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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 2 antimalarials (artemether, lumefantrine).1

Uses for Artemether and Lumefantrine

Malaria

Treatment of acute, uncomplicated malaria caused by Plasmodium falciparum, including malaria acquired in areas where chloroquine resistance has been reported.1 2 3 4 5 6 7 8 Recommended by CDC as a drug of choice for treatment of uncomplicated chloroquine-resistant P. falciparum malaria.2

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Not indicated for treatment of severe or complicated malaria infections caused by P. falciparum.1

Not indicated for prevention of malaria.1

Assistance with diagnosis or treatment of malaria available from CDC Malaria Hotline at 770-488-7788 from 8:00 a.m. to 4:30 p.m. Eastern Standard Time or CDC Emergency Operation Center at 770-488-7100 after hours, on weekends, and holidays.2

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.1 Rinse container with more water; patient should swallow rinse.1

If vomiting occurs within 2 hours of ingestion, repeat dose.1 2 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 is given over 3 days for a total of 6 doses.1 2

Dosage based on weight.1 2

Pediatric Patients

Malaria
Treatment of Uncomplicated Malaria
Oral
Recommended Pediatric Dosage for Treatment of Acute, Uncomplicated Malaria caused by P. falciparum12

Weight

Dosage Expressed as Number of Tablets of Artemether and Lumefantrine

5 kg to <15 kg

1 tablet as initial dose, 1 tablet 8 hours after the initial dose, then 1 tablet twice daily (morning and evening) for the next 2 days (total course of 6 tablets)

15 kg to <25 kg

2 tablets as initial dose, 2 tablets 8 hours after the initial dose, then 2 tablets twice daily (morning and evening) for the next 2 days (total course of 12 tablets)

25 kg to <35 kg

3 tablets as initial dose, 3 tablets 8 hours after the initial dose, then 3 tablets twice daily (morning and evening) for the next 2 days (total course of 18 tablets)

≥ 35 kg

4 tablets as initial dose, 4 tablets 8 hours after the initial dose, then 4 tablets twice daily (morning and evening) for the next 2 days (total course of 24 tablets)

Adults

Malaria
Treatment of Uncomplicated Malaria
Oral

Adults >16 years of age and weighing ≥35 kg: 4 tablets as initial dose, 4 tablets 8 hours after the initial dose, and then 4 tablets twice daily (morning and evening) for the next two days (total course of 24 tablets).1 2

Adults >16 years of age and weighing <35 kg: Use pediatric dosage.1

Special Populations

No dosage adjustments needed in those with mild to moderate hepatic impairment.1

No dosage adjustments needed in those with mild to moderate renal impairment.1

Cautions for Artemether and Lumefantrine

Contraindications

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

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 class IA or III antiarrhythmic agents, antipsychotics (e.g., pimozide, ziprasidone), antidepressants, certain anti-infectives (e.g., macrolides, fluoroquinolones, imidazole- or triazole-derivative antifungal agents), cisapride (available in the US only under a limited-use protocol), or drugs known to be CYP2D6 substrates with cardiac effects.1 (See Drug Interactions: Specific Drugs.)

Interactions

Concomitant use with certain drugs requires particular caution (e.g., other antimalarial drugs, antiretroviral agents).1 (See Drug Interactions: Specific Drugs.)

Malaria Recrudescence

Increased risk of treatment failure in patients who are unable to eat; monitor these individuals closely.1

Repeated use not recommended following failure of the drug for treatment of malaria.1

P. vivax Infection

Has been effective in a limited number of patients in treating the erythrocytic stage of malaria caused by P. vivax.1 Relapse occurs; additional therapy indicated to achieve a radical cure (eradication of hypnozoites that remain dormant in the liver).1

Specific Populations

Pregnancy

Category C.1

Observational data indicate use not associated with adverse pregnancy outcomes or teratogenic effects, including data from women exposed during the first trimester.1

Efficacy for the treatment of acute uncomplicated malaria has not been established in pregnant women.1 CDC states that the drug may be used in pregnant women for treatment of uncomplicated malaria caused by chloroquine-resistant P. falciparum if other treatment options are not available or are not tolerated and if potential benefits outweigh risks.2

Lactation

Not known whether artemether and lumefantrine are distributed into human milk.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 with weight of ≥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 studied in patients with hepatic impairment.1 Not evaluated in patients with severe hepatic impairment.1

