General Information

Coartem is a fixed dose oral combination of artemether (20 mg), an artemisinin derivative, and lumefantrine (120 mg), two anti-malarials.

Coartem is specifically indicated for the treatment of acute, uncomplicated malaria infections due to Plasmodium falciparum in patients of 5 kg bodyweight and above.

Coartem is supplied as a tablet designed for oral administration. Coartem tablets should be taken with food. In the event the patient is unable to swallow the tablets, such as infants and children, the tablets may be crushed and mixed with a small amount of water. The recommended initial dose of the drug is as follows:

Adults (aged 16 years and above)
A 3-day treatment schedule with a total of 6 doses is recommended for adult patients with a bodyweight of 35 kg and above. The tablets should be administered the following way: four tablets as a single initial dose, four tablets again after 8 hours and then four tablets twice daily (morning and evening) for the following two days (total course of 24 tablets). For patients weighing less than 35 kg, see the sosage for pediatrics.

Pediatrics (below 16 years of age)
A 3-day treatment schedule with a total of 6 doses is recommended as below:
5 kg to less than 15 kg bodyweight: one tablet as an initial dose, one tablet again after 8 hours and then one tablet twice daily (morning and evening) for the following two days (total course of 6 tablets); 15 kg to less than 25 kg bodyweight: two tablets as an initial dose, two tablets again after 8 hours and then two tablets twice daily (morning and evening) for the following two days (total course of 12 tablets); 25 kg to less than 35 kg bodyweight: three tablets as an initial dose, three tablets again after 8 hours and then three tablets twice daily (morning and evening) for the following two days (total course of 18 tablets); 35 kg bodyweight and above: four tablets as a single initial dose, four tablets again after 8 hours and then four tablets twice daily (morning and evening) for the following two days (total course of24 tablets).

Mechanism of Action

Coartem is a fixed dose oral combination of artemether (20 mg), an artemisinin derivative, and lumefantrine (120 mg), two anti-malarials. Both components are blood schizontocides. Aremether is rapidly metabolized into an active metabolite dihydroartemisinin (DHA). The anti-malarial activity of artemether and DHA has been attributed to endoperoxide moiety. The exact mechanism by which lumefantrine, exerts its anti-malarial effect is not well defined. However, available data suggests lumefantrine inhibits the formation of ß-hematin by forming a complex with hemin.

Side Effects

Adverse events associated with the use of Coartem include, but are not limited to, the following:

• Headache
• Anorexia
• Dizziness
• Asthenia
• Pyrexia
• Cough
• Vomiting

Clinical Trial Results

FDA approval of Coartem was based on 8 clinical studies. The studies enrolled HIV-negative subjects with acute, uncomplicated malaria caused by P. falciparum, in China, Thailand, sub-Saharan Africa, Europe, and South America. The studies include two 4-dose studies assessing the effcacy of the components of the regimen, a study comparing a 4-dose versus a 6-dose regimen, and 5 additional 6-dose regimen studies. Coartem Tablets were administered at 0, 8, 24, and 48 hours in the 4-dose regimen, and at 0, 8, 24, 36, 48, and 60 hours in the 6-dose regimen. The efficacy endpoints included the following: 28-day cure rate, defined as clearance of asexual parasites (the erythrocytic stage) within 7 days without recrudescence by day 28, parasite clearance time (PCT), defined as time from first dose until first total and continued disappearance of asexual parasite which continues for a further 48 hours, and fever clearance time (FCT), defined as time from first dose until the first time body temperature fell below 37.5°C and remained below 37.5°C for at least a further 48 hours (only for patients with temperature:; 37.5°C at baseline).

Studies 1 and 2
These randomized, double-blind, comparative, single center studies assessed the efficacy of Coartem tablets (4 doses of 4 tablets of 20 mg artemether/120 mg lumefantrine) compared to each component alone. Data supported that the combination of artemether and lumefantrine in Coartem Tablets had a significantly higher 28-day cure rate compared to artemether and had a significantly faster parasite clearance time (p< 0.001) and fever clearance time (p< 0.05) compared to lumefantrine.

Study 3
This randomized, double-blind, two-center study was conducted in Thailand in adults and children (aged two years and above), which compared the 4-dose regimen (administered over 48 hours) of Coartem Tablets to a 6-dose regimen (administered over 60 hours). Twenty-eight day cure rate in modified intent-to-treat subjects was 81% for the Coartem Tablets 6-dose arm as compared to 71% in the 4-dose arm.

Studies 4, 5, 6, 7 and 8
In all these studies Coartem Tablets were administered as the 6 dose regimen.

Study 4
This study enrolled 150 adults and children aged 2 years and above in Thailand. In the evaluable population (148 subjects): the 28-day cure rate was 97%; the median fever clearance time (FCT) was 22 hours and the median parasite clearance time (PCT) was not available.

Study 5
This study enrolled 164 adults and children in Thailand. In the evaluable population (155 subjects): the 28-day cure rate was 95.5%; the median fever clearance time (FCT) was 29 hours and the median parasite clearance time (PCT) was 29 hours.

Study 6
This study enrolled 165 non-immune adults residing in regions non-endemic for malaria (Europe and Colombia) who contracted acute uncomplicatedfalciparum malaria when traveling in endemic regions. In the evaluable population (119 subjects): the 28-day cure rate was 96%; the median fever clearance time (FCT) was 37 hours and the median parasite clearance time (PCT) was 42 hours.

Study 7
This African study enrolled 310 infants and children aged 2 months to 9 years, weighing 5 kg to 25 kg, with an axillar temperature ~7.5 °C. In the evaluable population (267 subjects): the 28-day cure rate was 89%; the median fever clearance time (FCT) was 8 hours and the median parasite clearance time (PCT) was 24 hours.

Study 8
This African study enrolled 452 infants and children, aged 3 months to 12 years, weighing 5 kg to 35 kg, with fever (greater than 37.5°C axillary or greater than 8°C rectally) or history of fever in the preceding 24 hours. In the evaluable population (370 subjects): the 28-day cure rate was 88.3%; the median fever clearance time (FCT) was 8 hours and the median parasite clearance time (PCT) was 35 hours.

P. falciparum infections mixed with P. vivax
Of the 43 patients with mixed infections at baseline, all cleared their parasitemia within 48 hours. However, parasite relapse occurred commonly (14/43; 33%). Relapsing malaria caused by P. vivax requires additional treatment with other antimalarial agents to achieve radical cure.