Artemether lumefantrine warnings and precautions

# 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) .
- receiving medications that are metabolized by the cytochrome enzyme CYP2D6 which also have cardiac effects (e.g., flecainide, imipramine, amitriptyline, clomipramine) .

## 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 .
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; ECG monitoring is advised if use of drugs that prolong the QT interval is medically required .
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 .

## 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 antimalarial efficacy .
Drugs that have a mixed effect on CYP3A4, especially antiretroviral drugs such as HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, and those that have an effect on the QT interval should be used with caution in patients taking Coartem Tablets .
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 .

## 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) .

## Recrudescence
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 .
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 .

## 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.