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  • CLASSES

    Antimalarials

    DEA CLASS

    Rx

    DESCRIPTION

    Fixed artemisinin-based combination tablet
    For the treatment of acute, uncomplicated malaria infections in patients 2 months and older with a bodyweight of at least 5 kg
    Artemisinin-based therapies are potent with rapid onset of anti-parasitic activity

    COMMON BRAND NAMES

    Coartem

    HOW SUPPLIED

    Coartem Oral Tab: 20-120mg

    DOSAGE & INDICATIONS

    For the treatment of malaria.
    For the treatment of malaria in patients with acute, uncomplicated infections due to P. falciparum.
    Oral dosage
    Adults

    4 tablets (20 mg artemether; 120 mg lumefantrine per tablet) PO as initial dose and 4 tablets PO at 8 hours after initial dose, then 4 tablets PO twice daily (morning and evening) for 2 days for a total course of 24 tablets. Guidelines recommend for chloroquine-resistant infections and for infections of unknown resistance; may also use for chloroquine-sensitive infections if necessary. Not recommended for persons who have received mefloquine prophylaxis.[35401] [63990] [64059]

    Children and Adolescents weighing 35 kg or more

    4 tablets (20 mg artemether; 120 mg lumefantrine per tablet) PO as initial dose and 4 tablets PO at 8 hours after initial dose, then 4 tablets PO twice daily (morning and evening) for 2 days for a total course of 24 tablets. Guidelines recommend for chloroquine-resistant infections and for infections of unknown resistance; may also use for chloroquine-sensitive infections if necessary. Not recommended for persons who have received mefloquine prophylaxis.[35401] [63990] [64059]

    Children and Adolescents weighing 25 to 34 kg

    3 tablets (20 mg artemether; 120 mg lumefantrine per tablet) PO as initial dose and 3 tablets PO at 8 hours after initial dose, then 3 tablets PO twice daily (morning and evening) for 2 days for a total course of 18 tablets. Guidelines recommend for chloroquine-resistant infections and for infections of unknown resistance; may also use for chloroquine-sensitive infections if necessary. Not recommended for persons who have received mefloquine prophylaxis.[35401] [63990] [64059]

    Infants and Children 2 months or older weighing 15 to 24 kg

    2 tablets (20 mg artemether; 120 mg lumefantrine per tablet) PO as initial dose and 2 tablets PO at 8 hours after initial dose, then 2 tablets PO twice daily (morning and evening) for 2 days for a total course of 12 tablets. Guidelines recommend for chloroquine-resistant infections and for infections of unknown resistance; may also use for chloroquine-sensitive infections if necessary. Not recommended for persons who have received mefloquine prophylaxis.[35401] [63990] [64059]

    Infants and Children 2 months or older and weighing 5 to 14 kg

    1 tablet (20 mg artemether; 120 mg lumefantrine per tablet) PO as initial dose and 1 tablet PO at 8 hours after initial dose, then 1 tablet PO twice daily (morning and evening) for 2 days for a total course of 6 tablets. Guidelines recommend for chloroquine-resistant infections and for infections of unknown resistance; may also use for chloroquine-sensitive infections if necessary. Not recommended for persons who have received mefloquine prophylaxis.[35401] [63990] [64059]

    For the treatment of severe malaria† prior to the availability of IV artesunate.
    Oral dosage
    Adults

    4 tablets (20 mg artemether; 120 mg lumefantrine per tablet) PO as initial dose and 4 tablets PO at 8 hours after initial dose if still needed. Discontinue when IV artesunate therapy is started.

    Children and Adolescents weighing 35 kg or more

    4 tablets (20 mg artemether; 120 mg lumefantrine per tablet) PO as initial dose and 4 tablets PO at 8 hours after initial dose if still needed. Discontinue when IV artesunate therapy is started.

    Children and Adolescents weighing 25 to 34 kg

    3 tablets (20 mg artemether; 120 mg lumefantrine per tablet) PO as initial dose and 3 tablets PO at 8 hours after initial dose if still needed. Discontinue when IV artesunate therapy is started.

    Infants and Children 2 months or older weighing 15 to 24 kg

    2 tablets (20 mg artemether; 120 mg lumefantrine per tablet) PO as initial dose and 2 tablets PO at 8 hours after initial dose if still needed. Discontinue when IV artesunate therapy is started.

    Infants and Children 2 months or older weighing 5 to 14 kg

    1 tablet (20 mg artemether; 120 mg lumefantrine per tablet) PO as initial dose and 1 tablet PO at 8 hours after initial dose if still needed. Discontinue when IV artesunate therapy is started.

    For the treatment of severe malaria† after IV artesunate therapy is completed.
    Oral dosage
    Adults

    4 tablets (20 mg artemether; 120 mg lumefantrine per tablet) PO as initial dose and 4 tablets PO at 8 hours after initial dose, then 4 tablets PO twice daily (morning and evening) for 2 days for a total course of 24 tablets.

    Children and Adolescents weighing 35 kg or more

    4 tablets (20 mg artemether; 120 mg lumefantrine per tablet) PO as initial dose and 4 tablets PO at 8 hours after initial dose, then 4 tablets PO twice daily (morning and evening) for 2 days for a total course of 24 tablets.

    Children and Adolescents weighing 25 to 34 kg

    3 tablets (20 mg artemether; 120 mg lumefantrine per tablet) PO as initial dose and 3 tablets PO at 8 hours after initial dose, then 3 tablets PO twice daily (morning and evening) for 2 days for a total course of 18 tablets.

    Infants and Children 2 months or older weighing 15 to 24 kg

    2 tablets (20 mg artemether; 120 mg lumefantrine per tablet) PO as initial dose and 2 tablets PO at 8 hours after initial dose, then 2 tablets PO twice daily (morning and evening) for 2 days for a total course of 12 tablets.

    Infants and Children 2 months or older weighing 5 to 14 kg

    1 tablet (20 mg artemether; 120 mg lumefantrine per tablet) PO as initial dose and 1 tablet PO at 8 hours after initial dose, then 1 tablet PO twice daily (morning and evening) for 2 days for a total course of 6 tablets.

    MAXIMUM DOSAGE

    Adults

    35 kg or more: 8 tablets/day PO.
    25 kg to 34 kg: 6 tablets/day PO.

    Geriatric

    35 kg or more: 8 tablets/day PO.
    25 kg to 34 kg: 6 tablets/day PO.

    Adolescents

    35 kg or more: 8 tablets/day PO.
    25 kg to 34 kg: 6 tablets/day PO.

    Children

    35 kg or more: 8 tablets/day PO.
    25 kg to 34 kg: 6 tablets/day PO.
    15 kg to 24 kg: 4 tablets/day PO.
    5 kg to 14 kg: 2 tablets/day PO.

    Infants

    at least 2 months old and 15 kg to 24 kg: 4 tablets/day PO.
    at least 2 months old and 5 kg to 14 kg: 2 tablets/day PO.
    younger than 2 months old or less than 5 kg: Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available. It appears that no dosage adjustments are needed for patients with mild to moderate impairment. Most patients with acute malaria present with some degree of related hepatic and/or renal impairment. In clinical studies, the adverse event profile did not differ in patients with mild or moderate hepatic impairment compared to patients with normal hepatic function. Caution should be used when administering artemether; lumefantrine to patients with severe hepatic impairment.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available. It appears that no dosage adjustments are needed for patients with mild to moderate impairment. Most patients with acute malaria present with some degree of related hepatic and/or renal impairment. There were few patients with severe renal impairment in clinical studies. Caution should be used when administering artemether; lumefantrine to patients with severe renal impairment.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.

    Oral Administration

    Although patients with acute malaria are frequently intolerant of food, administer artemether; lumefantrine with fluids (particularly drinks containing fats, such as milk or formula) and if possible, with a normal diet as soon as the patient can tolerate food.
    If a patient vomits within 1—2 hours of administration, repeat the dose. If the repeat dose is vomited, administer alternative antimalarial therapy.

    Oral Solid Formulations

    For patients who are unable to swallow the tablets (e.g., infants and children), the tablets may be crushed and mixed with a small amount of water (1 to 2 teaspoons or 5 to 10 mL) in a clean container immediately prior to use. Rinse the container with more water and have patient swallow the contents to ensure correct dosage delivery. The dose should be followed whenever possible by food/drink (e.g., milk, formula, pudding, broth, and porridge). Tablets can be crushed and administered in breast milk to enhance absorption in small infants.

    STORAGE

    Coartem:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Artemether; lumefantrine is metabolized primarily by CYP3A4 and is contraindicated with the concomitant use of strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort). Concurrent use of strong CYP3A4 inducers can lead to a marked decrease in artemether; lumefantrine concentrations and loss of anti-malarial efficacy.

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease, torsade de pointes

    QT prolongation is associated with many antimalarial agents (e.g., halofantrine, quinine, quinidine), including artemether; lumefantrine. The manufacturer recommends avoiding artemether; lumefantrine in patients with a history of symptomatic cardiac arrhythmias, clinically relevant bradycardia, or severe cardiac disease. Additionally, avoid artemether; lumefantrine in patients with a family history of congenital QT prolongation or sudden death, history of torsade de pointes, known electrolytic imbalances (hypokalemia or hypomagnesemia), or who are receiving other medications that prolong the QT interval. Similarly, use artemether; lumefantrine with caution in other conditions that may increase the risk of QT prolongation including congenital long QT syndrome, heart failure, myocardial infarction, hypertension, coronary artery disease, and hypocalcemia. Females, elderly patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation. Consider ECG monitoring if other QT prolonging medications must be used with or after artemether; lumefantrine treatment. Lumefantrine and its major metabolite, desbutyl-lumefantrine, have a much weaker proarrhythmic potential than halofantrine. In a healthy adult volunteer parallel group trial (n = 42), a 6-dose regimen of artemether; lumefantrine was associated with prolongation of the QT interval, with a maximum (placebo adjusted) mean change from baseline QTc of 7.5 msec (1-sided, 95% upper CI: 11 msec). In pediatric clinical trials, no patient had a QTc > 500 msec, but > 5% of patients had an increase in QTc of > 60 msec from baseline. In adult clinical trials, QTc prolongation of > 500 msec occurred in 0.3% of patients, and > 6% of patients had a QTc increase of > 60 msec from baseline. In a randomized, double-blind, double-dummy, two-period, single dose, crossover study comparing halofantrine and artemether; lumefantrine in healthy males, no statistically significant changes in QT interval were noted with artemether; lumefantrine. However, halofantrine increased mean QT interval (28 msec +/- 15.6), reaching its maximum of 448 msec (+/- 19.9) 6 hours after administration. There was also a statistically significant difference of the maximum QT intervals between treatment with artemether; lumefantrine and halofantrine (12.5 msec, p = 0.0001). In an open-label, multicenter, noncomparative trial (n = 165), artemether; lumefantrine failed to produce QT values > 500 msec, and the majority of patients had QT interval increases < 30 msec from baseline.

