Supplement

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

9. Drugs for the Prevention and Treatment of Malaria

Travellers should be reminded that antimalarials, like all drugs, have the potential to cause adverse effects. These drugs should be prescribed after an individual risk assessment (as outlined in Section 2) to ensure that only those travellers truly at risk of malaria infection receive antimalarial chemoprophylaxis. Any drugs taken for chemoprophylaxis should be used in conjunction with personal protective methods to prevent mosquito bites (see Section 2). Most people using antimalarial chemoprophylaxis will have no or only minor adverse reactions, which can be minimized by careful adherence to dosing guidelines, precautions, and contraindications.

This chapter will review the drugs (in alphabetical order) used for the prevention (chemoprophylaxis) and treatment of malaria. This information is not designed to be comprehensive. It is important to note that product recommendations are subject to change, and therefore providers should consult up-to-date information, including recent drug monographs, for any updates, particularly with respect to compatibility, adverse reactions, contraindications, and precautions. Further details and discussion on recommendations concerning the use of these drugs for chemoprophylaxis and treatment can be found in Sections 3 and 8 respectively. Table 8 summarizes information, including doses, for the antimalarial drugs routinely used in Canada.

Figure 4 depicts the malaria lifecycle and the sites of action of recommended chemoprophylactic drugs.

ATOVAQUONE/PROGUANIL (ATQ/PG)

Trade Name: Malarone® . Licensed in Canada for malaria chemoprophylaxis in adults weighing > 40 kg and for treatment of uncomplicated malaria in adults and children.

Mechanism of Action: Atovaquone/proguanil is a fixed drug combination of atovaquone 250 mg and proguanil 100 mg, in a single tablet. The two components are synergistic, atovaquone inhibiting parasite mitochondria and proguanil, along with its active metabolite cycloguanil, causing inhibition of parasite folate synthesis through effects on dihydrofolate reductase. Atovaquone/proguanil is effective as a causal (acting at the liver stage) as well as suppressive (acting at the blood stage) prophylactic agent. Atovaquone/proguanil must be taken DAILY. Because of the causal effects, atovaquone/proguanil can be discontinued 1 week after departure from a malaria-endemic area.

Indications and Efficacy: For malaria chemo-prophylaxis, atovaquone/proguanil has equal efficacy (i.e., > 95%) to doxycycline and mefloquine against chloroquine-resistant falciparum malaria (A I evidence-based medicine); it is also effective along the borders of Thailand, where chloroquine and mefloquine resistance is documented.

In clinical trials of treatment of acute, uncomplicated P. falciparum malaria conducted in Southeast Asia, South America, and Africa, the efficacy of the combination of atovaquone/proguanil (dosed once daily for 3 days) has exceeded 95%. As well, published case reports have documented that it successfully treated multidrug-resistant malaria that had failed to respond to other therapies (AI - evidence-based medicine recommendation, see Appendix II). Therefore, atovaquone/proguanil, an effective and well-tolerated therapy, is considered first-line treatment of non-complicated P. falciparum infection, including multidrug-resistant P. falciparum (A I - evidence-based medicine recommendation.

There is insufficient evidence at this time to recommend atovaquone/proguanil for the routine treatment of non-falciparum malaria, although limited data suggest efficacy for the treatment of P. vivax
(C - evidence-based medicine).

Figure 4. Malaria life cycle and primary areas of drug activity
(modified from the U.S. Centers for Disease Control and Prevention DPDx site)

The malaria parasite life cycle involves two hosts. During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host (1).Sporozoites infect liver cells (2) and mature into schizonts (3) which rupture and release merozoites (4). (Of note, in P. vivax and P. ovale a dormant stage [hypnozoites] can persist in the liver and cause relapses by invading the bloodstream weeks or even years later.) After this initial replication in the liver (exo-erythrocytic schizogony A), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony B). Merozoites infect red blood cells (5). The ring stage trophozoites mature into schizonts, which rupture releasing merozoites (6). Some parasites differentiate into sexual erythrocytic stages (gametocytes) (7). Blood stage parasites are responsible for the clinical manifestations of the disease.

Daily atovaquone/proguanil can now be considered as first-line chemoprophylaxis for travellers to areas with multi-drug resistant falciparum malaria (with attention to contraindications and precautions) (A I - evidence-based medicine recommendation).

