[Table of Contents]

Volume: 26S2 - March 2000

2000 Canadian recommendations for the prevention and treatment of malaria among international travellers
prepared by the
COMMITTEE TO ADVISE ON TROPICAL MEDICINE AND TRAVEL (CATMAT)

3. CHEMOPROPHYLACTIC REGIMENS

a. Introduction

Medications to reduce the risk of developing clinical malaria should be considered for visitors to the following areas:

URBAN AND RURAL AREAS OF

(Higher risk) -sub-Saharan Africa (except most of South Africa), and Oceania (including Papua New Guinea, Irian Jaya, Solomon Islands and Vanuatu).

(Lower risk) - Haiti, India, Bangladesh, Pakistan, and Nepal (Terai region).

EVENING OR OVERNIGHT EXPOSURE IN RURAL AREAS OF

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

Travellers should be informed that although antimalarials can markedly decrease the risk of acquiring symptomatic malaria, NONE OF THESE AGENTS CAN GUARANTEE COMPLETE PROTECTION AGAINST MALARIA. Personal protection measures are an important adjunct to malaria prevention, even for those taking chemo-prophylactic 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 leaving a malaria region whether or not chemoprophylaxis has been used. In most travellers who acquire P. falciparum infection, symptoms develop 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.

There is no global consensus on malaria chemo-prophylactic regimens. During their travels many individuals will encounter other travellers or health care providers who will counsel them to change or stop their antimalarials (especially mefloquine), leaving them at high risk of acquiring potentially life-threatening malaria. One should warn travellers of this possibility and reinforce the antimalarial guidelines and the risks and benefits of effective chemoprophylaxis. Appendix IV , entitled "Misconceptions about malaria and mefloquine", may aid the practitioner in answering travellers' questions.

Table 1 summarizes the different chemo-prophylactic regimens according to regions of drug resistance. This information can be utilized along with Appendix I to determine the appropriate antimalarial for an individual traveller.

TABLE 1 Malaria Chemoprophylaxis Regimens for At-Risk Individuals^a According to Regions of Drug Resistance Region Drug(s) of Choice^b,c Alternatives Chloroquine sensitive Chloroquine 1^st Choice: mefloquine 2^nd Choice: doxycycline^d Chloroquine resistant Mefloquine 1^st Choice: doxycycline^d 2^nd Choice: primaquine^e or Malarone^f 3^rd Choice: chloroquine plus proguanil^g Chloroquine and mefloquine resistant Doxycycline^d Malarone^{f 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 (1) Chloroquine and mefloquine are taken weekly, beginning 1 week before entering a malarial region, continued while in that region, and for 4 weeks after departure from the malarial region. (2) Doxycycline and proguanil are taken daily, starting 1 day before entering a malarial region, continued daily while in that region, and for 4 weeks after departure. (3) Primaquine and Malarone are taken daily, starting 1 day before entering a malarial region, continued during stay in that region, and for 1 week after departure. ^c Adult and pediatric dosing information provided in Table 2. ^d Contraindicated in pregnancy, during breastfeeding and in those < 8 years. ^e Contraindicated in G6PD deficiency and in pregnancy. ^f Limited data, not currently licensed for chemoprophylaxis. ^g Chloroquine plus proguanil is less effective than mefloquine or doxycycline in these areas. Note: CATMAT does not recommend proguanil as a single agent for prophylaxis.

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, South America and most of 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. 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. (A I - evidence-based medicine recommendations - see Appendix II). Chloroquine is suitable for people of all ages and for pregnant women (see section 3f, for contraindications and adverse effects). There is insufficient drug excretion in breast milk to protect a breastfeeding infant, and therefore nursing infants should be given chloroquine (adjusted for changing weight, see Table 2). Since chloroquine overdoses are frequently fatal, instructions for childhood doses should be carefully followed, and the medication should be kept out of the reach of children.

Alternatives: For individuals unable to tolerate chloroquine, mefloquine or doxycycline should be used (see section 3f, for contraindications and adverse effects).

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).

Drug of choice: mefloquine is the drug of choice for most travellers to chloroquine-resistant regions. Mefloquine is an effective chemoprophylactic and therapeutic agent against drug-resistant P. falciparum. It is significantly more effective than the combination of chloroquine and proguanil for malaria chemoprophylaxis in sub-Saharan Africa (A I - evidence-based medicine recommendations - see Appendix II).

Mefloquine is taken once weekly, beginning 1 week before entering a malarial region, continued during the period of exposure, and for 4 weeks after leaving the malarial region. There is no evidence that toxic metabolites of mefloquine accumulate, and long-term (> 1 year) use of mefloquine by Peace Corps volunteers in Africa has not been associated with additional adverse effects. It is recommended, therefore, that the duration of use of mefloquine NOT be arbitrarily restricted in individuals who are at risk of acquiring malaria (B II - evidence-based medicine recommendations - see Appendix II).

