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Mechanism of Action

Coartem (artemether lumefantrine tablets) Tablets, a fixed dose combination of artemether and lumefantrine in the ratio of 1:6, is an antimalarial agent.

Pharmacokinetics

Absorption

Following administration of Coartem (artemether lumefantrine tablets) Tablets to healthy volunteers and patients with malaria, artemether is absorbed with peak plasma concentrations reached about 2 hours after dosing. Absorption of lumefantrine, a highly lipophilic compound, starts after a lag-time of up to 2 hours, with peak plasma concentrations about 6 to 8 hours after administration. The single dose (4 tablets) pharmacokinetic parameters for artemether, dihydroartemisinin (DHA), an active antimalarial metabolite of artemether, and lumefantrine in adult Caucasian healthy volunteers are given in Table 3. Multiple dose data after the 6-dose regimen of Coartem (artemether lumefantrine tablets) Tablets in adult malaria patients are given in Table 4.

Table 3: Single Dose Pharmacokinetic Parameters^a for Artemether, Dihydroartemisinin (DHA), and Lumefantrine under Fed Conditions

Food enhances the absorption of both artemether and lumefantrine. In healthy volunteers, the relative bioavailability of artemether was increased between two- to three-fold, and that of lumefantrine sixteen-fold when Coartem (artemether lumefantrine tablets) Tablets were taken after a high-fat meal compared under fasted conditions.. Patients should be encouraged to take Coartem (artemether lumefantrine tablets) Tablets with a meal as soon as food can be tolerated [See DOSAGE AND ADMINISTRATION].

Distribution

Artemether and lumefantrine are both highly bound to human serum proteins in vitro (95.4% and 99.7%, respectively). Dihydroartemisinin is also bound to human serum proteins (47% to 76%). Protein binding to human plasma proteins is linear.

Biotransformation

In human liver microsomes and recombinant CYP450 enzymes, the metabolism of artemether was catalyzed predominantly by CYP3A4/5. Dihydroartemisinin (DHA) is an active metabolite of artemether. The metabolism of artemether was also catalyzed to a lesser extent by CYP2B6, CYP2C9 and CYP2C19. In vitro studies with artemether at therapeutic concentrations revealed no significant inhibition of the metabolic activities of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11.

During repeated administration of Coartem (artemether lumefantrine tablets) Tablets, systemic exposure of artemether decreased significantly, while concentrations of DHA increased, although not to a statistically significant degree. The artemether/DHA AUC ratio is 1.2 after a single dose and 0.3 after 6 doses given over 3 days. This suggests that there was induction of CYP3A4/5 responsible for the metabolism of artemether.

In human liver microsomes and in recombinant CYP450 enzymes, lumefantrine was metabolized mainly by CYP3A4 to desbutyl-lumefantrine. The systemic exposure to the metabolite desbutyl-lumefantrine was less than 1% of the exposure to the parent compound. In vitro, lumefantrine significantly inhibits the activity of CYP2D6 at therapeutic plasma concentrations.

Caution is recommended when combining Coartem (artemether lumefantrine tablets) Tablets with substrates, inhibitors, or inducers of CYP3A4, especially anti-retroviral drugs and those that prolong the QT interval (e.g., macrolide antibiotics, pimozide, terfenadine, astemizole, cisapride) [see WARNINGS AND PRECAUTIONS].

Co-administration of Coartem (artemether lumefantrine tablets) Tablets with CYP2D6 substrates may result in increased plasma concentrations of the CYP2D6 substrate and increase the risk of adverse reactions. In addition, 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., flecainide, imipramine, amitriptyline, clomipramine) [see WARNINGS AND PRECAUTIONS].

Artemether and DHA are cleared from plasma with an elimination half-life of about 2 hours. Lumefantrine is eliminated more slowly, with a terminal half-life of 3-6 days in healthy volunteers and in patients with falciparum malaria. Demographic characteristics such as sex and weight appear to have no clinically relevant effects on the pharmacokinetics of artemether and lumefantrine.

No urinary excretion data are available for humans. In animal studies, artemether metabolites were largely excreted in the urine. However, urinary excretion of artemether, lumefantrine and lumefantrine metabolites was negligible. While animal data are informative, they do not always predict human results.

Hepatic and Renal Impairment

No specific pharmacokinetic studies have been performed in patients with either hepatic or renal impairment [See DOSAGE AND ADMINISTRATION].

Pediatric Patients

The PK of artemether, DHA, and lumefantrine were obtained in two pediatric studies by sparse sampling using a population based approach. PK estimates derived from a composite plasma concentration profile for artemether, DHA, and lumefantrine are provided in Table 4.

