Artemether/ Lumefantrine

These indications are based on manufacturer information for both originator and generic products. For product specific registered indications, please refer to product specific manufacturer information

Registered South African indications:

• Uncomplicated Plasmodium falciparum malaria, including chloroquine-resistant Plasmodium falciparum
• Acute stage of Plasmodium vivax malaria

Contraindications 

• Hypersensitivity to the active ingredient of any of the excipients in this combination product
• Porphyria
• Severe malaria according to World Health Organisation definition - presence of one or more of the following:
  - Prostration
  - Impaired consciousness or unarousable coma
  - Failure to feed
  - Deep breathing
  - Respiratory distress (acidotic breathing)
  - Multiple convulsions
  - Circulatory collapse or shock
  - Pulmonary oedema (radiological)
  - Abnormal bleeding
  - Clinical jaundice
  - Severe monocytic anaemia
  - Hypoglycemia
  - Haemoglobuniuria
  - Metabolic acidosis
  - Renal impairment
  - Hyperlactatemia
  - Hyperparasitemia
• Family history of sudden death or of congenital prolongation of the QTc interval on electrocardiograms, or with any other clinical condition known to prolong the QTc interval
• History of symptomatic cardiac arrhythmias or with clinically significant bradycardia or with congestive cardiac failure accompanied by reduced left ventricle ejection fraction
• Electrolyte balance disturbances
  - Hypokalemia
  - Hypomagnesemia
• Coadministration with CYP3A4 inducers
  - Rifampin
  - Carbamazepine
  - Phenytoin
  - St John's wort
• Coadministration with drugs metabolised by CYP2D6
  - Metoprolol
  - Imipramine
  - Amitriptyline
  - Clomipramine
• Coadministration with agents causing QT interval prolongation (proarrhythmic)
  - Class IA and III antiarrhythmics
  - Neuroleptics, antidepressive agents
  - Certain antibiotics including macrolides, fluoroquinolones, imidazole or triazole antifungal agents
  - Certain non-sedating antihistamines including terfenadine or astemizole
  - Cisapride
  - Flecainide

Cautions 

• Pregnancy
• Breastfeeding
• Severe renal impairment
• Severe hepatic impairment
• Patients who remain averse to food during treatment
• Patients taking quinine after use of artemether/ lumefantrine
• Patients taking artemether/ lumefantrine after use of mefloquine
• Patients taking artemether/ lumefantrine in less then one month after use of halofantrine
• Coadministration with drugs exhibiting variable patterns of inhibition, moderate induction or competition for CYP3A4 or that have mixed inhibitory/ induction effect on CYP3A4
  - Antiretrovirals, such as HIV protease inhibitors and non nucleoside reverse transcriptase inhibitors
• Coadministration with hormonal contraceptives
• Coadministration with other antimalarial agents (unless no other treatment option is available)
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: tab

Adult dosages below include:

• General dosing range
• South African Standard Treatment Guideline recommendations
• International manufacturer recommendations
• South African manufacturer recommendations

Infections caused by Plasmodium species

General dosing range

Artemether/ Lumefantrine
20/120 (mg)

• Oral (tab): Initial: 4 tabs; Then: 4 tabs after 8hrs; Then: 4 tabs, 12hrly for 2 days; Max: 24 tabs total

Specific doses based on individual indications

Please note that the dosages below should be used in combination with regional guidelines, taking into account local antibiotic sensitivities

South African Standard Treatment Guidelines recommendations

Non-severe uncomplicated malaria 

Artemether/ Lumefantrine
20/120 (mg)

• Oral (tab): >35kg: 4 tabs at diagnosis; Repeat 8hrs later: Then: 12hrly for another 2 days: Total number of doses in 3 days: 6
  Refer to malaria, non-severe/uncomplicated: STG, PHC 2020

Severe malaria

Artemether/ Lumefantrine
20/120 (mg)

• Oral (tab): 4 tabs at diagnosis, repeated at 8hrs; Then: 12hrly on day 2 and day 3; Total course: 24 tabs
  Refer to malaria: STG, Adult 2019

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International manufacturer recommendations

Treatment of acute uncomplicated Plasmodium falciparum malaria

Artemether/ Lumefantrine
20/120 (mg)

• Oral (tab): >35kg: Initial: 4 tabs, at diagnosis; Then: 4 tabs, after 8hrs; Then: 4 tabs, after 24hrs; Then: 4 tabs, after 36hrs; Then: 4 tabs, after 48hrs; Then: 4 tabs, after 60hrs; Max: 24 tabs/60hrs

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Doses should be taken with food or a milky drink

In the event of vomiting within 1hr of administration, a repeat dose should be taken

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South African manufacturer recommendations

Uncomplicated Plasmodium falciparum malaria, including chloroquine resistant Plasmodium falciparum 
- in patients up to 65kg body weight living in malaria endemic and non-endemic areas
Acute stage of Plasmodium vivax malaria
- in patients up to 65kg body weight living in malaria endemic and non-endemic areas

Artemether/ Lumefantrine
20/120 (mg)

