Drugs List

Therapeutic Indications

Uses

Treatment of acute uncomplicated Plasmodium falciparum malaria in adults, children and infants of 5kg and above.

For up to date advice on geographical resistance patterns and appropriate prophylaxis, current guidelines should be consulted.
Guidelines for malaria Prevention from the Health Protection Agency specifically developed for travellers from the United Kingdom may be obtained on the HPA website:https://www.hpa.org.uk/webw/HPAweb&HPAwebStandard/HPAweb_C/1195733823080?p=1191942128258 )

Unlicensed Uses

Treatment of benign malaria

Administration

For oral administration.

Tablets should be taken with food or a milky drink to increase absorption. If patients are unable to tolerate food, tablets should be administered, but systemic exposure may be reduced.
Patients who vomit within 1 hour of taking the medication should repeat the dose.

The tablets may be crushed when administered to small children and infants.

Contraindications

Severe malaria.

Family history of sudden death or of congenital prolongation of the QTc interval on electrocardiograms.

Clinical conditions known to prolong the QTc interval.

History of symptomatic cardiac arrhythmias.
Clinically relevant bradycardia.
Congestive cardiac failure accompanied by reduced left ventricle ejection fraction.

Electrolyte imbalance (e.g. hypokalaemia or hypomagnesaemia).

Breastfeeding - see 'Lactation' section.

Precautions and Warnings

Artemether with lumefantrine has not been evaluated for the treatment of severe malaria, including cases of cerebral malaria or other severe manifestations such as pulmonary oedema or renal failure.

Due to the lack of data on safety and efficacy, artemether with lumefantrine should not be given concurrently with any other antimalarial agent.

If the patient deteriorate during therapy, alternative treatment of malaria should be initiated immediately. In these cases, ECG should be monitored and any electrolyte disturbances should be corrected.

Artemether with lumefantrine is not indicated for, and has not been evaluated in, the treatment of malaria due to P. vivax,P. malariae or P. ovale, although some patients in clinical studies had co-infection with P. falciparum and P. vivax at baseline. Artemether with lumefantrine is active against blood stages of Plasmodium vivax, but is not active against hypnozoites.

Artemether with lumefantrine is not indicated and has not been evaluated for prophylaxis.

Caution is advised when administering artemether with lumefantrine to patients with severe renal, hepatic or cardiac impairment. In these patients, ECG and blood potassium monitoring is advised.

Artemether with lumefantrine, as with other anti-malarials, has the potential to cause QT prolongation.

In clinical trials in adults and adolescents, asymptomatic prolongation of QTc interval by more than 30 msec was seen in 36% of patients. In young children, asymptomatic prolongation of QTc interval by more than 30 msec was seen in 34% of children weighing 5 to 10kg, 31% of children weighing 10 to 15kg, 24% of children weighing 15 to 25kg and 32% of children weighing 25 to 35kg.

Caution is advised when administering artemether with lumefantrine to patients in whom there may be detectable concentrations of antimalarial drugs in the plasma following prior treatments.

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

Patients should be advised to refrain from drinking grapefruit juice during therapy with artemether and lumefantrine.

Pregnancy - see 'Pregnancy' section.

Use in Porphyria

Some sources advise against use of artemether with lumefantrine in porphyria and list as probably porphyrogenic.

Pregnancy and Lactation

Pregnancy

Use with caution during pregnancy.

At the time of writing there is little published experience concerning the use of artemether with lumefantrine during pregnancy. Artemether with lumefantrine treatment must not be used during the first trimester of pregnancy in situations where other suitable and effective anti-malarials are available. However, it should not be withheld in life-threatening situations, where no other effective anti-malarials are available. During the second and third trimester, treatment should only be considered if the expected benefit to the mother outweighs the risk to the foetus. Schaefer concludes that inadvertent use during the first trimester does not require termination of the pregnancy, however a detailed ultrasound should be considered to evaluate foetal morphologic development (Schaefer 2007).

Based on animal data, artemether with lumefantrine is suspected to cause serious birth defects when administered during the first trimester of pregnancy. Reproductive studies with artemether have shown evidence of post-implantation losses and teratogenicity in rats and rabbits. Other artemisin derivatives have also demonstrated teratogenic potential with an increased risk during early pregnancy. Reproductive toxicity studies performed with the artemether and lumefantrine caused maternal toxicity and increased post-implantation loss in rats and rabbits at doses greater than or equal to 50mg/kg/day. These effects were not observed at lower doses.

The World Health Organization currently states that artemisin derivatives should be used to treat uncomplicated falciparum malaria in the second and third trimesters of pregnancy but should not be used in the first trimester until more information becomes available. Lumefantrine has not been sufficiently evaluated to permit positive recommendations.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Licensed in pregnancy? - No

Recommended for use in pregnancy? - No but treatment should not be withheld in in life-threatening situations. It should only be considered if the expected benefit to the mother outweighs the risk to the foetus.

Known human teratogen? - Unknown. However other artemisin derivatives have demonstrated teratogenic potential, with an increased risk in the first trimester.

