Pharmacology Update
Malarone—A New Antimalarial Combination
By William T. Elliott, MD, FACP and James Chan, PharmD, PhD
The fda approved a combination of atovaquone and proguanil for the treatment and prophylaxis of malaria caused by Plasmodium falciparum. Atovaquone and proguanil are blood schizonticides with some synergistic activity. This fixed-combination has been available in more than 30 countries. It will be marketed in this country by Glaxo Wellcome under the trade name Malarone.
Indication
Atovaquone/proguanil is indicated for the prophylaxis of P. falciparum malaria including in areas where chloroquine resistance has been reported.
It is also indicated for the treatment of acute, uncomplicated P. falciparum malaria. Atovaquone/proguanil should not be used in patients with recrudescent P. falciparum infections if they have already used this combination for treatment or prophylaxis. Resistant strains may be selected.1
Dosage
For the treatment of P. falciparum in adults, the dose is four tablets taken once daily for three days. For pediatric patients, the dose is based upon body weight: 11-20 kg (1 adult strength tablet), 21-30 kg (2 adult strength tablets), 31-40 kg (3 adult strength tablets), and more than 40 kg (4 adult strength tablets) taken for three consecutive days. For prophylaxis in adults, the dose is one tablet starting one or two days before entering a malaria-endemic region and continuing daily during the stay and seven days after leaving the region. For pediatric prophylaxis, the dose is based on body weight: 11-20 kg (1 pediatric strength tablet), 21-30 kg (2 pediatric strength tablets), 31-40 kg (3 pediatric strength tablets), more than 40 kg (1 adult strength tablet).
Malarone is supplied as atovaquone 250 mg and proguanil 100 mg (adult strength) and 62.5 mg atovaquone and 25 mg proguanil (pediatric strength). Tablets should be taken with food or a milky drink at the same time each day. If vomiting occurs within one hour after dosing, a repeat dose should be taken.1
Potential Advantages
Atovaquone/proguanil has been shown to be effective in regions where unacceptable failure rates have been reported with other antimalarials including chloroquine, halofantrine, mefloquine, and amodiaquine.1 The combination of atovaquone/proguanil is reported to be more effective than mefloquine in the treatment of acute uncomplicated multidrug-resistant falciparum malaria.2 An open-label trial (n = 158) was conducted in Thailand in adult patients with acute P. falciparum malaria. Subjects were randomized to atovaquone/proguanil four tablets daily for three doses or mefloquine (750 mg) followed by 500 mg six hours apart. Efficacy was assessed by cure rate defined as the percent of patients with parasitemia eliminated and not recurring during a 28-day follow-up, parasite clearance time, and fever clearance time. The cure rate was 100% for atovaquone/proguanil and 86% for mefloquine (P < 0.002). There were no differences in parasite clearance time or fever clearance time.
Potential Disadvantages
Atovaquone/proguanil is not FDA-approved for the treatment or prophylaxis of Plasmodium vivax since relapse is common when P. vivax is treated with this combination.1 The most common adverse events reported during treatment in adults were abdominal pain (17%), nausea (12%), vomiting (12%), headache (10%), diarrhea (8%), asthenia (8%), anorexia (5%), and dizziness (5%). In pediatric patients, vomiting (10%) and pruritus (6%) were most commonly reported.1 Elevation of liver enzymes, which may persist for up to four weeks, has been reported.1 Drug interactions have been reported with tetracycline, metoclopramide, and rifampin.1
Comments
Malarone is a fixed-dose combination of atovaquone and proguanil. Atovaquone is believed to act as a site-specific uncoupler of parasite mitochondrial electron transport and cycloguanil, the metabolite of proguanil, is a dihydrofolate reductase inhibitor.1,3 Proguanil has also been reported to act in synergy with atovaquone to collapse mitochondrial membrane potential.3 Atovaquone/proguanil is active against both the blood and liver stages of P. falciparum. It has been studied for the treatment of acute uncomplicated malaria caused by P. falciparum in eight phase III studies in about 500 adults and children. Studies were conducted in Brazil, Thailand, France, Kenya, Zambia, Gabon, Philippines, and Peru with an overall success rate of 98.7% (range, 93.8-100%).1,2,4,5 Prophylaxis studies were conducted in malaria-endemic areas in Kenya, Zambia, and Gabon.6-8 The success rates ranged from 98-100%.
Wholesale cost for adult treatment for atovaquone/proguanil (4 tablets ´ 3 days) is $56 compared to $45 for mefloquine (5 ´ 250 mg). For prophylaxis, the costs are $33 per week for atovaquone/ proguanil (1 tablet daily) compared to $9 per week for mefloquine (1 tablet weekly).
Clinical Implications
Malaria is a serious health problem in certain parts of the world, although not in the United States. However, many U.S. residents visit malaria-endemic areas annually. Treatment varies with the infecting species, severity of the disease, and geographic area where the disease is acquired. Multiresistant P. falciparum has been especially problematic in Southeast Asia.9
Atovaquone/proguanil, available in 30 countries, now provides an effective option for treatment and prophylaxis of P. falciparum in the United States.
References
1. Malarone Product Information. Glaxo Wellcome. July 2000.
2. Looareesuwan S, et al. Am J Trop Med Hyg 1999; 60(4):526-532.
3. Srivastava IK, Vaiya AB. Antimicrob Agents Chemother 1999;43(6):1334-1339.
4. Radloff PD, et al. Lancet 1996;347:1511-1514.
5. Aanbwani G, et al. Pediatr Infect Dis J 1999;18:456-461.
6. Lell B, et al. Lancet 1998;351:709-713.
7. Shanks GD, et al. Clin Infect Dis 1998;27:494-499.
8. Sukwa TY, et al. Am J Trop Med Hyg 1999;60:521-525.
9. Rosenblatt JE. Mayo Clin Proc 1999;74:1161-1175.
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