[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)

9. NEW DRUGS FOR THE PREVENTION AND TREATMENT OF MALARIA

a. Atovaquone/Proguanil (Malarone^®) for the Treatment and Prevention of Malaria

Atovaquone (ATQ), a hydroxynapthaquinone, is a member of a novel class of antimalarials first described in the 1920s. ATQ is an analog of ubiquinone, which selectively inhibits parasite mitochondrial electron transport. ATQ has similar activity against both chloroquine-sensitive and chloroquine-resistant P. falciparum isolates. However, when ATQ is used as monotherapy, resistance develops rapidly. ATQ displays in vitro antagonism with artemisinin compounds and quinolines but synergy with proguanil and tetracycline. Proguanil displays its synergistic activity with ATQ even in the context of documented proguanil resistance.

The fixed drug combination Malarone^® (tablet: 250 mg ATQ and 100 mg proguanil) is licensed in Canada for the treatment of uncomplicated malaria, but it is not currently licensed for chemoprophylaxis.

Compared with other standard antimalarial regimens, the ATQ/proguanil combination has demonstrated excellent safety and tolerance with fewer reported adverse events than mefloquine and quinine plus tetracycline. During treatment, the most frequent adverse events are those associated with the gastrointestinal tract. Approximately 8% to 15% of adults and children will experience nausea, vomiting, abdominal pain or diarrhea, and in 5% to 10% there will be transient, asymptomatic elevations in transaminases and amylase. Serious adverse events associated with ATQ/proguanil are rare. One episode of anaphylaxis has been attributed to this combination. Three patients experienced convulsions 2 to 5 days after initiation of therapy, each with a history of seizure disorders. ATQ has been associated with fever and rash in HIV-infected patients, requiring discontinuation of therapy. It has been shown to be teratogenic in rabbits but not in rat models (FDA category C drug). Pregnancy and hypersensitivity to either component are the only contraindications to ATQ/proguanil.

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 ATQ and proguanil (dosed once daily for 3 days) has exceeded 95%. As well, published case reports have documented that this combination drug successfully treated multidrug-resistant malaria that had failed to respond to other therapies. (AI - evidence-based medicine - see Appendix II).

ATQ/proguanil combination therapy has also been effective in pediatric populations at a dose of 20 mg/kg/day of ATQ and 8 mg/kg/day of proguanil for 3 days.

Three placebo-controlled studies have demonstrated a greater than 95% efficacy of ATQ/proguanil as a chemoprophylactic agent against P. falciparum malaria in semi-immune adults and children at an adult dose of 1 tablet per day. Mounting evidence indicates that ATQ/proguanil is effective as a causal (acting at the liver stage) as well as suppressive (acting at the blood stage) prophylactic agent and can therefore be discontinued 1 week after departure from a malaria-endemic area. Additional studies in non-immune adults and children are required in order to satisfy regulatory agencies of its safety and effectiveness as a chemoprophylactic agent.

Recommendations

i. ATQ combined with proguanil (Malarone^®), an effective and well-tolerated therapy, can now be considered as first line therapy (with attention to contraindications and precautions) for uncomplicated multidrug-resistant P. falciparum malaria. (A I - evidence-based medicine recommendations - see Appendix II).

ii. There are insufficient data at present to recommend its use for malaria caused by other Plasmodium species (vivax, ovale, malariae). (C - evidence-based medicine recommendations - see Appendix II).

iii. ATQ/ proguanil may be considered for the treatment of falciparum malaria that fails standard drug regimens (A I - evidence-based medicine recommendations - see Appendix II).

iv. At present ATQ/proguanil (Malarone^®) is not licensed for prophylaxis use in Canada; however, there may be limited use for ATQ/proguanil as a prophylactic agent (with attention to contraindications and precautions) when other recommended options are either inappropriate or contraindicated. (B I - evidence-based medicine recommendations - see Appendix II).

b. Primaquine and Tafenoquine for the Prevention of Malaria

Primaquine is an 8-aminoquinolone that has been used for decades to prevent relapses of P. vivax and P. ovale infections (radical cure) and as a gametocidal agent to decrease the transmission of P. falciparum in malaria-endemic areas. Because primaquine has activity against both blood and tissue (liver) stages of malaria, it can eliminate P. vivax and P. falciparum infections that are developing in the liver (causal prophylaxis) and prevent symptomatic or clinical infection.

Recent randomized double blind, placebo-controlled studies have examined the efficacy of primaquine as a prophylactic agent in partially immune Kenyan children and non-immune Indonesian and Colombian men. 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 persons who were not G6PD deficient. 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. Primaquine is contraindicated in patients with severe G6PD deficiency. 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/week; adult dose 45 mg base weekly for 6 weeks); however, this reduced dose is insufficient for chemoprophylactic activity. When used at prophylactic doses (0.5 mg base/kg/day) in children and men with normal G6PD activity, mean methemoglobin rates (5.8%) were below those associated with toxicity (>10%).

