July 2002

Malarone has now been licensed for prophylactic use in adults in Canada

Although Malarone has been licensed in the United States as a preventative drug for malaria for over a year, it was only  licensed in Canada as a treatment drug recently . The Canadian Malaria recommendations advise it’s use as a preventative drug in limited situations (see below). This will be updated in the new recommendations

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,   Is now licensed for Prophylaxis in adults

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.

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).

 *Now licensed for Prophylactic use

Canada Communicable Disease Report - Supplement Volume 26S2 March 2000

www.hc-sc.gc.ca/hpb/lcdc/publicat/ccdr/00vol26/26s2/26s2j_e.html

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FDA APPROVES MALARONE FOR THE PREVENTION AND TREATMENT OF MALARIA

FDA today approved Malarone, a new combination drug for the prevention and treatment of acute, uncomplicated P. falciparum malaria. Malarone is a combination of atovaquone and proguanil HCL. Atovaquone is currently marketed in the United States under the trade name Mepron for pneumocystis carinii pneumonia. Proguanil was approved in the US in 1948 for use in malaria. Because it was not widely used in this country, it ceased to be marketed here in the 1970s. It continues to be used in combination with other drugs in Canada and a number of European countries.

Malarone has been shown to be effective in regions where resistance to other anti-malarial drugs has developed. Malaria is transmitted from person to person by the bite of an infected Anopheles mosquito. These mosquitoes are present in almost all tropical countries. Persons contemplating travel to certain endemic tropical areas should see their doctor and ask about malaria prevention.

The early symptoms of malaria include fever, chills, headache, muscle ache, and malaise. Without prompt treatment complications such as coma, kidney failure, and respiratory distress may occur resulting in death. Travelers who become ill with a fever during or after travel in an area of malaria transmission should seek prompt medical attention and inform their physician of their recent travel history.

Malarone was evaluated for the treatment of malaria in adults, children, partially immune, and non-immune individuals. Eight active- controlled clinical trials were conducted in countries in Africa, Asia, South America, and Europe. Overall efficacy in 521 evaluable patients was 98.7 percent.

Malaria can be prevented by the use of prophylactic antimalarial drugs and protection against mosquito bites through the use of protective clothing, insect repellents, and bednets.

Malarone was evaluated for the prophylaxis (prevention) of malaria due to P. falciparum in four clinical trials in Africa. Over a period of approximately 3 months, malaria occurred in 2 out of 279 patients who received Malarone. For those patients who were given a placebo, 92 out of 297 patients contracted malaria.

Additional information from challenge studies indicated that Malarone was effective against the early liver stage of malaria as well as the blood stage. The early liver stage is the form of the parasite before it appears in the blood and before symptoms, such as fever and chills, occur. A challenge study showed that Malarone is active against the early liver as well as the blood stage.

Among adults who received Malarone for treatment of malaria, the side effects included abdominal pain, nausea, vomiting and headache. Among pediatric patients, vomiting and itching were reported adverse reactions. In subjects given Malarone for prevention of malaria, the most commonly reported side effects were headache and abdominal pain.

Malarone should be taken at the same time each day with food or milk. In the event of vomiting, a repeat dose should be taken within 1 hour of dosing. For the treatment of adults with malaria, Malarone is given as a single dose of four tablets (total daily dose 1 g atovaquone/400 mg proguanil hydrochloride)for three consecutive days. The dose for prophylactic treatment with Malarone is one tablet (250 mg atovaquone/100 mg proguanil hydrochloride) per day for adults. Prophylactic treatment with Malarone should be started 1 or 2 days before entering a malaria-endemic area and continued daily during the stay and for 7 days after return. Body weight determines the dose for malaria treatment and prevention in children.

Malarone is manufactured by Glaxo Wellcome Inc. of Research Triangle Park, N.C.

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