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Coartem (artemether/lumefantrine)

Company: Novartis
Approval Status: Approved April 2009
Treatment for: malaria infections due to Plasmodium falciparum
Areas: Immune System

| General Information | Clinical Results | Side Effects | Mechanism of Action | Literature References | Additional Information |


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).


Clinical Results

FDA Approval
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.

Omgoing Study Commitments

  • Novartis has agreed to conduct a descriptive study of the use of Coartem Tablets in non-immune travelers. For a period of five years following approval, collect baseline patient demographic information (including age, weight, height, sex, race, prior medications and concomitant medications, as well as immune status), adverse reactions, including potential nervous system and cardiac adverse reactions, and efficacy outcomes. Novartis should include representation of adults greater than 65 years, children leass than 16 years, and overweight patients (BMI greater than 25 kg/m2). Submit yearly reports summarizing data on patients treated with Coartem Tablets within the previous year and the final report integrating information on all patients in the Final Report Submission.
    Final Protocol Submission: by March 2010
    Study Start Date: by October 2010
    Final Report Submission: by April 2016
  • Novartis has agreed to submit surveillance reports to evaluate the potential development of resistance to Coartem Tablets. For a period of five years following approval, submit a yearly report describing the reported resistance to a combination ofartemether and lumefantrine in malaria endemic countries as obtained from ongoing resistance monitoring programs on antimalarials collected by international consortia and organizations (e.g., World Health Organization).
    Submission of Study Report Plan: by July of 2009
    Study Reporting Start Date: by October of 2009
    Final Report Submission: by August 2016
  • Novartis has agreed to Conduct a neurotoxicity study of oral artemether in juvenile rats including neurologic functional batteries, toxicokinetics, and extensive brain histopathology. Conduct a neurotoxicity study of oral artemether in juvenile rats to assess how exposure and toxicity in young animals compares with older animals and humans, and whether neurologic deterioration occurs following the terminal dose. This study should consist of a main study group, a toxicokinetic group, and a recovery group. In this study, comprehensive histopathological examination of the central nervous system should be conducted.
    Final Protocol Submission: by July 2009
    Study Start Date: by December 2009
    Final Report Submission: by December 2011
  • Novartis has agreed to conduct bacterial reverse mutation studies (Ames assays) for lumefantrine impurities and artemether impurities. Lumefantrine impurities and artemether impurities have structural alerts for genotoxicity, and the proposed release limits for these compounds are higher than levels that are qualified by available toxicology studies.
    Study Start Date: redaction by December 2009
    Final Report Submission: by June 2010
  • Novartis has agreed to Perform spectral characterization of all specified impurities for lumefantrine impurities and artemether impurities.
    Study Start Date: by June 2009
    Final Report Submission: by December 2009
  • Novartis has agreed to conduct an in vitro study to characterize the induction potential of artemether, dihydroartemisinin (DHA), and lumefantrine on the metabolism of substrates of CYP3A4. Conduct an in vitro study to evaluate the induction potential of artemether, DHA, and lumefantrine on the metabolism ofco-administered drugs that are substrates of the Cytochrome P450 3A4 (CYP3A4) enzyme system (e.g., oral contraceptives).
    Final Protocol Submission: by December 2009
    Study Start Date: by March 2010
    Final Report Submission: by March 2011
  • Novartis has agreed to conduct an in vitro study to characterize the potential interaction between artemether and lumefantrine, the components of Coartem Tablets, and rifampin. If, upon review, it is determined that the clinical trial discussed in Item 11 below adequately addresses the potential interaction between artemether and lumefantrine and rifampin, then this in vitro study will not be needed.
    Final Protocol Submission: by June 2011
    Study Start Date: by January 2012
    Final Report Submission: by January 2013
  • Novartis has agreed to Conduct an in vitro study to characterize the potential interaction between artemether and lumefantrine, the components of Coartem Tablets, and protease inhibitors (PIs). If, upon review, it is determined that the clinical trial discussed in Item 12 below adequately addresses the potential interaction between artemether and lumefantrine and PIs, then this in vitro study will not be needed.
    Final Protocol Submission: by June 2011
    Study Start Date: by January 2012
    Final Report Submission: by January 2013
  • Novartis has agreed to conduct an in vitro study to characterize the potential interaction between artemether and lumefantrine, the components of Coartem Tablets, and nonnucleoside reverse transcriptase inhibitors (NNRTIs). If, upon review, it is determined that the clinical trial discussed in Item 13 below adequately addresses the potential interaction between artemether and lumefantrine and NNRTIs, then this in vitro study will not be needed.
    Final Protocol Submission: by June 2011
    Study Start Date: by January 2012
    Final Report Submission: by January 2013
  • Novartis has agreed to complete the currently ongoing trial "An open label, single center study of the effects of Coartem, Malarone and artesunate-mefloquine on auditory function following the treatment of acute uncomplicated P. jalciparum malaria in patients 12 years of age or older in Columbia."
    Trial Start Date: ongoing
    Final Report Submission: by March 2010
  • Novartis has agreed to complete a clinical drug interaction trial to evaluate the effect of a co-administered CYP3A4 inducer on the pharmacokinetics of artemether and lumefantrine, the components of Coartem Tablets.
    Protocol Submission: by June 2009
    Trial Start Date: ongoing
    Final Report Submission: by March 2011
  • Novartis has agreed to complete a clinical drug interaction trial to evaluate the two-way interaction between artemether and lumefantrine, the components of Coartem Tablets, and a protease inhibitor (PI).
    Protocol Submission: by June 2009
    Trial Start Date: ongoing
    Final Report Submission: by March 2011
  • Novartis has agreed to complete a clinical trial to evaluate the two-way interaction between artemether and lumefantrine, the components of Coartem Tablets, and a non-nucleoside reverse transcriptase inhibitor (NNRTI).
    Protocol Submission: by June 2009
    Trial Start Date: ongoing
    Final Report Submission: by March 2011
  • Novartis has agreed to conduct a clinical interaction trial to evaluate the induction potential of artemether and lumefantrine, the components of Coartem Tablets, on CYP3A4 substrates.
    Final Protocol Submission: by June 2011
    Trial Start Date: by October 2011
    Final Report Submission: by October 2012

