Formulations

• Film-coated tablets containing 250 mg of atovaquone and 100 mg of proguanil hydrochloride (adult strength).
• Paediatric tablets containing 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride.

Efficacy

Atovaquone was originally developed as an antimalarial compound, but was registered for the treatment of opportunistic infections caused by Pneumocystis carinii and Toxoplasma gondii associated with AIDS. Atovaquone alone has weak antimalarial activity and recrudescence of parasitaemia occurs in one-third of patients with P. falciparum when used alone. Such recrudescent parasites are highly resistant (146). In combination with proguanil, however, a synergistic effect is seen. Atovaquone-proguanil is highly efficacious against P. falciparum, including strains that are resistant to chloroquine and mefloquine, with cure rates of 94-100% (144, 306-308).

Limited information exists on the efficacy of this combination against other species of malaria parasites, but it appears to be effective at eliminating blood stage infections. Relapses are common with P. vivax infections unless primaquine is given at the same time.

There are no data available on use in children weighing < 11 kg.

Recommended treatment

For adults, 1 g of atovaquone plus 400 mg of proguanil (4 tablets) daily for 3 days.

The manufacturer does not envisage active commercialization of the drug in malaria endemic countries. Instead, a Malarone ^®Donation Program has been launched with a commitment to provide up to 1 million free treatments annually to national malaria control programmes. This Program has already begun at several sites in Kenya and Uganda. Under the guidelines of the Donation Program, use of the drug is to be restricted to patients who fail to respond to treatment with current first-and second-line drugs.

Active marketing of atovaquone-proguanil is being promoted in non-endemic countries for both treatment and chemoprophylaxis in travellers to malarious areas. The recommended treatment regimens are shown in Table 17.

Chemoprophylaxis

For adults, 250 mg of atovaquone plus 100 mg of proguanil (one tablet) daily.

Atovaquone-proguanil offers an alternative for chemoprophylaxis in those persons travelling to chloroquine-resistant P. falciparum areas who cannot take mefloquine or doxycycline. The prophylactic dose in adults is one tablet daily beginning one day before entering the malarious area, continuing throughout the stay in the malarious area and for 7 days after leaving. Studies have shown that atovaquone-proguanil has good chemoprophylactic activity in semi-immune persons (309-311), and there are some data on its effectiveness in non-immune persons (312, 313). Prophylactic dosage schedules for children are shown in Table 18.

Use in pregnancy

Atovaquone alone and atovaquone-proguanil are not teratogenic in rats. Proguanil is safe during pregnancy but there is insufficient information on the safety of atovaquone or the combination drug in pregnant or lactating women.

Drug disposition

Atovaquone is absorbed slowly from the gastrointestinal tract and is subject to wide individual variability. Absorption is greatly increased if the drug is taken with a fatty meal. The half-life of atovaquone is approximately 60 h compared with about 15 h for proguanil. There does not appear to be significant metabolism of atovaquone.

Adverse effects

Adverse effects include abdominal pain, nausea, vomiting, diarrhoea, headache, anorexia and coughing.

With the exception of vomiting, the frequency of these symptoms is similar to that seen during acute malarial attacks. During clinical trials, one case of anaphylaxis following treatment with atovaquone-proguanil was observed. In double-blind placebo-controlled chemoprophylaxis trials, the frequency of adverse events was similar to that in the placebo group, indicating that the combination is very well tolerated (310-313).

Contraindications

Atovaquone-proguanil is contraindicated in persons with hypersensitivity to atovaquone and/or proguanil.

It is not recommended at present for use in pregnancy because of lack of data. Caution is indicated in persons with severe renal failure (creatinine clearance < 60 ml/min).