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Artemether and Lumefantrine

Class: Antimalarials
VA Class: AP101
Chemical Name: (3R,5aS,6R,8aS,9R,10S,12R,12aR) - decahydro - 10 - methoxy - 3,6,9 - trimethyl - 3,12 - epoxy - 12H - pyrano[4,3 - j] - 1,2 - benzodioxepine
Molecular Formula: C16H26O5C30H32Cl3NO
CAS Number: 71963-77-4
Brands: Coartem

Introduction

Antimalarial; fixed combination containing artemether (artemisinin-derivative antimalarial)1 161 and lumefantrine (aryl aminoalcohol antimalarial).161

Uses for Artemether and Lumefantrine

Treatment of Uncomplicated Malaria

Treatment of acute, uncomplicated malaria caused by Plasmodium falciparum (including chloroquine-resistant P. falciparum)1 3 4 5 6 7 8 143 144 or chloroquine-resistant P. vivax.1

For treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum or treatment of uncomplicated malaria when plasmodial species not identified, CDC recommends fixed combination of atovaquone and proguanil (atovaquone/proguanil), fixed combination of artemether and lumefantrine (artemether/lumefantrine), or regimen of quinine in conjunction with doxycycline, tetracycline, or clindamycin.143 144

For treatment of uncomplicated malaria caused by chloroquine-susceptible P. falciparum, P. malariae, or P. knowlesi or treatment of uncomplicated malaria when plasmodial species not identified and infection acquired in areas where chloroquine resistance not reported, CDC recommends chloroquine (or hydroxychloroquine).143 144 Alternatively, CDC states that any of the regimens recommended for treatment of uncomplicated chloroquine-resistant P. falciparum malaria may be used if preferred, more readily available, or more convenient.143 144

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Pediatric patients with uncomplicated malaria generally can receive same treatment regimens recommended for adults using age- and weight-appropriate drugs and dosages.143 144 For treatment of uncomplicated chloroquine-resistant P. falciparum in children <8 years of age, atovaquone/proguanil or artemether/lumefantrine usually recommended, but mefloquine can be considered if no other options available.144 For treatment of chloroquine-resistant P. vivax malaria in children <8 years of age, CDC recommends mefloquine given in conjunction with primaquine.143 144 Alternatively, if mefloquine not available or not tolerated and if potential benefits outweigh risks, atovaquone/proguanil or artemether/lumefantrine can be used for treatment of chloroquine-resistant P. vivax in this age group.143 144

Because artemether/lumefantrine active only against asexual erythrocytic forms of Plasmodium (not exoerythrocytic stages), 14-day regimen of primaquine indicated to eradicate hypnozoites and prevent delayed primary attacks or relapse and provide a radical cure whenever artemether/lumefantrine used for treatment of P. vivax or P. ovale malaria.134 143 144

Not indicated for treatment of severe or complicated malaria.1

Not indicated for prevention of malaria.1

Assistance with diagnosis or treatment of malaria is available from CDC Malaria Hotline at 770-488-7788 or 855-856-4713 from 9:00 a.m. to 5:00 p.m. Eastern Standard Time or CDC Emergency Operation Center at 770-488-7100 after hours and on weekends and holidays.143 144

Presumptive Self-treatment of Malaria

Presumptive self-treatment of malaria in travelers.115 134

In consultation with their health-care provider, some travelers (e.g., those who elect not to use prophylaxis, those who use a prophylaxis regimen that may not have optimal efficacy, those who use effective prophylaxis but will be in very remote areas) may elect to take along an appropriate antimalarial to use for presumptive self-treatment if necessary.115 134

Self-treatment in these situations should be initiated promptly in the event of an influenza-like illness (e.g., fever, chills) if professional medical care not readily available.115 134

CDC and other experts recommend atovaquone/proguanil or artemether/lumefantrine for presumptive self-treatment of malaria.115 134

Presumptive self-treatment of possible malarial infection is a temporary measure; it is imperative that a professional medical evaluation be obtained as soon as possible.115

Artemether and Lumefantrine Dosage and Administration

Administration

Oral Administration

Administer orally with food.1

Patients who are unable to swallow the tablets: Crush tablets and mix with a small amount of water (5–10 mL) just prior to administration. Rinse container with more water; patient should swallow rinse.1

Patient should have food or drink (e.g., milk, formula, pudding, broth, porridge) after each dose of tablets or crushed tablet preparation.1

If vomiting occurs within 1–2 hours after taking a dose, repeat the dose.1 If the repeat dose is vomited, give an alternative antimalarial agent.1

Dosage

Dosage expressed as number of tablets of the fixed combination containing 20 mg of artemether and 120 mg of lumefantrine.1

Treatment regimen includes a total of 6 doses given over 3 days.1 144

Dosage is based on weight.1 144

Pediatric Patients

Malaria
Treatment of Uncomplicated Malaria
Oral

Dosage is based on weight.1 134 144 (See Table 1.)

