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Mechanism of Action
Coartem Tablets, a fixed dose combination of artemether and lumefantrine in the ratio of 1:6, is an antimalarial agent.
Following administration of Coartem 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 Tablets in adult malaria patients are given in Table 4.
Table 3: Single Dose
Pharmacokinetic Parametersa for Artemether, Dihydroartemisinin
(DHA), and Lumefantrine under Fed Conditions
|Cmax (ng/mL)||60.0 ± 32.5||83.8 ± 59.7|
|AUClast (ng•h/mL)||146 ± 72.2||259± 150|
|t½ (h)||1.6 ± 0.7||2.2 ± 1.9|
|Cmax (ng/mL)||104 ± 35.3||90.4 ± 48.9|
|AUClast (ng-h/mL)||284 ± 83.8||285 ± 98.0|
|t½ (h)||1.6 ± 0.6||2.2 ± 1.5|
|Cmax (μg/mL)||7.38 ± 3.19||9.80 ± 4.20|
|AUClast (μg•h/mL)||158 ± 70.1||243 ± 117|
|t½ (h)||101 ± 35.6||119 ± 51.0|
|aMean ± SD Cmax, AUClast, t½ and Median tmax|
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 Tablets were taken after a high-fat meal compared under fasted conditions. Patients should be encouraged to take Coartem Tablets with a meal as soon as food can be tolerated [see DOSAGE AND ADMINISTRATION].
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.
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. In vitro studies with artemether, DHA, and lumefantrine at therapeutic concentrations revealed no significant induction of the metabolic activities of CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, or CYP3A5.
During repeated administration of Coartem 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 enzymes 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 Tablets with substrates, inhibitors, or inducers of CYP3A4, especially antiretroviral drugs and those that prolong the QT interval (e.g., macrolide antibiotics, pimozide) [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS].
Co-administration of Coartem 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 Tablets due to the potential additive effect on the QT interval (e.g., flecainide, imipramine, amitriptyline, clomipramine) [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Artemether and DHA are cleared from plasma with an elimination half-life of about 2 hours. Lumefantrine is eliminated more slowly, with an elimination 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.
In 16 healthy volunteers, neither lumefantrine nor artemether was found in the urine after administration of Coartem, and urinary excretion of DHA amounted to less than 0.01% of the artemether dose.
Hepatic and Renal Impairment
No specific pharmacokinetic studies have been performed in patients with either hepatic or renal impairment. There is no significant renal excretion of lumefantrine, artemether and DHA in healthy volunteers and while clinical experience in this population is limited, no dose adjustment in renal impairment is recommended [see DOSAGE AND ADMINISTRATION].
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 Tablets
|Drug||Adults1||Pediatric patients (body weight, kg2)|
|5 - < 15||15 - < 25||25 - < 35|
|Mean Cmax, range (μg/mL)||5.60 - 9.0||4.71||- 12.6||Not Available|
|Mean AUClast, range (μg•h/mL)||410 - 561||372||- 699||Not Available|
|Mean Cmax ± SD (ng/mL)||186± 125||223 ± 309||198± 179||174± 145|
|Mean Cmax ± SD (ng/mL)||101 ± 58||54.7 ± 58.9||79.8 ± 80.5||65.3 ± 23.6|
|1There are a total of 181 adults for lumefantrine
pharmacokinetic parameters and a total of 25 adults for artemether and
dihydroartemisinin pharmacokinetic parameters.
2There are 477 children for the lumefantrine pharmacokinetic parameters; for artemether and dihydroartemisinin pharmacokinetic parameters there are 55, 29, and 8 children for the 5 to < 15, 15 to < 25 and the 25 to < 35 kg groups, respectively.
No specific pharmacokinetic studies have been performed in patients older than 65 years of age.
Rifampin (strong CYP3A4 inducer)
Oral administration of rifampin (600 mg daily), a strong CYP3A4 inducer, with Coartem Tablets (6-dose regimen over 3 days) in six HIV-1 and tuberculosis co-infected adults without malaria resulted in significant decreases in exposure, in terms of AUC, to artemether, DHA 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].
