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The drug combination atovaquone/proguanil (INNs, trade names Malarone, Malanil) is an antimalarial medication used in both the treatment and prevention of malaria. Atovaquone alone is not indicated for treatment or prevention of malaria as monotherapy (i.e., without proguanil). Atovaquone/proguanil has been commercially available from GlaxoSmithKline since 2000, and its patent expired in 2013. Malarone has applications for treating chloroquine-resistant malaria.
A standard tablet of Malarone contains 100 mg of proguanil hydrochloride and 250 mg of atovaquone. A pediatric tablet contains 25 mg of proguanil hydrochloride and 62.5 mg of atovaquone.
The adult treatment dose is four standard tablets once a day for three days. In children, the drug is prescribed by body weight:
- 11 to 20 kg: 1 standard tablet once daily for 3 days;
- 21 to 30 kg: 2 standard tablets once daily for 3 days;
- 31 to 40 kg: 3 standard tablets once daily for 3 days;
- 41 kg and above: use adult dose.
Atovaquone/proguanil is not licensed for use in children weighing 10 kg or less. The pediatric tablets are not used in malaria treatment, but are used for prophylaxis.
Atovaquone/proguanil is not normally used to treat severe malaria, when an injectable drug such as quinine is used instead.
A patient should always seek medical advice before choosing a medication for malaria prevention. Since some malaria strains are resistant to atovaquone/proguanil, it is not effective in all parts of the world. It must be taken with a fatty meal, or at least some milk, for the body to absorb it adequately—and to avoid painful stomach irritation, which proguanil frequently causes if taken without food. Also, stomach irritation may occur if one lies down within a half hour after taking this medicine.
The adult dose is one standard tablet daily starting one or two days before traveling into a malaria-endemic area, and continuing throughout the stay and then for another seven days after returning from the area.
The child dose is prescribed according to body weight:
- 11–20 kg: 1 pediatric tablet once daily;
- 21–30 kg: 2 pediatric tablets once daily;
- 31–40 kg: 3 pediatric tablets once daily;
- 41 kg and above use adult dose.
The duration of treatment is the same as for adults.
Proguanil acts as a mitochondrial sensitiser and synergizes with atovaquone. When atovaquone is used as a sole agent, a high natural frequency of cytochrome b mutants leads to a high failure rate. This is potentially due to the high lipophilicity and slow uptake of atovaquone, which results in a relatively prolonged period of parasite exposure at ineffective concentrations. Specific mutations (Y268S, Y268C) have been shown to confer resistance in vivo, but the other mechanisms of resistance remain unknown.
Malarone is notable for having far fewer side effects than other, older malaria drugs. While some people experience side effects, such as coughing, diarrhea, dizziness, headache, loss of appetite, mouth sores, nausea, stomach pain, vomiting, or weakness, the majority have none or few of these.
Mechanism of action
Atovaquone selectively inhibits the malarial cytochrome bc1 complex in the parasitic electron transport chain, collapsing the mitochondrial membrane potential. The malarial electron transport chain does not contribute significantly to ATP synthesis; thus, it is believed that parasite death is due to the indirect inhibition of dihydroorotate dehydrogenase, which requires transport chain function and is essential to pyrimidine biosynthesis.
Glaxo Wellcome patented the combination of atovaquone and proguanil to treat malaria in 1999. Patent protection expired in 2013. The U.S. Food and Drug Administration (FDA) approved a generic formulation from Glenmark Generics in 2011. In February 2013, the United Kingdom High Court revoked Glaxo's patent on grounds of obviousness, which clears the way for firms to sell generic versions there.
- Glaxo Smith Kline monograph on MALARONE
- Generic Malarone Availability
- Nakato, Halima; Vivancos, Roberto; Hunter, Paul R. (2007-11-01). "A systematic review and meta-analysis of the effectiveness and safety of atovaquone–proguanil (Malarone) for chemoprophylaxis against malaria". Journal of Antimicrobial Chemotherapy. 60 (5): 929–936. doi:10.1093/jac/dkm337. ISSN 0305-7453. PMID 17848375.
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- Schwartz E, Bujanover S, Kain KC (2003). "Genetic confirmation of atovaquone-proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveller to east Africa". Clin Infect Dis. 37 (3): 450–51. doi:10.1086/375599. PMID 12884171.
- Wichmann O, Muehlen M, Gruss H, et al. (2004). "Malarone treatment failure not associated with previously described mutations in the cytochrome b gene". Malaria Journal. 3: 14. doi:10.1186/1475-2875-3-14. PMC 425592. PMID 15186499.
- Fry, Mitchell; Pudney, Mary (1992-04-01). "Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4'-chlorophenyl) cyclohexyl]-3- hydroxy-1,4-naphthoquinone (566C80)". Biochemical Pharmacology. 43 (7): 1545–1553. doi:10.1016/0006-2952(92)90213-3.
- Srivastava, Indresh K.; Rottenberg, Hagai; Vaidya, Akhil B. (1997-02-14). "Atovaquone, a Broad Spectrum Antiparasitic Drug, Collapses Mitochondrial Membrane Potential in a Malarial Parasite". Journal of Biological Chemistry. 272 (7): 3961–3966. doi:10.1074/jbc.272.7.3961. ISSN 0021-9258.
- Drug Details
- Atovaquone Proguanil (Malarone) Patent Revoked & Glenmark Launches First UK Generic