Collectively, these data indicate that primaquine appears to be a safe and effective prophylactic agent in semi-immune children and non-immune adults. Theoretically, because primaquine is a causal agent, individuals should be required to take it only during periods of exposure and for 1 week after departure from the malaria-endemic area. This would avoid the requirement to complete 4 weeks of chemoprophylaxis following exposure (a common reason for non-adherence with standard regimens) and may be particularly useful for travellers with short exposures (2 to 7 days) in high-risk areas such as sub-Saharan Africa and New Guinea. Primaquine should be taken daily starting 1 day before entering a malaria-endemic area, continued while in the area and for 1 week after departure.

Tafenoquine (WR 238605) 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. Phase 2 studies are ongoing in semi- and non-immune people. In the future, tafenoquine may provide another option for chemo-prophylaxis in those without G6PD deficiency.

Recommendations

i. Primaquine chemoprophylaxis is contraindicated in individuals with G6PD deficiency and during pregnancy (E II - evidence-based medicine recommendations - see appendix II).

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

c. Artemisinin Derivatives (Qinghaosu) for the Treatment of Drug-Resistant Malaria Artemisinin (qinghaosu) is a naturally occurring sesquiterpene lactone peroxide structurally unrelated to any known antimalarial. Qinghaosu, derived from cultivated Artemisia annua, is available as the parent compound artemisinin (oral, parenteral, and suppository formulations) and as three semi-synthetic derivatives: a water-soluble hemisuccinate salt (artesunate) for parenteral or oral administration; and two oil-soluble compounds (artemether and arteether) for intramuscular injection. All are metabolized to a biologically active metabolite, dihydroartemisinin. Artesunate is a prodrug for dihydroartemisinin and as such is the most rapidly active of the derivatives examined to date. All compounds have their antiparasitic effects on the younger ring-form parasites, thereby decreasing the numbers of late parasite forms that can obstruct the host's microvasculature.

All artemisinin preparations have been studied and used only for treatment. They are recommended for treatment use only and not for prophylaxis. All compounds are at least as efficacious as quinine in the treatment of severe and complicated malaria. Qinghaosu and its derivatives lead to faster parasite (mean: 32% faster) and fever (mean: 17% faster) clearance times than do any other anti-malarials. In spite of the more rapid antiparasitic action of qinghaosu compounds, these agents have not been shown to decrease mortality 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 less than 5 days. Recent studies have examined longer durations of therapy (7 days) and combinations of qinghaosu derivatives and mefloquine in order 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 by 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 toxicity. Neurologic 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 toxicity in humans have not been performed. The safety of qinghaosu derivatives in pregnancy has not been established. Because of their short half-life artemisinin and its derivatives should not be used for prophylaxis.

Artemisinin and its derivatives are now available and increasingly used in Southeast Asia and Africa; none is licensed in Canada. Combinations of artesunate and mefloquine appear to be the most active drug regimens for treatment of multidrug-resistant falciparum malaria in Southeast Asia. The quality of artemisinin derivatives available in developing countries is 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

i. Artemisinin compounds are effective alternative therapies for multidrug-resistant malaria (complicated and uncomplicated). However, at present, there are insufficient toxicity data or evidence of clinical superiority over standard therapy to routinely recommend these as first-line agents, particularly for P. falciparum infections acquired in Africa (A I - evidence-based medicine recommendations - see Appendix II).

ii. Artemisinin compounds should not be used for chemoprophylaxis. (C III - evidence-based medicine recommendations - see Appendix II).

iii. 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 (A I - evidence-based medicine recommendations - see Appendix II).

Artemisinin derivatives are not currently available in North America or Europe.

d. Azithromycin for the Prevention of Malaria Azithromycin (Zithromax^®) is a macrolide antibiotic that has been shown to have only limited effectiveness in the prevention of malaria (A II - evidence-based medicine recommendations - see Appendix II).

Studies performed to date are small and suggest that azithromycin is less effective than mefloquine or doxycycline. Azithromycin should be considered for chemoprophylaxis only in highly selected groups. It is considered to be safe in pregnancy and in children, and is available in suspension. However, in view of the serious consequences of malaria in pregnancy, utilization of this suboptimal antimalarial would not routinely be recommended. If used, azithromycin requires daily dosing (adult dose of 1 tablet per day) starting the day before exposure, continued during exposure and for 4 weeks after departure from the malarial region.

Recommendations

There is insufficient evidence to recommend azithromycin as an alternative antimalarial except in circumstances in which other, more effective and safer medications are not available or are contraindicated. (CI - evidence-based medicine recommendations - see Appendix II).

e. Halofantrine for the Treatment of Malaria 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 market because of concerns about cardiotoxicity. It remains widely available in the tropics, and travellers should be made aware of the danger of this drug. The World Health Organization has reported cardiac deaths associated with the use of halofantrine and no longer recommends its use.

Recommendations

i. Halofantrine should not be used for self-directed therapy (D II - evidence-based medicine recommendations - see Appendix II).

ii. 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 recommendations - see Appendix II).

iii. Travellers who inquire about halofantrine or who are likely to encounter its use (e.g. West Africa) should be informed of its potential cardiotoxicity (C III - evidence-based medicine recommendations - see Appendix II).

f. Pyronaridine for the Treatment of Malaria

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. The drug has been shown to be very 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.

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