Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Coartem: Artemether 20 mg and lumefantrine 120 mg
Pharmacology
Mechanism of Action
A coformulation of artemether and lumefantrine with activity against Plasmodium falciparum. Artemether and major metabolite dihydroartemisinin (DHA) are rapid schizontocides with activity attributed to the endoperoxide moiety common to each substance. Artemether inhibits an essential calcium adenosine triphosphatase. The exact mechanism of lumefantrine is unknown, but it may inhibit the formation of β-hematin by complexing with hemin. Both artemether and lumefantrine inhibit nucleic acid and protein synthesis. Artemether rapidly reduces parasite biomass and lumefantrine eliminates residual parasites.
Pharmacokinetics/Pharmacodynamics
Absorption
Artemether: Rapid; Lumefantrine: Initial absorption at 2 hours; enhanced with food
Metabolism
Artemether is hepatically metabolized to an active metabolite, dihydroartemisinin (DHA), catalyzed predominately by CYP3A4/5 and to a lesser extent by CYP2B6, CYP2C9 and CYP2C19. The artemether/DHA AUC ratio is 1.2 after 1 dose and 0.3 after 6 doses which may indicate autoinduction.
Lumefantrine is hepatically metabolized to desbutyl-lumefantrine by CYP3A4.
Time to Peak
Plasma: Artemether: ~2 hours; Lumefantrine: ~6-8 hours
Half-Life Elimination
Artemether: 1-2 hours; DHA: 2 hours; Lumefantrine: 72-144 hours
Protein Binding
Artemether: 95%; Dihydroartemisinin (DHA): 47% to 76%; Lumefantrine: 99.7%
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)
Dosage and Administration
Dosing: Adult
Treatment of uncomplicated malaria: Three-day schedule: Oral:
Patients 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)
Patients ≥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)
Dosing: Geriatric
Refer to adult dosing.
Dosing: Pediatric
Malaria, treatment; uncomplicated (due to P. falciparum, including chloroquine resistant P. falciparum): Note: Not for treatment of severe or complicated Plasmodium falciparum malaria or prevention of malaria.
Infants ≥2 months, Children, and Adolescents: Oral (artemether 20 mg / lumefantrine 120 mg per tablet):
5 kg to <15 kg: One tablet at hour 0 and at hour 8 on the first day and then one tablet twice daily (in the morning and evening) on days 2 and 3 (total of 6 tablets per treatment course)
15 kg to <25 kg: Two tablets at hour 0 and at hour 8 on the first day and then two tablets twice daily (in the morning and evening) on days 2 and 3 (total of 12 tablets per treatment course)
25 kg to <35 kg: Three tablets at hour 0 and at hour 8 on the first day and then three tablets twice daily (in the morning and evening) on day 2 and 3 (total of 18 tablets per treatment course)
≥35 kg: Four tablets at hour 0 and at hour 8 on the first day and then four tablets twice daily (in the morning and evening) on days 2 and 3 (total of 24 tablets per treatment course)
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.
Dietary Considerations
Administer with a full meal for best absorption. Patients should be encouraged to take with a meal as soon as food can be tolerated. Patients who remain averse to food during treatment should be closely monitored as the risk of recrudescence may be great.
Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Drug 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
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
Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
CloZAPine: CYP3A4 Inducers (Weak) may decrease the serum concentration of CloZAPine. Monitor therapy
CYP2D6 Substrates (High risk with Inhibitors): Lumefantrine may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
CYP3A4 Inducers (Strong): May decrease serum concentrations of the active metabolite(s) of Artemether. Specifically, dihydroartemisinin concentrations may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Artemether. Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Lumefantrine. Avoid combination
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Lumefantrine. Monitor therapy
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). 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
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Efavirenz: May decrease the serum concentration of Artemether. Concentrations of dihydroartemisinin (active metabolite of artemether) may also be decreased by efavirenz Monitor therapy
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Estrogen Derivatives (Contraceptive): Artemether may decrease the serum concentration of Estrogen Derivatives (Contraceptive). 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
Etravirine: May decrease serum concentrations of the active metabolite(s) of Artemether. Specifically, concentrations of dihydroartemisinin may be decreased. Artemether may increase the serum concentration of Etravirine. Etravirine may increase the serum concentration of Artemether. 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
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification
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
Mequitazine: Lumefantrine may enhance the arrhythmogenic effect of Mequitazine. Management: Consider alternatives to lumefantrine or mequitazine when possible. While this combination is not specifically contraindicated, mequitazine labeling describes this combination as discouraged. Consider therapy modification
Nevirapine: May decrease the serum concentration of Artemether. Nevirapine may also increase or decrease serum concentrations of lumefantrine. Monitor therapy
NiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine. Monitor therapy
Progestins (Contraceptive): Artemether may decrease the serum concentration of Progestins (Contraceptive). 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
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
St John's Wort: May decrease serum concentrations of the active metabolite(s) of Artemether. Specifically, dihydroartemisinin concentrations may be reduced. St John's Wort may decrease the serum concentration of Artemether. Avoid combination
St John's Wort: May decrease the serum concentration of Lumefantrine. Avoid combination
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Ubrogepant: CYP3A4 Inducers (Weak) may decrease the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a weak CYP3A4 inducer. Consider therapy modification
Adverse Reactions
>10%:
Cardiovascular: Palpitation (adults: 18%)
Central nervous system: Headache (adults 56%; children 13%), dizziness (adults 39%; children 4%), fever (25% to 29%), chills (adults 23%; children 5%), sleep disorder (adults: 22%), fatigue (adults 17%; children 3%)
Gastrointestinal: Anorexia (adults 40%; children 13%), nausea (adults 26%; children 5%), vomiting (17% to 18%), abdominal pain (8% to 17%)
Infection: Plasmodium falciparum (exacerbation: children: 17%)
Neuromuscular & skeletal: Weakness (adults 38%; children 5%), arthralgia (adults 34%; children 3%), myalgia (adults 32%; children 3%)
Respiratory: Cough (adults 6%; children 23%)
Miscellaneous: Fever (25% to 29%)
3% to 10%:
Central nervous system: Insomnia (adults: 5%), malaise (adults: 3%), vertigo (adults: 3%)
Dermatologic: Pruritus (adults: 4%), skin rash (3%)
Gastrointestinal: Diarrhea (7% to 8%)
Hematologic & oncologic: Anemia (4% to 9%)
Hepatic: Hepatomegaly (6% to 9%), increased serum AST (≤4%)
Infection: Malaria (≤3%)
Respiratory: Rhinitis (4%), nasopharyngitis (≤3%)
<3%, postmarketing, and/or case reports: Abnormal gait, abnormal lymphocytes, abscess, agitation, anapylaxis, angioedema, asthma, ataxia, back pain, bronchitis, bullous dermatitis, change in platelet count (increased), clonus, conjunctivitis, constipation, decreased hematocirt, decreased platelet count, decreased white blood cell count, dermatitis (hands and feet), dyspepsia, dysphagia, emotional lability, eosinophilia, fine motor control disorder, gastroenteritis, helminthiasis, hematuria, hemolytic anemia (delayed), hookworm infection, hyper-reflexia, hypoesthesia, hypokalemia, impetigo, increased serum ALT, influenza, leukocytosis, leukopenia, lower respiratory tract infection, nystagmus, oral herpes, otic infection, peptic ulcer, pharyngolaryngeal pain, pneumonia, proteinuria, respiratory tract infection, subcutaneous abscess, tinnitus, tremor, upper respiratory tract infection, urinary tract infection, urticaria
Warnings/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:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
- Drugs that prolong the QT interval: Avoid use in patients receiving other agents that prolong the QT interval; consider alternative therapy. ECG monitoring is advised if concomitant use of agents that prolong the QT interval is medically required. In addition, do not use halofantrine (not available in the US) and artemether/lumefantrine within one month of one another due to the potential additive effects on the QT interval. After discontinuation of artemether/lumefantrine, drugs that prolong the QT interval, including quinidine and quinine, should be used with caution.
- Duplicate therapy: Antimalarials should not be given concomitantly unless there is no other treatment option.
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 Parameters
Monitor patients for adequate food consumption (to ensure absorption and efficacy); ECG monitoring is advised if concomitant use of other agents that prolong the QT interval is medically required
Pregnancy
Pregnancy Considerations
A meta-analysis of observational pregnancy studies, which included 500 pregnant women exposed to artemether/lumefantrine in their first trimester, and data from observational and open-label studies of >1,200 pregnant women exposed to artemether/lumefantrine in their second or third trimesters have not shown an increased risk of major birth defects, miscarriage, or adverse maternal/fetal outcomes.
Malaria infection in pregnant women may be more severe than in nonpregnant women. Infection may increase the risk of adverse pregnancy outcomes, including miscarriage, premature delivery, low birth weight, congenital infection, or perinatal death (CDC 2019b).
Artemether/lumefantrine may be used to treat uncomplicated malaria during the second and third trimesters. Artemether/lumefantrine also may be used as an alternative treatment during the first trimester when preferred agents are not available. Dosing is the same as nonpregnant patients (Ballard [CDC] 2018; CDC 2019b).
Artemether may reduce the effectiveness of hormonal contraceptives. An additional nonhormonal method of birth control should be used during therapy.
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience headache, chills, nausea, vomiting, cough, abdominal pain, lack of appetite, muscle pain, joint pain, diarrhea, or trouble sleeping. Have patient report immediately to prescriber fast heartbeat, abnormal heartbeat, severe dizziness, passing out, severe loss of strength and energy, or difficulty swallowing (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.