For travellers who will be at immediate high risk of drug-resistant falciparum malaria, consideration may be given to the use of a loading dose of mefloquine. Data from several trials indicate that mefloquine taken once daily for 3 days before travel followed by a once weekly dose (as above) is a well-tolerated and effective way to rapidly achieve therapeutic blood levels (reaching steady state levels in 4 days compared with 7 to 9 weeks with standard weekly dosing of mefloquine) (A I - evidence-based medicine recommendations - see Appendix II). Only about 1% to 2% of loading dose recipients discontinued mefloquine, and most of these did so during the first week. The loading dose strategy permits an assessment of drug tolerance before travel and allows a change to a suitable alternative if required. Alternatively, when time permits, mefloquine may be initiated up to 3 weeks before travel in order to assess tolerance and achieve higher blood levels before entry to malaria-endemic areas.

Alternatives: For individuals unable to take mefloquine, alternatives are doxycycline (alternative of choice), primaquine (contraindicated in glucose-6-phosphate dehydrogenase [G6PD] deficiency, see section 9b), Malarone^® (see section 9a) or, less optimally, chloroquine and proguanil. In comparative trials in Irian Jaya and Africa, doxycycline has been shown to be as effective as mefloquine (A I - evidence-based medicine recommendations - see Appendix II). Chloroquine plus proguanil is approximately 60% more effective in sub-Saharan Africa than chloroquine alone but it is less effective than doxycycline or mefloquine (A I - evidence-based medicine recommendations - see Appendix II).

In some instances, one may need to consider less well-established alternatives. Evidence is accumulating that primaquine is an effective chemosuppressive for P. falciparum malaria (A I - evidence-based medicine recommendations - see Appendix II). Recent studies have shown efficacy in semi-immune and non-immune subjects, although data for travellers and for varied geographic regions are limited. Primaquine phosphate is given at adult doses of 30 mg (base) daily and continued for 1 week after exposure. All subjects need to be evaluated for G6PD deficiency before primaquine is initiated. This significantly complicates the prescription process (see section 9b). Daily Malarone^® also shows promise for chemoprophylaxis (A I - evidence-based medicine recommendations - see Appendix II), although there are only limited data regarding its efficacy in non-immune travellers. Malarone^® is not currently licensed in Canada for this indication.

In deciding between the alternative drugs, the health care provider must weigh the drug efficacy, risks and character of adverse drug reactions with the likelihood that the traveller will be exposed to chloroquine-resistant malaria. As discussed, such a decision must take into account personal health factors, destination and activities during travel.

d. Chloroquine- and Mefloquine-Resistant Regions

Resistance to both chloroquine and mefloquine is not a significant problem except in rural, wooded regions where Thailand borders with Myanmar (Burma) and Cambodia (areas infrequently visited by tourists). See Figure 1b showing map of China and Thailand.

Drug of choice: doxycycline alone is the chemoprophylaxis of choice in these regions. It is taken once daily (100 mg), beginning 1 day before entering a malarial area, continued during the period of exposure and for 4 weeks after exposure. Doxycycline is an effective chemoprophylactic agent against mefloquine-sensitive and mefloquine-resistant falciparum malaria (AI - evidence-based medicine recommendations - see Appendix II) but must be taken DAILY to work. The main reason for doxycycline failure is non-compliance with this daily regimen.

Alternatives: there are no proven alternatives for travellers to this region in whom doxycycline is contraindicated or not tolerated. Consultation should be sought from a travel medicine specialist and such travellers should be advised to re-evaluate their travel plans. Limited data suggest that Malarone^® may become an alternative chemopro-phylaxis in this situation.

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 liver stages of P. vivax and P. ovale. Primaquine terminal prophylaxis is administered after the traveller has left a malaria-endemic area, usually during or following the last 2 weeks of chemoprophylaxis. Terminal prophylaxis with primaquine is generally indicated only for persons 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 section 3f, below, for adverse effects and precautions).

f. Antimalarial Drug Adverse Effects and Precautions 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. Any antimalarial drugs utilized for chemoprophylaxis should be used in conjunction with personal protection methods to prevent mosquito bites (see section 2). Most users of antimalarial chemoprophylaxis will have no or only minor adverse reactions. Careful adherence to dosing guidelines and warnings will decrease the risk of adverse events (see Table 2).

