WARNINGS AND PRECAUTIONS
Prolongation of the QT Interval
Some antimalarials (e.g., halofantrine, quinine, quinidine) including Coartem Tablets have been associated with prolongation of the QT interval on the electrocardiogram.
Coartem 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 (12.5) ].
- 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 (5.4), Drug Interactions (7.4) and Clinical Pharmacology (12.3) ].
Use of QT Prolonging Drugs and Other Antimalarials
Halofantrine and Coartem 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 (5.1), and Clinical Pharmacology (12.3) ].
Antimalarials should not be given concomitantly with Coartem 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 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 (5.1), Drug Interactions (7.5), and Clinical Pharmacology (12.3) ].
If mefloquine is administered immediately prior to Coartem 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 (2.1), Drug Interactions (7.2), and Clinical Pharmacology (12.3) ].
Drug Interactions with CYP3A4
When Coartem 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 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 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 (7.1) ].
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 (7.3) ].
Coartem 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 (7.3) ].
Drug Interactions with CYP2D6
Administration of Coartem 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 Tablets due to the potential additive effect on the QT interval (e.g., flecainide, imipramine, amitriptyline, clomipramine) [ see Warnings and Precautions (5.1), Drug Interactions (7.4) and Clinical Pharmacology (12.3) ].
Food enhances absorption of artemether and lumefantrine following administration of Coartem 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 (2.1) ].
In the event of recrudescent P. falciparum infection after treatment with Coartem Tablets, patients should be treated with a different antimalarial drug .
Hepatic and Renal Impairment
Coartem Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment [ see Dosage and Administration (2.4) ].
Plasmodium vivax Infection
Coartem 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.
USE IN SPECIFIC POPULATIONS
Pregnancy Category C
Safety data from an observational pregnancy study of approximately 500 pregnant women who were exposed to Coartem Tablets (including a third of patients who were exposed in the first trimester), and published data of over 1,000 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 Tablets in the treatment of acute, uncomplicated malaria in pregnant women has not been established.
Coartem 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 (13.2) ]. These data cannot rule out an increased risk for early pregnancy loss or fetal defects in humans.
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 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.
The safety and effectiveness of Coartem Tablets have been established for the treatment of acute, uncomplicated malaria in studies involving pediatric patients weighing 5 kg or more [ see Clinical Studies (14.1) ]. 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.
Clinical studies of Coartem 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 Tablets.
Hepatic and Renal Impairment
No specific pharmacokinetic studies have been performed in patients with either hepatic or renal impairment. Coartem Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment. Based on the pharmacokinetic data in 16 healthy subjects showing no or insignificant renal excretion of lumefantrine, artemether and DHA, no dose adjustment for the use of Coartem in patients with renal impairment is advised. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. [ see Dosage and Administration (2.4) and Warnings and Precautions (5.6) ].