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 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 (1.5fold), and lumefantrine (1.6-fold) in 13 healthy subjects. The pharmacokinetics of ketoconazole were not evaluated. Based on this study, dose adjustment of Coartem 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 Tablets should be used cautiously with other drugs that inhibit CYP3A4 (e.g., antiretroviral drugs, macrolide antibiotics, antidepressants, imidazole antifungal agents) [see WARNINGS AND PRECAUTIONS].
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 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 mefloquine-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 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 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 Tablets due to the long elimination half-life of lumefantrine and the potential for additive effects on the QT interval; ECG monitoring is advised if use of quinine is medically required [see WARNINGS AND PRECAUTIONS].
The oral administration of lopinavir/ritonavir (400 mg/100 mg twice daily for 26 days) in 10 healthy volunteers co-administered with Coartem Tablets (6-dose regimen over 3 days), resulted in a decrease in systemic exposures, in terms of AUC, to artemether and DHA by approximately 40%, but an increase in exposure to lumefantrine by approximately 2.3-fold. The oral administration of efavirenz (600 mg once daily for 26 days) in 12 healthy volunteers co-administered with Coartem Tablets (6-dose regimen over 3 days), resulted in a decrease in exposures to artemether, DHA, and lumefantrine by approximately 50%, 45%, and 20%, respectively. Exposures to lopinavir/ritonavir and efavirenz were not significantly affected by concomitant use of Coartem Tablets. Coartem Tablets should be used cautiously in patients on antiretroviral drugs such as HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors 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 and DRUG INTERACTIONS].
No clinical drug-drug interaction studies between Coartem Tablets and hormonal contraceptives have been performed. In vitro studies revealed that 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, co-administration of Coartem Tablets may potentially reduce the effectiveness of hormonal contraceptives [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Mechanism of Action
Coartem 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 antimalarial activity of artemether and DHA has been attributed to endoperoxide moiety. The exact mechanism by which lumefantrine, exerts its antimalarial effect is not well defined. Available data suggest lumefantrine inhibits the formation of β-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.
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 Tablets was associated with prolongation of QTcF (Fridericia). Following administration of a 6-dose regimen of Coartem 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.
Neonatal rats (7-21 days old) were more sensitive to the toxic effects of artemether (a component of Coartem) than older juvenile rats or adults. Mortality and severe clinical signs were observed in neonatal rats at doses which were well tolerated in pups above 22 days old.
Treatment of Acute, Uncomplicated P. falciparum Malaria
The efficacy of Coartem 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 symptomatic P. falciparum malaria without signs and symptoms of severe malaria or evidence of vital organ dysfunction. Baseline parasite density ranged from 500/μL - 200,000/μL (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 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 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 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 Tablets versus
Components (mITT Population)1
|Study No. Region/patient ages||28-day cure rate2 n/N (%) patients||Median FCT3 [25th,75th percentile]||Median PCT [25th,75th percentile]|
|China, ages 13 - 57 years|
|Coartem Tablets||50/51 (98.0)||24 hours [9, 48]||30 hours [24, 36]|
|Artemether4||24/52 (46.2)||21 hours [12, 30]||30 hours [24, 33]|
|Lumefantrine5||47/52 (90.4)||60 hours [36, 78]||54 hours [45, 66]|
|China, ages 12 - 65 years|
|Coartem Tablets||50/52 (96.2)||21 hours [6, 33]||30 hours [24, 36]|
|Lumefantrine 6||45/51 (88.2)||36 hours [12, 60]||48 hours [42, 60]|
|1In mITT analysis, patients whose status was uncertain were
classified as treatment failures.
2Efficacy cure rate based on blood smear microscopy.
3For patients who had a body temperature > 37.5°C at baseline only
495% CI (Coartem Tablets – artemether) on 28-day cure rate: 37.8%, 66.0%
5P-value comparing Coartem Tablets to lumefantrine on parasite clearance time (PCT) and fever clearance time (FCT): < 0.001
6P-value comparing Coartem Tablets to lumefantrine on parasite clearance time (PCT): < 0.001 and on fever clearance time (FCT): < 0.05
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 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 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 Tablets were administered as the 6-dose regimen.