35kg-<65kg

• Oral (tab): Initial: 4 tabs; Then: 4 tabs after 8hrs; Then: 4 tabs, 12hrly for 2 days; Total course: 24 tabs  

≥65kg

• Not established for use

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There is no adequate experience in patients weighing over 65kg

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The dose should be taken with food or drinks rich in fat such as milk

In the event of vomiting within 1hr of administration, a repeat dose should be taken

Forms avail. in SA and covered in this monograph: tab

Paed. dosages below include:

• General dosing range
• South African Standard Treatment Guideline recommendations
• International manufacturer recommendations
• South African manufacturer recommendations

Infections caused by Plasmodium species

General dosing range

Younger than 2 months

• Oral (tab): <5kg: Not recommended for use

Older than 2 months

• Oral (tab): 5kg-<15kg: Initial: 1 tab; Then: 1 tab, after 8hrs; Then: 1 tab, 12hrly for 2 days
• Oral (tab): 15kg-<25kg: Initial: 2 tabs; Then: 2 tabs, after 8hrs; Then: 2 tabs, 12hrly for 2 days
• Oral (tab): 25kg-<35kg: Initial: 3 tabs; Then: 3 tabs, after 8hrs; Then: 3 tabs, 12hrly for 2 days
• Oral (tab): ≥35kg: See adult dosage

Specific doses based on individual indications

Please note that the dosages below should be used in combination with regional guidelines, taking into account local antibiotic sensitivities

South African Standard Treatment Guideline recommendations

Acute uncomplicated malaria 

Artemether/ Lumefantrine
20/120 (mg)

• Oral (tab): 5-15kg: 1 tab at diagnosis, repeated at 8hrs; Then: 12hrly on day 2 and 3; Total course: 6 tabs
• Oral (tab): 15-25kg: 2 tabs at diagnosis, repeated at 8hrs; Then: 12hrly on day 2 and 3; Total course: 12 tabs
• Oral (tab): >25kg: See adult dosage
  Refer to P.Falciparum malaria, non-severe, uncomplicated: STG Paed. 2017
  Refer to malaria, non-severe/uncomplicated: STG, PHC 2020

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International manufacturer recommendations

Treatment of acute uncomplicated Plasmodium falciparum malaria

Artemether/ Lumefantrine
20/120 (mg)

• Oral (tab): <5kg: Not established for use
• Oral (tab): 5-<15kg: Initial: 1 tab, at diagnosis; Then: 1 tab, after 8hrs; Then: 1 tab, after 24hrs; Then: 1 tab, after 36hrs; Then: 1 tab, after 48hrs; Then: 1 tab, after 60hrs
• Oral (tab): 15-<25kg: 2 tabs, at diagnosis; Then: 2 tabs, after 8hrs; Then: 2 tabs, after 24hrs; Then: 2 tabs, after 36hrs; Then: 2 tabs, after 48hrs; Then: 2 tabs, after 60hrs
• Oral (tab): 25-<35kg: 3 tabs; Then: 3 tabs, after 8hrs; Then: 3 tabs, after 24hrs; Then: 3 tabs, after 36hrs; Then: 3 tabs, after 48hrs; Then: 3 tabs, after 60hrs
• Oral (tab): ≥35kg: See adult dosage

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Doses should be taken with food or a milky drink

In the event of vomiting within 1hr of administration, a repeat dose should be taken

---

For administration to small children and infants, the tablets may be crushed

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South African manufacturer recommendations

Uncomplicated Plasmodium falciparum malaria, including chloroquine resistant Plasmodium falciparum 
- in patients up to 65kg body weight living in malaria endemic and non-endemic areas
Acute stage of Plasmodium vivax malaria
- in patients up to 65kg body weight living in malaria endemic and non-endemic areas

Artemether/ Lumefantrine
20/120 (mg)

• Oral (tab): 5-<15kg: Initial: 1 tab at diagnosis; Then: 1 tab, after 8hrs; Then: 1 tab, 12hrly for 2 days; Total course: 6 tabs total
• Oral (tab): 15-<25kg: Initial: 2 tabs at diagnosis; Then: 2 tabs, after 8hrs; Then: 2 tabs, 12hrly for 2 days; Max: 12 tabs total
• Oral (tab): 25-<35kg: Initial: 3 tabs at diagnosis; Then: 3 tabs, after 8hrs; Then: 3 tabs, 12hrly for 2 days; Max: 18 tabs total
• Oral (tab): 35-<65kg: See adult dosage

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Tablets may be crushed for administration to infants and children

---

There is no adequate experience in patients weighing over 65kg

---

The dose should be taken with food or drinks rich in fat such as milk

---

In the event of vomiting within 1hr of administration, a repeat dose should be taken