Animal data - Artemether with lumefantrine is suspected to cause serious birth defects when administered during the first trimester of pregnancy. Reproductive studies with artemether have shown evidence of post-implantation losses and teratogenicity in rats and rabbits.

Lactation

Artemether with lumefantrine is contraindicated during breastfeeding.

At the time of writing there is little published experience concerning the use of artemether with lumefantrine during breastfeeding. Due to the long elimination half-life of lumefantrine (4 to 6 days), it is recommended that breast feeding should not resume until at least one week after the last dose of artemether with lumefantrine (unless potential benefits to the mother outweigh the possible risks to the neonate). Antimalarials are unsuitable for administration to breastfeeding mothers because serious adverse effects may be anticipated on theoretical grounds.

Animal data suggest excretion into breast milk but no data are available in humans.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Drug excreted in breast milk? - Animal data suggest excretion into breast milk but no data available in humans.

Considered suitable or recommended by manufacturer? - No

UK Drugs in Lactation Advisory Service Classification - Serious adverse effects may be anticipated on theoretical grounds.

Side Effects

Headache
Dizziness
Sleep disturbances
Palpitations
Abdominal pain
Anorexia
Diarrhoea
Vomiting
Nausea
Pruritus
Rash
Cough
Arthralgia
Myalgia
Asthenia
Fatigue
Hypersensitivity reactions
Prolongation of QT interval
Paraesthesia
Somnolence
Involuntary muscle contractions
Hypoaesthesia
Gait abnormality
Ataxia
Clonus
Altered liver function tests
Insomnia
Urticaria
Angioedema

Presentation

Tablets containing artemether 20mg and lumefantrine 120mg.

Drugs List

Therapeutic Indications

Uses

Treatment of acute uncomplicated Plasmodium falciparum malaria in adults, children and infants of 5kg and above.

For up to date advice on geographical resistance patterns and appropriate prophylaxis, current guidelines should be consulted.
Guidelines for malaria Prevention from the Health Protection Agency specifically developed for travellers from the United Kingdom may be obtained on the HPA website:https://www.hpa.org.uk/webw/HPAweb&HPAwebStandard/HPAweb_C/1195733823080?p=1191942128258 )

Unlicensed Uses

Treatment of benign malaria

Dosage

Adults

Elderly

Children

Patients with Renal Impairment

Patients with Hepatic Impairment

Additional Dosage Information

Administration

For oral administration.

Tablets should be taken with food or a milky drink to increase absorption. If patients are unable to tolerate food, tablets should be administered, but systemic exposure may be reduced.
Patients who vomit within 1 hour of taking the medication should repeat the dose.

The tablets may be crushed when administered to small children and infants.

Contraindications

Severe malaria.

Family history of sudden death or of congenital prolongation of the QTc interval on electrocardiograms.

Clinical conditions known to prolong the QTc interval.

History of symptomatic cardiac arrhythmias.
Clinically relevant bradycardia.
Congestive cardiac failure accompanied by reduced left ventricle ejection fraction.

Electrolyte imbalance (e.g. hypokalaemia or hypomagnesaemia).

Breastfeeding - see 'Lactation' section.

Precautions and Warnings

Artemether with lumefantrine has not been evaluated for the treatment of severe malaria, including cases of cerebral malaria or other severe manifestations such as pulmonary oedema or renal failure.

Due to the lack of data on safety and efficacy, artemether with lumefantrine should not be given concurrently with any other antimalarial agent.

If the patient deteriorate during therapy, alternative treatment of malaria should be initiated immediately. In these cases, ECG should be monitored and any electrolyte disturbances should be corrected.

Artemether with lumefantrine is not indicated for, and has not been evaluated in, the treatment of malaria due to P. vivax,P. malariae or P. ovale, although some patients in clinical studies had co-infection with P. falciparum and P. vivax at baseline. Artemether with lumefantrine is active against blood stages of Plasmodium vivax, but is not active against hypnozoites.

Artemether with lumefantrine is not indicated and has not been evaluated for prophylaxis.

Caution is advised when administering artemether with lumefantrine to patients with severe renal, hepatic or cardiac impairment. In these patients, ECG and blood potassium monitoring is advised.

Artemether with lumefantrine, as with other anti-malarials, has the potential to cause QT prolongation.

In clinical trials in adults and adolescents, asymptomatic prolongation of QTc interval by more than 30 msec was seen in 36% of patients. In young children, asymptomatic prolongation of QTc interval by more than 30 msec was seen in 34% of children weighing 5 to 10kg, 31% of children weighing 10 to 15kg, 24% of children weighing 15 to 25kg and 32% of children weighing 25 to 35kg.

Caution is advised when administering artemether with lumefantrine to patients in whom there may be detectable concentrations of antimalarial drugs in the plasma following prior treatments.

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

Patients should be advised to refrain from drinking grapefruit juice during therapy with artemether and lumefantrine.

Pregnancy - see 'Pregnancy' section.

Use in Porphyria

Some sources advise against use of artemether with lumefantrine in porphyria and list as probably porphyrogenic.

