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Included as part of the PRECAUTIONS section.

Prolongation of the QT Interval

Some antimalarials (e.g., halofantrine, quinine, quinidine) including Coartem (artemether lumefantrine tablets) Tablets have been associated with prolongation of the QT interval on the electrocardiogram.

Coartem (artemether lumefantrine tablets) Tablets should be avoided in patients:

• with congenital prolongation of the QT interval (e.g., long QT syndrome) or any other clinical condition known to prolong the QTc interval such as patients with a history of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease.
• with a family history of congenital prolongation of the QT interval or sudden death.
• with known disturbances of electrolyte balance, e.g., hypokalemia or hypomagnesemia.
• receiving other medications that prolong the QT interval, such as class IA (quinidine, procainamide, disopyramide), or class III (amiodarone, sotalol) antiarrhythmic agents; antipsychotics (pimozide, ziprasidone); antidepressants; certain antibiotics (macrolide antibiotics, fluoroquinolone antibiotics, imidazole, and triazole antifungal agents); certain non-sedating antihistaminics (terfenadine, astemizole), or cisapride [see CLINICAL PHARMACOLOGY].
• receiving medications that are metabolized by the cytochrome enzyme CYP2D6 which also have cardiac effects (e.g., flecainide, imipramine, amitriptyline, clomipramine) [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

Use of QT Prolonging Drugs and Other Antimalarials

Halofantrine and Coartem (artemether lumefantrine tablets) Tablets should not be administered within one month of each other due to the long elimination half-life of lumefantrine (3-6 days) and potential additive effects on the QT interval [see WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].

Antimalarials should not be given concomitantly with Coartem (artemether lumefantrine tablets) Tablets, unless there is no other treatment option, due to limited safety data.

Drugs that prolong the QT interval, including antimalarials such as quinine and quinidine, should be used cautiously following Coartem (artemether lumefantrine tablets) Tablets, due to the long elimination half-life of lumefantrine (3-6 days) and the potential for additive effects on the QT interval, [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].

If mefloquine is administered immediately prior to Coartem (artemether lumefantrine tablets) Tablets there may be a decreased exposure to lumefantrine, possibly due to a mefloquine-induced decrease in bile production. Therefore, patients should be monitored for decreased efficacy and food consumption should be encouraged while taking Coartem Tablets [See DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].

Drug Interactions with CYP3A4

When Coartem (artemether lumefantrine tablets) Tablets are co-administered with substrates of CYP3A4 it may result in decreased concentrations of the substrate and potential loss of substrate efficacy. When Coartem (artemether lumefantrine tablets) Tablets are co-administered with an inhibitor of CYP3A4, including grapefruit juice it may result in increased concentrations of artemether and/or lumefantrine and

potentiate QT prolongation. When Coartem (artemether lumefantrine tablets) Tablets are co-administered with inducers of CYP3A4 it may result in decreased concentrations of artemether and/or lumefantrine and loss of anti-malarial efficacy [see DRUG INTERACTIONS].

Drugs that have a mixed effect on CYP3A4, especially Anti-Retroviral drugs, and those that have an effect on the QT interval should be used with caution in patients taking Coartem Tablets [see DRUG INTERACTIONS].

Coartem (artemether lumefantrine tablets) Tablets may reduce the effectiveness of hormonal contraceptives. Therefore, patients using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to use an additional non-hormonal method of birth control [see DRUG INTERACTIONS].

Drug Interactions with CYP2D6

Administration of Coartem (artemether lumefantrine tablets) Tablets with drugs that are metabolized by CYP2D6 may significantly increase plasma concentrations of the co-administered drug and increase the risk of adverse effects. Many of the drugs metabolized by CYP2D6 can prolong the QT interval and should not be administered with Coartem (artemether lumefantrine tablets) Tablets due to the potential additive effect on the QT interval (e.g., fiecainide, imipramine, amitriptyline, clomipramine) [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

Recrudescence

Food enhances absorption of artemether and lumefantrine following administration of Coartem (artemether lumefantrine tablets) Tablets. Patients who remain averse to food during treatment should be closely monitored as the risk of recrudescence may be greater [See DOSAGE AND ADMINISTRATION].

In the event of recrudescent P. falciparum infection after treatment with Coartem (artemether lumefantrine tablets) Tablets, patients should be treated with a different antimalarial drug.

Hepatic and Renal Impairment

Coartem (artemether lumefantrine tablets) Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment [See DOSAGE AND ADMINISTRATION].

Plasmodium vivax Infection

Coartem (artemether lumefantrine tablets) Tablets have been shown in limited data (43 patients) to be effective in treating the erythrocytic stage of P. vivax infection. However, relapsing malaria caused by P. vivax requires additional treatment with other antimalarial agents to achieve radical cure i.e., eradicate any hypnozoites forms that may remain dormant in the liver.

Patient Counseling Information

See FDA-Approved Patient Labeling.