    Infants, neonates

    Safety and efficacy of artemether; lumefantrine have not been established in neonates or infants younger than 2 months of age or weighing less than 5 kg.

    Pregnancy

    A meta-analysis of observational studies that included over 500 first trimester exposures, observational and open-label studies that included more than 1,200 second and third-trimester exposures, and pharmacovigilance data have not established an association with artemether; lumefantrine use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes.[35401] Guidelines suggest artemether; lumefantrine may be used for the treatment of malaria in the second and third trimesters of pregnancy as well as in the first trimester of pregnancy if no other treatment options are available.[64059] Malaria during and after pregnancy increases the risk for adverse pregnancy and neonatal outcomes, including maternal anemia, severe malaria, spontaneous abortion, stillbirths, preterm delivery, low birth weight, intrauterine growth restriction, congenital malaria, and maternal and neonatal mortality.[35401]

    Breast-feeding

    There are no data on the presence of artemether or lumefantrine in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for artemether; lumefantrine and any potential adverse effects on the breast-fed infant from artemether; lumefantrine or the underlying maternal condition.[35401] Guidelines do not recommend artemether; lumefantrine for the treatment of malaria in women breast-feeding an infant weighing less than 5 kg. In general, very small amounts of antimalarial drugs are excreted in the breast milk. Because the quantity of antimalarial drugs transferred in breast milk is insufficient to provide adequate protection against malaria, an infant who requires chemoprophylaxis must receive the recommended dosages of antimalarial drugs.[63990] Tablets can be crushed and administered in breast milk to enhance absorption in small children.[48457]

    Geriatric

    Clinical studies of artemether; lumefantrine did not include a sufficient number of geriatric patients (>= 65 years) to determine differences in adverse events compared to younger patients; however, there is generally a greater frequency of decreased hepatic, renal, and cardiac function as well as concomitant diseases and drug therapy that should be considered when administering artemether; lumefantrine to an elderly patient.

    Hepatic disease, renal failure, renal impairment

    Safety and efficacy of artemether; lumefantrine therapy has not been established in patients with severe hepatic disease or severe renal impairment (e.g., renal failure); however, no dosage adjustment is necessary in mild to moderate hepatic or renal disease.

    Contraception requirements

    Artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives. Advise women with contraception requirements to use a non-hormonal contraceptive method or to add a barrier method of contraception during treatment with artemether; lumefantrine.[35401]

    ADVERSE REACTIONS

    Severe

    peptic ulcer / Delayed / 0-3.0
    proteinuria / Delayed / 0-3.0
    hemolytic anemia / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    palpitations / Early / 18.0-18.0
    hepatomegaly / Delayed / 6.0-9.0
    anemia / Delayed / 4.0-9.0
    splenomegaly / Delayed / 9.0-9.0
    elevated hepatic enzymes / Delayed / 0-4.0
    nystagmus / Delayed / 0-3.0
    ataxia / Delayed / 0-3.0
    hyperreflexia / Delayed / 0-3.0
    constipation / Delayed / 0-3.0
    hypokalemia / Delayed / 0-3.0
    thrombocytosis / Delayed / 0-3.0
    eosinophilia / Delayed / 0-3.0
    thrombocytopenia / Delayed / 0-3.0
    leukopenia / Delayed / 0-3.0
    conjunctivitis / Delayed / 0-3.0
    hematuria / Delayed / 0-3.0
    QT prolongation / Rapid / 0-1.0
    dysphagia / Delayed / 2.0

    Mild

    headache / Early / 13.0-56.0
    anorexia / Delayed / 13.0-40.0
    dizziness / Early / 4.0-39.0
    asthenia / Delayed / 5.0-38.0
    arthralgia / Delayed / 3.0-34.0
    myalgia / Early / 3.0-32.0
    fever / Early / 25.0-29.0
    nausea / Early / 5.0-26.0
    chills / Rapid / 5.0-23.0
    cough / Delayed / 6.0-23.0
    vomiting / Early / 17.0-18.0
    abdominal pain / Early / 8.0-17.0
    fatigue / Early / 3.0-17.0
    infection / Delayed / 0-17.0
    diarrhea / Early / 7.0-8.0
    insomnia / Early / 5.0-5.0
    rhinitis / Early / 4.0-4.0
    hypoesthesia / Delayed / 0-3.0
    tinnitus / Delayed / 0-3.0
    vertigo / Early / 3.0-3.0
    tremor / Early / 0-3.0
    dyspepsia / Early / 0-3.0
    malaise / Early / 3.0-3.0
    back pain / Delayed / 0-3.0
    agitation / Early / 0-3.0
    leukocytosis / Delayed / 0-3.0
    pharyngitis / Delayed / 3.0-3.0
    influenza / Delayed / 0-3.0