Pregnancy and Lactation

Pregnancy

Use with caution during pregnancy.

At the time of writing there is little published experience concerning the use of artemether with lumefantrine during pregnancy. Artemether with lumefantrine treatment must not be used during the first trimester of pregnancy in situations where other suitable and effective anti-malarials are available. However, it should not be withheld in life-threatening situations, where no other effective anti-malarials are available. During the second and third trimester, treatment should only be considered if the expected benefit to the mother outweighs the risk to the foetus. Schaefer concludes that inadvertent use during the first trimester does not require termination of the pregnancy, however a detailed ultrasound should be considered to evaluate foetal morphologic development (Schaefer 2007).

Based on animal data, artemether with lumefantrine is suspected to cause serious birth defects when administered during the first trimester of pregnancy. Reproductive studies with artemether have shown evidence of post-implantation losses and teratogenicity in rats and rabbits. Other artemisin derivatives have also demonstrated teratogenic potential with an increased risk during early pregnancy. Reproductive toxicity studies performed with the artemether and lumefantrine caused maternal toxicity and increased post-implantation loss in rats and rabbits at doses greater than or equal to 50mg/kg/day. These effects were not observed at lower doses.

The World Health Organization currently states that artemisin derivatives should be used to treat uncomplicated falciparum malaria in the second and third trimesters of pregnancy but should not be used in the first trimester until more information becomes available. Lumefantrine has not been sufficiently evaluated to permit positive recommendations.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Licensed in pregnancy? - No

Recommended for use in pregnancy? - No but treatment should not be withheld in in life-threatening situations. It should only be considered if the expected benefit to the mother outweighs the risk to the foetus.

Known human teratogen? - Unknown. However other artemisin derivatives have demonstrated teratogenic potential, with an increased risk in the first trimester.

Animal data - Artemether with lumefantrine is suspected to cause serious birth defects when administered during the first trimester of pregnancy. Reproductive studies with artemether have shown evidence of post-implantation losses and teratogenicity in rats and rabbits.

Lactation

Artemether with lumefantrine is contraindicated during breastfeeding.

At the time of writing there is little published experience concerning the use of artemether with lumefantrine during breastfeeding. Due to the long elimination half-life of lumefantrine (4 to 6 days), it is recommended that breast feeding should not resume until at least one week after the last dose of artemether with lumefantrine (unless potential benefits to the mother outweigh the possible risks to the neonate). Antimalarials are unsuitable for administration to breastfeeding mothers because serious adverse effects may be anticipated on theoretical grounds.

Animal data suggest excretion into breast milk but no data are available in humans.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Drug excreted in breast milk? - Animal data suggest excretion into breast milk but no data available in humans.

Considered suitable or recommended by manufacturer? - No

UK Drugs in Lactation Advisory Service Classification - Serious adverse effects may be anticipated on theoretical grounds.

Effects on Ability to Drive and Operate Machinery

Patients receiving artemether with lumefantrine should be warned that dizziness, fatigue or asthenia may occur in which case they should not drive or use machines.

Counselling

Patients receiving artemether with lumefantrine should be warned that dizziness, fatigue or asthenia may occur in which case they should not drive or use machines.

Tablets should be taken with food to increase absorption. If patients are unable to tolerate food, tablets should be administered, but systemic exposure may be reduced.
Patients who vomit within 1 hour of taking the medication should repeat the dose.

Advise patient to refrain from drinking grapefruit juice during therapy with artemether and lumefantrine.

Advise patient not to take St. John's wort concurrently.

Side Effects

Headache
Dizziness
Sleep disturbances
Palpitations
Abdominal pain
Anorexia
Diarrhoea
Vomiting
Nausea
Pruritus
Rash
Cough
Arthralgia
Myalgia
Asthenia
Fatigue
Hypersensitivity reactions
Prolongation of QT interval
Paraesthesia
Somnolence
Involuntary muscle contractions
Hypoaesthesia
Gait abnormality
Ataxia
Clonus
Altered liver function tests
Insomnia
Urticaria
Angioedema

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Shelf Life and Storage

Store at or below 30 degrees C.

Further Information

Last Full Review Date: January 2011

Reference Sources

British National Formulary, 62nd Edition (2011) Pharmaceutical Press, London.

BNF for Children (2010-2011) Pharmaceutical Press, London.

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Summary of Product Characteristics: Riamet tablets. Novartis Pharmaceuticals UK Ltd. Revised February 2010.

UK Drugs in Lactation Advisory Service.
Available at: https://www.ukmicentral.nhs.uk/drugpreg/qrg_p1.asp
Last accessed: January 11, 2011

World Health organisation; Guidelines for the Treatment of Malaria.
Available at: https://apps.who.int/malaria/docs/TreatmentGuidelines2006.pdf
Last accessed: January 11, 2011

Napos. The drug database for acute porphyria.
Available at https://www.drugs-porphyria.org/languages/UnitedKingdom/s1.php?l=gbr
Artemether with lumefantrine Last revised: October 1, 2004
Last accessed: December 2, 2011