Adverse Effects, Contraindications and Precautions: Compared with other standard antimalarial regimens, the atovaquone/proguanil combination for chemoprophylaxis has demonstrated excellent safety and tolerance. During treatment, the most frequent adverse events are those associated with the gastrointestinal tract: approximately 8% to 15% of adults and children experience nausea, vomiting, abdominal pain, or diarrhea, and 5% to 10% develop transient, asymptomatic elevations in transaminase and amylase levels. Serious adverse events associated with atovaquone/proguanil, such as seizure and rash, are rare. Atovaquone has been associated with fever and rash in HIV-infected patients, requiring discontinuation of therapy, and has been shown to be teratogenic in rabbits but not in rat models (Food and Drug Administration category C drug). Proguanil is well tolerated, and although oral aphthous ulcerations are not uncommon they are rarely severe enough to warrant discontinuing this medication.

Pregnancy, severe renal insufficiency (creatinine clearance < 30 mL/min) and hypersensitivity to either component are the only contraindications to atovaquone/proguanil.

AZITHROMYCIN

Trade Name: Zithromax™

Mechanism of Action: Azithromycin is a macrolide antibiotic that inhibits parasite protein synthesis.

Indications and Efficacy: Azithromycin has not been shown to be very effective in the prevention of malaria (AII - evidence-based medicine). Studies performed to date are small and suggest that azithro-mycin is less effective than atovaquone/proguanil, doxycycline, mefloquine, or primaquine. Azithromycin, which must be taken daily, should be considered for chemoprophylaxis only in very selective groups.

There is insufficient evidence to recommend azithromycin as an alternative antimalarial except under circumstances in which other, more effective and safer, medications are not available or are contra-indicated (CI - evidence-based medicine recommendation).

Adverse Effects, Contraindications and Precautions: Azithromycin is considered to be safe in pregnancy and for children, and is available in suspension. However, in view of the serious consequences of malaria in pregnancy, use of this suboptimal antimalarial would not routinely be recommended.

CHLOROQUINE

Trade Name: Aralen®

Mechanism of Action: Chloroquine is a synthetic 4-aminoquinoline, which acts against the intra-erythrocytic stage of parasite development. It interferes with the digestion of hemoglobin within the red cell and leads to toxic metabolite formation within the parasite's food vacuole.

Indications and Efficacy: Chloroquine, taken once weekly, is effective for malaria prevention and treatment in travellers to areas with chloroquine-sensitive malaria (A I - evidence-based medicine recommendation). It remains the drug of choice for malaria chemoprophylaxis of travellers to areas with chloroquine-sensitive malaria and the drug of choice for the treatment of chloroquine-sensitive falciparum malaria, chloroquine sensitive P. vivax as well as P. ovale and P. malariae infections. Chloroquine is suitable for people of all ages and for pregnant women. There is insufficient drug excretion in breast milk to protect a breast-feeding infant, and therefore nursing infants should be given chloroquine (adjusted for changing weight, see Table 8). Since overdoses are frequently fatal, instructions for childhood doses should be carefully followed, and the medication should be kept out of the reach of children.

Weekly chloroquine plus daily proguanil is approximately 60% more efficacious in subSaharan Africa than weekly chloroquine alone, but it is much less efficacious than atovaquone/proguanil, doxycycline or mefloquine (A I - evidence-based medicine recommendation) and is not routinely recommended for Canadian travellers.

Adverse Effects, Contraindications and Precautions: Except for its bitter taste, chloroquine is usually well tolerated. Taking the drug with food may reduce other mild side effects, such as nausea and headache. Black-skinned people 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, is extremely unlikely with chloroquine given as a 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 recommendation). Concurrent use of chloroquine interferes with antibody response to intradermal human diploid cell rabies vaccine.

CLINDAMYCIN

Trade Name: Dalacin C®

Mechanism of Action: Clindamycin is an antibiotic that inhibits parasite protein synthesis.

Indications and Efficacy: Clindamycin is indicated only for treatment of malaria in restricted circumstances. Clindamycin, although less effective than doxycycline or atovaquone/proguanil, is used in combination with quinine for those unable to tolerate or who have contraindications (e.g., pregnant women and young children) to the use of first-line agents.

