CRPF If concerned about drug tolerance could start as early as 3-4 weeks before travel Specific warning: avoid purchase of chemoprophylactic drugs overseas - may be of suboptimal quality

13. Overall recommendations (III) Disseminate more information on ADRs Focus group data also supported this concept – people want information to make informed decision Advantages and disadvantages of the various options in a table Try to provide rates of mild/moderate and severe ADRs Provide information on rates of discontinuation of drug due to ADRs Important to communicate some key points Risk of malaria Prevention works

14. CQ & hydroxy-CQ CQ 1st choice (much more data than hydroxy-CQ) No eye exams needed even with long-term use since risk very low at malaria prophylaxis doses Maintain option of twice weekly dosing (but caveat is no data) No G6PD screening needed prior to use Further discussion needed: tolerance of CQ vs hydroxy-CQ; longterm use of hydroxy-CQ in children

15. Doxycycline No evidence that doxycycline interferes with effectiveness of oral contraceptives Doxycycline preferred to minocycline for malaria prophylaxis (if on minocycline, recommend change to doxy if at all possible) Further discussion needed: use during breastfeeding; long-term use

16. Primaquine Increase dose for terminal prophylaxis (all geographic areas) to 30 mg base/day No new insights on refining decisions on who are candidates for terminal prophylaxis Avoid use for primary or terminal prophylaxis in those w/ G6PD deficiency Further discussion needed: use in young children and in persons with myelosuppression

17. Atovaquone/proguanil Efficacy adequate to recommend as 1st line option for non-immune persons Efficacy adequate against P. vivax to recommend for use in areas with substantial P. vivax transmission Still need terminal prophylaxis with primaquine in those persons where it is indicated (may not prevent establishment of hypnozoites) Further discussion needed: long-term use; use in children 5-11 kg

18. Mefloquine (I) Comment from panel: getting hard to prescribe… No good explanation for long-lasting neuropsychiatric ADRs Should include information on gender differences in tolerance in health communications materials People need to know ADRs can last weeks given the long half life OK for use in those w/ history febrile seizures

19. Mefloquine (II) No precautionary statement planned on use of concomitant use of alcohol and mefloquine (MQ) Can use in those who performing tasks that require fine motor coordination (eg pilots) but best to start 3-4 weeks early Permissive language to use loading dose Needs further discussion: split dosing (twice weekly); need for monitoring LFTS*; use in those with cardiovascular problems; safety concerns during pregnancy

20. Self-treatment and treatment Sulfadoxine-pyrimethamine (SP) no longer recommended – therefore, atovaquone/proguanil is 1st choice agent Stronger language on avoiding halofantrine

21. Next steps Summary report – review by panel Revise evidence-based documents Revise overall and drug-specific recommendations, indicating level of evidence for each recommendation Update all health communications materials – Health Information for International Travel, website, travelers’ brochure Peer-reviewed publications as well as possible publication in MMWR