Information for Safe Use

• Instruct patients to take Coartem (artemether lumefantrine tablets) Tablets with food. Patients who do not have an adequate intake of food are at risk for recrudescence of malaria.
• Patients hypersensitive to artemether, lumefantrine, or to any of the excipients should not receive Coartem (artemether lumefantrine tablets) Tablets.
• Instruct patients to inform their physician of any personal or family history of QT prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or recent myocardial ischemia.
• Instruct patients to inform their physician if they are taking any other medications that prolong the QT interval, such as class IA (quinidine, procainamide, disopyramide), or class III (amiodarone, sotalol) antiarrhythmic agents; antipsychotics (pimozide, ziprasidone); antidepressants; certain antibiotics (macrolide antibiotics, fluoroquinolone antibiotics, imidazole, and triazole antifungal agents); certain nonsedating antihistamines (terfenadine, astemizole), or cisapride.
• Instruct patients to notify their physicians if they have any symptoms of prolongation of the QT interval, including prolonged heart palpitations or a loss of consciousness.
• Instruct patients to avoid medications that are metabolized by the cytochrome enzyme CYP2D6 while receiving Coartem (artemether lumefantrine tablets) Tablets since these drugs also have cardiac effects (e.g., flecainide, imipramine, amitriptyline, clomipramine).
• Inform patients that based on animal data, Coartem (artemether lumefantrine tablets) Tablets administered during pregnancy may result in fetal loss. Fetal defects have been reported when artemisinins are administered to animals.
• Halofantrine and Coartem (artemether lumefantrine tablets) Tablets should not be administered within one month of each other due to potential additive effects on the QT interval.
• Antimalarials should not be given concomitantly with Coartem (artemether lumefantrine tablets) Tablets, unless there is no other treatment option, due to limited safety data.
• QT prolonging drugs, including quinine and quinidine, should be used cautiously following Coartem (artemether lumefantrine tablets) Tablets due to the long elimination half-life of lumefantrine and the potential for additive effects on the QT interval.
• Closely monitor food intake in patients who received mefloquine immediately prior to treatment with Coartem (artemether lumefantrine tablets) Tablets.
• Use Coartem (artemether lumefantrine tablets) Tablets cautiously in patients receiving other drugs that are substrates, inhibitors or inducers of CYP3A4, including grapefruit juice, especially those that prolong the QT interval or are anti-retroviral drugs.
• Coartem (artemether lumefantrine tablets) Tablets may reduce the effectiveness of hormonal contraceptives. Therefore, patients using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to use an additional non-hormonal method of birth control.
• Inform patients that Coartem (artemether lumefantrine tablets) Tablets can cause hypersensitivity reactions. Instruct patients to discontinue the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (e.g., swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies were not conducted.

Mutagenesis

No evidence of mutagenicity was detected. The artemether: lumefantrine combination was evaluated using the Salmonella and iisc/zen'cAza/mammalian-microsome mutagenicity test, the gene mutation test with Chinese hamster cells V79, the cytogenetic test on Chinese hamster cells in vitro, and the rat micronucleus test, in vivo.

Impairment of Fertility

Pregnancy rates were reduced by about one half in female rats dosed for 2 to 4 weeks with the artemether-lumefantrine combination at 1000 mg/kg (about 9 times the clinical dose based on body surface area comparisons). Male rats dosed for 70 days showed increases in abnormal sperm (87 % abnormal) and increased testes weights at 30 mg/kg doses (about one third the clinical dose). Higher doses (about 9 times the clinical dose) resulted in decreased sperm motility and 100 % abnormal sperm cells.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Safety data from an observational pregnancy study of approximately 500 pregnant women who were exposed to Coartem (artemether lumefantrine tablets) Tablets (including a third of patients who were exposed in the first trimester), and published data of over 1000 pregnant patients who were exposed to artemisinin derivatives, did not show an increase in adverse pregnancy outcomes or teratogenic effects over background rate.

The efficacy of Coartem (artemether lumefantrine tablets) Tablets in the treatment of acute, uncomplicated malaria in pregnant women has not been established.

Coartem (artemether lumefantrine tablets) Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnant rats dosed during the period of organogenesis at or higher than a dose of about half the highest clinical dose of 1120 mg artemether-lumefantrine per day (based on body surface area comparisons), showed increases in fetal loss, early resorptions and post implantation loss. No adverse effects were observed in animals dosed at about one-third the highest clinical dose. Similarly, dosing in pregnant rabbits at about three times the clinical dose (based on body surface area comparisons) resulted in abortions, preimplantation loss, post implantation loss and decreases in the number of live fetuses. No adverse reproductive effects were detected in rabbits at two times the clinical dose. Embryo-fetal loss is a significant reproductive toxicity. Other artemisinins are known to be embryotoxic in animals. However, because metabolic profiles in animals and humans are dissimilar, artemether exposures in animals may not be predictive of human exposures [see Nonclinical Toxicology]. These data cannot rule out an increased risk for early pregnancy loss or fetal defects in humans.

Nursing Mothers

It is not known whether artemether or lumefantrine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Coartem (artemether lumefantrine tablets) Tablets are administered to a nursing woman. Animal data suggest both artemether and lumefantrine are excreted into breast milk. The benefits of breastfeeding to mother and infant should be weighed against potential risk from infant exposure to artemether and lumefantrine through breast milk.

Pediatric Use

The safety and effectiveness of Coartem (artemether lumefantrine tablets) Tablets have been established for the treatment of acute, uncomplicated malaria in studies involving pediatric patients weighing 5 kg or more [see Clinical Studies]. The safety and efficacy have not been established in pediatric patients who weigh less than 5 kg. Children from non-endemic countries were not included in clinical trials.

Geriatric Use

Clinical studies of Coartem (artemether lumefantrine tablets) Tablets did not include sufficient numbers of subjects aged 65 years and over to determine they respond differently from younger subjects. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing Coartem (artemether lumefantrine tablets) Tablets.

Hepatic and Renal Impairment

No specific pharmacokinetic studies have been performed in patients with either hepatic or renal impairment. Coartem (artemether lumefantrine tablets) Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment. No dosage adjustment is necessary in patients with mild to moderate hepatic and/or renal impairment [See DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Last reviewed on RxList: 5/4/2009
This monograph has been modified to include the generic and brand name in many instances.