Adverse Effects, Contraindications and Precautions: The most frequent adverse events with clindamycin are diarrhea and rash. Clostridium difficile associated disease, including pseudo membranous colitis, has been reported.

DOXYCYCLINE

Trade Name: Vibra-Tabs™

Mechanism of Action: Doxycycline is an antibiotic that inhibits parasite protein synthesis.

Indications and Efficacy: Doxycycline is effective for the prevention and treatment of chloroquine-resistant P. falciparum. It has been shown to have equivalent efficacy to atovaquone/proguanil and mefloquine for the prevention of chloroquine-resistant P. falciparum (A I - evidence-based medicine). Doxycycline is an efficacious chemoprophylactic agent against mefloquine-sensitive and mefloquine-resistant P. falciparum malaria (A I - evidence-based medicine recommendation) but must be taken DAILY to work. The major reason for doxycycline failures is non-compliance with this daily regimen.

Adverse Effects, Contraindications and Precautions: 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. Because doxycycline is photosensitizing, it may make the skin burn more easily; use of a sunscreen that blocks ultraviolet A rays may reduce this problem. Doxycycline may also increase the risk of vaginal candidiasis; 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 doxy-cycline with barbiturates, carbamazapine, or phenytoin may result in a 50% decrease in doxycycline serum concentration because of induction of microsomal enzyme activity and resulting reduction of the half-life of doxycycline. Adjustment of doxycycline dosage may be necessary, using either a twice daily dosing schedule (100 mg bid) or a single dose of 200 mg daily.

Doxycycline is contraindicated during pregnancy, in breast-feeding 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.

MEFLOQUINE

Trade Name: Lariam®

Mechanism of Action: Mefloquine is a quinoline-methanol. It is a lipophylic drug that acts on the intraerythrocytic asexual stages of parasite development causing degradation of hemozoin within the food vacuole.

Indications and Efficacy: Mefloquine is an effective chemoprophylactic and therapeutic agent against drug-resistant P. falciparum. In Canada, it is routinely recommended ONLY for chemoprophylaxis because of the high rate of adverse effects with treatment doses. It is one of the drugs of choice, along with atovaquone/proguanil and doxycycline, for the prevention of malaria in travellers to chloroquine-resistant regions (A I - evidence-based medicine recommendation).

There is no evidence that toxic metabolites of mefloquine accumulate, and long-term use of mefloquine (> 1 year) 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 tolerate this medication and are at risk of acquiring malaria (B II - evidence-based medicine recommendation).

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 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 recommendation). In controlled studies 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 also permits an assessment of drug tolerance before travel and allows a change to a suitable alternative if required. Alternatively, if time permits, mefloquine may be initiated up to 3 weeks before travel in order to assess tolerance and achieve higher blood levels before the traveller enters malaria-endemic areas.

Adverse Effects: 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 vivid dreams, dizziness, mood changes, insomnia, headache, and diarrhea. Approximately 1% to 4% of mefloquine users may have to discontinue prophylaxis because of adverse effects, a rate not significantly different from other chemoprophylaxis regimens. Over 13 million travellers have used mefloquine prophylaxis, and severe reactions (seizure, psychosis) to this drug are rare (reported from 1 in 10,000 to 1 in 13,000 users). The great majority of mefloquine users (95% to 99%) have either no side effects or only mild and temporary ones. Occasionally, a traveller (in particular, women) will experience a less severe but still troublesome neuropsychological reaction (e.g., anxiety, mood change) to mefloquine (1 in 250 to 500 users), requiring a change to an alternative drug. These reactions are almost always reversible. On occasions, neuropsychological complaints have persisted long after mefloquine has been stopped. Rare cases of suicidal ideation and suicide have been reported, though no relation to drug administration has been confirmed.

When mefloquine is prescribed for prophylactic use, individuals should be advised that if they experience psychiatric symptoms such as acute anxiety, depression, restlessness, or confusion, these may be prodromal to more serious adverse events. They should report these adverse events immediately, the drug should be discontinued, and an alternative medication should be substituted.

