Pharmacology Update
Artemether and Lumefan-trine Tablets (Coartem®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.
The FDA has approved a new drug combination for acute, uncomplicated malaria infection. The treatment is a fixed combination of two antimalarial drugs, artemether and lumefantrine (AL). Artemether is derived from the leaves of the Artemisia annua plant. Both artemether and lumefantrine are active against the erythrocytic stages of Plasmodium falciparum.1 The combination is marketed by Novartis Pharmaceuticals, Inc., as Coartem®.
Indications
AL is indicated for the treatment of acute, uncomplicated malaria infections due to Plasmodium falciparum in children (≥ 5 kg) and adults.1
Dosage
The adult (≥ 35 kg) dose is 4 tablets per dose with 6 doses taken over 3 days. The initial dose is taken on day 1 with the second dose taken 8 hours later. The subsequent doses are taken twice daily (morning and evening) for the next 2 days. Dosing for patients with body weight less than 35 kg is based on body weight. The tablets should be taken with food and may be crushed and given with 1-2 teaspoons of water.
AL is available as tablets, each containing artemether (20 mg) and lumefantrine (120 mg).
Potential Advantages
AL appears to be effective in geographic regions where chloroquine resistance has been reported.1 Treatment with AL has been reported to select for chloroquine-susceptible alleles.2 AL is more effective than other commonly used combinations (amiodiaquine plus sulfadoxine-pyrimethamine [ASP] and amiodiaquine plus artesunate [AA]).3
Potential Disadvantages
AL is not indicated for malaria prophylaxis or treatment of severe malaria. It is only active against the erythrocytic stages of Plasmodium falciparum. AL has been associated with prolongation of QT interval. Both A and L are metabolized by CYP3A4. Substrates, inhibitors, or inducers of this isoenzyme may affect effectiveness or increase the risk of adverse events. Lumefantrine is an inhibitor of CYP2D6. AL should be used with caution in patients at risk for QT prolongation (e.g., hypokalemia) or in combination with drugs that may prolong QT interval. AL is contraindicated in the first trimester of pregnancy and benefit and risk should be assessed if used in the second or third trimester. Mefloquine use immediately before AL (≤ 12 hours) may reduce the AL effectiveness due to reduced absorption resulting from decreased bile secretion caused by mefloquine. Common adverse events (> 30%) in adults include headache (56%), anorexia (40%), dizziness (39%), asthenia (38%), arthralgia (34%), and myalgia (32%). In pediatrics patients, pyrexia (29%) and cough (23%) were most common.
Comments
The 6-dose treatment regimen of AL was evaluated in 5 studies. Two studies (n = 314) were conducted in adults and children in Thailand. Two studies (n = 762) were conducted in infants and children in Africa. One study (n = 165) was conducted with non-immune adults in non-endemic regions (Europe and Columbia) who were infected when traveling in endemic regions. Clinical efficacy was based on 28-day cure rate, defined as clearance of asexual parasites based on blood smear microscopy, parasite clearance time (time from first dose to disappearance of parasites and maintained for 48 hours), and fever clearance time (from first doses to temperature < 37.5° and maintained for at least 48 hours). Analyses were based on modified intent-to-treat (mITT, confirmed diagnosis and received at least 1 dose) and evaluable (had day 7 and day 28 parasitological assessment). Cure rates at 28 days (mITT) were 87.2% and 90.2% in the Thailand studies, 82.7% and 86.5% in the African studies, and 74.1% for the non-endemic study. The cure rates for evaluable subjects were 95% and 97% for the Thailand studies, 88% and 89% for the African studies, and 96% for the non-endemic study. In patients with a baseline temperature of 37.5° C, the median time ranged from 22 to 37 hours in adults and children and 8 hours in infants and children. The median time to parasite clearance ranged from 22 to 48 hours. In a comparative trial of 3 combinations, AL showed a 28-day risk of treatment failure of 6.7% compared to 26.1% for ASP and 17.4% for AA.3 In a study in an area of very high malaria transmission (Uganda), AL was associated with a higher risk of parasitemia and gametocytemia than dihydroartemisinin-piperaquine (DP).4 After 42-day follow-up, the risk of treatment failure adjusted by genotyping was 16% for AL and 6.9% for DP (P = 0.006).
Clinical Implications
Malaria is a serious global disease. In the United States, the majority of cases occur among travelers and immigrants from high-risk areas such as South Asia and sub-Saharan Africa. AL offers another option for treating malaria.
References
1. Coartem Product Information. East Hanover, NJ: Novartis Pharmaceutical, Inc.; April 2009.
2. Sisowath C, et al. In vivo selection of Plasmodium falciparum parasites carrying the chloroquine-susceptible pfcrt K76 allele after treatment with artemether-lumefantrine in Africa. J Infect Dis 2009;199:750-757.
3. Dorsey G, et al. Combination therapy for uncomplicated falciparum malaria in Ugandan children: A randomized trial. JAMA 2007;297:2210-2219
4. Kamya MR, et al. Artemether-lumefantrine versus dihydroartemisinin-piperaquine for treatment of malaria: A randomized trial. PLos Clin Trials 2007;2:e20.
The FDA has approved a new drug combination for acute, uncomplicated malaria infection.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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