In study 4, a total of 150 adults and children aged ≥ 2 years received Coartem Tablets. In study 5, a total 164 adults and children ≥ 12 years received Coartem Tablets. Both studies were conducted in Thailand.
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 Tablets
|Study No. Region/ages||28-day cure rate1 n/N (%) patients||Median FCT2||Median PCT|
|mITT3||Evaluable||[25th, 75th percentile]||[25th, 75th percentile]|
|Study 3 Thailand, ages 3 - 62 years||96/118 (81.4)||93/96 (96.9)||35 hours||44 hours|
|Early failure4||0||0||[20, 46]||[22, 47]|
|Late failure5||4 (3.4)||3 (3.1)|
|Lost to follow up||18 (15.3)|
|Study 4 Thailand, ages 2 - 63 years||130/149 (87.2)||130/134 (97.0)||22 hours [19, 44]||NA|
|Late failure5||4 (2.7)||4 (3.0)|
|Lost to follow up||13 (8.7)|
|Study 5 Thailand, ages 12 - 71 years||148/164 (90.2)||148/155 (95.5)||29 hours [8, 51]||29 hours [18, 40]|
|Late failure5||7 (4.3)||7 (4.5)|
|Lost to follow up||9 (5.5)|
|Study 6 Europe/Columbia, ages 16 - 66 years||120/162 (74.1)||119/124 (96.0)||37 hours [18, 44]||42 hours [34, 63]|
|Early failure4||6 (3.7)||1 (0.8)|
|Late failure5||3 (1.9)||3 (2.4)|
|Lost to follow up||17 (10.5)|
|Other6||16 (9.9)||1 (0.8)|
|Study 7 Africa, ages 2 months -9 years||268/310 (86.5)||267/300 (89.0)||8 hours [8, 24]||24 hours [24, 36]|
|Early failure4||2 (0.6)||0|
|Late failure5||34 (11.0)||33 (11.0)|
|Lost to follow up||2 (0.6)|
|Study 8 Africa, ages 3 months -12 years||374/452 (82.7)||370/419 (88.3)||8 hours [8, 23]||35 hours [24, 36]|
|Early failure4||13 (2.9)||0|
|Late failure5||49 (10.8)||49 (11.7)|
|Lost to follow up||6 (1.3)|
|1Efficacy cure rate based on blood smear microscopy
2For patients who had a body temperature > 37.5°C at baseline only
3In mITT analysis, patients whose status was uncertain were classified as treatment failures.
4Early failures were usually defined as patients withdrawn for unsatisfactory therapeutic effect within the first 7 days or because they received another antimalarial medication within the first 7 days
5Late failures were defined as patients achieving parasite clearance within 7 days but having parasite reappearance including recrudescence or new infection during the 28 day follow-up period
6Other includes withdrawn due to protocol violation or non-compliance, received additional medication after day 7, withdrew consent, missing day 7 or 28 assessment
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
|Study No. Age category||Coartem Tablets 6-dose Regimen|
|mITT population1||Evaluable populatioi|
|Median PCT [25th,75th percentile]||28-day cure rate2 n/N (%) patients||28-day cure rate2 n/N (%) patients|
|5 - < 10 kg||24 [24, 36]||133/154 (86.4)||133/149 (89.3)|
|10 - < 15 kg||35 [24, 36]||94/110 (85.5)||94/107 (87.9)|
|15 -25 kg||24 [24, 36]||41/46 (89.1)||40/44 (90.9)|
|5 - < 10 kg||36 [24, 36]||61/83 (73.5)||61/69 (88.4)|
|10 - < 15 kg||35 [24, 36]||160/190 (84.2)||157/179 (87.7)|
|15 - < 25 kg||35 [24, 36]||123/145 (84.8)||123/140 (87.9)|
|25 - < 35 kg||26 [24, 36]||30/34 (88.2)||29/31 (93.5)|
|1In mITT analysis, patients whose status was
uncertain were classified as treatment failures.
2Efficacy cure rate based on blood smear microscopy
3Coartem Tablets administered as crushed tablets
The efficacy of Coartem Tablets for the treatment P. falciparum infections mixed with P. vivax was assessed in a small number of patients. Coartem 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: 5/28/2013
This monograph has been modified to include the generic and brand name in many instances.
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