CATMAT does not routinely recommend mefloquine for the treatment of malaria, because in treatment doses (25 mg base/kg) it 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: These include known hypersensitivity or past severe reaction to mefloquine; history of serious psychiatric disorder (e.g., psychosis, severe depression, generalized anxiety disorder, schizophrenia or other major psychiatric disorders); and seizure disorder.

Precautions: Precautions for the use of mefloquine include use in children < 5 kg ; use in those with 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, see Section 9); underlying cardiac conduction disturbances or arrhythmia; and 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 people concurrently taking 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 pharmacokinetic 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.

PRIMAQUINE

Trade Name: Primaquine (primaquine phosphate)

Mechanism of Action: Primaquine is an 8-aminoquinoline antimalarial that is active against multiple life cycle stages of the plasmodia that infect humans and has been used for over 50 years. Its mechanism of action is incompletely understood. However, it has activity against the developing liver stages (causal effect) thereby preventing establishment of infection; against liver hypnozoites, preventing relapses in established P. vivax and P. ovale infections; against blood stages; and against gametes, thereby preventing transmission.

Indications and Efficacy: Evidence is accumulating that primaquine is an effective chemosuppressive for P. falciparum malaria (A I - evidence-based medicine recommendation). Recent studies have shown efficacy in semi-immune and non-immune subjects, although data for travellers and for varied geographic regions are limited. Given at a dose of 0.5 mg/kg base per day (adult dose 30 mg base per day) for 11 to 50 weeks, primaquine had a protective efficacy of 85% to 95% against both P. falciparum and P. vivax infections. Primaquine was better tolerated than other standard chemoprophylactic regimens in people who were not G6PD deficient. Because of the causal effects of primaquine, it can be discontinued 1 week after departure from a malaria-endemic area. All travellers need to be evaluated for G6PD deficiency before primaquine is initiated. This significantly complicates the prescription process.

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 Domin-ican 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 after the last 2 weeks of chemoprophylaxis. Terminal prophylaxis with primaquine is generally indicated only for people who have had prolonged exposure in malaria- endemic regions (e.g., long-term travellers or expatriates).

None of the other currently recommended chemoprophylaxis regimens will prevent relapses due to P. vivax and P. ovale. In order to reduce the risk of relapse following the treatment of symptomatic P. vivax or P. ovale infection, primaquine is indicated to provide "radical cure". Primaquine should be initiated for radical cure after chloroquine therapy has been completed and the acute febrile illness is over (about 1 to 2 weeks).

P. vivax isolates with a decreased responsiveness to primaquine are well documented in Southeast Asia and, in particular, Papua New Guinea and Irian Jaya. Recently, primaquine radical treatment failure has been reported from Thailand and Somalia. On the basis of increasing numbers of reports of resistance to primaquine at the standard dose of 0.25 mg/kg, the recommended dose has been increased to 30 mg (0.5 mg/kg) of primaquine base daily for 14 days (B I - evidence-based medicine recommendation).

Although not a first-line chemoprophylactic agent, primaquine may be considered an alternative chemo-prophylactic agent (with attention to contraindications and precautions) for those without G6PD deficiency when other regimens are either inappropriate or contraindicated (AI - evidence-based medicine recommendation).

Adverse Effects, Contraindications and Precautions: Primaquine is generally well tolerated but may cause nausea and abdominal pain, which can be decreased by taking the drug with food. More importantly, primaquine may cause oxidant-induced hemolytic anemia with methemoglobinemia, particularly among individuals with G6PD deficiency, which is more common in those of Mediterranean, African, and Asian ethnic origin. As well, those receiving > 15 mg base/day have a greater risk of hemolysis. Therefore, ALL individuals should have their G6PD level measured before primaquine therapy is initiated.

Primaquine is contraindicated in patients with severe G6PD deficiencies. In mild variants of G6PD deficiency, primaquine has been used safely at a lower dose for radical cure to prevent P. vivax and P. ovale relapses (0.8 mg base/kg weekly; adult dose 45 mg base weekly for 8 weeks); however, this reduced dose is insufficient for chemoprophylactic activity. When used at prophylactic doses (0.5 mg base/kg daily) in children and men with normal G6PD activity, mean methemoglobin rates (5.8%) were below those associated with toxicity (> 10%). Patients should be advised to stop their medication and report to a physician immediately if jaundice or abnormally dark or brown urine is noted.

