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Artemether and Lumefantrine

Pronunciation

(ar TEM e ther & loo me FAN treen)

Index Terms

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

Dosage Forms

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

Tablet:

Coartem: Artemether 20 mg and lumefantrine 120 mg

Brand Names: U.S.

  • Coartem

Pharmacologic Category

  • Antimalarial Agent

Pharmacology

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.

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)

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

Treatment of uncomplicated malaria: Three-day schedule: Oral:

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: Refer to adult dosing.

Dosing: Renal Impairment

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

Dosing: Hepatic Impairment

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

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

ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor response. Reduce oral aripiprazole dose to 10-15 mg/day (for adults) if the inducer is discontinued. Avoid use of CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Consider therapy modification

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. 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: Lumefantrine may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. 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. 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. 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

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

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

HYDROcodone: CYP3A4 Inducers (Weak) may decrease the serum concentration of HYDROcodone. Monitor therapy

Indapamide: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Consider therapy modification

Ivabradine: May enhance the QTc-prolonging effect of 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

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

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

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

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

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

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%), increased serum aspartate aminotransferase (<3% to 4%)

Hematologic & oncologic: Anemia (4% to 9%)

Hepatic: Hepatomegaly (6% to 9%)

Infection: Malaria (≤3%)

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

<3% (Limited to important or life-threatening): Abnormal gait, abnormal lymphocytes, abscess, agitation, asthma, ataxia, back pain, bullous dermatitis, conjunctivitis, decreased hematocirt, decreased platelet count, decreased white blood cell count, dysphagia, emotional lability, eosinophilia, fine motor control disorder, hematuria, hyper-reflexia, hypoesthesia, hypokalemia, impetigo, leukocytosis, nystagmus, oral herpes, otic infection, peptic ulcer, pneumonia, proteinuria, 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 U.S.) 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 Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. 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). Malaria infection in pregnant women may be more severe than in nonpregnant women. Because P. falciparum malaria can cause maternal death and fetal loss, pregnant women traveling to malaria-endemic areas must use personal protection against mosquito bites. Artemether and lumefantrine may be used as an alternative treatment of malaria in pregnant women but use in the first trimester is generally avoided; consult current CDC guidelines.

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, or insomnia. Have patient report immediately to prescriber angina, tachycardia, abnormal heartbeat, severe dizziness, passing out, severe loss of strength and energy, difficulty swallowing, or inability to eat (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.

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