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Major) The barbiturates are inducers and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Acetaminophen; Butalbital; Caffeine: (Major) The barbiturates are inducers and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) The barbiturates are inducers and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity. (Moderate) Concomitant use of codeine with lumefantrine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of lumefantrine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If lumefantrine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lumefantrine is a moderate inhibitor of CYP2D6.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Artemether; lumefantrine is an inhibitor and dihydrocodeine is a substrate of the CYP2D6 isoenzyme; therefore, coadministration with acetaminophen; caffeine; dihydrocodeine may lead to increased dihydrocodeine concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Concomitant use of dihydrocodeine with lumefantrine may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of lumefantrine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If lumefantrine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Lumefantrine is a moderate inhibitor of CYP2D6.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Lumefantrine is an inhibitor and chlorpheniramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased chlorpheniramine concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Lumefantrine is an inhibitor and chlorpheniramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased chlorpheniramine concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Lumefantrine is an inhibitor and chlorpheniramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased chlorpheniramine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with lumefantrine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of lumefantrine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If lumefantrine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lumefantrine is a moderate inhibitor of CYP2D6.
    Acetaminophen; Dextromethorphan: (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Acetaminophen; Diphenhydramine: (Moderate) Lumefantrine is an inhibitor and diphenhydramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased diphenhydramine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with artemether; lumefantrine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of artemether; lumefantrine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If artemether; lumefantrine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Artemether; lumefantrine is a moderate inhibitor of CYP2D6.
    Acetaminophen; Propoxyphene: (Moderate) Lumefantrine is an inhibitor and propoxyphene is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased propoxyphene concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Acetaminophen; Tramadol: (Moderate) Lumefantrine is an inhibitor and tramadol is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased tramadol concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 is an inhibitor and artemether is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Aldesleukin, IL-2 is an inhibitor and lumefantrine is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Alfuzosin: (Major) Concurrent use of alfuzosin and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring alfuzosin must be used with or after artemether; lumefantrine treatment. Administration of artemether; lumefantrine is associated with prolongation of the QT interval. Alfuzosin has a slight QT prolonging effect, based on electrophysiology studies performed by the manufacturer. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg. (Major) Concurrent use of alfuzosin and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if alfuzosin must be used with or after artemether; lumefantrine treatment. Administration of artemether; lumefantrine is associated with prolongation of the QT interval. Alfuzosin has a slight QT prolonging effect, based on electrophysiology studies performed by the manufacturer. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg.
    Amiodarone: (Major) Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with other drugs that prolong the QT interval such as amiodarone should be avoided. Consider ECG monitoring if amiodarone must be used with or after artemether; lumefantrine treatment. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Additionally, amiodarone is a substrate and inhibitor of the CYP3A4 isoenzyme. Both components of artemether; lumefantrine are CYP3A4 substrates; therefore, concomitant use may increase the serum concentrations of artemether; lumefantrine, thereby potentiating QT prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amobarbital: (Major) The barbiturates are inducers and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Amoxapine: (Major) Because most cyclic antidepressants are partially metabolized by CYP2D6, caution is advisable during co-administration of amoxapine and potent CYP2D6 inhibitors such as artemether; lumefantrine. Elevated plasma concentrations of amoxapine may result in more pronounced anticholinergic effects and the risk of seizures may be increased.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Concurrent use of artemether; lumefantrine and clarithromycin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if clarithromycin must be used with or after artemether; lumefantrine treatment. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. Artemether; lumefantrine is also associated with a possible risk for QT prolongation and TdP. In addition, clarithromycin is an inhibitor and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased concentrations of artemether; lumefantrine.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Concurrent use of artemether; lumefantrine and clarithromycin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if clarithromycin must be used with or after artemether; lumefantrine treatment. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. Artemether; lumefantrine is also associated with a possible risk for QT prolongation and TdP. In addition, clarithromycin is an inhibitor and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased concentrations of artemether; lumefantrine.
    Amprenavir: (Moderate) Artemether is a substrate and amprenavir is an inhibitor of the CYP3A4 isoenzyme; therefore, concomitant use may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Lumefantrine is an inhibitor and amprenavir is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased amprenavir concentrations. Additionally lumefantrine is a substrate and amprenavir is an inhibitor of the CYP3A4 isoenzyme; therefore, concomitant use may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include artemether; lumefantrine.
    Apalutamide: (Severe) Concomitant use of apalutamide and artemether is contraindicated. Apalutamide is a strong inducer of CYP3A4 and artemether is a substrate of this isoenzyme; therefore, coadministration may lead to decreased artemether concentrations and possible reduction in antimalarial activity. Coadministration of another strong CYP3A4 inducer reduced the AUC of artemether and dihydroartemisinin (metabolite of artemether) by 89% and 85%, respectively. (Severe) Concomitant use of apalutamide and lumefantrine is contraindicated due to the risk of decreased lumefantrine concentrations and possible reduction in antimalarial activity. Apalutamide is a strong inducer of CYP3A4 and lumefantrine is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inducer reduced the AUC of lumefantrine by 68%.
    Apomorphine: (Major) Concurrent use of apomorphine and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if apomorphine must be used with or after artemether; lumefantrine treatment. Administration of artemether; lumefantrine is associated with prolongation of the QT interval. Limited data indicate that QT prolongation is also possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines. In one study, a single mean dose of 5.2 mg (range 2 to 10 mg) prolonged the QT interval by about 3 msec. However, large increases (> 60 msecs from pre-dose) have occurred in two patients receiving 6 mg doses. Doses <= 6 mg SC are associated with minimal increases in QTc; doses > 6 mg SC do not provide additional clinical benefit and are not recommended.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if artemether and multi-day regimens of oral aprepitant are used concurrently and monitor for an increase in artemether-related adverse effects for several days after administration of a multi-day aprepitant regimen. Artemether is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of artemether. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. (Moderate) Use caution if artemether; lumefantrine and aprepitant, fosaprepitant are used concurrently and monitor for an increase in artemether- and lumefantrine-related adverse effects for several days after administration of a multi-day aprepitant regimen. Artemether and lumefantrine are both CYP3A4 substrates. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of both artemether and lumefantrine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aripiprazole: (Major) Because both artemether; lumefantrine and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, because aripiprazole is metabolized by CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving potent inhibitors of CYP2D6 such as lumefantrine. Adults receiving 300 mg or 400 mg of Abilify Maintena should have a dose reduction to 200 mg or 300 mg, respectively, during coadministration of a potent CYP2D6 inhibitor if used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP2D6 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP2D6 inhibitors because the dose of Aristada Initio cannot be modified.
    Armodafinil: (Major) Armodafinil is an inducer of CYP3A4/5, and a reversible inhibitor of CYP2C19. Artemether is predominantly metabolized by the CYP3A4/5 isoenzyme, with lesser contributions from CYP2C19. Coadministration may lead to decreased artemether; lumefantrine concentrations and warrants caution due to a possible reduction in antimalarial activity.
    Arsenic Trioxide: (Major) Concurrent use of arsenic trioxide and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If possible, artemether; lumefantrine should be discontinued prior to initiating arsenic trioxide therapy. Consider ECG monitoring if arsenic trioxide must be used with or after artemether; lumefantrine treatment. Administration of artemether; lumefantrine is associated with prolongation of the QT interval. QT prolongation should also be expected with the administration of arsenic trioxide. Additionally, TdP and complete atrioventricular block have been reported with arsenic trioxide.
    Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have this effect. The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Consider ECG monitoring if asenapine must be used with or after artemether; lumefantrine treatment.
    Aspirin, ASA; Butalbital; Caffeine: (Major) The barbiturates are inducers and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) The barbiturates are inducers and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity. (Moderate) Concomitant use of codeine with lumefantrine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of lumefantrine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If lumefantrine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lumefantrine is a moderate inhibitor of CYP2D6.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Artemether; lumefantrine is an inhibitor and dihydrocodeine is a substrate of the CYP2D6 isoenzyme; therefore, coadministration with acetaminophen; caffeine; dihydrocodeine may lead to increased dihydrocodeine concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Concomitant use of dihydrocodeine with lumefantrine may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of lumefantrine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If lumefantrine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Lumefantrine is a moderate inhibitor of CYP2D6.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with lumefantrine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of lumefantrine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If lumefantrine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lumefantrine is a moderate inhibitor of CYP2D6.
    Atazanavir: (Moderate) Atazanavir is a substrate/inhibitor and artemether is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Atazanavir is a substrate/inhibitor and lumefantrine is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Atazanavir; Cobicistat: (Moderate) Atazanavir is a substrate/inhibitor and artemether is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Atazanavir is a substrate/inhibitor and lumefantrine is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation. (Moderate) Caution is warranted when cobicistat with artemether; lumefantrine as there is a potential for elevated artemether, lumefantrine, and cobicistat concentrations. Both artemether and lumefantrine are CYP3A4 substrate and lumefantrine is CYP2D6 inhibitor. Cobicistat is a strong inhibitor of CYP3A4 and a substrate of CYP2D6. Coadministration with another strong CYP3A4 inhibitor increased lumefantrine exposure by 1.6-fold. (Moderate) Caution is warranted when cobicistat with artemether; lumefantrine as there is a potential for elevated artemether, lumefantrine, and cobicistat concentrations. Both artemether and lumefantrine are CYP3A4 substrates and lumefantrine is CYP2D6 inhibitor. Cobicistat is a strong inhibitor of CYP3A4 and a substrate of CYP2D6. In a drug interaction study, administration of a strong CYP3A4 inhibitor, resulted in a moderate increase in exposure to artemether, DHA, and lumefantrine.
    Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Both atomoxetine and artemether; lumefantrine are considered drugs with a possible risk of torsade de pointes (TdP); therefore, the combination should be used cautiously and with close monitoring. In addition, atomoxetine is primarily metabolized by CYP2D6 and lumefantrine is a strong CYP2D6 inhibitor. In children and adolescents up to 70 kg receiving a strong CYP2D6 inhibitor or who are known CYP2D6 poor metabolizers (PMs), atomoxetine should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. In children and adolescents over 70 kg and adults receiving a strong CYP2D6 inhibitor or who are known CYP2D6 poor metabolizers, atomoxetine should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. If concurrent use is necessary, monitor for adverse effects, such as dizziness, drowsiness, nervousness, insomnia, and cardiac effects (e.g., hypertension, increased pulse rate, QT prolongation).
