Supplement

Canadian Recommendations for the Prevention and Treatment of Malaria Among International Travellers

3. Chemoprophylactic Regimens

a. Introduction

Medications to reduce the risk of visitors acquiring clinical malaria should be considered during evening or overnight exposure in the following areas:

URBAN AND RURAL AREAS OF

(Higher risk) - subSaharan Africa (except most of South Africa) and Oceania (including Papua New Guinea, Papua, Solomon Islands and Vanuatu)

(Low to moderate risk) - Haiti, India, Bangladesh, Pakistan, and Nepal (Terai region)

RURAL AREAS OF

Southeast Asia, Central and South America, and certain parts of Mexico, North Africa, and the Domini-can Republic (adjacent to Haitian border).

Travellers should be informed that antimalarial medication can markedly decrease the risk of acquiring symptomatic malaria. However, none of these agents can guarantee complete protection against malaria. Personal protective measures are an important adjunct to malaria prevention, even for those taking chemoprophylactic drugs (see Section 2, for prevention). Symptoms due to malaria may occur as early as 1 week after first exposure and as late as several years after travellers leave a malarial region whether or not chemoprophylaxis has been used. Most travellers who acquire P. falciparum infection will develop symptoms within 3 months of exposure. Falciparum malaria can be effectively treated early in its course, but delay in therapy may result in a serious and even fatal outcome.

FEVER OCCURRING IN A TRAVELLER WITHIN 3 MONTHS OF DEPARTURE FROM A MALARIA- ENDEMIC AREA IS A MEDICAL EMERGENCY AND SHOULD BE INVESTIGATED URGENTLY BY MEANS OF THICK AND THIN BLOOD FILMS; IF SYMPTOMS PERSIST, THESE FILMS SHOULD BE REPEATED TWICE AT 12 TO 24 HOUR INTERVALS IF THE PATIENT REMAINS SYMPTOMATIC (SEE SECTION 8 AND FIGURE 3)

There is no global consensus on malaria chemoprophylactic regimens. During their travels many individuals will encounter other travellers or health care providers who will counsel them to change or stop their antimalarial medication (especially mefloquine), leaving them at high risk of acquiring potentially life-threatening malaria. Travellers should be warned of this possibility; as well, the antimalarial guidelines and the risks and benefits of effective chemoprophylaxis should be reinforced. Appendix V , entitled "Frequently Asked Questions about Malaria", may aid the practitioner in answering travellers' questions. If desired, this text can be copied and provided to the traveller.

Table 3 summarizes the different chemoprophylactic options according to the presence of drug resistance. See Section 9 for details regarding individual chemoprophylactic agents.

b. Chloroquine-sensitive Regions

Chloroquine-sensitive regions are those malarial areas where chloroquine resistance has not been documented or is not widely present. These include Haiti, the Dominican Republic, Central America north of the Panama Canal, North Africa and parts of the Middle East, and west/central China. See individual countries in Appendix I for precise recommendations.

Drug of choice: chloroquine (Aralen®) is the drug of choice for travellers to areas with chloroquine-sensitive malaria (A I - evidence-based medicine recommendation, see Appendix II). Chloroquine is taken once weekly, beginning 1 week before entering a chloroquine-sensitive malarial region, during the period of exposure, and for 4 weeks after leaving the malarial region.

Alternatives: For individuals unable to tolerate chloroquine, atovaquone/proguanil, doxycycline, or mefloquine should be used (see Section 3c, and Section 9).

c. Chloroquine-resistant Regions

The chloroquine-resistant regions refer to most of Africa, South America, Oceania and Asia. See individual countries in Appendix I for specific recommendations. Note that some border areas of Thailand, Myanmar, and Cambodia are also mefloquine-resistant regions (see Section 3d).

There are sufficient data in semi-immune and non-immune hosts in various geographic locations to conclude that atovaquone/proguanil, doxycycline, and mefloquine are equally efficacious in the prevention of chloroquine-resistant malaria.

Drugs of choice: Atovaquone/proguanil, doxycycline, or mefloquine (A I - evidence-based medicine recommendation); see Table 3 and Section 9 for details on each medication.

Atovaquone/proguanil is taken daily, beginning 1 day before entering the malarial region, during the period of exposure, and for 1 week after leaving the malarial region.

Doxycycline is taken daily, beginning 1 day before entering the malarial region, during the period of exposure, and for 4 weeks after leaving the malarial region.

Mefloquine is taken weekly, beginning 1 week before entering the malarial region, during the period of exposure, and for 4 weeks after leaving the malarial region.

Alternative: primaquine is taken daily, beginning 1 day before entry into the malarial region, during the period of exposure, and for 4 weeks after leaving the malarial region.

NOTE: Primaquine is CONTRAINDICATED in G6PD (glucose-6-phosphate dehydrogenase) deficiency and CONTRAINDICATED in pregnancy. See Table 8 for details on medication.

d. Chloroquine and Mefloquine-resistant Regions

Resistance to both chloroquine and mefloquine has been reported sporadically from various countries in Asia, Africa, and in the Amazon basin. However, it has not been found to be a significant problem except in rural, wooded regions where Thailand borders with Myanmar (Burma) and Cambodia. These are areas that are infrequently visited by tourists. See Figure 1b for a map of this area. In addition to chemoprophylaxis, personal protective measures should be optimized.

Drug of choice: Doxycycline (see Table 3 and Section 9). Doxycycline is taken daily, beginning 1 day before entering the malarial region, during the period of exposure, and for 4 weeks after leaving the malarial region.

