COARTEM (Page 3 of 7)

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Coartem Tablets. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  • Hypersensitivity Reactions: anaphylaxis, urticaria, angioedema, and serious skin reactions (bullous eruption) have been reported.
  • Blood and Lymphatic System Disorders: Cases of delayed hemolytic anemia have been reported following treatment with artemether-lumefantrine, mostly when used for treatment of severe malaria in patients initially treated with IV/parenteral artesunate. Coartem Tablets should not be used to treat severe malaria as it is not an approved indication.

7 DRUG INTERACTIONS

7.1 Rifampin

Oral administration of rifampin, a strong CYP3A4 inducer, with Coartem Tablets resulted in significant decreases in exposure to artemether, DHA (metabolite of artemether), and lumefantrine by 89%, 85%, and 68%, respectively, when compared to exposure values after Coartem Tablets alone. Concomitant use of strong inducers of CYP3A4 such as rifampin, carbamazepine, phenytoin, and St. John’s wort is contraindicated with Coartem Tablets [see Contraindications (4) and Clinical Pharmacology (12.3)].

7.2 Ketoconazole

Concurrent oral administration of ketoconazole, a potent CYP3A4 inhibitor, with a single dose of Coartem Tablets resulted in a moderate increase in exposure to artemether, DHA, and lumefantrine in a study of 15 healthy subjects. No dose adjustment of Coartem Tablets is necessary when administered with ketoconazole or other potent CYP3A4 inhibitors. However, due to the potential for increased concentrations of lumefantrine which could lead to QT prolongation, Coartem Tablets should be used cautiously with drugs that inhibit CYP3A4 [see Warnings and Precautions (5.1, 5.3) and Clinical Pharmacology (12.3)].

7.3 Antiretroviral Drugs

Both artemether and lumefantrine are metabolized by CYP3A4. Antiretroviral drugs, such as protease inhibitors and non-nucleoside reverse transcriptase inhibitors, are known to have variable patterns of inhibition, induction or competition for CYP3A4. Therefore, the effects of antiretroviral drugs on the exposure to artemether, DHA, and lumefantrine are also variable [see Clinical Pharmacology (12.3)]. Coartem Tablets should be used cautiously in patients on antiretroviral drugs because decreased artemether, DHA, and/or lumefantrine concentrations may result in a decrease of antimalarial efficacy of Coartem Tablets, and increased lumefantrine concentrations may cause QT prolongation [see Warnings and Precautions (5.3)].

7.4 Prior Use of Mefloquine

Administration of 3 doses of mefloquine followed 12 hours later by a 6-dose regimen of Coartem Tablets in 14 healthy volunteers demonstrated no effect of mefloquine on plasma concentrations of artemether or the artemether/DHA ratio. However, exposure to lumefantrine was reduced, possibly due to lower absorption secondary to a mefloquine-induced decrease in bile production. Patients should be monitored for decreased efficacy and food consumption should be encouraged with administration of Coartem Tablets [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

7.5 Hormonal Contraceptives

In vitro , the metabolism of ethinyl estradiol and levonorgestrel was not induced by artemether, DHA, or lumefantrine. However, artemether has been reported to weakly induce, in humans, the activity of CYP2C19, CYP2B6, and CYP3A4. Therefore, Coartem Tablets may potentially reduce the effectiveness of hormonal contraceptives. Patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method or add a barrier method of contraception during treatment with Coartem [see Warnings and Precautions (5.3), Use in Specific Populations (8.3) and Clinical Pharmacology (12.3)].

7.6 CYP2D6 Substrates

Lumefantrine inhibits CYP2D6 in vitro. Administration of Coartem Tablets with drugs that are metabolized by CYP2D6 may significantly increase plasma concentrations of the coadministered 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, 5.4) and Clinical Pharmacology (12.3)].

7.7 Sequential Use of Quinine

A single dose of intravenous quinine (10 mg/kg bodyweight) concurrent with the final dose of a 6-dose regimen of Coartem Tablets demonstrated no effect of intravenous quinine on the systemic exposure of DHA or lumefantrine. Quinine exposure was also not altered. Exposure to artemether was decreased. This decrease in artemether exposure is not thought to be clinically significant. However, quinine and other drugs that prolong the QT interval should be used cautiously following treatment with Coartem Tablets due to the long elimination half-life of lumefantrine and the potential for additive QT effects; ECG monitoring is advised if use of drugs that prolong the QT interval is medically required [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

7.8 Interaction With Drugs That are Known to Prolong the QT Interval

Coartem Tablets are to be used with caution when coadministered with drugs that may cause prolonged QT interval such as antiarrhythmics of Classes IA and III, neuroleptics and antidepressant agents, certain antibiotics including some agents of the following classes: macrolides, fluoroquinolones, imidazole, and triazole antifungal agents [see Warnings and Precautions (5.1, 5.2)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Published data from clinical studies and pharmacovigilance data have not established an association with artemether/lumefantrine use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Malaria during and after pregnancy increases the risk for adverse pregnancy and neonatal outcomes, including maternal anemia, severe malaria, spontaneous abortion, stillbirths, preterm delivery, low birth weight, intrauterine growth restriction, congenital malaria, and maternal and neonatal mortality.

Data

Human Data

While available studies cannot definitively establish the absence of risk, a meta-analysis of observational studies including over 500 artemether-lumefantrine exposed women in their first trimester of pregnancy, data from observational, and open label studies including more than 1200 pregnant women in their second- or third trimester exposed to artemether-lumefantrine compared to other antimalarials, and pharmacovigilance data have not demonstrated an increase in major birth defects, miscarriage, or adverse maternal or fetal outcomes. Published epidemiologic studies have important methodological limitations which hinder interpretation of data, including inability to control for confounders, such as underlying maternal disease, and maternal use of concomitant medications and missing information on the dose and duration of use.

Animal Data

Pregnant rats dosed orally during the period of organogenesis [gestational days (GD) 7 through 17] at 50 mg/kg/day artemether-lumefantrine combination (corresponding to 7 mg/kg/day artemether or higher, a dose of less than half the maximum recommended human dose (MRHD) of 1120 mg artemether-lumefantrine per day (based on body surface area (BSA) comparisons), showed increases in fetal loss, early resorptions, and postimplantation loss. No adverse effects were observed in animals dosed at 25 mg/kg/day artemether-lumefantrine (corresponding to 3.6 mg/kg/day of artemether), about one-third the MRHD (based on BSA comparison). Similarly, oral dosing in pregnant rabbits during organogenesis (GD 7 through GD 19) at 175 mg/kg/day, (corresponding to 25 mg/kg/day artemether) about 3 times the MRHD (based on BSA 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 105 mg/kg/day artemether-lumefantrine (corresponding to 15 mg/kg/day artemether), about 2 times the MRHD. Artemether and other artemisinins are associated with maternal toxicity and embryotoxicity and malformations in animals at clinically relevant exposures; however, lumefantrine doses as high as 1000 mg/kg/day, showed no evidence to suggest maternal, embryo- or fetotoxicity or teratogenicity in rats and rabbits. The relevance of the findings from the animal reproductive studies to human risk is unclear.

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