Usage
- Artemether + Lumefantrine is prescribed for the treatment of uncomplicated Plasmodium falciparum malaria. It is effective against chloroquine-resistant strains.
- Pharmacological classification: Antimalarial.
- Mechanism of action: Artemether, a derivative of artemisinin, is thought to interfere with parasite heme metabolism. It forms free radicals that alkylate vital parasite proteins. Lumefantrine inhibits the formation of hemozoin within the food vacuole of the parasite, thereby preventing heme detoxification. This leads to accumulation of toxic heme byproducts, ultimately killing the parasite.
Alternate Names
- Artemether-lumefantrine.
- Brand names: Coartem®, Riamet®.
How It Works
- Pharmacodynamics: Artemether is rapidly absorbed and converted to its active metabolite, dihydroartemisinin (DHA). DHA is responsible for the rapid clearance of parasitemia. Lumefantrine contributes to sustained parasite clearance and reduces the risk of recrudescence.
- Pharmacokinetics:
- Absorption: Artemether is rapidly absorbed. Lumefantrine absorption is enhanced by food.
- Metabolism: Artemether is rapidly metabolized in the liver by CYP3A4 to DHA. Lumefantrine is also extensively metabolized by CYP3A4.
- Elimination: Both artemether and lumefantrine and their metabolites are eliminated primarily via the fecal route.
- Mode of action: The combination targets multiple stages of the parasite life cycle. Artemether (through its metabolite DHA) acts rapidly against asexual blood stages, while lumefantrine provides longer-lasting activity and reduces the risk of recurrence.
- Receptor binding, enzyme inhibition, or neurotransmitter modulation: The primary mode of action is not through receptor binding, enzyme inhibition, or neurotransmitter modulation but rather by disruption of essential parasite metabolic pathways.
- Elimination pathways: Primarily fecal excretion via biliary elimination.
Dosage
The dosage of Artemether + Lumefantrine is weight-based and administered orally with food to enhance absorption, especially of lumefantrine. The total treatment course involves six doses over three days (24 tablets total for adults weighing over 35 kg): four tablets initially, four tablets 8 hours later, and then four tablets twice daily for the next two days.
Standard Dosage
Adults:
-
35 kg: Four tablets initially, four tablets after 8 hours, then four tablets twice daily for the next two days (morning and evening).
Children:
- 5 kg to < 15 kg: One tablet per dose following the same schedule as for adults.
- 15 kg to < 25 kg: Two tablets per dose following the same schedule as for adults.
- 25 kg to < 35 kg: Three tablets per dose following the same schedule as for adults.
- Pediatric dosing is based on weight bands and the same six-dose schedule as adults. Safety and effectiveness in children younger than 5 kg or less than two months of age have not been established.
Special Cases:
- Elderly Patients: No specific dosage adjustments are recommended, but careful monitoring is advised.
- Patients with Renal Impairment: No dosage adjustment is needed.
- Patients with Hepatic Dysfunction: Caution is advised, and dose reductions may be considered in severe hepatic impairment.
- Patients with Comorbid Conditions: Care should be taken with co-administration of drugs metabolized by CYP3A4.
Clinical Use Cases
Artemether + Lumefantrine is specifically indicated for the treatment of uncomplicated malaria and is not used in settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like cardiac arrest.
Dosage Adjustments
Dosage adjustments may be needed in patients with severe hepatic impairment. Drug interactions with CYP3A4 inhibitors or inducers may require dosage modification.
Side Effects
Common Side Effects
- Headache
- Dizziness
- Anorexia
- Nausea
- Vomiting
- Abdominal pain
- Arthralgia
- Myalgia
- Cough
- Asthenia
- Pyrexia
Rare but Serious Side Effects
- QT prolongation
- Severe hepatic dysfunction
- Neutropenia
- Thrombocytopenia
- Anemia
Long-Term Effects
Long-term side effects are rare with the standard three-day course of treatment.