Renal Impairment

Pharmacokinetics not studied in patients with renal impairment.1 Not evaluated 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 Hepatic Microsomal Enzymes

Artemether is metabolized predominantly by CYP 3A4/5 isoenzyme; metabolism also catalyzed by CYP2B6, 2C9, and 2C19.1 Artemether induces CYP3A4.1 Artemether does not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11.1

Lumefantrine is metabolized principally by CYP3A4.1 Lumefantrine inhibits CYP2D6.1

Potential pharmacokinetic interactions with drugs metabolized by CYP3A4 (decreased concentrations of the drug metabolized by CYP3A4).1 Potential pharmacokinetic interactions with drugs that inhibit or induce CYP3A4 (altered metabolism of artemether and/or lumefantrine).1

Potential pharmacokinetic interactions with drugs metabolized by CYP2D6 (increased concentrations of the drug metabolized by CYP2D6).1 Avoid concurrent use of artemether and lumefantrine with drugs that are CYP2D6 substrates and have the potential to cause QT interval prolongation.1

Drugs that Prolong the QT Interval

Additive effect on the QT interval might occur if artemether and lumefantrine is administered with other agents that prolong the QT interval.1 Avoid concomitant use of artemether and lumefantrine with drugs known to prolong QT interval.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

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 plasma concentrations of artemether, the active metabolite of artemether, and lumefantrine1 12

Avoid concomitant use with drugs known to prolong QT interval1

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

Antimalarial agents

Antimalarial agents: Safety data on concomitant use limited1

Mefloquine: Decreased plasma concentrations of lumefantrine; no change in artemether or mefloquine concentrations when mefloquine is administered immediately before artemether and lumefantrine1 11

Quinidine: Possible additive effects on prolongation of QT interval1

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

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

Mefloquine: Monitor for effectiveness of artemether and lumefantrine; encourage food consumption1 11

Quinidine: Caution advised if quinidine administered after artemether and lumefantrine1

Quinine: Caution advised if quinine administered after artemether and lumefantrine1

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

Antiretroviral agents

Antiretroviral agents: Possible pharmacokinetic interaction; altered plasma concentrations of the antiretroviral agent, artemether, or lumefantrine; possible additive effects on prolongation of QT interval1

Lopinavir/ritonavir: Increased plasma concentrations of lumefantrine; slightly decreased concentrations of artemether and the active metabolite of artemether9

Antiretroviral agents: Caution advised1

Lopinavir/ritonavir: Manufacturer of lopinavir/ritonavir recommends that the drug not be used with drugs known to prolong QT interval10

Cisapride

Possible additive effects on prolongation of QT interval1

Avoid concomitant use with drugs known to prolong QT interval1

Hormonal contraceptives

Possible decreased plasma concentrations of the components of the contraceptive1

Use additional nonhormonal methods of contraception1

Artemether and Lumefantrine Pharmacokinetics

Absorption

Following oral administration, artemether is rapidly metabolized to an active metabolite, dihydroartemisinin.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: 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 twofold 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; metabolism also catalyzed 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 and lumefantrine is a fixed combination of 2 antimalarial agents; both components are blood schizonticides.1

  • Artemether is rapidly metabolized into an active metabolite dihydroartemisinin.1 The antimalarial activity of artemether and dihydroartemisinin has been attributed to the endoperoxide moiety.1

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

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

  • Artemether has a rapid onset of action and is eliminated rapidly; lumefantrine has a longer elimination half-life (about 4.5 days).3 6 11 The rationale behind the fixed-combination preparation is that artemether provides rapid symptomatic relief by reducing the number of malaria parasites and then lumefantrine clears any residual parasites.3 6 11

Advice to Patients

  • Importance of taking artemether and lumefantrine with food and to repeat dose if vomiting occurs within 2 hours of ingestion.1 2

  • Importance of informing clinician if unable to eat or if any doses of artemether and lumefantrine are vomited.1

  • Importance of informing clinician if malaria does not improve or flu symptoms, heart rhythm changes, or loss of consciousness occurs.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

  • 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 January 1, 2010. 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. Coartem (artemether/lumefantrine) tablets prescribing information. East Hanover, NJ; 2009 Apr.

2. 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). From the CDC website. Accessed 2009 Jul 1.

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.

11. Lefèvre G, Bindschedler M, Ezzert F et al. Pharmacokinetic interaction trial between co-artemether and mefloquine. Eur J Pharm Sci. 2000; 10:141-51.

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.

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