COARTEM (Page 4 of 7)

8.2 Lactation

Risk Summary

There are no data on the presence of artemether or lumefantrine in human milk, the effects on the breastfed infant or the effects on milk production. Artemether and lumefantrine are transferred into rat milk. When a drug is transferred into animal milk, it is likely that the drug will also be transferred into human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Coartem and any potential adverse effects on the breastfed infant from Coartem or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Contraception

Use of Coartem may reduce the efficacy of hormonal contraceptives. Advise patients using hormonal contraceptives to use an alternative non-hormonal contraceptive method or add a barrier method of contraception during treatment with Coartem [see Drug Interactions (7.5)].

Infertility

In animal fertility studies, administration of repeated doses of artemether-lumefantrine combination to female rats (for 2 to 4 weeks) resulted in pregnancy rates that were reduced by one half. In male rats dosed for approximately 3 months with artemether-lumefantrine combination, abnormal sperm cells, decreased sperm motility, and increased testes weight were observed [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of Coartem Tablets have been established in pediatric patients aged 2 months and older with a bodyweight of 5 kg and above for the treatment of acute, uncomplicated malaria [see Clinical Studies (14.1)]. The safety and effectiveness of Coartem Tablets have not been established in pediatric patients younger than 2 months old or who weigh less than 5 kg. Pediatric patients from non-endemic countries were not included in clinical trials.

8.5 Geriatric Use

Clinical studies of Coartem Tablets did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing Coartem Tablets.

8.6 Hepatic and Renal Impairment

No specific pharmacokinetic studies have been performed in patients with either hepatic or renal impairment. Coartem Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment. Based on the pharmacokinetic data in 16 healthy subjects showing no or insignificant renal excretion of lumefantrine, artemether, and DHA, no dose adjustment for the use of Coartem Tablets in patients with renal impairment is advised. No dosage adjustment is necessary in patients with mild-to-moderate hepatic impairment [see Dosage and Administration (2.4) and Warnings and Precautions (5.6)].

10 OVERDOSAGE

There is no information on overdoses of Coartem Tablets higher than the doses recommended for treatment.

In cases of suspected overdosage, symptomatic and supportive therapy, which would include ECG and blood electrolyte monitoring, should be given as appropriate.

11 DESCRIPTION

Coartem Tablets contain a fixed combination of 2 antimalarial active ingredients, artemether, an artemisinin derivative, and lumefantrine. Both components are blood schizontocides. The chemical name of artemether is (3R ,5aS ,6R ,8aS ,9R ,10S ,12R ,12aR)-10-methoxy-3,6,9-trimethyldecahydro-3,12-epoxypyrano[4,3-j ]-1,2-benzodioxepine. Artemether is a white, crystalline powder that is freely soluble in acetone, soluble in methanol and ethanol, and practically insoluble in water. It has the empirical formula C16 H26 O5 with a molecular weight of 298.4 g/mol, and the following structural formula:

Artemether structural formula

The chemical name of lumefantrine is (1RS)-2-(dibutylamino)-1-{(9Z)-2,7-dichloro-9-[(4-chlorophenyl)methylene]-9H -fluorene-4-yl}ethanol. Lumefantrine is a yellow, crystalline powder that is freely soluble in N,N-dimethylformamide, chloroform, and ethyl acetate; soluble in dichloromethane; slightly soluble in ethanol and methanol; and insoluble in water. It has the empirical formula C30 H32 Cl3 NO with a molecular weight of 528.9 g/mol, and the following structural formula:

Lumefantrine structural formula

Coartem Tablets are for oral administration. Each Coartem Tablet contains 20 mg of artemether and 120 mg lumefantrine. The inactive ingredients are colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, and polysorbate 80.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Coartem Tablets, a fixed dose combination of artemether and lumefantrine in the ratio of 1:6, is an antimalarial agent [see Microbiology (12.4)].

12.3 Pharmacokinetics

Absorption

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, 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, and Lumefantrine Under-Fed Conditions
Abbreviations: DHA, dihydroartemisinin; SD, standard deviation; AUC, area under the curve.a Mean ± SD Cmax , AUClast , t½ and Median Tmax .
Study 2102 (n = 50) Study 2104 (n = 48)
Artemether
Cmax (ng/mL) 60.0 ± 32.5 83.8 ± 59.7
Tmax (h) 1.50 2.00
AUClast (ng·h/mL) 146 ± 72.2 259 ± 150
t½ (h) 1.6 ± 0.7 2.2 ± 1.9
DHA
Cmax (ng/mL) 104 ± 35.3 90.4 ± 48.9
Tmax (h) 1.76 2.00
AUClast (ng·h/mL) 284 ± 83.8 285 ± 98.0
t½ (h) 1.6 ± 0.6 2.2 ± 1.5
Lumefantrine
Cmax (µg/mL) 7.38 ± 3.19 9.80 ± 4.20
Tmax (h) 6.01 8.00
AUClast (µg·h/mL) 158 ± 70.1 243 ± 117
t½ (h) 101 ± 35.6 119 ± 51.0

Food enhances the absorption of both artemether and lumefantrine. In healthy volunteers, the relative bioavailability of artemether was increased between 2- to 3-fold, and that of lumefantrine 16-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 (2.1)].

Distribution

Artemether and lumefantrine are both highly bound to human serum proteins in vitro (95.4% and 99.7%, respectively). Dihydroartemisinin (DHA) 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. 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 area under the curve (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 (4), Warnings and Precautions (5.1, 5.2, 5.3), and Drug Interactions (7)].

Coadministration 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 (5.1, 5.4) and Drug Interactions (7.6)].

Elimination

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 to 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 Tablets, and urinary excretion of DHA amounted to less than 0.01% of the artemether dose.

Specific Populations

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 (2.4)].

Pediatric Patients

The PK of artemether, DHA, and lumefantrine were obtained in 2 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 an mg/kg body weight basis in pediatric patients (greater than or equal to 5 to less than 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
Adults1 Pediatric Patients (body weight, kg)2
Drug 5 to < 15 15 to < 25 25 to < 35
Lumefantrine
Mean Cmax , range (mcg/mL) 5.60-9.0 4.71–12.6 Not Available
Mean AUClast , range (mcg·h/mL) 410-561 372–699 Not Available
Artemether
Mean Cmax ± SD (ng/mL) 186 ± 125 223 ± 309 198 ± 179 174 ± 145
Dihydroartemisinin
Mean Cmax ± SD (ng/mL) 101 ± 58 54.7 ± 58.9 79.8 ± 80.5 65.3 ± 23.6
Abbreviations: AUC, area under the curve; DHA, dihydroartemisinin; SD, standard deviation.1 There are a total of 181 adults for lumefantrine pharmacokinetic parameters and a total of 25 adults for artemether and dihydroartemisinin pharmacokinetic parameters.2 There 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 less than 15, 15 to less than 25 and the 25 to less than 35 kg groups, respectively.

Geriatric Patients

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

Drug Interaction Studies

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 6 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 (4)].

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 AUC, of artemether (2.3-fold), DHA (1.5-fold), and lumefantrine (1.6-fold) in 13 healthy subjects. The pharmacokinetics of ketoconazole was 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 (5.1, 5.3)].

Antimalarials

The oral administration of mefloquine in 14 healthy volunteers administered as 3 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 (5.2)].

Antiretroviral Drugs

The oral administration of lopinavir/ritonavir (400 mg/100 mg twice daily for 26 days) in 10 healthy volunteers coadministered 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 coadministered 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 (5.3) and Drug Interactions (7.3)].

Hormonal Contraceptives

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 CYP3A4. Therefore, coadministration of Coartem Tablets may potentially reduce the effectiveness of hormonal contraceptives [see Warnings and Precautions (5.3) and Drug Interactions (7.5)].

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