Adverse Drug Reactions (ADR)
Clinically significant ADRs include QT prolongation, severe hepatic dysfunction, and significant hematological abnormalities.
Contraindications
- Hypersensitivity to artemether, lumefantrine, or any of the excipients.
- First trimester of pregnancy.
- Concomitant use with drugs that prolong the QT interval and are metabolized by CYP2D6.
- Severe malaria (e.g., cerebral malaria, severe anemia).
Drug Interactions
- CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) may increase lumefantrine concentrations.
- CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin) may decrease lumefantrine concentrations.
- Artemether + Lumefantrine may prolong the QT interval and should be used with caution with other QT-prolonging drugs.
- Co-administration with artemether + lumefantrine can reduce the efficacy of hormonal contraceptives.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: C (second and third trimesters). Contraindicated in the first trimester.
- The drug should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
- Breastfeeding: Lumefantrine is excreted in breast milk. Breastfeeding should be interrupted during treatment and for at least 1 week after the last dose.
Drug Profile Summary
- Mechanism of Action: Artemether interferes with parasite heme metabolism, while lumefantrine inhibits hemozoin formation.
- Side Effects: Headache, dizziness, gastrointestinal disturbances, arthralgia, myalgia. Rare: QT prolongation, hepatic dysfunction, hematological abnormalities.
- Contraindications: Hypersensitivity, first trimester of pregnancy, concomitant use of QT prolonging or CYP2D6-metabolized drugs, severe malaria.
- Drug Interactions: CYP3A4 inhibitors and inducers, QT-prolonging drugs, hormonal contraceptives.
- Pregnancy & Breastfeeding: Contraindicated in the first trimester of pregnancy. Breastfeeding should be interrupted during treatment and for at least 1 week after the last dose.
- Dosage: Weight-based, six doses over three days.
- Monitoring Parameters: ECG (for QT interval), liver function tests, complete blood count.
Popular Combinations
Artemether + Lumefantrine is typically used as monotherapy. It is not combined with other antimalarials within the same regimen. However, primaquine may be added to prevent relapse in certain cases (especially with Plasmodium vivax infections, for which artemether + lumefantrine is not typically used).
Precautions
- Assess for any history of cardiac abnormalities or QT prolongation.
- Evaluate liver function tests.
- Caution in patients with a history of psychiatric disorders.
- Food intake with doses is important for lumefantrine absorption.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Artemether + Lumefantrine?
A: The dosage is weight-based and given over three days. Adults >35 kg: four tablets initially, followed by four tablets after 8 hours, then four tablets twice daily for the following two days. Pediatric dosing is also weight-based and follows the same schedule.
Q2: Can Artemether + Lumefantrine be used in pregnancy?
A: It is contraindicated in the first trimester. In the second and third trimesters, it should only be used if the benefit outweighs the potential risk to the fetus.
Q3: What are the most common side effects?
A: Headache, dizziness, nausea, vomiting, abdominal pain, and general malaise are common.
Q4: Are there any serious side effects?
A: Although rare, QT prolongation, liver dysfunction, and blood count abnormalities can occur.
Q5: What are the contraindications to using this drug?
A: Hypersensitivity, first trimester of pregnancy, concomitant use of certain QT-prolonging or CYP2D6-metabolized drugs, and severe malaria.
Q6: Does Artemether + Lumefantrine interact with other medications?
A: Yes, it can interact with drugs metabolized by CYP3A4 (inhibitors and inducers), drugs that prolong the QT interval, and hormonal contraceptives.
Q7: Can Artemether + Lumefantrine be used in patients with renal impairment?
A: Yes, no dosage adjustment is required for renal impairment.
Q8: What is the role of food in the administration of this medication?
A: Administering Artemether + Lumefantrine with food, particularly fatty food, significantly improves the absorption of lumefantrine, enhancing its effectiveness.
Q9: How should I monitor patients on Artemether + Lumefantrine?
A: Monitor patients for QT prolongation with ECGs, check liver function tests, and obtain a complete blood count to assess for potential adverse events.