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

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.


Literature References

Juma EA, Obonyo CO, Akhwale WS, Ogutu BR A randomized, open-label, comparative efficacy trial of artemether-lumefantrine suspension versus artemether-lumefantrine tablets for treatment of uncomplicated Plasmodium falciparum malaria in children in western Kenya. Malaria Journal 2008 Dec 22;7:262

Kobbe R, Klein P, Adjei S, Amemasor S, Thompson WN, Heidemann H, Nielsen MV, Vohwinkel J, Hogan B, Kreuels B, Bührlen M, Loag W, Ansong D, May J A randomized trial on effectiveness of artemether-lumefantrine versus artesunate plus amodiaquine for unsupervised treatment of uncomplicated Plasmodium falciparum malaria in Ghanaian children. Malaria Journal 2008 Dec 19;7:261

Falade CO, Ogunkunle OO, Dada-Adegbola HO, Falade AG, de Palacios PI, Hunt P, Virtanen M, Oduola AM, Salako LA Evaluation of the efficacy and safety of artemether-lumefantrine in the treatment of acute uncomplicated Plasmodium falciparum malaria in Nigerian infants and children. Malaria Journal 2008 Nov 27;7:246

Sagara I, Diallo A, Kone M, Coulibaly M, Diawara SI, Guindo O, Maiga H, Niambele MB, Sissoko M, Dicko A, Djimde A, Doumbo OK A randomized trial of artesunate-mefloquine versus artemether-lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in Mali. The American Journal of Tropical Medicine and Hygiene 2008 Nov;79(5):655-61

Adjei GO, Kurtzhals JA, Rodrigues OP, Alifrangis M, Hoegberg LC, Kitcher ED, Badoe EV, Lamptey R, Goka BQ Amodiaquine-artesunate vs artemether-lumefantrine for uncomplicated malaria in Ghanaian children: a randomized efficacy and safety trial with one year follow-up. Malaria Journal 2008 Jul 11;7:127

Hatz C, Soto J, Nothdurft HD, Zoller T, Weitzel T, Loutan L, Bricaire F, Gay F, Burchard GD, Andriano K, Lefèvre G, De Palacios PI, Genton B Treatment of acute uncomplicated falciparum malaria with artemether-lumefantrine in nonimmune populations: a safety, efficacy, and pharmacokinetic study. The American Journal of Tropical Medicine and Hygiene 2008 Feb;78(2):241-7

Zurovac D, Ndhlovu M, Sipilanyambe N, Chanda P, Hamer DH, Simon JL, Snow RW Paediatric malaria case-management with artemether-lumefantrine in Zambia: a repeat cross-sectional study. Malaria Journal 2007 Mar 16;6:31

Mueller EA, van Vugt M, Kirch W, Andriano K, Hunt P, de Palacios PI Efficacy and safety of the six-dose regimen of artemether-lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in adolescents and adults: a pooled analysis of individual patient data from randomized clinical trials. Acta Tropica 2006 Nov;100(1-2):41-53

Fanello CI, Karema C, van Doren W, Van Overmeir C, Ngamije D, D'Alessandro U A randomised trial to assess the safety and efficacy of artemether-lumefantrine (Coartem) for the treatment of uncomplicated Plasmodium falciparum malaria in Rwanda. Transactions of the Royal Society of Tropical Medicine and Hygiene 2007 Apr;101(4):344-50

Lefèvre G, Looareesuwan S, Treeprasertsuk S, Krudsood S, Silachamroon U, Gathmann I, Mull R, Bakshi R A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand. The American Journal of Tropical Medicine and Hygiene 2001 May-Jun;64(5-6):247-56


Additional Information

For additional information regarding Coartem or malaria, please visit the Coartem web page.


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Coartem Drug Information

The Coartem drug information shown above is licensed from Thomson CenterWatch. The information provided here is for general educational purposes only and does not constitute medical or pharmaceutical advice which should be sought from qualified medical and pharmaceutical advisers.





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