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) The barbiturates are inducers and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Azithromycin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), concurrent use of azithromycin with artemether; lumefantrine should be avoided. Consider ECG monitoring if azithromycin must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with prolongation of the QT interval, and rare cases of QT prolongation and TdP have been reported during post-market use of azithromycin. Although no studies have examined the effects of administering these medications together, their concurrent use may result in additive QT prolongation and should be avoided. (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), concurrent use of azithromycin with artemether; lumefantrine should be avoided. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with prolongation of the QT interval, and cases of QT prolongation and TdP have been reported during post-market use of azithromycin. Although no studies have examined the effects of administering these medications together, their concurrent use may result in additive QT prolongation and should be avoided.
    Barbiturates: (Major) The barbiturates are inducers and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Bedaquiline: (Major) Concurrent use of artemether; lumefantrine and bedaquiline should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Both drugs have been associated with prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) The barbiturates are inducers and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Bexarotene: (Major) Bexarotene is a moderate CYP3A4 inducer and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include artemether; lumefantrine.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include artemether; lumefantrine.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering artemether; lumefantrine with boceprevir due to an increased potential for artemether; lumefantrine-related adverse events. If artemether; lumefantrine dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of artemether; lumefantrine. Artemether; lumefantrine is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated artemether; lumefantrine plasma concentrations. (Moderate) Close clinical monitoring is advised when administering artemether; lumefantrine with telaprevir due to an increased potential for artemether; lumefantrine-related adverse events. If artemether; lumefantrine dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of artemether; lumefantrine. Artemether; lumefantrine is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated artemether; lumefantrine plasma concentrations.
    Bosentan: (Major) Bosentan is a substrate/inducer and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Brexpiprazole: (Major) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-half of the usual dose in patients receiving a strong CYP2D6 inhibitor and one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Artemether; lumefantrine is a strong inhibitor of CYP2D6. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. It should be noted that no dosage adjustment is needed in patients taking a strong CYP2D6 inhibitor who are receiving brexpiprazole as adjunct treatment for major depressive disorder because CYP2D6 considerations are already factored into general dosing recommendations.
    Brimonidine; Timolol: (Moderate) Lumefantrine is an inhibitor and timolol is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased timolol concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with artemether; lumefantrine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of artemether; lumefantrine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If artemether; lumefantrine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Artemether; lumefantrine is a moderate inhibitor of CYP2D6.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with artemether; lumefantrine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of artemether; lumefantrine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If artemether; lumefantrine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Artemether; lumefantrine is a moderate inhibitor of CYP2D6.
    Buprenorphine: (Major) The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If coadministration is necessary, consider ECG monitoring.
    Buprenorphine; Naloxone: (Major) The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If coadministration is necessary, consider ECG monitoring.
    Butabarbital: (Major) The barbiturates are inducers and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Carbamazepine: (Severe) Concomitant use of carbamazepine and artemether; lumefantrine is contraindicated. Carbamazepine is a substrate/inducer of CYP3A4 and both components of artemether; lumefantrine are substrates of this isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations and possible reduction in antimalarial activity.
    Carbetapentane; Chlorpheniramine: (Moderate) Lumefantrine is an inhibitor and chlorpheniramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased chlorpheniramine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Lumefantrine is an inhibitor and chlorpheniramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased chlorpheniramine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Lumefantrine is an inhibitor and diphenhydramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased diphenhydramine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with artemether; lumefantrine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of artemether; lumefantrine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If artemether; lumefantrine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Artemether; lumefantrine is a moderate inhibitor of CYP2D6.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with artemether; lumefantrine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of artemether; lumefantrine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If artemether; lumefantrine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Artemether; lumefantrine is a moderate inhibitor of CYP2D6.
    Carvedilol: (Moderate) Lumefantrine is an inhibitor and carvedilol is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased carvedilol concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Ceritinib: (Major) Avoid coadministration of ceritinib with artemether due to the risk of QT prolongation; plasma concentrations of artemether may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and periodically monitor electrolytes; also watch for artemether-related adverse reactions. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib is a strong CYP3A4 inhibitor that causes a concentration-dependent prolongation of the QT interval. Artemether is a CYP3A4 substrate that has also been associated with QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased artemether exposure by 2.3-fold. (Major) Avoid coadministration of ceritinib with lumefantrine due to the risk of QT prolongation; plasma concentrations of lumefantrine may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and periodically monitor electrolytes; also watch for lumefantrine-related adverse reactions. An interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib is a strong CYP3A4 inhibitor that causes a concentration-dependent prolongation of the QT interval. Lumefantrine is a CYP3A4 substrate that has also been associated with QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased lumefantrine exposure by 1.6-fold.
    Cevimeline: (Moderate) Lumefantrine is an inhibitor and cevimeline is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased cevimeline concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Chloramphenicol: (Moderate) Chloramphenicol is an inhibitor and artemether a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Chloramphenicol is an inhibitor and lumefantrine a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Chloroquine: (Major) Artemether; lumefantrine is associated with prolongation of the QT interval and should be avoided in combination with other QT prolonging drugs, such as chloroquine. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses.
    Chlorpheniramine: (Moderate) Lumefantrine is an inhibitor and chlorpheniramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased chlorpheniramine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with lumefantrine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of lumefantrine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If lumefantrine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lumefantrine is a moderate inhibitor of CYP2D6. (Moderate) Lumefantrine is an inhibitor and chlorpheniramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased chlorpheniramine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Chlorpheniramine; Dextromethorphan: (Moderate) Lumefantrine is an inhibitor and chlorpheniramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased chlorpheniramine concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Lumefantrine is an inhibitor and chlorpheniramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased chlorpheniramine concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Artemether; lumefantrine is an inhibitor and dihydrocodeine is a substrate of the CYP2D6 isoenzyme; therefore, coadministration with acetaminophen; caffeine; dihydrocodeine may lead to increased dihydrocodeine concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Concomitant use of dihydrocodeine with lumefantrine may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of lumefantrine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If lumefantrine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Lumefantrine is a moderate inhibitor of CYP2D6. (Moderate) Lumefantrine is an inhibitor and chlorpheniramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased chlorpheniramine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Artemether; lumefantrine is an inhibitor and dihydrocodeine is a substrate of the CYP2D6 isoenzyme; therefore, coadministration with acetaminophen; caffeine; dihydrocodeine may lead to increased dihydrocodeine concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Concomitant use of dihydrocodeine with lumefantrine may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of lumefantrine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If lumefantrine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Lumefantrine is a moderate inhibitor of CYP2D6. (Moderate) Lumefantrine is an inhibitor and chlorpheniramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased chlorpheniramine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with artemether; lumefantrine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of artemether; lumefantrine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If artemether; lumefantrine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Artemether; lumefantrine is a moderate inhibitor of CYP2D6. (Moderate) Lumefantrine is an inhibitor and chlorpheniramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased chlorpheniramine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with artemether; lumefantrine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of artemether; lumefantrine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If artemether; lumefantrine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Artemether; lumefantrine is a moderate inhibitor of CYP2D6. (Moderate) Lumefantrine is an inhibitor and chlorpheniramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased chlorpheniramine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with artemether; lumefantrine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of artemether; lumefantrine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If artemether; lumefantrine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Artemether; lumefantrine is a moderate inhibitor of CYP2D6. (Moderate) Lumefantrine is an inhibitor and chlorpheniramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased chlorpheniramine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with artemether; lumefantrine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of artemether; lumefantrine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If artemether; lumefantrine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Artemether; lumefantrine is a moderate inhibitor of CYP2D6. (Moderate) Lumefantrine is an inhibitor and chlorpheniramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased chlorpheniramine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Chlorpheniramine; Phenylephrine: (Moderate) Lumefantrine is an inhibitor and chlorpheniramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased chlorpheniramine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Lumefantrine is an inhibitor and chlorpheniramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased chlorpheniramine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Chlorpromazine: (Major) Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, such as chlorpromazine, coadministration may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with other drugs that prolong the QT interval should be avoided. Consider ECG monitoring if chlorpromazine must be used with or after artemether; lumefantrine treatment. (Major) Artemether; lumefantrine is an inhibitor of and chlorpromazine is metabolized by the CYP2D6 isoenzyme; therefore, coadministration may lead to increased chlorpromazine concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as chlorpromazine, should be avoided. Consider ECG monitoring if chlorpromazine must be used with or after artemether; lumefantrine treatment.
    Cimetidine: (Moderate) Cimetidine is an inhibitor and artemether a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Cimetidine is an inhibitor and lumefantrine a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Cinacalcet: (Moderate) Lumefantrine is an inhibitor and cinacalcet is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased cinacalcet concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Ciprofloxacin: (Major) Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, such as ciprofloxacin, coadministration may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with other drugs that prolong the QT interval should be avoided. Consider ECG monitoring if ciprofloxacin must be used with or after artemether; lumefantrine treatment. (Major) Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, such as ciprofloxacin, coadministration may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with other drugs that prolong the QT interval should be avoided. Consider ECG monitoring if ciprofloxacine must be used with or after artemether; lumefantrine treatment.
    Cisapride: (Severe) Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, such as cisapride, coadministration may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with other drugs that prolong the QT interval should be avoided. (Severe) QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. Because of the potential for TdP, use of cisapride is contraindicated with artemether; lumefantrine.
    Citalopram: (Major) Artemether; lumefantrine is an inhibitor of and citalopram is metabolized by the CYP2D6 isoenzyme; therefore, coadministration may lead to increased citalopram concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as citalopram, should be avoided. According to the manufacturer of citalopram, ECG monitoring is recommended in patients receiving concurrent drugs that prolong the QT interval.