Primaquine use is contraindicated in pregnancy. P. vivax or P. ovale infections occurring during pregnancy should be treated with standard doses of chloroquine (Table 8). Relapses can be prevented by weekly chemoprophylaxis with choloroquine until after delivery, when primaquine can be safely used for mothers with normal G6PD levels.

QUININE AND QUINIDINE

Mechanism of Action: These quinoline-containing antimalarials are alkaloid derivatives of cinchona bark that act on the intraerythrocytic asexual stage of the parasite.

Indications and Efficacy: Quinine and quinidine are indicated only for the treatment of malaria. Quinine (or quinidine) should not be used alone: a second drug such as doxycycline should be used concurrently (see Section 8).

Oral therapy with quinine (with a second agent) is indicated for the treatment of non-complicated falciparum malaria and as step-down therapy (with a second agent) after parenteral treatment of complicated malaria. Oral quinidine is often used for these purposes in children, because quinidine is easier to suspend into liquid formulation.

Quinine is the preferred drug for parenteral therapy of severe or complicated malaria (see Table 5, WHO criteria) because of the significant cardiotoxic effects associated with parenteral quinidine and the requirement for cardiac monitoring.

Adverse Effects, Contraindications and Precautions: Minor adverse events are common with quinine and quinidine use. These include cinchonism (tinnitus, nausea, headache, blurred vision), hypoglycemia, nausea, and vomiting. Occasionally, hypersensitivity and nerve deafness have been reported. Parenteral quinidine has the potential to increase the QTc and therefore requires electrocardiographic monitoring.

OTHER DRUGS NOT AVAILABLE OR NOT ROUTINELY RECOMMENDED IN CANADA (IN ALPHABETICAL ORDER)

It is important for travellers and providers to understand that the medical management of malaria in countries where the disease is endemic may differ significantly from management in Canada. In countries where malaria is endemic there may be a limited number of effective medications available for treatment, indeed some of the drugs used may be ineffective in non-immune travellers or be associated with unacceptable adverse outcomes. As well, the level of health care available in some of these countries may put travellers at risk of other infectious diseases.

AMODIAQUINE is a 4-aminoquinoline that was first introduced as an alternative to chloroquine. Unfortunately, resistance to this drug has followed the path of chloroquine resistance.

ARTEMISININ AND DERIVATIVES are endoperoxide-containing natural antimalarials from sweet wormwood (Artemisia annua). They are being used for the treatment of malaria in many parts of the world. Artemesinin (qinghaosu) derivatives - including artesunate, artemether, arteether, and dihydroartesinin - are available in oral, parenteral, and suppository formulations. They are all metabolized to a biologically active metabolite, dihydro-artemesinin, and have their antiparasitic effects on the younger, ring-forming parasites. They thereby decrease the numbers of late parasite forms that can obstruct the host's microvasculature.

All artemisinin preparations have been studied and used for treatment only. They are not recommended for prophylaxis because of their short half-life. For the treatment of severe and complicated malaria, all compounds are at least as efficacious as quinine. Qinghaosu and its derivatives lead to faster clearance times of parasites (mean: 32% faster) and fever (mean: 17% faster) than do any other antimalarials. In spite of the more rapid antiparasitic action of qinghaosu compounds, these agents have not been shown to decrease mortality as compared with quinine.

Artemisinin-related compounds act rapidly against drug-resistant P. falciparum strains but have high recrudescence rates (about 10% to 50%) when used as monotherapy for < 5 days. Recent studies have examined longer durations of therapy (7 days), and combinations of qinghaosu derivatives and mefloquine to prevent recrudescence. In vitro synergy has been demonstrated between artemisinin derivatives, mefloquine, and tetracycline. In Thailand, treatment with oral artesunate (over 3 to 5 days) combined with mefloquine (15 to 25 mg/kg) was more effective than mefloquine or artesunate alone. Combination therapy results in > 90% cure rates of primary and recrudescent P. falciparum infections.

