Artemether / Lumefantrine

Pronunciation: AR-te-meth-er/LOO-me-FAN-treen
Class: Antimalarial preparations

Trade Names

Coartem
- Tablets artemether 20 mg/lumefantrine 120 mg

Pharmacology

Artemether and lumefantrine are blood schizontocides. Artemether is rapidly metabolized into an active metabolite dihydroartemisinin. Artemether and lumefantrine are active against the erythrocytic stages of Plasmodium falciparum . Both are shown to inhibit nucleic acid and protein synthesis. The exact mechanism by which they exert antimalarial effect is not well defined.

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Pharmacokinetics

Special Populations

Renal Function Impairment

No specific pharmacokinetic studies have been performed.

Hepatic Function Impairment

No specific pharmacokinetic studies have been performed.

Elderly

No specific pharmacokinetic studies have been performed in patients older than 65 years of age.

Children

Systemic exposure is comparable with adult patients.

Gender

No clinically relevant effects.

Indications and Usage

Treatment of acute, uncomplicated malaria infections caused by P. falciparum .

Contraindications

Standard considerations.

Dosage and Administration

Adults A 3-day treatment schedule with a total of 6 doses is recommended for adult patients with a body weight of 35 kg and above

PO 4 tablets as a single initial dose, 4 tablets again after 8 h, and then 4 tablets twice daily (morning and evening) for the following 2 days (total course of 24 tablets).

Children 16 years of age or younger or weighing less than 35 kg

PO A 3-day treatment schedule with a total of 6 doses is recommended as below:

35 kg body weight and above

4 tablets as a single initial dose, 4 tablets again after 8 h, and then 4 tablets twice daily (morning and evening) for the following 2 days (total course of 24 tablets).

25 kg to less than 35 kg body weight

3 tablets as an initial dose, 3 tablets again after 8 h, and then 3 tablets twice daily (morning and evening) for the following 2 days (total course of 18 tablets).

15 kg to less than 25 kg body weight

2 tablets as an initial dose, 2 tablets again after 8 h, and then 2 tablets twice daily (morning and evening) for the following 2 days (total course of 12 tablets).

5 kg to less than 15 kg body weight

1 tablet as an initial dose, 1 tablet again after 8 h, and then 1 tablet twice daily (morning and evening) for the following 2 days (total course of 6 tablets).

General Advice

• Artemether/lumefantrine tablets should be taken with food. Patients should be encouraged to resume normal eating as soon as food can be tolerated since this improves absorption of artemether and lumefantrine.
• For patients who are unable to swallow the tablets such as infants and children, artemether/lumefantrine tablets may be crushed and mixed with a small amount of water (1 to 2 teaspoons) in a clean container for administration immediately prior to use. The container can be rinsed with more water and the contents swallowed by the patient. The crushed tablet preparation should be followed whenever possible by food/drink (eg, milk, formula, pudding, broth, porridge).
• In the event of vomiting within 1 to 2 hours of administration, a repeat dose should be taken. If the repeat dose is vomited, the patient should be given an alternative antimalarial for treatment.

Storage/Stability

Store at 25°C (77°F).

Drug Interactions

Antibiotics (eg, macrolides, fluoroquinolone, imidazole, triazole antifungals)

Potential for additive effects on the QT interval. Avoid coadministration.

Antidepressants

Potential for additive effects on the QT interval. Avoid coadministration.

Antimalarials (eg, quinine, quinidine)

Potential for additive effects on the QT interval. Avoid coadministration.

Antipsychotics (eg, pimozide, ziprasidone)

Potential for additive effects on the QT interval. Avoid coadministration.

Antiretroviral drugs (eg, protease inhibitors, non-nucleoside reverse transcriptase inhibitors)

May result in increased lumefantrine concentrations causing QT prolongation, decreased concentration of antiretroviral resulting in loss of efficacy, or decrease in artemether/lumefantrine concentrations resulting in loss of efficacy.

Contraceptive, hormonal

May reduce the effectiveness of hormonal contraceptives. Advise patients to use an additional nonhormonal method of birth control.

Cisapride

Potential for additive effects on the QT interval. Avoid coadministration.

Class IA antiarrhythmic (eg, quinidine, procainamide, disopyramide)

Potential for additive effects on the QT interval. Avoid coadministration.

Class III antiarrhythmic agents (eg, amiodarone, sotalol)

Potential for additive effects on the QT interval. Avoid coadministration.

CYP3A4 inducers

May result in decreased concentrations of artemether/lumefantrine and loss of anti-malarial efficacy.