Systemic exposure to artemether, DHA, and lumefantrine, when dosed on a mg/kg body weight basis in pediatric patients (≥ 5 to < 35 kg body weight), is comparable to that of the recommended dosing regimen in adult patients.

Table 4: Summary of Pharmacokinetic Parameters for Lumefantrine, Artemether and DHA in Pediatric and Adult Patients with Malaria Following Administration of a 6-dose Regimen of Coartem (artemether lumefantrine tablets) Tablets

Geriatric Patients

No specific pharmacokinetic studies have been performed in patients older than 65 years of age.

Drug Interactions

Ketoconazole (potent CYP3A4 inhibitor)

Concurrent oral administration of ketoconazole (400 mg on Day 1 followed by 200 mg on days 2, 3, 4 and 5) with Coartem (artemether lumefantrine tablets) Tablets (single dose of 4 tablets of 20 mg artemether/120 mg lumefantrine per tablet) with a meal led to an increase in exposure, in terms of area under the curve (AUC), of artemether (2.3-fold), DHA (1.5 fold), and lumefantrine (1.6-fold) in 13 healthy subjects. The pharmacokinetics of ketoconazole were not evaluated. Based on this study, dose adjustment of Coartem (artemether lumefantrine tablets) Tablets is considered unnecessary when administered with ketoconazole or other CYP3A4 inhibitors. However, due to the potential for increased concentrations of lumefantrine which could lead to QT prolongation, Coartem (artemether lumefantrine tablets) Tablets should be used cautiously with other drugs that inhibit CYP3A4 (e.g., anti-retroviral drugs, macrolide antibiotics, antidepressants, imidazole antifungal agents) [see WARNINGS AND PRECAUTIONS].

Antimalarials

The oral administration of mefloquine in 14 healthy volunteers administered as three doses of 500 mg, 250 mg and 250 mg, followed 12 hours later by Coartem (artemether lumefantrine tablets) Tablets (6 doses of 4 tablets of 20 mg artemether/120 mg lumefantrine per tablet), had no effect on plasma concentrations of artemether or the artemether/DHA ratio. In the same study, there was a 30% reduction in Cmax and 40% reduction in AUC of lumefantrine, possibly due to lower absorption secondary to a mefioquine-induced decrease in bile production.

Intravenous administration of a single dose of quinine (10 mg/kg bodyweight) concurrent with the last dose of a 6-dose regimen of Coartem (artemether lumefantrine tablets) Tablets had no effect on systemic exposure of DHA, lumefantrine or quinine in 14 healthy volunteers. Mean AUC of artemether were 46% lower when administered with quinine compared to Coartem (artemether lumefantrine tablets) Tablets alone. This decrease in artemether exposure is not thought to be clinically significant. However, quinine should be used cautiously in patients following treatment with Coartem (artemether lumefantrine tablets) Tablets due to the long elimination half-life of lumefantrine and the potential for additive effects on the QT interval [see WARNINGS AND PRECAUTIONS].

Anti-Retroviral Drugs

No formal drug-drug interaction studies between Coartem (artemether lumefantrine tablets) Tablets and Anti-Retroviral drugs (ARTs), such as protease inhibitors, non-nucleoside reverse transcriptase inhibitors, have been performed. Due to variable patterns of inhibition, induction or competition for CYP3A4 with anti-retroviral drugs, Coartem (artemether lumefantrine tablets) Tablets should be used cautiously in patients on ARTs as the result may be an increase in lumefantrine concentrations causing QT prolongation, a decrease in concentrations of the ART resulting in loss of efficacy, or a decrease in artemether and/or lumefantrine concentrations resulting in loss of antimalarial efficacy of Coartem Tablets [see WARNINGS AND PRECAUTIONS].

Hormonal Contraceptives

No formal drug-drug interaction studies between Coartem (artemether lumefantrine tablets) Tablets and hormonal contraceptives have been performed. However, artemether may induce CYP3A4/5, reducing the effectiveness of hormonal contraceptives [see WARNINGS AND PRECAUTIONS].

Microbiology

Mechanism of Action

Coartem (artemether lumefantrine tablets) Tablets, a fixed ratio of 1:6 parts of artemether and lumefantrine, respectively, is an antimalarial agent. Artemether is rapidly metabolized into an active metabolite dihydroartemisinin (DHA). The anti-malarial activity of artemether and DHA has been attributed to endoperoxide moiety. The exact mechanism by which lumefantrine, exerts its anti-malarial effect is not well defined. Available data suggest lumefantrine inhibits the formation of [3-hematin by forming a complex with hemin. Both artemether and lumefantrine were shown to inhibit nucleic acid and protein synthesis.