Table 1. Pediatric Dosage of Artemether/lumefantrine for Treatment of Uncomplicated P. falciparum Malaria1144

Weight

Dosage Expressed as Number of Tablets of Artemether/lumefantrine

5 kg to <15 kg

1 tablet as initial dose, 1 tablet 8 hours after initial dose, then 1 tablet twice daily (morning and evening) for next 2 days (total of 6 tablets given in 6 doses over 3 days)

15 kg to <25 kg

2 tablets as initial dose, 2 tablets 8 hours after initial dose, then 2 tablets twice daily (morning and evening) for next 2 days (total of 12 tablets given in 6 doses over 3 days)

25 kg to <35 kg

3 tablets as initial dose, 3 tablets 8 hours after initial dose, then 3 tablets twice daily (morning and evening) for next 2 days (total of 18 tablets given in 6 doses over 3 days)

≥ 35 kg

4 tablets as initial dose, 4 tablets 8 hours after initial dose, then 4 tablets twice daily (morning and evening) for next 2 days (total of 24 tablets given in 6 doses over 3 days)

For treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax, CDC and other experts recommend the same dosage used for treatment of uncomplicated P. falciparum malaria.134 144 Because artemether/lumefantrine cannot prevent relapse of P. vivax malaria, 14-day regimen of primaquine indicated in conjunction with artemether/lumefantrine to provide a radical cure.134 143 144

Presumptive Self-treatment of Malaria
Oral

Use pediatric dosage recommended for treatment of uncomplicated P. falciparum malaria.115 (See Table 1.)

Initiate promptly if malaria suspected (fever, chills, or other influenza-like illness) and professional medical care not readily available.115 134

Only a temporary measure; obtain professional medical evaluation as soon as possible.115

Adults

Malaria
Treatment of Uncomplicated Malaria
Oral

Adults >16 years of age weighing ≥35 kg with P. falciparum malaria: 4 tablets as initial dose, 4 tablets 8 hours after initial dose, and then 4 tablets twice daily (morning and evening) for next two days (total course of 24 tablets).1 144

Adults >16 years of age weighing <35 kg with P. falciparum malaria: Use pediatric dosage.1 (See Table 1.)

For treatment of uncomplicated malaria caused by chloroquine-resistant P. vivax, CDC and other experts recommend the same dosage used for treatment of uncomplicated P. falciparum malaria.134 144 Because artemether/lumefantrine cannot prevent relapse of P. vivax malaria, 14-day regimen of primaquine indicated in conjunction with artemether/lumefantrine to provide a radical cure.134 143 144

Presumptive Self-treatment of Malaria
Oral

Use dosage recommended for treatment of uncomplicated P. falciparum malaria.115 134

Initiate promptly if malaria suspected (fever, chills, or other influenza-like illness) and professional medical care not readily available.115 134

Only a temporary measure; obtain professional medical evaluation as soon as possible.115

Special Populations

Hepatic Impairment

Dosage adjustments not needed in those with mild to moderate hepatic impairment;1 use with caution in those with severe hepatic impairment.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustments not needed in those with mild to moderate renal impairment;1 use with caution in those with severe renal impairment.1 (See Renal Impairment under Cautions.)

Cautions for Artemether and Lumefantrine

Contraindications

  • Hypersensitivity to artemether, lumefantrine, or any ingredient in the formulation.1

  • Concomitant use with drugs that are potent inducers of CYP3A4 (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort [Hypericum perforatum]); such use can result in decreased concentrations of artemether and/or lumefantrine and may be associated with loss of antimalarial efficacy.1 (See Interactions.)