CYP3A4 inhibitors (eg, grapefruit juice, ketoconazole)

May result in increased concentrations of artemether/lumefantrine and potentiate QT prolongation.

CYP3A4 substrates

May result in decreased concentrations of the substrate and potential loss of substrate efficacy.

CYP2D6 metabolized drugs (eg, amitriptyline, clomipramine, flecainide, imipramine)

Coadministration may significantly increase plasma concentrations and increase the risk for adverse effects, including QT interval prolongation.

Halofantrine

Potential for additive effects on the QT interval. Avoid coadministration.

Mefloquine

If mefloquine is administered immediately prior to artemether/lumefantrine, there may be decreased exposure to lumefantrine. Monitor patients for decreased efficacy and encourage food consumption.

Nonsedating antihistaminics (eg, terfenadine, astemizole)

Potential for additive effects on the QT interval. Avoid coadministration.

Laboratory Test Interactions

None specified.

Adverse Reactions

CNS

Headache (56%); dizziness (39%); asthenia (38%); sleep disorder (22%); fatigue (17%); insomnia (5%); malaise, vertigo (3%); agitation, ataxia, clonus, fine motor delay, gait disturbance, hyperreflexia, hypoesthesia, mood swings, nystagmus, tremor (less than 3%).

Dermatologic

Pruritis (4%), rash (3%); impetigo, urticaria (less than 3%).

EENT

Conjunctivitis, ear infection, tinnitus (less than 3%).

GI

Anorexia (40%); nausea (26%); abdominal pain, vomiting (17%); diarrhea (7%); constipation, dyspepsia, dysphagia, gastroenteritis, peptic ulcer (less than 3%).

Genitourinary

Hematuria, proteinuria, UTI (less than 3%).

Hematologic-Lymphatic

Splenomegaly (9%); anemia (4%); eosinophilia, hematocrit decreased, lymphocyte morphology abnormal, platelet count decreased, platelet count increased, white blood cell count decreased, white blood cell count increased (less than 3%).

Hepatic

Hepatomegaly (9%); AST increased (4% in children); ALT increased, AST increased (less than 3%).

Hypersensitivity

Angioedema, serious skin reactions (bullous eruption), urticaria (postmarketing).

Musculoskeletal

Arthralgia (34%); myalgia (32%).

Respiratory

Cough (6%, 23% in children); nasopharyngitis (3%); rhinitis (4% in children); asthma, bronchitis, lower respiratory tract infection, pharyngolaryngeal pain, pneumonia, respiratory tract infection, upper respiratory tract infection (less than 3%).

Miscellaneous

Pyrexia (25%); chills (23%); palpitations (18%); malaria, rash (3%); abscess, acrodermatitis, back pain, helminthic infection, hookworm infection, hypokalemia, influenza, malaria, oral herpes, subcutaneous abscess (less than 3%).

Precautions

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established in children who weigh less than 5 kg.

Elderly

Clinical studies did not include sufficient numbers of patients 65 yr of age and older to determine if they respond differently from younger patients.

Renal Function

Artemether/lumefantrine has not been studied for efficacy and safety in patients with severe renal impairment. No dosage adjustment is necessary in patients with mild to moderate renal impairment.

Hepatic Function

Artemether/lumefantrine has not been studied for efficacy and safety in patients with severe hepatic impairment. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment.

Plasmodium vivax infection

Effectiveness in treating the erythrocytic stage of P. vivax infection is limited.

QT prolongation

Has been associated with prolongation of the QT interval. Monitor for cardiac arrhythmias and signs of QT prolongation.

Recrudescence

Patients who remain averse to food during treatment should be closely monitored as the risk of recrudescence may be greater.

Overdosage

Symptoms

None known.

Patient Information

• Instruct patients to take with food. Patients who do not have an adequate intake of food are at risk for recrudescence of malaria.
• Instruct patients to inform their health care provider of any personal or family history of QT prolongation or proarrhythmic conditions, such as hypokalemia, bradycardia, or recent myocardial ischemia.
• Instruct patients to inform their health care provider if they are taking any other medications that prolong the QT interval.
• Instruct patients to notify their doctor if they have any symptoms of QT prolongation such as prolonged heart palpitations or loss of consciousness.
• Advise patients that artemether/lumefantrine may reduce the effectiveness of hormonal contraceptives. Instruct patients who are using oral, transdermal, or other systemic hormonal contraceptives to use an additional nonhormonal method of birth control.
• Inform patients that hypersensitivity reactions may occur. Instruct patients to discontinue the drug at the first sign of skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (eg, swelling of the lips, tongue, or face; tightness of the throat; hoarseness), or other symptoms of an allergic reaction.

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