Alternatives: There are no trials of alternative prophylactic agents for travellers to this region. Therefore unnecessary travel to the area, especially by pregnant women and children < 8 years of age, should be avoided. Atovaquone/proguanil has been a successful treatment for multi-drug resistant malaria in Thailand, and therefore this medication may be considered for travellers at risk in whom doxycycline is contraindicated or not tolerated. Atovaquone/proguanil is taken daily, beginning 1 day before entering the malarial region, during the period of exposure, and for 1 week after leaving the malarial region.

Table 3.
Malaria chemoprophylaxis regimens for at-risk individuals^a according to presence of drug resistance

Region	Drug(s) of choiceb	Alternatives
Chloroquine sensitive	Chloroquine	Atovaquone/proguanil, doxycycline, mefloquine
Chloroquine resistant	Atovaquone/proguanil, doxycycline, or mefloquine	Primaquinec
Chloroquine and mefloquine resistant	Doxycyclined	Atovaquone/proguanil
a IMPORTANT NOTE: Protection from mosquito bites (bed nets, insect repellents, etc) is the first line of defence against malaria for ALL travellers. In the Americas and Southeast Asia, chemoprophylaxis is recommended ONLY for travellers who will be exposed outdoors in rural areas during evening or night-time. b See text and Table 8 for adult and pediatric dosing information. c Contraindicated in G6PD (glucose-6-phosphate dehydrogenase) deficiency and in pregnancy. d Contraindicated in pregnancy, during breast-feeding, and in children < 8 years.

e. Primaquine Terminal Prophylaxis for Prevention of Relapses of P. vivax and P. ovale

P. vivax and P. ovale parasites can persist in the liver and cause relapses for as long as 5 years after routine chemoprophylaxis has been discontinued. Since most malarial areas of the world (except Haiti and the Dominican Republic) have at least one species of relapsing malaria, travellers to these areas have some risk of acquiring either P. vivax or P. ovale, although actual risk for an individual traveller is difficult to define. Primaquine decreases the risk of relapses by acting against the persistent liver stages (hypnozoites) of P. vivax and P. ovale. Primaquine terminal prophylaxis is administered after the traveller has left a malaria-endemic area, usually during or after the last 2 weeks of chemoprophylaxis. It is generally indicated only for people who have had prolonged exposure in malaria-endemic regions (e.g., long-term travellers or expatriates). Primaquine is contraindicated in pregnant women and individuals deficient in G6PD (see Table 3 and Section 9).

f. Selection of Antimalarial Drugs for Individual Travellers

Malaria causes severe illness that may be life-threatening. Mortality is at least 1% and increases to 20% or more in severe or complicated cases. Therefore it is always preferable to prevent the disease rather than treat someone after symptoms develop. Given the variety of choices in medication, a traveller at risk of malaria should always be encouraged to use chemoprophylaxis along with personal protective measures against insect bites (see Section 2).

All antimalarial drugs have the potential to cause side effects and should be prescribed only after completion of an individual risk assessment (as outlined in Section 2), to ensure that only travellers truly at risk of malaria infection receive antimalarial chemoprophylaxis. In deciding between the various chemoprophylactic options, the health care provider must weigh the traveller's underlying health status, other medications, malaria drug efficacy, risks and character of adverse drug reactions as well as the individual's preference against the likelihood that he or she will be exposed to malaria.

Most users of antimalarial chemoprophylaxis will have no or only minor adverse reactions. However, preconceived ideas about side effects may profoundly influence the traveller's confidence in a particular medication option and should be considered in the selection process. If adverse events do occur, they can have a significant impact not only on the traveller's health but also on his or her compliance with the medication. One option available is a trial of medication in advance of travel to test for tolerability. To keep adverse effects to a minimum, it is essential that all travellers be educated about the dosing schedule, including time of day and association with food, as well as precautions regarding sun exposure or other advice, depending on the drug used. Remember that while several antimalarial drugs may be equally efficacious when studied in clinical trials, their effectiveness is a measure of protection offered in real life. The more educated and compliant the patient, the closer the effectiveness is to the efficacy of a given chemoprophylactic agent.

Fatal malaria has occurred in travellers who have discontinued an effective antimalarial drug in favour of one that is less protective. Therefore, travellers should be warned to continue their malaria chemoprophylaxis regardless of what they are told by other travellers. Different medications used in other areas of the world may be less effective or associated with serious adverse effects, and are not recommended. Examples include proguanil alone (Paludrine®), pyrimethamine (Daraprim®), dapsone/pyrimethamine (Maloprim®), and mefloquine/sulfadoxine-pyrimethamine (Fansimef®).

SUMMARY POINTS TO KEEP IN MIND DURING THE DISCUSSION OF CHEMOPROPHYLAXIS INCLUDE THE FOLLOWING:

1. Inform patients that malaria can kill, but medications rarely cause serious adverse events if selected and used with care.
2. Select a medication that is least likely to exacerbate any past or present medical problems.
3. Indicate that medication should be taken in the recommended fashion to minimize significant side effects.
4. Discuss the option of a drug trial before the trip to check tolerability, if this is a concern.
5. Discuss strategies to change medication if serious adverse effects should arise during the trip.
6. Do not try to talk someone into a particular medication choice if there are alternatives that are considered to be just as efficacious.
7. Recommend that, if a malaria medication is tolerated well, the traveller should continue taking it regardless of what others say.

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