Warnings/Precautions

Warnings

Prolongation of the QT Interval

QT interval prolongation reported.1

Do not use in patients with congenital long QT syndrome, clinical conditions known to prolong the QTc interval (e.g., symptomatic cardiac arrhythmias, clinically important bradycardia, severe cardiac disease), family history of congenital long QT syndrome or sudden death, or in those with electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia).1

Do not use in those receiving treatment with other drugs known to prolong QT interval, including class IA or III antiarrhythmic agents, antipsychotics (e.g., pimozide, ziprasidone), antidepressants, certain antimalarials (e.g., quinine, quinidine, halofantrine [not commercially available in US]), certain other anti-infectives (e.g., macrolides, fluoroquinolones, imidazole- or triazole-derivative antifungal agents), or with drugs metabolized by CYP2D6 that are known to have cardiac effects.1 (See Interactions: Specific Drugs.)

If concomitant use with drugs that prolong the QT interval considered medically necessary, monitor ECGs.1

Interactions

Concomitant or sequential use with certain drugs not recommended or requires particular caution (e.g., other antimalarials, certain antiretroviral agents).1 (See Interactions: Specific Drugs.)

Malaria Recrudescence

Increased risk of recrudescence and treatment failure in patients who are unable to eat since food is needed to enhance absorption; monitor such individuals closely.1

Do not use for retreatment in patients who had recrudescence of malaria after treatment with the drug.1

Selection and Use of Antimalarials

Do not use for initial treatment of severe malaria.1 143 Life-threatening, serious, or overwhelming malaria requires aggressive treatment with a parenteral antimalarial regimen.143 144

Has been effective in limited number of patients for treatment of erythrocytic stage of malaria caused by P. vivax.1 Relapse occurs; primaquine indicated to achieve a radical cure (i.e., eradication of hypnozoites that remain dormant in the liver).1 143 144

Specific Populations

Pregnancy

Category C.1

Manufacturer states efficacy for treatment of acute uncomplicated malaria not established in pregnant women; use during pregnancy only if potential benefits justify potential risks to fetus.1

CDC states use in pregnant women can be considered for treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum when other treatment options not available or not tolerated and if potential benefits outweigh risks.143

Observational data indicate use during pregnancy (including during first trimester) not associated with adverse pregnancy outcomes or teratogenic effects.1

Lactation

Not known whether artemether and lumefantrine are distributed into human milk;1 animal data suggest both drugs are distributed into milk.1

Use with caution in nursing women;1 weigh benefits against potential risks.1

Pediatric Use

Safety and efficacy not established in children weighing <5 kg.1

Evaluated in children ≥2 months of age weighing ≥5 kg.1

Not evaluated in nonimmune children (children residing in nonendemic countries) in clinical studies.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1

Use with caution and monitor because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Hepatic Impairment

Pharmacokinetics not specifically studied in patients with hepatic impairment;1 safety and efficacy not evaluated in those with severe hepatic impairment.1

Use with caution in patients with severe hepatic impairment.1

Renal Impairment

Pharmacokinetics not studied in patients with renal impairment;1 safety and efficacy not evaluated in those with severe renal impairment.1

Use with caution in patients with severe renal impairment.1

Common Adverse Effects

Adults: Headache, anorexia, dizziness, asthenia, arthralgia, myalgia.1

Children: Pyrexia, cough, vomiting, anorexia, headache.1

Interactions for Artemether and Lumefantrine

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Artemether: Metabolized predominantly by CYP 3A4/5 isoenzyme and, to a lesser extent, by CYP isoenzymes 2B6, 2C9, and 2C19.1 May be a weak inducer of CYP isoenzymes 2C19, 2B6, and 3A4.1 Does not inhibit CYP isoenzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11.1

Lumefantrine: Metabolized principally by CYP3A4.1 Inhibits CYP2D6.1

Potential pharmacokinetic interactions with drugs metabolized by CYP3A4 (decreased concentrations of CYP3A4 substrate).1

Potential pharmacokinetic interactions with drugs that inhibit or induce CYP3A4 (altered metabolism of artemether and/or lumefantrine).1

Potential pharmacokinetic interactions with CYP2D6 (increased concentrations of CYP2D6 substrate).1 Avoid concurrent use with drugs that are CYP2D6 substrates and are known to have cardiac effects (e.g., flecainide, imipramine, amitriptyline, clomipramine).1

Drugs that Prolong the QT Interval

Additive effect on the QT interval might occur if artemether/lumefantrine used with other agents that prolong the QT interval;1 avoid concomitant use.1

