indication

Artemether and lumefantrine combination therapy is indicated for the treatment of acute uncomplicated malaria caused by Plasmodium falciparum, including malaria acquired in chloroquine-resistant areas. May also be used to treat uncomplicated malaria when the Plasmodium species has not been identified. Indicated for use in adults and children greater than 5 kg.

pharmacology

In the body, artemether is metabolized into the active metabolite metabolite dihydroartemisinin. The drug works against the erythrocytic stages of P. falciparum by inhibiting nucleic acid and protein synthesis. Artemether is administered in combination with lumefantrine for improved efficacy. Artemether has a rapid onset of action and is rapidly cleared from the body. It is thought that artemether provides rapid symptomatic relief by reducing the number of malarial parasites. Lumefantrine has a much longer half life and is believed to clear residual parasites.

mechanism of action

Involves an interaction with ferriprotoporphyrin IX (“heme”), or ferrous ions, in the acidic parasite food vacuole, which results in the generation of cytotoxic radical species. The generally accepted mechanism of action of peroxide antimalarials involves interaction of the peroxide-containing drug with heme, a hemoglobin degradation byproduct, derived from proteolysis of hemoglobin. This interaction is believed to result in the formation of a range of potentially toxic oxygen and carbon-centered radicals.

toxicity

Common side effects of combination artemether/lumefantrine therapy in adults include headache, anorexia, dizziness, and asthenia. Common side effects in children include pyrexia, cough, vomiting, anorexia, and headache. Possible serious adverse effects include QT prolongation, bullous eruption, urticaria, splenomegaly (9%), hepatomegaly (adults, 9%; children, 6%), hypersensitivty reaction, and angioedema.

biotransformation

Rapidly metablized to its active metabolite, dihydroartemisinin.

absorption

Food increases absorption.

half life

Artemether, 1.6 +/- 0.7 and 2.2 +/- 1.9 hr; Dihydroartemisinin, 1.6 +/- 0.6 and 2.2 +/- 1.5 hr

drug interactions

Amiodarone: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Amitriptyline: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Amoxapine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Apomorphine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Arsenic trioxide: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Azithromycin: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Bepridil: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Chloroquine: Chloroquine may increase the adverse effects of artemether. Combination therapy is contraindicated unless there are no other treatment options.

Chlorpromazine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Cisapride: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Citalopram: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Clarithromycin: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Clomipramine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Conivaptan: Conivaptan, a strong CYP3A inhibitor, may increase the toxicity of artemether by inhibiting its metabolism. Consider alternate therapy or allow at least 7 days to elapse between conivaptan and artemether therapy.

Dasatinib: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Degarelix: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Desipramine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Desogestrel: Artemether may decrease the effectiveness of desogestrel by increasing its metabolism via CYP3A4. Consider an alternate non-hormonal means of contraception during artemether therapy.

Disopyramide: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Dofetilide: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Dolasetron: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Domperidone: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Doxepin: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Droperidol: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Drospirenone: Artemether may decrease the effectiveness of drospirinone by increasing its metabolism via CYP3A4. Consider an alternate non-hormonal means of contraception during artemether therapy.

Erythromycin: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Escitalopram: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Ethinyl Estradiol: Artemether may decrease the effectiveness of ethinyl estradiol by increasing its metabolism via CYP3A4. Consider an alternate non-hormonal means of contraception during artemether therapy.

Ethynodiol Diacetate: Artemether may decrease the effectiveness of ethynodiol diacetate by increasing its metabolism via CYP3A4. Consider an alternate non-hormonal means of contraception during artemether therapy.

Etonogestrel: Artemether may decrease the effectiveness of etonogestrel by increasing its metabolism via CYP3A4. Consider an alternate non-hormonal means of contraception during artemether therapy.

Flecainide: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Fluconazole: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Fluoxetine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Flupenthixol: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Foscarnet: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Gadobutrol: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Gadofosveset trisodium: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Halofantrine: Halofantrine may increase the adverse effects of artemether. Combination therapy is contraindicated unless there are no other treatment options.

Haloperidol: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Hydroxychloroquine: Hydroxychloroquine may increase the adverse effects of artemether. Combination therapy is contraindicated unless there are no other treatment options.

Ibutilide: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Imipramine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Indapamide: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Isradipine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Lapatinib: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Levofloxacin: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Levonorgestrel: Artemether may decrease the effectiveness of levonorgestrel by increasing its metabolism via CYP3A4. Consider an alternate non-hormonal means of contraception during artemether therapy.

Loxapine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Maprotiline: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Medroxyprogesterone: Artemether may decrease the effectiveness of medroxyprogesterone by increasing its metabolism via CYP3A4. Consider an alternate non-hormonal means of contraception during artemether therapy.

Mefloquine: Mefloquine may increase the adverse effects of artemether. Combination therapy is contraindicated unless there are no other treatment options.

Mesoridazine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Mestranol: Artemether may decrease the effectiveness of mestranol by increasing its metabolism via CYP3A4. Consider an alternate non-hormonal means of contraception during artemether therapy.

Methadone: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Methotrimeprazine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Moxifloxacin: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Nilotinib: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Norelgestromin: Artemether may decrease the effectiveness of norelgestromin by increasing its metabolism via CYP3A4. Consider an alternate non-hormonal means of contraception during artemether therapy.

Norethindrone: Artemether may decrease the effectiveness of norethindrone by increasing its metabolism via CYP3A4. Consider an alternate non-hormonal means of contraception during artemether therapy.

Norfloxacin: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Norgestimate: Artemether may decrease the effectiveness of norgestimate by increasing its metabolism via CYP3A4. Consider an alternate non-hormonal means of contraception during artemether therapy.

Nortriptyline: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Octreotide: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Pentamidine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Perflutren: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Pimozide: Additive QTc-prolongation may occur. Concomitant therapy is contraindicated.

Primaquine: Primaquine may increase the adverse effects of artemether. Combination therapy is contraindicated unless there are no other treatment options.

Probucol: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Procainamide: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Proguanil: Proguanil may increase the adverse effects of artemether. Combination therapy is contraindicated unless there are no other treatment options.

Propafenone: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Protriptyline: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Pyrimethamine: Pyrimethamine may increase the adverse effects of artemether. Combination therapy is contraindicated unless there are no other treatment options.

Quetiapine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Quinidine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Quinine: Quinine may increase the adverse effects of artemether. Combination therapy is contraindicated unless there are no other treatment options.

Ranolazine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Risperidone: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Saquinavir: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Sotalol: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Sparfloxacin: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Sunitinib: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Tacrolimus: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Telithromycin: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Tetrabenazine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Thioridazine: Additive QTc-prolongation may occur. Concomitant therapy is contraindicated.

Thiothixene: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Toremifene: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Trimipramine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Voriconazole: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Vorinostat: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Ziprasidone: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.