Pregnancy

• First trimester: Caution; not recommended
• Second and third trimester: Caution
• A meta-analysis of observational studies including over 500 artemether/ lumefantrine exposed women in their first trimester of pregnancy assessed adverse pregnancy outcomes. The data showed that compared to quinine, arteminsinin treatment, including artemether/ lumefantrine, was not associated with an increased risk of miscarriage, stillbirth or congenital abnormalities. However, due to the limitations of these studies, the risk of adverse pregnancy outcomes for artemether/ lumefantrine exposed women in early pregnancy cannot be excluded
• Studies in animals have shown reproductive toxicity
• Artemether/ lumefantrine treatment is not recommended during the first trimester of pregnancy in situations where other suitable and effective antimalarials are available. However, it should not be withheld in life-threatening situations, where no other effective antimalarials are available
• Safety data from pregnancy studies including over 1200 pregnant women who were exposed to artemether/ lumefantrine during the second or third trimester did not show an increase in adverse pregnancy outcomes or teratogenic effects over background rates
• During the second and third trimester, artemether/ lumefantrine treatment should be considered if the expected benefit to the mother outweighs the risk to the foetus
• Women using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to use an additional non-hormonal method of birth control for about one month

Breastfeeding

• Caution; not recommended
• Animal data suggest excretion into breast milk but no data are available in humans. Women taking artemether/ lumefantrine should not breastfeed during their treatment. Due to the long elimination half-life of lumefantrine (2 to 6 days), it is recommended that breastfeeding should not resume until at least one week after the last dose of artemether/ lumefantrine unless potential benefits to the mother and child outweigh the risks of artemether/ lumefantrine treatment

Fertility

• There is no information on the effects of artemether/ lumefantrine on human fertility

Renal Impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended 
  ECG and blood potassium monitoring advised in severe renal impairment
  There is no significant renal excretion of lumefantrine, artemether and dihydroartemisinin in studies conducted in healthy volunteers and clinical significance is limited

Hepatic Impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended 
  ECG and blood potassium monitoring advised in severe hepatic impairment
  In patients with severe hepatic impairment, a clinically relevant increase of exposure to artemether and lumefantrine and/or their metabolites cannot be ruled out

Elderly

• No dose adjustment recommended

Porphyria Information

• Probably porphyrinogenic (PRP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Dizziness
• Paraesthesia
• Ataxia
• Hypoaesthesia
• Somnolence
• Clonus
• Sleep disorders
• Insomnia
• Fatigue
• Gait disturbance

Cardiovascular Disorders

• Palpitations
• Electrocardiogram QT interval prolongation

Respiratory Disorders

• Cough

Gastrointestinal Disorders

• Nausea and vomiting
• Abdominal pain
• Diarrhoea

Hepatobiliary Disorders

• Increased hepatic function level  

Endocrine and Metabolic Disorders

• Decreased appetite

Musculoskeletal Disorders

• Arthralgia
• Myalgia

Skin and Subcutaneous Tissue Disorders

• Rash
• Pruritus
• Urticaria
• Angioedema

Immune, Blood and Lymphatic System Disorders

• Delayed haemolytic anaemia
• Hypersensitivity

• CYP3A4 inducers
• Rifampicin
• Carbamazepine
• Phenytoin
• Metoprolol
• Imipramine
• Amitriptyline
• Clomipramine
• Agents that prolong the QTc interval
• Class IA and III antiarrhythmics
• Neuroleptics
• Tricyclic antidepressants
• Certain antibiotics
• Macrolides
• Fluoroquinolones
• Imidazole
• Triazole antifungal agents
• Certain non-sedating antihistamines
• Terfenadine
• Astemizole
• Cisapride
• Flecainide
• Other antimalarial agents
• Mefloquine
• Quinine
• Halofantrine
• CYP3A4 inhibitors
• Ketoconazole
• Antiretroviral agents
• Protease inhibitors
• Non-nucleoside reverse transcriptase inhibitors
• Lopinavir/ ritonavir
• Nevirapine
• Efavirenz
• Hormonal contraceptives
• CYP450 enzyme substrates

Other

• Grapefruit juice
• St John's wort

None routine. Specific cases may require

• ECG
• Blood potassium

Additional observations

• Food consumption

New infections

• Data for a limited number of patients in a malaria endemic area show that new infections can be treated with a second course of artemether/ lumefantrine. In the absence of carcinogenicity study data, and due to lack of clinical experience, more than two courses cannot be recommended

Artemether/ lumefantrine comprises of a fixed ratio of 1:6 parts of artemether and lumefantrine, respectively. The site of antiparasitic action of both components is the food vacuole of the malarial parasite, where they are thought to interfere with the conversion of haem, a toxic intermediate produced during haemoglobin breakdown, to the nontoxic haemozoin, malaria pigment. Lumefantrine is thought to interfere with the polymerisation process, while artemether generates reactive metabolites as a result of the interaction between its peroxide bridge and haem iron. Both artemether and lumefantrine have a secondary action involving inhibition of nucleic acid- and protein synthesis within the malarial parasite. Artemether/ lumefantrine has been reported to have potent activity in terms of clearing gametocytes.

Spectrum of activity: Plasmodium species

COMBINATION PREPARATIONS

Artemether/ Lumefantrine

Tablet 20mg/120mg

• Coartem (Novartis) originator