Activity In Vitro and In Vivo

Artemether and lumefantrine are active against the erythrocytic stages of Plasmodium falciparum.

Drug Resistance

Strains of P. falciparum with a moderate decrease in susceptibility to artemether or lumefantrine alone can be selected in vitro or in vivo, but not maintained in the case of artemether. The clinical relevance of such an effect is not known.

Effects on the Electrocardiogram

In a healthy adult volunteer parallel group study including a placebo and moxifloxacin control group (n=42 per group), the administration of the 6-dose regimen of Coartem (artemether lumefantrine tablets) Tablets was associated with prolongation of QTcF (Fridericia). Following administration of a 6-dose regimen of Coartem (artemether lumefantrine tablets) Tablets consisting of 4 tablets per dose (total of 4 tablets of 80 mg artemether/480 mg lumefantrine) taken with food, the maximum mean change from baseline and placebo adjusted QTcF was 7.5 msec (1-sided 95% Upper CI: 11 msec). There was a concentration-dependent increase in QTcF for lumefantrine.

In clinical trials conducted in children, no patient had QTcF > 500 msec. Over 5% of patients had an increase in QTcF of over 60 msec.

In clinical trials conducted in adults, QTcF prolongation of > 500 msec was reported in 3 (0.3%) of patients. Over 6% of adults had a QTcF increase of over 60 msec from baseline.

Animal Toxicology and/or Pharmacology

Reproductive Toxicity

Pregnant rats dosed during the period of organogenesis, at or higher than 60 mg/kg/day with the artemether-lumefantrine combination (a dose about half the highest clinical dose based on body surface area comparisons), showed increases in the number of dead fetuses, early resorptions and post implantation losses. No adverse effects were observed in animals dosed at 40 mg/kg (about one third the clinical dose). Similarly, dosing in pregnant rabbits at 175 mg/kg/day (about three times the highest clinical dose based on body surface area comparisons) resulted in abortions, preimplantation losses, post implantation losses, and decreases in the number of live fetuses. No adverse reproductive effects were detected in rabbits at 105 mg/kg/day, about two times the clinical dose based on body surface area comparisons.

Other artemisinins are known to be embryotoxic in animals. Reproductive toxicity studies with artemisinin derivatives (e.g, artesunate) demonstrated increased post-implantation loss and teratogenicity (a low incidence of cardiovascular and skeletal malformations) in rats and rabbits. Similar findings were not seen in animal reproductive studies using artemether.

Neurotoxicity

Studies in dogs and rats have shown that intramuscular injections of artemether resulted in brain lesions. Changes observed mainly in brainstem nuclei included chromatolysis, eosinophilic cytoplasmic granulation, spheroids, apoptosis, and dark neurons. Lesions were observed in rats dosed with artemether at 25 mg/kg for 7 or 14 days and dogs dosed at 20 mg/kg for 8 days or longer, but lesions were not observed after shorter courses of drug or after oral dosing. The estimated artemether 24 h AUC after 7 days of dosing at the no observed effect level (10 mg/kg/day given intramuscularly) is approximately 7fold greater than the estimated artemether 24 h AUC in humans on day 1 of the standard 3-day oral treatment regimen; oral exposure in humans decreases on subsequent days, thus the exposure margin increases. Dogs dosed orally with 143 mg/kg artemether showed a statistically measureable effect on the hearing threshold at 20 dB. This dose is equivalent to about 29 times the highest artemether clinical dose (160 mg/day) based on body surface area comparisons. Most nervous system disorder adverse events in the studies of the 6-dose regimen were mild in intensity and resolved by the end of the study [see ADVERSE REACTIONS].

Clinical Studies

Treatment of Acute, Uncomplicated P. falciparum Malaria

The efficacy of Coartem (artemether lumefantrine tablets) Tablets was evaluated for the treatment of acute, uncomplicated malaria caused by P. falciparum in HIV negative patients in 8 clinical studies. Uncomplicated malaria was defined as symptomaticP. falciparum malaria without signs and symptoms of severe malaria or evidence of vital organ dysfunction. Baseline parasite density ranged from 500/uL - 200,000/uL (0.01% to 4% parasitemia) in the majority of patients. Studies were conducted in partially immune and non-immune adults and children ( ≥ 5kg body weight) with uncomplicated malaria in China, Thailand, sub-Saharan Africa, Europe, and South America. Patients who had clinical features of severe malaria, severe cardiac, renal, or hepatic impairment were excluded.

The studies include two 4-dose studies assessing the efficacy of the components of the regimen, a study comparing a 4-dose versus a 6-dose regimen, and 5 additional 6-dose regimen studies.