Avoid concomitant use with class IA antiarrhythmic agents (e.g., quinidine, procainamide, disopyramide), class III antiarrhythmic agents (e.g., amiodarone, sotalol), antipsychotics (e.g., pimozide, ziprasidone), antidepressants, certain other antimalarials (e.g., quinine, quinidine, halofantrine [not commercially available in US]), and certain anti-infectives (e.g., macrolides, fluoroquinolones, imidazole- or triazole-derivative antifungal agents).1 Also avoid concomitant use with drugs metabolized by CYP2D6 that can prolong QT interval (e.g., flecainide, imipramine, amitriptyline, clomipramine).1

If concomitant use with drugs that prolong the QT interval considered medically necessary, monitor ECGs.1

Specific Drugs

Drug

Interaction

Comments

Antiarrhythmics, class IA or III

Possible additive effects on prolongation of QT interval1

Avoid concomitant use with drugs known to prolong QT interval1

Anticonvulsants

Carbamazepine, phenytoin: Possible decreased concentrations of artemether and/or lumefantrine; possible loss of antimalarial efficacy1

Carbamazepine, phenytoin: Concomitant use contraindicated1

Antidepressants known to prolong QT interval

Possible additive effects on prolongation of QT interval1

Avoid concomitant use with drugs known to prolong QT interval1

Anti-infectives known to prolong QT interval (e.g., macrolides, fluoroquinolones, imidazole- or triazole-derivative antifungal agents)

Possible additive effects on prolongation of QT interval1

Ketoconazole: Increased concentrations of artemether, active metabolite of artemether, and lumefantrine;1 12 increased risk of QT prolongation1

Avoid concomitant use with drugs known to prolong QT interval1

Ketoconazole: Dosage adjustment for artemether/lumefantrine not needed;1 12 use concomitantly with caution1

Antimalarial agents

Antimalarial agents: Safety data on concomitant use limited1

Mefloquine: Decreased concentrations and AUC of lumefantrine possibly as the result of mefloquine-induced decrease in bile production; no effect on pharmacokinetics of artemether or mefloquine1 146

Quinidine: Possible additive effects on prolongation of QT interval1

Quinine: Pharmacokinetic interaction unlikely;1 13 possible additive effects on prolongation of QT interval1

Halofantrine (not commercially available in US): Possible additive effects on QT interval1

Antimalarial agents: Concurrent use not recommended unless there are no other treatment options1

Mefloquine: If artemether/lumefantrine given shortly after mefloquine, take dose with food and monitor for effectiveness1

Quinidine: Caution advised if quinidine administered after artemether/lumefantrine; monitor ECG1

Quinine: Caution advised if quinine administered after artemether/lumefantrine; monitor ECG1

Halofantrine: Allow one month to elapse between administration of halofantrine and artemether/lumefantrine and vice versa1

Antipsychotics known to prolong QT interval (e.g., pimozide, ziprasidone)

Possible additive effects on prolongation of QT interval1

Avoid concomitant use with drugs known to prolong QT interval1

Grapefruit Juice

Possible increased artemether and/or lumefantrine concentrations; possible increased risk of prolonged QT interval1

Avoid concomitant use1

HIV protease inhibitors (PIs)

PIs: Possible decreased antimalarial efficacy and increased risk of QT prolongation1

Ritonavir-boosted darunavir: Decreased AUC of artemether and active metabolite of artemether; increased AUC of lumefantrine; no effect on darunavir or ritonavir AUC14

Lopinavir/ritonavir: Decreased AUC of artemether and active metabolite of artemether; increased AUC of lumefantrine; no effect on lopinavir AUC1 9

PIs: Use concomitantly with caution.1

Hormonal contraceptives

Oral, transdermal, or other hormonal contraceptives: Possible decreased effectiveness of the hormonal contraceptive1

Use additional nonhormonal methods of contraception1

Nonnucleoside reverse transcriptase inhibitors (NNRTIs)

NNRTIs: Possible decreased antimalarial efficacy and increased risk of QT prolongation1

Efavirenz: Decreased AUC of artemether, active metabolite of artemether, and lumefantrine; no effect on efavirenz AUC1 15

Etravirine: Decreased AUC of artemether, active metabolite of artemether, and lumefantrine; no effect on etravirine AUC14

NNRTIs: Use concomitantly with caution1

Rifampin

Decreased AUC of artemether, active metabolite of artemether, and lumefantrine1

Concomitant use contraindicated1

Artemether and Lumefantrine Pharmacokinetics

Absorption

Following oral administration, artemether is rapidly metabolized to an active metabolite (dihydroartemisinin; DHA).1

