Artemether and Lumefantrine

When artemether/lumefantrine is co-administered with moderate inducers of CYP3A4, it may result in decreased concentrations of artemether and/or lumefantrine and loss of antimalarial efficacy.

Interaction with antiretroviral drugs such as protease inhibitors and non-nucleoside reverse transcriptase inhibitors

Both artemether and lumefantrine are metabolized by CYP3A4. ARTs, such as protease inhibitors and non-nucleoside reverse transcriptase inhibitors, are known to have variable patterns of inhibition, induction or competition for CYP3A4. Artemether/lumefantrine should be used cautiously in patients on ARTs since decreased artemether, DHA, and/or lumefantrine concentrations may result in a decrease of antimalarial efficacy of artemether/lumefantrine, and increased lumefantrine concentrations may cause QT prolongation.

Lopinavir/ritonavir:

In a clinical study in healthy volunteers, lopinavir/ritonavir decreased the systemic exposures to artemether and DHA by approximately 40% but increased the exposure to lumefantrine by approximately 2.3-fold. Exposures to lopinavir/ritonavir were not significantly affected by concomitant use of artemether/lumefantrine.

Nevirapine:

In a clinical study in HIV-infected adults, nevirapine significantly reduced the median C_max and AUC of artemether by approximately 61% and 72%, respectively and reduced the median C_max and AUC of dihydroartemisinin by approximately 45% and 37%, respectively. Lumefantrine C_max and AUC were non-significantly reduced by nevirapine. Artemether/lumefantrine reduced the median C_max and AUC of nevirapine by approximately 43% and 46% respectively.

Efavirenz:

Efavirenz decreased the exposures to artemether, DHA, and lumefantrine by approximately 50%, 45%, and 20%, respectively. Exposures to efavirenz were not significantly affected by concomitant use of artemether/lumefantrine.

Both artemether and lumefantrine are metabolised predominantly by the cytochrome enzyme CYP3A4, but do not inhibit this enzyme at therapeutic concentrations.

Artemether/lumefantrine should be used cautiously with drugs that inhibit CYP3A4, due to potential for increased concentrations of lumefantrine which could lead to QT prolongation.

Ketoconazole

The concurrent oral administration of ketoconazole with artemether/lumefantrine led to a modest increase (≤2-fold) in artemether, DHA, and lumefantrine exposure in healthy adult subjects. This increase in exposure to the antimalarial combination was not associated with increased side effects or changes in electrocardiographic parameters. Based on this study, dose adjustment of artemether/lumefantrine is considered unnecessary in falciparum malaria patients when administered in association with ketoconazole or other potent CYP3A4 inhibitors.

When artemether/lumefantrine is co-administered with substrates of CYP3A4 it may result in decreased concentrations of the substrate and potential loss of substrate efficacy. Studies in humans have demonstrated that artemisinins have some capacity to induce CYP3A4 and CYP2C19 and inhibit CYP2D6 and CYP1A2. Although the magnitude of the changes was generally low it is possible that these effects could alter the therapeutic response of drugs that are predominantly metabolised by these enzymes.

Grapefruit juice should be used cautiously during artemether/lumefantrine treatment. Administration of artemether with grapefruit juice in healthy adult subjects resulted in an approximately two fold increase in systemic exposure to the parent drug.

Caution is advised when administering artemether/lumefantrine to patients with severe renal impairment. In these patients, ECG and blood potassium monitoring is advised.

In patients with severe hepatic impairment, a clinically relevant increase of exposure to artemether and lumefantrine and/or their metabolites cannot be ruled out. Therefore caution should be exercised in dosing patients with severe hepatic impairment. In these patients, ECG and blood potassium monitoring is advised.

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 CYP3A. Therefore, artemether/lumefantrine may potentially reduce the effectiveness of hormonal contraceptives. Patients using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to use an additional nonhormonal method of birth control for about one month.

Data on safety and efficacy are limited, and artemether/lumefantrine should therefore not be given concurrently with other antimalarials unless there is no other treatment option.