    Clarithromycin: (Major) Concurrent use of artemether; lumefantrine and clarithromycin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if clarithromycin must be used with or after artemether; lumefantrine treatment. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. Artemether; lumefantrine is also associated with a possible risk for QT prolongation and TdP. In addition, clarithromycin is an inhibitor and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased concentrations of artemether; lumefantrine.
    Clofazimine: (Major) Avoid coadministration of clofazimine and artemether; lumefantrine due to the potential for additive QT prolongation. Monitor ECG for QT prolongation if coadministration is required. QT prolongation and torsade de pointes have been reported in patients receiving clofazimine in combination with QT prolonging medications. Artemether; lumefantrine is associated with QT interval prolongation.
    Clozapine: (Major) Artemether; lumefantrine is an inhibitor and clozapine is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased clozapine concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as clozapine, should be avoided. Consider ECG monitoring if clozapine must be used with or after artemether; lumefantrine treatment.
    Cobicistat: (Moderate) Caution is warranted when cobicistat with artemether; lumefantrine as there is a potential for elevated artemether, lumefantrine, and cobicistat concentrations. Both artemether and lumefantrine are CYP3A4 substrate and lumefantrine is CYP2D6 inhibitor. Cobicistat is a strong inhibitor of CYP3A4 and a substrate of CYP2D6. Coadministration with another strong CYP3A4 inhibitor increased lumefantrine exposure by 1.6-fold. (Moderate) Caution is warranted when cobicistat with artemether; lumefantrine as there is a potential for elevated artemether, lumefantrine, and cobicistat concentrations. Both artemether and lumefantrine are CYP3A4 substrates and lumefantrine is CYP2D6 inhibitor. Cobicistat is a strong inhibitor of CYP3A4 and a substrate of CYP2D6. In a drug interaction study, administration of a strong CYP3A4 inhibitor, resulted in a moderate increase in exposure to artemether, DHA, and lumefantrine.
    Codeine: (Moderate) Concomitant use of codeine with lumefantrine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of lumefantrine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If lumefantrine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lumefantrine is a moderate inhibitor of CYP2D6.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with lumefantrine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of lumefantrine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If lumefantrine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lumefantrine is a moderate inhibitor of CYP2D6.
    Codeine; Phenylephrine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include artemether; lumefantrine. Additionally, lumefantrine is an inhibitor and promethazine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased promethazine concentrations. Concomitant use warrants caution due to the potential for increased side effects, such as sedation. (Major) The administration of artemether is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Promethazine has been reported to cause QT prolongation. Consider ECG monitoring if co-administration is not avoidable. (Moderate) Concomitant use of codeine with lumefantrine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of lumefantrine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If lumefantrine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lumefantrine is a moderate inhibitor of CYP2D6.
    Codeine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include artemether; lumefantrine. Additionally, lumefantrine is an inhibitor and promethazine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased promethazine concentrations. Concomitant use warrants caution due to the potential for increased side effects, such as sedation. (Major) The administration of artemether is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Promethazine has been reported to cause QT prolongation. Consider ECG monitoring if co-administration is not avoidable. (Moderate) Concomitant use of codeine with lumefantrine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of lumefantrine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If lumefantrine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Lumefantrine is a moderate inhibitor of CYP2D6.
    Conivaptan: (Moderate) Conivaptan is a substrate/inhibitor and artemether is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Conivaptan is a substrate/inhibitor and lumefantrine is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Conjugated Estrogens; Medroxyprogesterone: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including progestin contraceptives (i.e. medroxyprogesterone). This may be due to a CYP3A4 interaction. Additional use of a non-hormonal method of birth control is recommended.
    Crizotinib: (Major) Avoid coadministration of lumefantrine with crizotinib if possible due to the risk of QT prolongation; an increase in lumefantrine-related adverse reactions may also occur. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both drugs have been associated with QT prolongation. Additionally, crizotinib is a moderate CYP3A inhibitor and lumefantrine is a CYP3A4 substrate. The potential for increased lumefantrine concentrations when administered with CYP3A inhibitors could further increase the risk of QT prolongation. (Major) Because both drugs have been associated with QT prolongation, avoid coadministration of artemether with crizotinib if possible; an increase in artemether-related adverse reactions may also occur. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; a dose reduction, interruption of therapy, or discontinuation of therapy may be needed for crizotinib patients if QT prolongation occurs. Crizotinib is a moderate CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Artemether is a CYP3A4 substrate that is also associated with QT prolongation.
    Danazol: (Moderate) Danazol is a inhibitor and artemether is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Danazol is a inhibitor and lumefantrine is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Darifenacin: (Moderate) Lumefantrine is an inhibitor and darifenacin is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased darifenacin concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Darunavir: (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of lumefantrine are elevated when artemether; lumefantrine, a CYP3A4 substrate, is administered concurrently with darunavir, a CYP3A4 substrate/inhibitor. Although dose adjustments are not required, concomitant use warrants caution due to the potential for increased side effects, including an increased potential for QT prolongation.
    Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat with artemether; lumefantrine as there is a potential for elevated artemether, lumefantrine, and cobicistat concentrations. Both artemether and lumefantrine are CYP3A4 substrate and lumefantrine is CYP2D6 inhibitor. Cobicistat is a strong inhibitor of CYP3A4 and a substrate of CYP2D6. Coadministration with another strong CYP3A4 inhibitor increased lumefantrine exposure by 1.6-fold. (Moderate) Caution is warranted when cobicistat with artemether; lumefantrine as there is a potential for elevated artemether, lumefantrine, and cobicistat concentrations. Both artemether and lumefantrine are CYP3A4 substrates and lumefantrine is CYP2D6 inhibitor. Cobicistat is a strong inhibitor of CYP3A4 and a substrate of CYP2D6. In a drug interaction study, administration of a strong CYP3A4 inhibitor, resulted in a moderate increase in exposure to artemether, DHA, and lumefantrine. (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of lumefantrine are elevated when artemether; lumefantrine, a CYP3A4 substrate, is administered concurrently with darunavir, a CYP3A4 substrate/inhibitor. Although dose adjustments are not required, concomitant use warrants caution due to the potential for increased side effects, including an increased potential for QT prolongation.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when cobicistat with artemether; lumefantrine as there is a potential for elevated artemether, lumefantrine, and cobicistat concentrations. Both artemether and lumefantrine are CYP3A4 substrate and lumefantrine is CYP2D6 inhibitor. Cobicistat is a strong inhibitor of CYP3A4 and a substrate of CYP2D6. Coadministration with another strong CYP3A4 inhibitor increased lumefantrine exposure by 1.6-fold. (Moderate) Caution is warranted when cobicistat with artemether; lumefantrine as there is a potential for elevated artemether, lumefantrine, and cobicistat concentrations. Both artemether and lumefantrine are CYP3A4 substrates and lumefantrine is CYP2D6 inhibitor. Cobicistat is a strong inhibitor of CYP3A4 and a substrate of CYP2D6. In a drug interaction study, administration of a strong CYP3A4 inhibitor, resulted in a moderate increase in exposure to artemether, DHA, and lumefantrine. (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of lumefantrine are elevated when artemether; lumefantrine, a CYP3A4 substrate, is administered concurrently with darunavir, a CYP3A4 substrate/inhibitor. Although dose adjustments are not required, concomitant use warrants caution due to the potential for increased side effects, including an increased potential for QT prolongation.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Ritonavir is a substrate, potent inhibitor, and inducer of the CYP3A4 isoenzyme, depending on the activity of the coadministered drug. Both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased or decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation due to increased drug concentrations, or loss of antimalarial activity depending on the artemether; lumefantrine concentrations. Consider ECG monitoring if ritonavir must be used with or after artemether; lumefantrine treatment. (Major) Ritonavir is a substrate, potent inhibitor, and inducer of the CYP3A4 isoenzyme, depending on the activity of the coadministered drug. Both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased or decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation due to increased drug concentrations, or loss of antimalarial activity depending on the artemether; lumefantrine concentrations. Consider ECG monitoring if ritonavir must be used with or after artemether; lumefantrine treatment.
    Dasatinib: (Major) Avoid the concomitant administration of dasatinib and artemether; lumefantrine due to the potential for QT prolongation. Consider ECG monitoring if coadministration cannot be avoided, In vitro studies have shown that dasatinib has the potential to prolong the QT interval. Artemether; lumefantrine is associated with prolongation of the QT interval. (Major) Avoid the concomitant administration of dasatinib and artemether; lumefantrine due to the potential for QT prolongation. Consider ECG monitoring if coadministration cannot be avoided. In vitro studies have shown that dasatinib has the potential to prolong the QT interval. Artemether; lumefantrine is associated with prolongation of the QT interval.
    Degarelix: (Major) The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be avoided with artemether; lumefantrine include degarelix. If coadministration is necessary, use with caution and consider ECG monitoring.
    Delavirdine: (Moderate) Delavirdine is a substrate/inhibitor and artemether is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Delavirdine is a substrate/inhibitor and lumefantrine is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Deutetrabenazine: (Major) Avoid concurrent use of deutetrabenazine and artemether; lumefantrine, if possible. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment. For patients taking a deutetrabenazine dosage more than 24 mg/day, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. Artemether; lumefantrine is associated with prolongation of the QT interval. (Major) Avoid concurrent use of deutetrabenazine and artemether; lumefantrine, if possible. Do not exceed 18 mg/dose or 36 mg/day of deutetrabenazine if concurrent use of deutetrabenazine with a strong CYP2D6 inhibitor, such as lumefantrine is necessary. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment. For patients taking a deutetrabenazine dosage more than 24 mg/day, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. Artemether; lumefantrine is associated with prolongation of the QT interval. Additionally, lumefantrine is a strong CYP2D6 inhibitor, and the metabolites of deutetrabenazine, alpha- and beta-HTBZ, are CYP2D6 substrates. The systemic exposure of alpha- and beta-HTBZ may be increased resulting in an increase in deutetrabenazine-related adverse reactions, like QT prolongation and drowsiness.
    Dexamethasone: (Major) Dexamethasone is a substrate/inducer and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan: (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Lumefantrine is an inhibitor and diphenhydramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased diphenhydramine concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Guaifenesin: (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include artemether; lumefantrine. Additionally, lumefantrine is an inhibitor and promethazine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased promethazine concentrations. Concomitant use warrants caution due to the potential for increased side effects, such as sedation. (Major) The administration of artemether is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Promethazine has been reported to cause QT prolongation. Consider ECG monitoring if co-administration is not avoidable. (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dextromethorphan; Quinidine: (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Artemether; lumefantrine is an inhibitor and dihydrocodeine is a substrate of the CYP2D6 isoenzyme; therefore, coadministration with acetaminophen; caffeine; dihydrocodeine may lead to increased dihydrocodeine concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Concomitant use of dihydrocodeine with lumefantrine may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of lumefantrine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If lumefantrine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Lumefantrine is a moderate inhibitor of CYP2D6.