Bioavailability

Artemether: Peak plasma concentrations attained approximately 2 hours after a dose.1

Dihydroartemisinin: Peak plasma concentrations attained approximately 2 hours after a dose.1

Lumefantrine: Highly lipophilic; absorption is delayed for up to 2 hours; peak plasma concentrations attained approximately 6–8 hours after a dose.1

Food

Food increases bioavailability of artemether and lumefantrine.1

Artemether: Relative bioavailability increased up to threefold when administered after a high-fat meal compared with fasting conditions.1

Lumefantrine: Relative bioavailability increased sixteen-fold when administered after a high-fat meal compared with fasting conditions.1

Distribution

Plasma Protein Binding

Artemether: 95.4%.1

Dihydroartemisinin: 47–76%.1

Lumefantrine: 99.7%.1

Elimination

Metabolism

Artemether: Metabolized predominately by CYP3A4/5; metabolized to a lesser extent by CYP2B6, 2C9, and 2C19.1

Lumefantrine: Metabolized mainly by CYP3A4.1

Elimination Route

No data on urinary excretion in humans.1

Half-life

Artemether: Approximately 2 hours.1

Dihydroartemisinin: Approximately 2 hours.1

Lumefantrine: 3–6 days.1

Special Populations

Pharmacokinetics not evaluated in individuals with renal or hepatic impairment.1

Systemic exposure to artemether, dihydroartemisinin, and lumefantrine in pediatric patients similar to that in adults.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Artemether/lumefantrine is a fixed combination of 2 antimalarial agents.1 Artemether is an artemisinin-derivative antimalarial;1 161 lumefantrine is an aryl aminoalcohol antimalarial.161 Both drugs are blood schizonticidal agents active against erythrocytic stages of Plasmodium.1

  • Artemether is rapidly metabolized to an active metabolite (dihydroartemisinin; DHA).1 Antimalarial activity of artemether and dihydroartemisinin has been attributed to the endoperoxide moiety.1

  • Exact mechanism by which lumefantrine exerts its antimalarial effect not well defined;1 available data suggest the drug inhibits formation of β-hematin by forming a complex with hemin.1

  • Both artemether and lumefantrine inhibit nucleic acid and protein synthesis.1

  • Artemether has rapid onset of action and the drug and its metabolite have elimination half-lives of about 2 hours; lumefantrine has a longer elimination half-life (about 3–6 days).3 6 The rationale behind the fixed-combination preparation is that the artemisinin derivative (artemether) provides rapid resolution of symptoms by reducing the number of malaria parasites and then lumefantrine clears any residual parasites.3 6 161

  • Although clinical importance not known, P. falciparum with decreased susceptibility to artemether or lumefantrine can be selected in vitro or in vivo.1 Use of the artemisinin-based combinations may delay or prevent emergence of resistance.161

Advice to Patients

  • Importance of taking each dose of artemether/lumefantrine with food.1

  • Advise patients that individuals with acute malaria are frequently averse to food; encourage them to resume normal eating as soon as food can be tolerated since this improves absorption of the drug.1

  • Advise patients to repeat a dose if vomiting occurs within 1–2 hours of ingestion and to contact their clinicians if they also vomit after the repeat dose.1

  • Advise patients that artemether/lumefantrine can cause hypersensitivity reactions.1 Importance of discontinuing the drug and contacting their clinicians if rash, hives, rapid heartbeat, difficulty swallowing or breathing, swelling of lips, tongue, or face, tightness of throat, or hoarseness occurs.1

  • Importance of informing clinicians of any personal or family history of prolonged QT interval or proarrhythmic conditions such as hypokalemia, bradycardia, or recent myocardial ischemia.1

  • Advise patients to inform their clinicians if they are taking any other medications that prolong the QT interval, including class IA antiarrhythmic agents (e.g., quinidine, procainamide, disopyramide), class III antiarrhythmic agents (e.g., amiodarone, sotalol), antipsychotics (e.g., pimozide, ziprasidone), antidepressants, or certain anti-infectives (e.g., macrolides, fluoroquinolones, imidazole- or triazole-derivative antifungal agents).1

  • Importance of informing clinician if any symptoms of QT interval prolongation, including prolonged heart palpitations or loss of consciousness occur.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise patients that artemether/lumefantrine may decrease effectiveness of oral, transdermal, or other systemic hormonal contraceptives and that additional nonhormonal methods of contraception should be used.1

  • Importance of informing patients of other precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Artemether and Lumefantrine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

20 mg of artemether and 120 mg of lumefantrine

Coartem

Novartis

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions March 4, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Novartis Pharmaceutics Corporation. Coartem (artemether/lumefantrine) tablets prescribing information. East Hanover, NJ; 2013 Apr.

