COARTEM (Page 5 of 7)

12.4 Microbiology

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 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 P. falciparum.

Drug Resistance

There is a potential for development of resistance to artemether and lumefantrine. 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. Alterations in some genetic regions of P. falciparum [multidrug resistant 1 (pfmdr1), chloroquine resistance transporter (pfcrt), and kelch 13 (K13)] based on in vitro testing and/or identification of isolates in endemic areas where artemether/lumefantrine treatment was administered, have been reported. The clinical relevance of these findings are not known.

12.6 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 confidence interval: 11 msec). There was a concentration-dependent increase in QTcF for lumefantrine.

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

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies were not conducted.

Mutagenesis

No evidence of mutagenicity was detected. The artemether-lumefantrine combination was evaluated using the Salmonella and Escherichia /mammalian-microsome mutagenicity test, the gene mutation test with Chinese hamster cells V79, the cytogenetic test on Chinese hamster cells in vitro , and the rat micronucleus test, in vivo.

Impairment of Fertility

Pregnancy rates were reduced by about one-half in female rats dosed for 2 to 4 weeks with the artemether-lumefantrine combination at 1000 mg/kg (about 9 times the clinical dose based on BSA comparisons). Male rats dosed for 89 to 93 days showed increases in abnormal sperm (87% abnormal) at 30 mg/kg doses (about one-third the clinical dose). Higher doses (about 9 times the MRHD) resulted in increased testes weights, decreased sperm motility, and 100% abnormal sperm cells.

13.2 Animal Toxicology and/or Pharmacology

Neonatal rats (7 to 21 days old) were more sensitive to the toxic effects of artemether (a component of Coartem Tablets) 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.

14 CLINICAL STUDIES

14.1 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/mcL to 200,000/mcL (0.01% to 4% parasitemia) in the majority of patients. Studies were conducted in partially immune and non-immune adults and children (greater than or equal to 5 kg 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 greater than 37.5°C at baseline)

The modified intent-to-treat (mITT) population includes all patients with malaria diagnosis confirmation who received at least 1 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 2 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 PCT and FCT compared to lumefantrine.

Table 5: Clinical Efficacy of Coartem Tablets Versus Components (mITT Population)1
Study No. Region/patient ages 28-day cure rate 2 n/N (%) patients Median FCT 3 [25th , 75th percentile] Median PCT [25th , 75th percentile]
Study 1 China, ages 13 to 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]
Study 2 China, ages 12 to 65 years
Coartem Tablets 50/52 (96.2) 21 hours [6, 33] 30 hours [24, 36]
Lumefantrine6 45/51 (88.2) 36 hours [12, 60] 48 hours [42, 60]
Abbreviations: FCT, fever clearance time; mITT, modified intent-to-treat; PCT, parasite clearance time.1 In mITT analysis, patients whose status was uncertain were classified as treatment failures.2 Efficacy cure rate based on blood smear microscopy.3 For patients who had a body temperature greater than 37.5°C at baseline only. 4 95% Confidence Interval (Coartem Tablets–artemether) on 28-day cure rate: 37.8%, 66.0%.5 P-value comparing Coartem Tablets to lumefantrine on PCT and FCT: < 0.001.6 P-value comparing Coartem Tablets to lumefantrine on PCT: < 0.001 and on 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, 2-center study conducted in Thailand in adults and children (aged greater than or equal to 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 greater than or equal to 2 years received Coartem Tablets. In study 5, a total 164 adults and children greater than or equal to 12 years received Coartem 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 P. 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 greater than or equal to 37.5ºC.

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

Results of 28-day cure rate, median PCT, and 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 rate 1 n/N (%) Patients Median FCT 2 [25th , 75th percentile] Median PCT [25th , 75th percentile]
mITT 3 Evaluable
Study 3 Thailand, ages 3–62 years 96/118 (81.4) 93/96 (96.9) 35 hours[20, 46] 44 hours[22, 47]
Early failure4 0 0
Late failure5 4 (3.4) 3 (3.1)
Lost to follow-up 18 (15.3)
Other6 0
Study 4 Thailand, ages 2–63 years 130/149 (87.2) 130/134 (97.0) 22 hours[19, 44] NA
Early failure4 0 0
Late failure5 4 (2.7) 4 (3.0)
Lost to follow-up 13 (8.7)
Other6 2 (1.3)
Study 5 Thailand, ages 12–71 years 148/164 (90.2) 148/155 (95.5) 29 hours[8, 51] 29 hours [18, 40]
Early failure4 0 0
Late failure5 7 (4.3) 7 (4.5)
Lost to follow-up 9 (5.5)
Other6 0
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)
Other6 4 (1.3)
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)
Other6 10 (2.2)
Abbreviations: FCT, fever clearance time; mITT, modified intent-to-treat; PCT, parasite clearance time; NA, not applicable.1 Efficacy cure rate based on blood smear microscopy.2 For patients who had a body temperature greater than 37.5°C at baseline only.3 In mITT analysis, patients whose status was uncertain were classified as treatment failures.4 Early 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.5 Late 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.6 Other 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 Population
Median PCT [25 th , 75 th percentile] 28-day cure rate 2 n/N (%) patients 28-day cure rate 2 n/N (%) patients
Study 7
5 to < 10 kg 24 [24, 36] 133/154 (86.4) 133/149 (89.3)
10 to < 15 kg 35 [24, 36] 94/110 (85.5) 94/107 (87.9)
15 to 25 kg 24 [24, 36] 41/46 (89.1) 40/44 (90.9)
Study 8 3
5 to < 10 kg 36 [24, 36] 61/83 (73.5) 61/69 (88.4)
10 to < 15 kg 35 [24, 36] 160/190 (84.2) 157/179 (87.7)
15 to < 25 kg 35 [24, 36] 123/145 (84.8) 123/140 (87.9)
25 to < 35 kg 26 [24, 36] 30/34 (88.2) 29/31 (93.5)
Abbreviations: mITT, modified intent-to-treat; PCT, parasite clearance time.1 In mITT analysis, patients whose status was uncertain were classified as treatment failures.2 Efficacy cure rate based on blood smear microscopy.3 Coartem 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.

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