    Diltiazem: (Moderate) Diltiazem is a substrate/inhibitor and artemether is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Diltiazem is a substrate/inhibitor and lumefantrine is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Diphenhydramine: (Moderate) Lumefantrine is an inhibitor and diphenhydramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased diphenhydramine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with artemether; lumefantrine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of artemether; lumefantrine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If artemether; lumefantrine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Artemether; lumefantrine is a moderate inhibitor of CYP2D6. (Moderate) Lumefantrine is an inhibitor and diphenhydramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased diphenhydramine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Diphenhydramine; Ibuprofen: (Moderate) Lumefantrine is an inhibitor and diphenhydramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased diphenhydramine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Diphenhydramine; Naproxen: (Moderate) Lumefantrine is an inhibitor and diphenhydramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased diphenhydramine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Diphenhydramine; Phenylephrine: (Moderate) Lumefantrine is an inhibitor and diphenhydramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased diphenhydramine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Disopyramide: (Major) Disopyramide administration is associated with QT prolongation and torsades de pointes (TdP). The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Consider ECG monitoring if disopyramide must be used with or after artemether; lumefantrine treatment.
    Dofetilide: (Major) Avoid coadministration of artemether; lumefantrine with dofetilide due to the potential for additive QT prolongation. Consider ECG monitoring if dofetilide must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with prolongation of the QT interval. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Dolasetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP) dolasetron and artemether; lumefantrine should be used together cautiously. Dolasetron has been associated with a dose-dependant prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Use of dolasetron injection for the prevention of chemotherapy-induced nausea and vomiting is contraindicated because the risk of QT prolongation is higher with the doses required for this indication; when the injection is used at lower doses (i.e., those approved for post-operative nausea and vomiting) or when the oral formulation is used, the risk of QT prolongation is lower and caution is advised. Artemether; lumefantrine is an inhibitor and dolasetron is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased dolasetron concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as dolasetron, should be avoided. Consider ECG monitoring if dolasetron must be used with or after artemether; lumefantrine treatment.
    Dolutegravir; Rilpivirine: (Major) Concurrent use of rilpivirine and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if rilpivirine must be used with or after artemether; lumefantrine treatment. Administration of artemether; lumefantrine is associated with prolongation of the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as artemether. In addition to avoiding drug interactions, the potential for torsade de pointes (TdP) can be reduced by avoiding the use of QT prolonging drugs in patients at substantial risk for TdP. Consider ECG monitoring if rilpivirine must be used with or after artemether; lumefantrine treatment.
    Donepezil: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Artemether; lumefantrine has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, co-administration of artemether; lumefantrine and donepezil could increase donepezil concentrations, potentially resulting in dose-related toxicity. Lumefantrine significantly inhibits CYP2D6, one isoenzyme partially involved in the metabolism of donepezil.
    Donepezil; Memantine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Artemether; lumefantrine has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, co-administration of artemether; lumefantrine and donepezil could increase donepezil concentrations, potentially resulting in dose-related toxicity. Lumefantrine significantly inhibits CYP2D6, one isoenzyme partially involved in the metabolism of donepezil.
    Dorzolamide; Timolol: (Moderate) Lumefantrine is an inhibitor and timolol is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased timolol concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Dronedarone: (Severe) Concomitant use of dronedarone and artemether; lumefantrine is contraindicated. Dronedarone is an inhibitor CYP3A. Artemether and lumefantrine are both substrates of CYP3A4. Coadministration of dronedarone and artemether; lumefantrine may result in elevated plasma concentrations of artemether; lumefantrine. In addition, artemether; lumefantrine has been established to have a possible risk of QT prolongation and Torsade de Pointes (TdP). Dronedarone is associated with a dose-related increase in the QTc interval. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Major) Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with droperidol include artemether; lumefantrine. Consider ECG monitoring if droperidol must be used with or after artemether; lumefantrine treatment.
    Drospirenone; Ethinyl Estradiol: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including oral contraceptives. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including oral contraceptives. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended.
    Duloxetine: (Moderate) Lumefantrine is an inhibitor and duloxetine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased duloxetine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Dutasteride; Tamsulosin: (Moderate) Use caution when administering tamsulosin with a strong CYP2D6 inhibitor such as artemether; lumefantrine. Tamsulosin is extensively metabolized by CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP2D6 inhibitor resulted in increases in tamsulosin exposure. If concomitant use in necessary, monitor patient closely for increased side effects.
    Duvelisib: (Moderate) Monitor for increased toxicity of lumefantrine, including QT prolongation, if coadministered with duvelisib. Coadministration may increase the exposure of lumefantrine. Lumefantrine is a CYP3A4 substrate; duvelisib is a moderate CYP3A4 inhibitor.
    Efavirenz: (Major) If possible, avoid coadministration of efavirenz and artemether; lumefantrine, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Artemether; lumefantrine is also associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Consider ECG monitoring if efavirenz must be used with or after artemether; lumefantrine treatment. In addition, coadministration may decrease concentrations of artemether; lumefantrine and/or dihydroartemisinin (active metabolite of artemether). The antimalarial efficacy of artemether; lumefantrine may be decreased. In a drug interaction study, when artemether; lumefantrine was co-administered with efavirenz, the Cmax and AUC of artemether; lumefantrine decreased by 21% and 51%, respectively. If these drugs are co-administered, monitor for decreased antimalarial efficacy of artemether; lumefantrine.
    Efavirenz; Emtricitabine; Tenofovir: (Major) If possible, avoid coadministration of efavirenz and artemether; lumefantrine, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Artemether; lumefantrine is also associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Consider ECG monitoring if efavirenz must be used with or after artemether; lumefantrine treatment. In addition, coadministration may decrease concentrations of artemether; lumefantrine and/or dihydroartemisinin (active metabolite of artemether). The antimalarial efficacy of artemether; lumefantrine may be decreased. In a drug interaction study, when artemether; lumefantrine was co-administered with efavirenz, the Cmax and AUC of artemether; lumefantrine decreased by 21% and 51%, respectively. If these drugs are co-administered, monitor for decreased antimalarial efficacy of artemether; lumefantrine.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) If possible, avoid coadministration of efavirenz and artemether; lumefantrine, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Artemether; lumefantrine is also associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Consider ECG monitoring if efavirenz must be used with or after artemether; lumefantrine treatment. In addition, coadministration may decrease concentrations of artemether; lumefantrine and/or dihydroartemisinin (active metabolite of artemether). The antimalarial efficacy of artemether; lumefantrine may be decreased. In a drug interaction study, when artemether; lumefantrine was co-administered with efavirenz, the Cmax and AUC of artemether; lumefantrine decreased by 21% and 51%, respectively. If these drugs are co-administered, monitor for decreased antimalarial efficacy of artemether; lumefantrine.
    Elbasvir; Grazoprevir: (Moderate) Administering artemether; lumefantrine with elbasvir; grazoprevir may result in elevated artemether; lumefantrine plasma concentrations. Artemether; lumefantrine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Major) In extensive or intermediate CYP2D6 metabolizers (EMs or IMs), coadministration of artemether; lumefantrine and eliglustat requires dosage reduction of eliglustat to 84 mg PO once daily; however, coadministration of eliglustat with both artemether; lumefantrine and a strong or moderate CYP3A inhibitor is contraindicated. Artemether; lumefantrine is a strong CYP2D6 inhibitor associated with QT prolongation. Eliglustat is a CYP2D6 and CYP3A substrate that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Coadministration of eliglustat and artemether; lumefantrine may result in additive effects on the QT interval, and potentially, increased plasma concentrations of eliglustat, further increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat with artemether; lumefantrine as there is a potential for elevated artemether, lumefantrine, and cobicistat concentrations. Both artemether and lumefantrine are CYP3A4 substrate and lumefantrine is CYP2D6 inhibitor. Cobicistat is a strong inhibitor of CYP3A4 and a substrate of CYP2D6. Coadministration with another strong CYP3A4 inhibitor increased lumefantrine exposure by 1.6-fold. (Moderate) Caution is warranted when cobicistat with artemether; lumefantrine as there is a potential for elevated artemether, lumefantrine, and cobicistat concentrations. Both artemether and lumefantrine are CYP3A4 substrates and lumefantrine is CYP2D6 inhibitor. Cobicistat is a strong inhibitor of CYP3A4 and a substrate of CYP2D6. In a drug interaction study, administration of a strong CYP3A4 inhibitor, resulted in a moderate increase in exposure to artemether, DHA, and lumefantrine.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat with artemether; lumefantrine as there is a potential for elevated artemether, lumefantrine, and cobicistat concentrations. Both artemether and lumefantrine are CYP3A4 substrate and lumefantrine is CYP2D6 inhibitor. Cobicistat is a strong inhibitor of CYP3A4 and a substrate of CYP2D6. Coadministration with another strong CYP3A4 inhibitor increased lumefantrine exposure by 1.6-fold. (Moderate) Caution is warranted when cobicistat with artemether; lumefantrine as there is a potential for elevated artemether, lumefantrine, and cobicistat concentrations. Both artemether and lumefantrine are CYP3A4 substrates and lumefantrine is CYP2D6 inhibitor. Cobicistat is a strong inhibitor of CYP3A4 and a substrate of CYP2D6. In a drug interaction study, administration of a strong CYP3A4 inhibitor, resulted in a moderate increase in exposure to artemether, DHA, and lumefantrine.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Concurrent use of rilpivirine and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if rilpivirine must be used with or after artemether; lumefantrine treatment. Administration of artemether; lumefantrine is associated with prolongation of the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as artemether. In addition to avoiding drug interactions, the potential for torsade de pointes (TdP) can be reduced by avoiding the use of QT prolonging drugs in patients at substantial risk for TdP. Consider ECG monitoring if rilpivirine must be used with or after artemether; lumefantrine treatment.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Concurrent use of rilpivirine and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if rilpivirine must be used with or after artemether; lumefantrine treatment. Administration of artemether; lumefantrine is associated with prolongation of the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as artemether. In addition to avoiding drug interactions, the potential for torsade de pointes (TdP) can be reduced by avoiding the use of QT prolonging drugs in patients at substantial risk for TdP. Consider ECG monitoring if rilpivirine must be used with or after artemether; lumefantrine treatment.
    Encainide: (Major) Artemether; lumefantrine is an inhibitor and encainide is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased encainide concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Encorafenib: (Major) Avoid coadministration of encorafenib and artemether; lumefantrine due to QT prolongation. Consider ECG monitoring if encorafenib must be used after artemether; lumefantrine treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Artemether; lumefantrine is associated with prolongation of the QT interval. (Major) Avoid coadministration of encorafenib and artemether; lumefantrine due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Artemether; lumefantrine is associated with prolongation of the QT interval.
    Entrectinib: (Major) Avoid coadministration of entrectinib with artemether; lumefantrine due to the risk of QT prolongation. Consider ECG monitoring if entrectinib must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with prolongation of the QT interval. Entrectinib has been associated with QT prolongation.
    Enzalutamide: (Severe) Coadministration of artemether with enzalutamide is contraindicated due to decreases in artemether plasma concentrations which may result in loss of antimalarial efficacy. Artemether is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exposures to artemether and dihydroartemisinin (DHA, metabolite of artemether) by 89% and 85%, respectively. (Severe) Coadministration of lumefantrine with enzalutamide is contraindicated due to decreases in lumefantrine plasma concentrations which may result in loss of antimalarial efficacy. Lumefantrine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exposure to lumefantrine by 68%.
    Eribulin: (Major) The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be avoided with artemether; lumefantrine include eribulin. If eribulin and another drug that prolongs the QT interval, such as artemether; lumefantrine must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Erythromycin: (Major) Avoid coadministration of artemether and erythromycin due to the increased potential of QT prolongation. Consider ECG monitoring if erythromycin must be used with or after artemether treatment. Additionally, erythromycin is an inhibitor of CYP3A4 and artemether is a substrate of CYP3A4; therefore, coadministration may lead to increased concentrations of artemether. (Major) Avoid coadministration of lumefantrine and erythromycin due to the increased potential of QT prolongation. Consider ECG monitoring if erythromycin must be used with or after lumefantrine treatment. Additionally, erythromycin is an inhibitor of CYP3A4 and lumefantrine is a substrate of CYP3A4; therefore, coadministration may lead to increased concentrations of lumefantrine.