Artemisinin derivatives have been used in over 1 million patients and are well tolerated. To date, there have been two human cases of complete heart block associated with their use, but most volunteer and clinical studies have found no evidence of cardiac or other toxic effects. Neurological lesions involving the brainstem have been seen in rats, dogs, and primates given repeated doses of artemisinin derivatives. To date, no clinical neurologic events have been observed in humans; however, studies addressing cumulative toxic effects in humans have not been performed. The safety of qinghaosu derivatives in pregnancy has not been established.

Artemisinin and its derivatives are now available and increasingly used in Southeast Asia and Africa; none is licensed in Canada. Coartemether (Riamet in Europe, Coartem in Africa) is a combination of artemether and lumefantrine that is currently licensed in some European countries and is becoming widely distributed in Africa for the treatment of malaria. Combinations of artesunate and mefloquine appear to be the most active drug regimens for treatment of multidrug-resistant falciparum malaria in Southeast Asia. There is concern that the quality of artemisinin derivatives available in developing countries may be questionable, as they may not be produced in accordance with the good manufacturing production standards required in North America.

Although there is good evidence that therapy with artemisinin compounds is safe, questions about cumulative neurologic toxicity require resolution.

Recommendations

1. Artemisinin compounds are effective alternative therapies for multidrug-resistant malaria (complicated and uncomplicated) (AI - evidence-based medicine recommendation). However, at present, there are insufficient toxicity data and evidence of clinical superiority over standard therapy to routinely recommend these as first-line agents, particularly for P. falciparum infections acquired in Africa.
2. Artemisinin compounds should not be used for chemoprophylaxis (C III - evidence-based medicine recommendation).
3. Artemisinin compounds may be considered for the treatment of laboratory-confirmed severe falciparum malaria acquired in areas where P. falciparum is known to be multidrug-resistant OR for the treatment of falciparum malaria that fails standard drug regimens. In such cases, they should be used in combination with mefloquine or tetracycline/doxycycline (A I - evidence-based medicine recommendation).

HALOFANTRINE is a phenanthrene methanol derivative related to mefloquine and quinine. It is available only in an oral formulation, which is limited by variable bio-availability. Halofantrine is not licensed in Canada and has recently been withdrawn from the world market because of concerns about cardiotoxicity. It does remain widely available in the tropics, and travellers should be made aware of the danger of this drug. The WHO has reported cardiac deaths associated with the use of halofantrine and no longer recommends its use.

Recommendations

1. Halofantrine should not be used for self-directed therapy (D II - evidence-based medicine recommendation).
2. Halofantrine is not indicated for the treatment of multidrug-resistant malaria (combined resistance to mefloquine and chloroquine) or for the treatment of recrudescent malaria (D II - evidence-based medicine recommendation).
3. Travellers who inquire about halofantrine or who are likely to encounter its use (e.g., in West Africa) should be informed of its potential cardiotoxic effects (C III - evidence-based medicine recommendation).

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

PYRIMETHAMINE-SULFADOXINE (Fansidar®) is a fixed drug combination antimetabolite that inhibits parasite folate synthesis. Historically, this drug has been used for treatment, including self-treatment, of P. falciparum, but increasing resistance means that it has limited utility for the treatment of P. falciparum and is no longer recommended. Resistance has been reported in the Amazon Basin, Southeast Asia, and increasingly throughout Africa.

Pyrimethamine-sulfadoxine is not recommended by CATMAT, the Centers for Disease Prevention and Control, or WHO for chemoprophylaxis because of the life-threatening complication of Stevens-Johnson syndrome and toxic epidermal necrolysis.

PYRONARIDINE is a benzonaphthyridine synthesized in China in 1970, which has been used for the treatment of P. vivax and P. falciparum for more than 20 years and has been shown to be effective in the treatment of falciparum malaria in children in Cameroon. It has more gastrointestinal side effects than chloroquine. There are insufficient data at present to recommend the use of pyronaridine for the treatment of malaria in non-immune travellers.

TAFENOQUINE is a long-acting, 8-aminoquinoline with a half-life measured in weeks rather than hours. Initial research has shown efficacy with weekly chemoprophylaxis and evidence of causal prophylaxis. Studies are ongoing in semi and non-immune individuals. In the future, tafenoquine may provide another option for chemoprophylaxis in those without G6PD deficiency.

Table 8. Drugs for the treatment and prevention of malaria

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