What are the dosing schedule, contraindications, adverse effects, and drug interactions for artemether‑lumefantrine (lumefantrine) in treating uncomplicated Plasmodium falciparum malaria in adults and children?

Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria

Artemether-lumefantrine (AL) is the WHO-endorsed first-line artemisinin-based combination therapy for uncomplicated P. falciparum malaria across all age groups and all trimesters of pregnancy, with PCR-corrected cure rates of 96-100%. 1, 2

Dosing Schedule

Standard Adult and Pediatric Dosing (>35 kg)

• 4 tablets at hour 0,4 tablets at hour 8 on day 1, then 4 tablets twice daily on days 2 and 3 (total 24 tablets over 72 hours). 3, 1
• Each tablet contains artemether 20 mg and lumefantrine 120 mg. 3

Critical Administration Requirement

• AL must be taken with a fatty meal or drink to achieve adequate absorption; failure to do so leads to subtherapeutic drug levels and treatment failure. 1, 2, 4
• This is the most common cause of treatment failure in clinical practice. 2
• The first dose should be directly observed to ensure co-administration with fat and monitor for immediate adverse reactions. 2

Weight-Based Dosing for Children

• Children >35 kg: follow adult dosing (4 tablets per dose). 2
• Children 36-75 kg: same 6-dose regimen with weight-appropriate tablet counts. 1

Extended Regimen Considerations

• Swiss guidelines recommend extending treatment to 5 days in patients with high body weight or suspected malabsorption. 2

Contraindications

Absolute Contraindications

• Patients with baseline QTc prolongation or those at risk of QTc prolongation. 1, 2, 4
• Patients taking concomitant medications that prolong the QTc interval. 1, 2
• Baseline ECG screening is advised in high-risk individuals. 2

Relative Contraindications

• Known hypersensitivity to artemether or lumefantrine. 5
• Severe malaria (requires intravenous artesunate instead). 1, 2

Special Population: Pregnancy

• AL is safe and recommended for use in all trimesters of pregnancy per WHO and CDC guidelines. 3, 1, 2
• Multiple trials and meta-analyses found no association between AL treatment and congenital malformations or miscarriage in second/third trimester. 3
• Treatment efficacy remains high at standard non-pregnant dosing despite initial concerns about reduced lumefantrine bioavailability. 3

Adverse Effects

Common Adverse Effects

• Headache, vertigo, and digestive disorders (nausea, vomiting, abdominal pain). 4, 5
• Early vomiting occurs in 15-17% of patients during the three dosing days. 6

Cardiovascular Effects

• QTc interval prolongation can occur; monitor ECG in high-risk patients. 1, 2, 4
• No clinical cardiac consequences were observed in clinical trials despite QTc changes. 7

Hematologic Effects

• Post-artemisinin delayed hemolysis (PADH) occurs in 10-15% of patients (up to 37% with strict diagnostic criteria). 2
• Monitor hemoglobin, haptoglobin, and lactate dehydrogenase at days 7,14,21, and 28 after treatment. 1, 2, 4
• Day 7 anemia may occur but is generally less frequent than with other antimalarials. 3

Neuropsychiatric Effects

• Neurological adverse events are rare (2.1% in pediatric studies). 6
• No detectable psychiatric adverse events in large pediatric trials. 6

Comparative Tolerability

• AL has superior tolerability compared to quinine, with significantly lower rates of tinnitus, dizziness, and vomiting. 3
• Fewer maternal adverse events occur with AL versus non-ACTs in pregnancy. 3

Drug Interactions

QTc-Prolonging Medications

• Avoid co-administration with other QT-prolonging agents including:
  • Class IA and III antiarrhythmics
  • Certain antipsychotics (haloperidol, ziprasidone)
  • Macrolide antibiotics (erythromycin, clarithromycin)
  • Fluoroquinolones (moxifloxacin)
  • Antifungals (fluconazole, ketoconazole). 1, 2

Food Interactions

• Fatty food is required for adequate absorption; this is a therapeutic requirement, not an interaction to avoid. 1, 2, 4

Limited Interaction Studies

• Studies on drug-drug interactions with quinine, mefloquine, and ketoconazole have been reported but data remain limited in African patients. 8
• Effects of co-infections (HIV, helminths) and malnutrition on AL pharmacokinetics are not well understood. 8

Efficacy Data

Cure Rates

• PCR-corrected cure rates consistently achieve 96-100% at day 28 in evaluable populations. 1, 5, 9
• Six-dose regimen provides cure rates of 96.9-99.1% versus 83.3% for four-dose regimen. 9
• Day 63 PCR-corrected adequate clinical and parasitological response (ACPR) rate: 90.9%. 6

Parasite and Fever Clearance

• Rapid parasite clearance: no detectable parasitemia at 72 hours in >94% of patients. 6
• Rapid fever clearance: <6% have fever at 72 hours. 6
• Significant gametocidal effect, reducing transmission potential. 5

Pregnancy-Specific Efficacy

• Cure rates of 99.3-100% in second and third trimester pregnant women. 3

Resistance Considerations

Emerging Resistance Patterns

• Artemisinin partial resistance with K13 mutations documented in Rwanda, Uganda, Horn of Africa, and Greater Mekong sub-region. 2
• Overall ACT efficacy remains high in most endemic areas despite emerging resistance. 2
• Late treatment failures occur in 13.9% of cases, often linked to suboptimal dosing in higher body weight patients. 2

Alternative Regimens in Resistance Settings

• In Southeast Asia with documented ACT resistance, atovaquone-proguanil is recommended as first-line. 2
• Mefloquine is not recommended for P. falciparum acquired in Southeast Asia due to documented resistance. 2

Common Pitfalls to Avoid

Administration Errors

• Failing to ensure adequate fat intake with every AL dose is the most frequent cause of treatment failure. 1, 2, 4
• Confusing AL feeding requirements (fat required) with dihydroartemisinin-piperaquine (fasting required) compromises efficacy. 2

Diagnostic Errors

• Delayed recognition of severe malaria requiring IV artesunate increases mortality. 1, 2
• Hyperparasitemia thresholds vary (2-5%); any WHO severe-malaria criterion mandates immediate IV artesunate. 2

Monitoring Failures

• Not monitoring for PADH during the first four weeks after treatment. 2, 4
• Failing to assess baseline ECG in high-risk patients before AL administration. 2

Treatment Selection Errors

• Using quinine or mefloquine when ACTs are available; these have inferior tolerability and resistance concerns. 2
• Prescribing AL to patients with QTc prolongation risk without ECG assessment. 1, 2