Chloroquine

Except for its bitter taste, chloroquine is usually well tolerated. Other mild side effects, such as nausea and headache, may be reduced by taking the drug with food. African-Canadians may experience generalized pruritus, which is not indicative of drug allergy. Transient, minor visual blurring may occur initially but should not be a reason to discontinue chloroquine. Retinal toxic effects, which may occur with long-term daily doses of chloroquine (>100 g total dose) used in the treatment of other diseases, are extremely unlikely with chloroquine given as weekly chemoprophylaxis. Chloroquine may worsen psoriasis and, rarely, is associated with seizures and psychosis. Therefore, chloroquine should not be used in individuals with a history of epilepsy or generalized psoriasis (C III - evidence-based medicine recommendations - see Appendix II). Concurrent use of chloroquine interferes with antibody response to intradermal human diploid rabies vaccine.

Mefloquine

Mefloquine is generally well tolerated when used for chemoprophylaxis. Approximately 20% to 30% of travellers will experience side effects from either mefloquine or chloroquine; most of these are mild and self-limiting. The most frequent minor side effects reported with mefloquine use are nausea, strange dreams, dizziness, mood changes, insomnia, headache, and diarrhea. Approximately 1% to 4% of mefloquine users discontinue prophylaxis because of adverse effects, a rate not significantly different from other chemoprophylaxis regimens. Severe neuropsychiatric reactions (psychosis, convulsions) are infrequent with prophylactic doses and are reported to occur in approximately 1/10,000 to 1/13,000 individuals. Less severe but nonetheless troublesome neuro-psychologic adverse events (anxiety, depression, nightmares, etc.) requiring drug discontinuation are reported in < 1% of users. In treatment doses (25 mg base/kg), which are not routinely recommended by CATMAT, mefloquine is less well tolerated. Severe neuropsychiatric reactions are reported to be 10 to 60 times more frequent, occurring in 1/215 to 1/1,700 users of treatment doses of mefloquine.

Contraindications for the use of mefloquine include

• known hypersensitivity or past severe reaction to mefloquine
• history of serious psychiatric disorder (e.g. psychosis or severe depression)
• seizure disorder

Precautions for the use of mefloquine include the following:

• children < 5 kg
• occupations requiring fine coordination or activities in which vertigo may be life-threatening, such as flying an aircraft
• concurrent use of chloroquine or quinine-like drugs (halofantrine and mefloquine should not be used concurrently)
• underlying cardiac conduction disturbances or arrhythmia
• first trimester of pregnancy

There have been concerns regarding the co-administration of mefloquine and agents known to alter cardiac conduction, including beta blockers, calcium channel blockers, phenothiazines, non-sedating antihistamines, and tricyclic antidepressants. However, at present these concerns remain theoretical, and the concurrent use of these agents is not contraindicated. A recent review of available data suggests that mefloquine may be used in persons concurrently receiving beta blockers if they have no underlying cardiac arrhythmia.

Insufficient mefloquine is excreted in breast milk to protect a nursing infant. Although the package insert recommends that mefloquine not be given to children weighing < 5 kg, it should be considered for children at high risk of acquiring chloroquine-resistant P. falciparum malaria. There are no pharma-cokinetic data upon which to recommend a correct dose for children weighing < 15 kg. The WHO has suggested a chemosuppressive dose of 5 mg base/kg weekly for children weighing > 5 kg.

Doxycycline

Doxycycline is contraindicated during pregnancy, in breastfeeding women and in children < 8 years of age. Although the long-term safety (> 3 months) of doxycycline has not been established, historically, tetracycline derivatives have been used at lower doses over many years for skin disorders. However, hepatic necrosis and serum sickness have been associated with prolonged use of minocycline, a tetracyline derivative.

Doxycycline may cause gastrointestinal upset and rarely esophageal ulceration, which are less likely to occur if the drug is taken with food and large amounts of fluid. It should not be taken simultaneously with Pepto-bismol^® or antacids. Doxycycline is photosensitizing and may make the skin more susceptible to sunburns. Using a sunscreen that blocks ultraviolet A rays may reduce this problem. Doxycycline may also increase the risk of candidal infections of the vagina; therefore, women should carry antifungal therapy for self-treatment of vaginal candidiasis.

Although tetracyclines and other antibiotics have been cited as a cause of oral contraceptive failure, a recent case-control analysis failed to demonstrate any significant association.

Concurrent use of doxycycline with barbiturates, carbamazapine, or phenytoin may result in decreased doxycycline serum concentration due to induction of microsomal enzyme activity and resulting 50% reduction of the half-life of doxycycline. Adjustment of doxycycline dosage may be necessary with either a twice daily dosing schedule (100 mg bid) or 200 mg daily.

Proguanil

Proguanil should not be used as a single agent for chemoprophylaxis. It is well tolerated, and although oral aphthous ulcerations are not uncommon they are rarely severe enough to warrant discontinuing this medication. Proguanil is considered safe during pregnancy and breastfeeding, but insufficient drug is excreted in the milk to protect a nursing infant.

Primaquine

See section 9b.

Malarone^®

See section 9a.

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