If artemether/lumefantrine is given following administration of mefloquine or quinine, close monitoring of food intake (for mefloquine) or of the ECG (for quinine) is advised. The long elimination half-life of lumefantrine must be taken into account when administering quinine in patients previously treated with artemether/lumefantrine. In patients previously treated with halofantrine, artemether/lumefantrine should not be administered earlier than one month after the last halofantrine dose.

Mefloquine

A drug interaction study with artemether/lumefantrine in man involved administration of a 6-dose regimen over 60 hours in healthy volunteers which was commenced at 12 hours after completion of a 3-dose regimen of mefloquine or placebo. Plasma mefloquine concentrations from the time of addition of artemether/lumefantrine were not affected compared with a group which received mefloquine followed by placebo.

Pre-treatment with mefloquine had no effect on plasma concentrations of artemether or the artemether/dihydroartemisinin ratio but there was a significant reduction in plasma levels of lumefantrine, possibly due to lower absorption secondary to a mefloquine-induced decrease in bile production. Patients should be encouraged to eat at dosing times to compensate for the decrease in bioavailability.

Quinine

A drug interaction study in healthy male volunteers showed that the plasma concentrations of lumefantrine and quinine were not affected when i.v. quinine (10 mg/kg BW over 2 hours) was given sequentially 2 hours after the last (sixth) dose of artemether/lumefantrine (so as to produce concurrent plasma peak levels of lumefantrine and quinine). Plasma concentrations of artemether and dihydroartemisinin (DHA) appeared to be lower. In this study, administration of artemether/lumefantrine to 14 subjects had no effect on QTc interval. Infusion of quinine alone in 14 other subjects caused a transient prolongation of QTc interval, which was consistent with the known cardiotoxicity of quinine. This effect was slightly, but significantly, greater when quinine was infused after artemether/lumefantrine in 14 additional subjects. It would thus appear that the inherent risk of QTc prolongation associated with i.v. quinine was enhanced by prior administration of artemether/lumefantrine.

A meta-analysis of observational studies including over 500 artemether-lumefantrine exposed women in their first trimester of pregnancy assessed adverse pregnancy outcomes. The data showed that compared to quinine, artemisinin treatment, including artemether-lumefantrine, was not associated with an increased risk of miscarriage, stillbirth or congenital anomalies. However, due to the limitations of these studies, the risk of adverse pregnancy outcomes for artemether-lumefantrine exposed women in early pregnancy cannot be excluded.

Safety data from pregnancy studies including over 1200 pregnant women who were exposed to artemether-lumefantrine during the second or third trimester did not show an increase in adverse pregnancy outcomes or teratogenic effects over background rates.

Studies in animals have shown reproductive toxicity.

Artemether/lumefantrine treatment is not recommended during the first trimester of pregnancy in situations where other suitable and effective antimalarials are available. However, it should not be withheld in life-threatening situations, where no other effective antimalarials are available. During the second and third trimester, artemether/lumefantrine treatment should be considered if the expected benefit to the mother outweighs the risk to the foetus.

Animal data suggest excretion into breast milk but no data are available in humans. Women taking artemether/lumefantrine should not breast-feed during their treatment. Due to the long elimination half-life of lumefantrine (2 to 6 days), it is recommended that breast-feeding should not resume until at least one week after the last dose of artemether/lumefantrine unless potential benefits to the mother and child outweigh the risks of artemether/lumefantrine treatment.

Women of childbearing potential

Women using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to use an additional non-hormonal method of birth control for about one month.

Fertility

There is no information on the effects of artemether/lumefantrine on human fertility.

Patients receiving artemether/lumefantrine should be warned that dizziness or fatigue/asthenia may occur in which case they should not drive or use machines.

The safety of artemether/lumefantrine has been evaluated in 20 clinical trials with more than 3500 patients. A total of 1810 adults and adolescents above 12 years of age as well as 1788 infants and children of 12 years of age and below have received artemether/lumefantrine in clinical trials.

Adverse reactions reported from clinical studies and post-marketing experience are listed below according to system organ class.

Adverse reactions are ranked under headings of frequency using the MedDRA frequency convention: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from available data).

Frequency of Undesirable effects:

^* These adverse reactions were reported during post-marketing experience. Because these spontaneously reported events are from a population of uncertain size, it is difficult to estimate their frequency.
^# Has been reported up to a few weeks after treatment has been stopped.