    Erythromycin; Sulfisoxazole: (Major) Avoid coadministration of artemether and erythromycin due to the increased potential of QT prolongation. Consider ECG monitoring if erythromycin must be used with or after artemether treatment. Additionally, erythromycin is an inhibitor of CYP3A4 and artemether is a substrate of CYP3A4; therefore, coadministration may lead to increased concentrations of artemether. (Major) Avoid coadministration of lumefantrine and erythromycin due to the increased potential of QT prolongation. Consider ECG monitoring if erythromycin must be used with or after lumefantrine treatment. Additionally, erythromycin is an inhibitor of CYP3A4 and lumefantrine is a substrate of CYP3A4; therefore, coadministration may lead to increased concentrations of lumefantrine.
    Escitalopram: (Major) Escitalopram has been associated with QT prolongation. Coadministration with other drugs that have a possible risk for QT prolongation and torsade de pointes (TdP), such as artemether; lumefantrine, should be done with caution and close monitoring. In addition, Aatemether; lumefantrine is an inhibitor and escitalopram is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased escitalopram concentrations. (Moderate) Lumefantrine is an inhibitor and escitalopram is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased escitalopram concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Eslicarbazepine: (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Estradiol Cypionate; Medroxyprogesterone: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including progestin contraceptives (i.e. medroxyprogesterone). This may be due to a CYP3A4 interaction. Additional use of a non-hormonal method of birth control is recommended.
    Estradiol; Levonorgestrel: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including progestin contraceptives (i.e. levonorgestrel). Additional use of a non-hormonal method of birth control is recommended.
    Estradiol; Norethindrone: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including non-oral combination contraceptives, oral contraceptives, and progestin contraceptives (i.e. norethindrone). This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal treatments, including progestin-only contraceptives (e.g., norethindrone). This may be due to a CYP3A4 interaction. Additional use of a non-hormonal method of birth control is recommended when norethindrone is used for birth control. Women receiving norethindrone hormone replacement or contraceptives with artemether; lumefantrine should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers.
    Estradiol; Progesterone: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including progestin contraceptives (i.e.progesterone). This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended.
    Ethinyl Estradiol: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including oral contraceptives. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended.
    Ethinyl Estradiol; Desogestrel: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including oral contraceptives. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including oral contraceptives. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended.
    Ethinyl Estradiol; Etonogestrel: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including non-oral combination contraceptives, oral contraceptives, and progestin contraceptives (i.e. norgestrel, progesterone, etonogestrel, levonorgestrel, medroxyprogesterone, and norethindrone). This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including oral contraceptives. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended.
    Ethinyl Estradiol; Levonorgestrel: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including oral contraceptives. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including progestin contraceptives (i.e. levonorgestrel). Additional use of a non-hormonal method of birth control is recommended.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including oral contraceptives. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including progestin contraceptives (i.e. levonorgestrel). Additional use of a non-hormonal method of birth control is recommended.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including oral contraceptives. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including progestin contraceptives (i.e. levonorgestrel). Additional use of a non-hormonal method of birth control is recommended.
    Ethinyl Estradiol; Norelgestromin: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including non-oral combination contraceptives. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including oral contraceptives. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including non-oral combination contraceptives, oral contraceptives, and progestin contraceptives (i.e. norethindrone). This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including oral contraceptives. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal treatments, including progestin-only contraceptives (e.g., norethindrone). This may be due to a CYP3A4 interaction. Additional use of a non-hormonal method of birth control is recommended when norethindrone is used for birth control. Women receiving norethindrone hormone replacement or contraceptives with artemether; lumefantrine should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including non-oral combination contraceptives, oral contraceptives, and progestin contraceptives (i.e. norethindrone). This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including oral contraceptives. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal treatments, including progestin-only contraceptives (e.g., norethindrone). This may be due to a CYP3A4 interaction. Additional use of a non-hormonal method of birth control is recommended when norethindrone is used for birth control. Women receiving norethindrone hormone replacement or contraceptives with artemether; lumefantrine should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers.
    Ethinyl Estradiol; Norethindrone: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including non-oral combination contraceptives, oral contraceptives, and progestin contraceptives (i.e. norethindrone). This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including oral contraceptives. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal treatments, including progestin-only contraceptives (e.g., norethindrone). This may be due to a CYP3A4 interaction. Additional use of a non-hormonal method of birth control is recommended when norethindrone is used for birth control. Women receiving norethindrone hormone replacement or contraceptives with artemether; lumefantrine should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including non-oral combination contraceptives, oral contraceptives, and progestin contraceptives (i.e. norethindrone). This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including oral contraceptives. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal treatments, including progestin-only contraceptives (e.g., norethindrone). This may be due to a CYP3A4 interaction. Additional use of a non-hormonal method of birth control is recommended when norethindrone is used for birth control. Women receiving norethindrone hormone replacement or contraceptives with artemether; lumefantrine should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers.
    Ethinyl Estradiol; Norgestimate: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including oral contraceptives. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended.
    Ethinyl Estradiol; Norgestrel: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including oral contraceptives. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including progestin contraceptives (i.e. norgestrel). This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended.
    Etonogestrel: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including non-oral combination contraceptives, oral contraceptives, and progestin contraceptives (i.e. norgestrel, progesterone, etonogestrel, levonorgestrel, medroxyprogesterone, and norethindrone). This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended.
    Etravirine: (Major) Pharmacokinetic parameters (AUC, Cmax, Cmin) of artemether, a CYP3A4 substrate, are reduced when administered concurrently with etravirine, a CYP3A4 inducer. Although dose adjustments are not required, concomitant use warrants caution due to the potential for decreased antimalarial efficacy. (Major) Pharmacokinetic parameters (AUC, Cmax, Cmin) of lumefantrine, a CYP3A4 substrate, are reduced when administered concurrently with etravirine, a CYP3A4 inducer. Although dose adjustments are not required, concomitant use warrants caution due to the potential for decreased antimalarial efficacy.
    Ezogabine: (Major) The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be avoided with artemether; lumefantrine include ezogabine. Consider ECG monitoring if ezogabine must be used with or after artemether; lumefantrine treatment.
    Fedratinib: (Moderate) Caution and close monitoring are advised if these drugs are used together. Concomitant use of fedratinib with artemether; lumefantrine may result in increased serum concentrations of artemether; lumefantrine. Artemether and lumefantrine are substrates of the hepatic isoenzyme CYP3A4; fedratinib is a moderate inhibitor of this enzyme.
    Fingolimod: (Major) Artemether; lumefantrine is associated with QT prolongation. If possible avoid coadministration of artemether; lumefantrine and fingolimod. If concomitant use cannot be avoided, overnight monitoring with continuous ECG in a medical facility after the first fingolimod dose is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of torsades de pointes in patients with bradycardia.
    Flecainide: (Major) Artemether; lumefantrine is an inhibitor and flecainide is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased flecainide concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as flecainide should be avoided. Consider ECG monitoring if flecainide must be used with or after artemether; lumefantrine treatment. (Major) Concurrent use of flecainide and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if flecainide must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with a possible risk for QT prolongation and TdP. Flecainide, a Class IC antiarrhythmic, is also associated with a possible risk for QT prolongation and/or TdP; although, the increase in QT interval is largely due to prolongation of the QRS interval. Causality for TdP has not been established for flecainide. Additionally, artemether; lumefantrine is an inhibitor and flecainide is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased flecainide concentrations.
    Fluconazole: (Severe) Concomitant administration of fluconazole and lumefantrine is contraindicated. Fluconazole has been associated with QT prolongation and is contraindicated for use with other drugs that both prolong the QT interval and are CYP3A4 substrates, such as lumefantrine. Coadministration of fluconazole with lumefantrine may result in elevated plasma concentrations of lumefantrine, causing an increased risk for adverse events, such as QT prolongation. (Severe) The concomitant administration of fluconazole and artemether is contraindicated. Fluconazole has been associated with QT prolongation and is contraindicated for use with other drugs that both prolong the QT interval and are CYP3A4 substrates, such as artemether. Coadministration of fluconazole with artemether may result in elevated plasma concentrations of artemether as well.
    Fluoxetine: (Major) Avoid coadministration of fluoxetine and artemether; lumefantrine due to the potential for additive QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Artemether; lumefantrine is also associated with QT interval prolongation. (Moderate) Lumefantrine is an inhibitor and fluoxetine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased fluoxetine concentrations. Additionally, lumefantrine is a substrate and fluoxetine is an inhibitor of the CYP3A4 isoenzyme; therefore, concomitant use may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Fluoxetine; Olanzapine: (Major) Artemether; lumefantrine is an inhibitor and olanzapine is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased olanzapine concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval such as olanzapine should be avoided. Consider ECG monitoring if olanzapine must be used with or after artemether; lumefantrine treatment. (Major) Avoid coadministration of fluoxetine and artemether; lumefantrine due to the potential for additive QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Artemether; lumefantrine is also associated with QT interval prolongation. (Moderate) Lumefantrine is an inhibitor and fluoxetine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased fluoxetine concentrations. Additionally, lumefantrine is a substrate and fluoxetine is an inhibitor of the CYP3A4 isoenzyme; therefore, concomitant use may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Fluphenazine: (Minor) Concurrent use of fluphenazine and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if fluphenazine must be used with or after artemether; lumefantrine treatment. Administration of artemether; lumefantrine is associated with prolongation of the QT interval. Fluphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Fluvoxamine: (Major) Artemether; lumefantrine is associated with QT prolongation and should be avoided if possible in combination with other QT prolonging drugs, such as fluvoxamine. QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of fluvoxamine. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment. In addition, artemether and lumefantrine are CYP3A substrates and fluvoxamine is a moderate CYP3A4 inhibitor while lumefantrine is a CYP2D6 inhibitor and fluvoxamine is a CYP2D6 substrate. Concomitant use may lead to increased artemether; lumefantrine or fluvoxamine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Fosamprenavir: (Major) Artemether; lumefantrine is an inhibitor and fosamprenavir is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased fosamprenavir concentrations. Additionally, artemether; lumefantrine is a substrate and fosamprenavir is an inhibitor of the CYP3A4 isoenzyme; therefore, concomitant use may lead to increased artemether; lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as artemether. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Artemether; lumefantrine is also associated with prolongation of the QT interval. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment. (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as lumefantrine. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Artemether; lumefantrine is also associated with prolongation of the QT interval. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fosphenytoin: (Severe) Concomitant use of phenytoin or fosphenytoin and artemether; lumefantrine is contraindicated. Phenytoin is an inducer of CYP3A4 and both components of artemether; lumefantrine are substrates of this isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations and possible reduction in antimalarial activity.