Coartem (artemether lumefantrine tablets) Tablets were administered at 0, 8, 24, and 48 hours in the 4-dose regimen, and at 0, 8, 24, 36, 48, and 60 hours in the 6-dose regimen. Efficacy endpoints consisted of:

• 28 day cure rate, defined as clearance of asexual parasites (the erythrocytic stage) within 7 days without recrudescence by day 28
• parasite clearance time (PCT), defined as time from first dose until first total and continued disappearance of asexual parasite which continues for a further 48 hours
• fever clearance time (FCT), defined as time from first dose until the first time body temperature fell below 37.5°C and remained below 37.5°C for at least a further 48 hours (only for patients with temperature > 37.5°C at baseline)

The modified intent to treat (mITT) population includes all patients with malaria diagnosis confirmation who received at least one dose of study drug. Evaluable patients generally are all patients who had a day 7 and a day 28 parasitological assessment or experienced treatment failure by day 28.

Studies 1 and 2: The two studies which assessed the efficacy of Coartem (artemether lumefantrine tablets) Tablets (4 doses of 4 tablets of 20 mg artemether/120 mg lumefantrine) compared to each component alone were randomized, double-blind, comparative, single center, conducted in China. The efficacy results (Table 5) support that the combination of artemether and lumefantrine in Coartem (artemether lumefantrine tablets) Tablets had a significantly higher 28-day cure rate compared to artemether and had a significantly faster parasite clearance time (PCT) and fever clearance time (FCT) compared to lumefantrine.

Table 5: Clinical Efficacy of Coartem (artemether lumefantrine tablets) Tablets versus Components (mITT Population1

Results of 4-dose studies conducted in areas with high resistance such as Thailand during 1995-96 showed lower efficacy results than the above studies. Therefore, Study 3 was conducted.

Study 3: Study 3 was a randomized, double-blind, two-center study conducted in Thailand in adults and children (aged ≥ 2 years), which compared the 4-dose regimen (administered over 48 hours) of Coartem (artemether lumefantrine tablets) Tablets to a 6-dose regimen (administered over 60 hours). Twenty-eight day cure rate in mITT subjects was 81% (96/118) for the Coartem (artemether lumefantrine tablets) Tablets 6-dose arm as compared to 71% (85/120) in the 4-dose arm.

Studies 4, 5, 6, 7, and 8: In these studies, Coartem (artemether lumefantrine tablets) Tablets were administered as the 6-dose regimen.

In study 4, a total of 150 adults and children aged ≥2 years received Coartem (artemether lumefantrine tablets) Tablets. In study 5, a total 164 adults and children ≥12 years received Coartem (artemether lumefantrine tablets) Tablets. Both studies were conducted in Thailand.

Study 6 was a study of 165 non-immune adults residing in regions non-endemic for malaria (Europe and Colombia) who contracted acute uncomplicated falciparum malaria when traveling in endemic regions.

Study 7 was conducted in Africa in 310 infants and children aged 2 months to 9 years, weighing 5 kg to 25 kg, with an axillary temperature ≥ 37.5 °C.

Study 8 was conducted in Africa in 452 infants and children, aged 3 months to 12 years, weighing 5 kg to < 35 kg, with fever ( ≥ 37.5°C axillary or ≥ 38°C rectally) or history of fever in the preceding 24 hours.

Results of 28-day cure rate, median parasite clearance time (PCT), and fever clearance time (FCT) for Studies 3 to 8 are reported in Table 6.

Table 6: Clinical Efficacy of 6-dose Regimen of Coartem (artemether lumefantrine tablets) Tablets

In all studies, patients' signs and symptoms of malaria resolved when parasites were cleared.

In studies conducted in areas with high transmission rates, such as Africa, reappearance of P. falciparum parasites may be due to recrudescence or a new infection.

The efficacy by body weight category for studies 7 and 8 is summarized in Table 7.

Table 7: Clinical Efficacy by Weight for Pediatric Studies

The efficacy of Coartem (artemether lumefantrine tablets) Tablets for the treatment P. falciparum infections mixed with P. vivax was assessed in a small number of patients. Coartem (artemether lumefantrine tablets) Tablets are only active against the erythrocytic phase of P. vivax malaria. Of the 43 patients with mixed infections at baseline, all cleared their parasitemia within 48 hours. However, parasite relapse occurred commonly (14 /43; 33%). Relapsing malaria caused by P. vivax requires additional treatment with other antimalarial agents to achieve radical cure i.e., eradicate any hypnozoite forms that may remain dormant in the liver.

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