3. Omari AA, Gamble C, Garner P. Artemether-lumefantrine (six-dose regimen) for treating uncomplicated falciparum malaria. Cochrane Database Syst Rev. 2005; :CD005564.

4. Vugt MV, Wilairatana P, Gemperli B et al. Efficacy of six doses of artemether-lumefantrine (benflumetol) in multidrug-resistant Plasmodium falciparum malaria. Am J Trop Med Hyg. 1999; 60:936-42. [PubMed 10403324]

5. van Vugt M, Looareesuwan S, Wilairatana P et al. Artemether-lumefantrine for the treatment of multidrug-resistant falciparum malaria. Trans R Soc Trop Med Hyg. 2000 Sep-Oct; 94:545-8.

6. Lefèvre G, Looareesuwan S, Treeprasertsuk S et al. A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg. 2001 May-Jun; 64:247-56.

7. Hatz C, Soto J, Nothdurft HD et al. Treatment of acute uncomplicated falciparum malaria with artemether-lumefantrine in nonimmune populations: a safety, efficacy, and pharmacokinetic study. Am J Trop Med Hyg. 2008; 78:241-7. [PubMed 18256423]

8. Falade C, Makanga M, Premji Z et al. Efficacy and safety of artemether-lumefantrine (Coartem) tablets (six-dose regimen) in African infants and children with acute, uncomplicated falciparum malaria. Trans R Soc Trop Med Hyg. 2005; 99:459-67. [PubMed 15837358]

9. German P, Parikh S, Lawrence J et al. Lopinavir/Ritonavir Affects Pharmacokinetic Exposure of Artemether/Lumefantrine in HIV-Uninfected Healthy Volunteers. J Acquir Immune Defic Syndr. 2009; 51:424-429. [PubMed 19506482]

10. Abbott Laboratories. Kaletra (lopinavir/ritonavir) oral tablets and solution prescribing information. North Chicago, IL; 2009 Apr.

12. Lefèvre G, Carpenter P. Souppart C et al. Pharmacokinetics and electrocardiographic pharmacodynamics of artemether-lumefantrine (Riamet) with concomitant administration of ketoconazole in healthy subjects. Br J Clin Pharmacol. 2002; 54:485-92.

13. Lefèvre G, Carpenter P. Souppart C et al. Interaction trial between artemether-lumefantrine (Riamet) and quinine in healthy subjects. J Clin Pharmacol. 2002: 42:1147-58.

14. Kakuda TN, DeMasi R, van Delft Y et al. Pharmacokinetic interaction between etravirine or darunavir/ritonavir and artemether/lumefantrine in healthy volunteers: a two-panel, two-way, two-period, randomized trial. HIV Med. 2013; 14:421-9. [PubMed 23441978]

15. Huang L, Parikh S, Rosenthal PJ et al. Concomitant efavirenz reduces pharmacokinetic exposure to the antimalarial drug artemether-lumefantrine in healthy volunteers. J Acquir Immune Defic Syndr. 2012; 61:310-6. [PubMed 22918158]

115. Centers for Disease Control and Prevention. CDC health information for international travel, 2014. Atlanta, GA: US Department of Health and Human Services. Updates may be available at CDC website.

134. Anon. Drugs for parasitic infections. Treat Guidel Med Lett. 2010; 8:e1-16.

143. Centers for Disease Control and Prevention. CDC treatment guidelines: Treatment of malaria (guidelines for clinicians). 2013 Jul. From the CDC website. Accessed 2013 Sep 27.

144. Centers for Disease Control and Prevention. Guidelines for treatment of malaria in the United States (based on drugs currently available for use in the United States–updated July 1, 2013). From the CDC website. Accessed 2013 Sep 27.

146. Lefèvre G, Bindschedler M, Ezzet F et al. Pharmacokinetic interaction trial between co-artemether and mefloquine. Eur J Pharm Sci. 2000; 10:141-51. [PubMed 10727880]

161. World Health Organization (WHO). Guidelines for the treatment of malaria. 2nd edition. Geneva, Switzerland: World Health Organization; 2010. Updates may be available at WHO website.

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