    Galantamine: (Moderate) Lumefantrine is a potent inhibitor of CYP2D6 in vitro and galantamine is a partial substrate of CYP2D6; therefore, coadministration may lead to increased galantamine concentrations. Monitor for galantamine-related adverse effects such as nausea, vomiting, loss of appetite, diarrhea, confusion, and excessive sweating.
    Gemifloxacin: (Major) Administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Consider ECG monitoring if gemifloxacin be used with or after artemether; lumefantrine treatment. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher. (Major) Administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher. Consider ECG monitoring if gemifloxacin must be used with or after artemether; lumefantrine treatment.
    Gemtuzumab Ozogamicin: (Major) Avoid coadministration of gemtuzumab ozogamicin with artemether; lumefantrine due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Artemether; lumefantrine is also associated with QT interval prolongation.
    Gilteritinib: (Major) Avoid concomitant use of artemether; lumefantrine with gilteritinib due to the potential for additive QT prolongation. Consider ECG monitoring if gilteritinib must be used with or after artemether; lumefantrine treatment. Both artemether; lumefantrine and gilteritinib have been associated with QT prolongation.
    Glasdegib: (Major) Avoid coadministration of glasdegib with artemether due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Artemether is also associated with prolongation of the QT interval. (Major) Avoid coadministration of glasdegib with lumefantrine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Artemether; lumefantrine is also associated with prolongation of the QT interval.
    Goserelin: (Major) Avoid coadministration of artemether with goserelin if possible due to the risk of QT prolongation. Consider ECG monitoring if goserelin must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with prolongation of the QT interval. Androgen deprivation therapy (i.e., goserelin) may prolong the QT/QTc interval. (Major) Avoid coadministration of lumefantrine with goserelin if possible due to the risk of QT prolongation. Consider ECG monitoring if goserelin must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with prolongation of the QT interval. Androgen deprivation therapy (i.e., goserelin) may prolong the QT/QTc interval.
    Granisetron: (Major) Concurrent use of granisetron and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if granisetron must be used with or after artemether; lumefantrine treatment. Both granisetron and artemether; lumefantrine are associated with prolongation of the QT interval.
    Grapefruit juice: (Moderate) Grapefruit juice is a inhibitor and artemether a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Grapefruit juice is a inhibitor and lumefantrine a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with artemether; lumefantrine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of artemether; lumefantrine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If artemether; lumefantrine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Artemether; lumefantrine is a moderate inhibitor of CYP2D6.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with artemether; lumefantrine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of artemether; lumefantrine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If artemether; lumefantrine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Artemether; lumefantrine is a moderate inhibitor of CYP2D6.
    Halogenated Anesthetics: (Major) Halogenated anesthetics should be avoided with artemether; lumefantrine. Halogenated anesthetics can prolong the QT interval. The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Consider ECG monitoring if halogenated anesthetics must be used with or after artemether; lumefantrine treatment.
    Haloperidol: (Major) Artemether; lumefantrine is an inhibitor of and haloperidol is partially metabolized by the CYP2D6 isoenzyme; therefore, coadministration may lead to increased haloperidol concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as haloperidol, should be avoided. Consider ECG monitoring if haloperidol must be used with or after artemether; lumefantrine treatment.
    Histrelin: (Major) Avoid coadministration of artemether with histrelin if possible due to the risk of QT prolongation. Consider ECG monitoring if histrelin must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with prolongation of the QT interval. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval. (Major) Avoid coadministration of lumefantrine with histrelin if possible due to the risk of QT prolongation. Consider ECG monitoring if histrelin must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with prolongation of the QT interval. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with artemether; lumefantrine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of artemether; lumefantrine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If artemether; lumefantrine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Artemether; lumefantrine is a moderate inhibitor of CYP2D6.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Lumefantrine is an inhibitor and metoprolol is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased metoprolol concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Lumefantrine is an inhibitor and propranolol is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased propranolol concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with artemether; lumefantrine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of artemether; lumefantrine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If artemether; lumefantrine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Artemether; lumefantrine is a moderate inhibitor of CYP2D6.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with artemether; lumefantrine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of artemether; lumefantrine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If artemether; lumefantrine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Artemether; lumefantrine is a moderate inhibitor of CYP2D6.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with artemether; lumefantrine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of artemether; lumefantrine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If artemether; lumefantrine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Artemether; lumefantrine is a moderate inhibitor of CYP2D6.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with artemether; lumefantrine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of artemether; lumefantrine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If artemether; lumefantrine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Artemether; lumefantrine is a moderate inhibitor of CYP2D6.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with artemether; lumefantrine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of artemether; lumefantrine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If artemether; lumefantrine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Artemether; lumefantrine is a moderate inhibitor of CYP2D6.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with artemether; lumefantrine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of artemether; lumefantrine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If artemether; lumefantrine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Artemether; lumefantrine is a moderate inhibitor of CYP2D6.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and artemether; lumefantrine. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes have been reported with the use of hydroxychloroquine. Artemether; lumefantrine is associated with prolongation of the QT interval and should be avoided in combination with other QT prolonging drugs. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment. In addition, other antimalarial agents, such as hydroxychloroquine, should not be given with artemether unless there is no other treatment option because limited safety data are available. (Major) Avoid coadministration of hydroxychloroquine and artemether; lumefantrine. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes have been reported with the use of hydroxychloroquine. Artemether; lumefantrine is associated with prolongation of the QT interval and should be avoided in combination with other QT prolonging drugs. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment. In addition, other antimalarial agents, such as hydroxychloroquine, should not be given with artemether unless there is no other treatment option because limited safety data are available.
    Hydroxyzine: (Major) Avoid coadministration of hydroxyzine and artemether; lumefantrine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Monitor ECG for QT prolongation if coadministration is required. Artemether; lumefantrine is associated with QT interval prolongation. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP.
    Ibutilide: (Major) Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval. The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Consider ECG monitoring if ibutilide must be used with or after artemether; lumefantrine treatment.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with artemether, a CYP3A substrate, as artemether toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. (Moderate) Coadministration of idelalisib with artemether; lumefantrine may increase the concentrations of artemether and lumefantrine resulting in an increased incidence of adverse events (e.g., QT prolongation). Idelalisib is a strong CYP3A4 inhibitor and artemether and lumefantrine are CYP3A substrates.
    Iloperidone: (Major) Avoid coadministration of iloperidone and artemether; lumefantrine due to the potential for QT prolongation. If coadministration cannot be avoided, reduce the iloperidone dose by one-half and consider ECG monitoring. If artemether; lumefantrine is discontinued, increase the iloperidone dose to the previous level. Increased iloperidone exposure may occur with concurrent use. Iloperidone is a CYP2D6 substrate that has been associated with QT prolongation. Artemether; lumefantrine is a strong CYP2D6 inhibitor that has also been associated with QT prolongation. Coadministration of other strong CYP2D6 inhibitors increased mean steady-state peak concentrations of iloperidone and its metabolite P88, by up to 3-fold, and decreased mean steady-state peak concentrations of its metabolite P95 by one-half.
    Imatinib: (Moderate) Imatinib, STI-571 is a substrate/inhibitor and artemether a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Imatinib, STI-571 is a substrate/inhibitor and lumefantrine a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Indinavir: (Moderate) Indinavir is a substrate/inhibitor and artemether a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Indinavir is a substrate/inhibitor and lumefantrine a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with artemether; lumefantrine due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Artemether; lumefantrine is also associated with QT interval prolongation.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with artemether; lumefantrine may result in increased serum concentrations of artemether; lumefantrine. Artemether and lumefantrine are substrates of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH: (Moderate) Administering artemether with isoniazid may result in elevated artemether plasma concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation. Artemether is a substrate of CYP3A; isoniazid is a weak CYP3A inhibitor. (Moderate) Administering lumefantrine with isoniazid may result in elevated lumefantrine plasma concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation. Lumefantrine is a substrate of CYP3A; isoniazid is a weak CYP3A inhibitor.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Severe) Concomitant use of rifampin and artemether; lumefantrine is contraindicated. Rifampin is a potent inducer of CYP3A4 and both components of artemether; lumefantrine are substrates of this isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations and possible reduction in antimalarial activity. Coadministration in 6 HIV and tuberculosis co-infected adults caused reductions in the AUC of artemether, dihydroartemisinin (metabolite of artemether), and lumefantrine by 89%, 85%, and 68%, respectively. (Moderate) Administering artemether with isoniazid may result in elevated artemether plasma concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation. Artemether is a substrate of CYP3A; isoniazid is a weak CYP3A inhibitor. (Moderate) Administering lumefantrine with isoniazid may result in elevated lumefantrine plasma concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation. Lumefantrine is a substrate of CYP3A; isoniazid is a weak CYP3A inhibitor.
    Isoniazid, INH; Rifampin: (Severe) Concomitant use of rifampin and artemether; lumefantrine is contraindicated. Rifampin is a potent inducer of CYP3A4 and both components of artemether; lumefantrine are substrates of this isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations and possible reduction in antimalarial activity. Coadministration in 6 HIV and tuberculosis co-infected adults caused reductions in the AUC of artemether, dihydroartemisinin (metabolite of artemether), and lumefantrine by 89%, 85%, and 68%, respectively. (Moderate) Administering artemether with isoniazid may result in elevated artemether plasma concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation. Artemether is a substrate of CYP3A; isoniazid is a weak CYP3A inhibitor. (Moderate) Administering lumefantrine with isoniazid may result in elevated lumefantrine plasma concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation. Lumefantrine is a substrate of CYP3A; isoniazid is a weak CYP3A inhibitor.
    Itraconazole: (Major) Caution is advised when administering itraconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as lumefantrine. Both lumefantrine and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with lumefantrine (a CYP3A4 substrate) may result in elevated lumefantrine plasma concentrations. No dosage adjustments are required by the manufacturer, but patients should be monitored for adverse events, including QT prolongation. (Major) Caution is advised when administering itraconazole with drugs that are known to prolong the QT interval and are metabolized by CYP3A4, such as artemether. