Artemether and Lumefantrine

General

Pronunciation
(ar TEM e ther & loo me FAN treen)

Trade Name(s)

• Artemether and Benflumetol
• Benflumetol and Artemether
• Lumefantrine and Artemether

• Antimalarial Agent

Indications

Use: Labeled Indications
Treatment of acute, uncomplicated malaria infections due to Plasmodium falciparum, including geographical regions where chloroquine resistance has been reported

Contraindications

Hypersensitivity to artemether, lumefantrine, or any component of the formulation; concurrent use with strong CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin, St John’s wort)

Dosing and Administration

Oral: Three-day schedule for the treatment of uncomplicated malaria (chloroquine-resistant uncomplicated P. falciparum):

Children 2 months to ≤16 years:

5 to <15 kg: One tablet at hour 0 and hour 8 on the first day, then 1 tablet twice daily on day 2 and day 3 (total of 6 tablets per treatment course)

15 to <25 kg: Two tablets at hour 0 and hour 8 on the first day, then 2 tablets twice daily on day 2 and day 3 (total of 12 tablets per treatment course)

25 to <35 kg: Three tablets at hour 0 and hour 8 on the first day, then 3 tablets twice daily on day 2 and day 3 (total of 18 tablets per treatment course)

≥35 kg: Four tablets at hour 0 and hour 8 on the first day, then 4 tablets twice daily on day 2 and day 3 (total of 24 tablets per treatment course)

Children >16 years and Adults:

25 to <35 kg: Three tablets at hour 0 and hour 8 on the first day, then 3 tablets twice daily on day 2 and day 3 (total of 18 tablets per treatment course)

≥35 kg: Four tablets at hour 0 and hour 8 on the first day, then 4 tablets twice daily on day 2 and day 3 (total of 24 tablets per treatment course)

Dosage adjustment in renal impairment: Dosage adjustment not recommended in mild or moderate impairment. Use caution in severe renal impairment (has not been studied).

Dosage adjustment in hepatic impairment: Dosage adjustments are not recommended in mild or moderate impairment. Use caution in severe impairment (has not been studied).

General Administration
Administer with a full meal for best absorption. For patients unable to swallow tablets: Crush tablet and mix with 5-10 mL of water. Administer to patient. Rinse container with water and administer contents to the patient. The crushed mixture should be followed with food/drink if possible. Repeat dose if vomiting occurs within 2 hours of administration; for persistent vomiting, explore alternative therapy.

Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Dosage Forms/Strengths

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet:

Coartem®: Artemether 20 mg and lumefantrine 120 mg

Interactions

Antimalarial Agents: Artemether may enhance the adverse/toxic effect of Antimalarial Agents. Management: Artemether/Lumefantrine (combination product) should not be used with other antimalarials unless there is no other treatment option. Avoid combination

Antimalarial Agents: May enhance the adverse/toxic effect of Lumefantrine. Management: Artemether/Lumefantrine (combination product) should not be used with other antimalarials unless there is no other treatment option. Avoid combination

Antipsychotic Agents (Phenothiazines): Antimalarial Agents may increase the serum concentration of Antipsychotic Agents (Phenothiazines). Monitor therapy

ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double aripiprazole dose when initiating concomitant therapy with a CYP3A4 inducer (e.g., carbamazepine). Monitor response and adjust aripiprazole dose as clinically indicated. If CYP3A4 inducer is discontinued, reduce aripiprazole dose to 10-15 mg/day. Consider therapy modification

ARIPiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Artemether: May enhance the adverse/toxic effect of Antimalarial Agents. Management: Artemether/Lumefantrine (combination product) should not be used with other antimalarials unless there is no other treatment option. Avoid combination

Axitinib: CYP3A4 Inducers (Weakly to Moderately Effective) may decrease the serum concentration of Axitinib. Avoid combination

Codeine: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Monitor therapy

Contraceptives (Estrogens): Artemether may decrease the serum concentration of Contraceptives (Estrogens). Management: Consider the use of an alternative (i.e., non-hormonal) means of contraception in all women of childbearing potential who are using artemether. Consider therapy modification

Contraceptives (Progestins): Artemether may decrease the serum concentration of Contraceptives (Progestins). Management: Consider the use of an alternative (i.e., non-hormonal) means of contraception in all women of childbearing potential who are using artemether. Consider therapy modification

CYP2D6 Substrates: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates. Exceptions: Tamoxifen. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Lumefantrine. Monitor therapy

Dapsone: May enhance the adverse/toxic effect of Antimalarial Agents. More specifically, dapsone may increase the risk for hemolytic reactions. Antimalarial Agents may enhance the adverse/toxic effect of Dapsone. More specifically, antimalarial agents may increase the risk for hemolytic reactions. Management: Closely monitor patients for signs/symptoms of hemolytic reactions with concomitant use of dapsone and antimalarial agents, particularly in patients deficient in glucose-6-phosphate dehydrogenase (G6PD), methemoglobin reductase, or with hemoglobin M. Consider therapy modification

Dapsone (Systemic): Antimalarial Agents may enhance the adverse/toxic effect of Dapsone (Systemic). Specifically, concomitant use of antimalarial agents with dapsone may increase the risk of hemolytic reactions. Dapsone (Systemic) may enhance the adverse/toxic effect of Antimalarial Agents. Specifically, concomitant use of dapsone with antimalarial agents may increase the risk for hemolytic reactions. Management: Closely monitor patients for signs/symptoms of hemolytic reactions with concomitant use of dapsone and antimalarial agents, particularly in patients deficient in glucose-6-phosphate dehydrogenase (G6PD), methemoglobin reductase, or with hemoglobin M. Consider therapy modification

Dapsone (Topical): Antimalarial Agents may enhance the adverse/toxic effect of Dapsone (Topical). Specifically, the risk of hemolytic reactions may be increased. Management: Closely monitor for signs/symptoms of hemolytic reactions with concomitant use of topical dapsone and antimalarial agents. Patients with glucose-6-phosphate dehydrogenase deficiency may be at particularly high risk for adverse hematologic effects. Consider therapy modification

Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Monitor therapy

Grapefruit Juice: May increase the serum concentration of Artemether. Monitor therapy

Halofantrine: Lumefantrine may enhance the QTc-prolonging effect of Halofantrine. Management: Halofantrine and lumefantrine (as artemether-lumefantrine combination) should not be used within 1 month of each other. Avoid combination

Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest Risk QTc-Prolonging Agents. Avoid combination

Lumefantrine: Antimalarial Agents may enhance the adverse/toxic effect of Lumefantrine. Management: Artemether/Lumefantrine (combination product) should not be used with other antimalarials unless there is no other treatment option. Avoid combination

Mefloquine: May decrease the serum concentration of Lumefantrine. Monitor therapy

Mifepristone: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Saxagliptin: CYP3A4 Inducers may decrease the serum concentration of Saxagliptin. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

TraMADol: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Palpitation (18%)

Central nervous system: Headache (adults 56%; children 13%), dizziness (adults 39%; children 4%), fever (25% to 29%), chills (adults 23%; children 5%), sleep disturbances (22%), fatigue (adults 17%; children 3%)

Gastrointestinal: Anorexia (adults 40%; children 13%), nausea (adults 26%; children 5%), vomiting (17% to 18%), abdominal pain (adults 17%; children 8%)

Neuromuscular & skeletal: Weakness (adults 38%; children 5%), arthralgia (adults 34%; children 3%), myalgia (adults 32%; children 3%)

Respiratory: Cough (adults 6%; children 23%)

3% to 10%:

Central nervous system: Insomnia (5%), malaise (3%), vertigo (3%)

Dermatologic: Pruritus (4%), rash (3%)

Gastrointestinal: Splenomegaly (9%), diarrhea (7% to 8%)

Hematologic: Anemia (4% to 9%)

Hepatic: Hepatomegaly (6% to 9%), AST increased (4%)

Respiratory: Rhinitis (4%), nasopharyngitis (3%)

<3% (Limited to important or life-threatening): Acrodermatitis, angioedema, agitation, ALT increased, asthma, ataxia, back pain, bronchitis, bullous skin eruption, conjunctivitis, constipation, clonus, dyspepsia, dysphagia, eosinophilia, fine motor delay, gait disturbance, hearing loss, hematocrit decreased, hematuria, hyper-reflexia, hypersensitivity reactions, hypoesthesia, hypokalemia, impetigo, infection (viral/bacterial/parasitic), leukocytosis, leukopenia, lymphocyte morphology abnormal, mood swings, nystagmus, peptic ulcer, pharyngolaryngeal pain, proteinuria, QT prolongation, tinnitus, thrombocytopenia, thrombocytosis, tremor, urticaria

Precautions

Concerns related to adverse effects:

• QT prolongation: Use associated with prolonging the QT interval; avoid use in patients at risk for QT prolongation, including patients with a history of long QT syndrome, family history of congenital QT prolongation or sudden death, symptomatic arrhythmias, clinically relevant bradycardia, severe heart disease, known hypokalemia, hypomagnesemia or concurrent administration of antiarrhythmics (eg, Class Ia or III), drugs metabolized by CYP2D6 known to have cardiac effects (eg, flecainide, tricyclic antidepressants), or other drugs known to prolong the QT interval (eg, antipsychotics, antidepressants, macrolides, fluoroquinolones, triazole antifungals, or cisapride).

Disease-related concerns:

• Hepatic impairment: Use caution in patients with severe hepatic impairment; has not been adequately studied.

• Renal impairment: Use caution in patients with severe renal impairment; has not been adequately studied.

Concurrent drug therapy issues:

• Drugs metabolized by CYP enzymes: Use with caution in patients receiving CYP3A4 inhibitors, substrates, or inducers as loss of concomitant drug efficacy or QT prolongation may occur. Use contraindicated in patients receiving strong CYP3A4 inducers. Avoid use in patients receiving medications metabolized by CYP2D6 as plasma concentrations of theses coadministered medications may increase.

• Drugs that prolong the QT interval: Do not use within 1 month of halofantrine (not available in the U.S.) due to the potential additive effects on the QT interval. Concomitant use of agents that prolong the QT interval or promote hypokalemia or hypomagnesemia should be avoided; consider alternative therapy. After discontinuation of artemether/lumefantrine, drugs that prolong the QT interval, including quinidine and quinine, should be used with caution.

• Mefloquine: If mefloquine is administered prior to lumefantrine, decreased lumefantrine exposure may occur due to mefloquine-induced decreased bile production; encourage food consumption and monitor efficacy.

• Duplicate therapy: Antimalarials should not be given concomitantly unless there is no other treatment option.

• Hormonal contraceptives: Concomitant use may decrease effectiveness of hormonal contraceptives; patients should be advised to use additional nonhormonal contraception.

Other warnings/precautions:

• Appropriate use: Not indicated for the treatment of severe or complicated malaria or for the prevention of malaria.

• Recrudescence: In the event of disease reappearance after a quiescent period, patients should be treated with a different antimalarial drug.

Monitoring
Monitor patients for adequate food consumption (to ensure absorption and efficacy)

Pregnancy Risk Factor
C

Pregnancy Considerations
Animal studies have demonstrated increased fetal resorption and postimplantation loss during the period of organogenesis. Safety data from an observational pregnancy study included 500 pregnant women exposed to artemether/lumefantrine and did not show an increased in adverse outcomes or teratogenic effects over background rate. Approximately one-third of these patients were in the third trimester. Efficacy has not been established in pregnant patients. Treatment failures with standard doses have been reported in pregnant women in areas where drug resistant parasites are prevalent. This may be attributed to lower serum concentration of both artemether and lumefantrine in this population (McGready, 2008). Use during pregnancy only if potential benefit justifies potential risk to the fetus.

Lactation
Excretion in breast milk unknown/use caution

Patient and Family Education

Should be taken with food (a full meal if possible). May cause upset stomach, nausea, or loss of appetite. Report chest pain or palpitation, rash, unusual fatigue, or muscle weakness or pain.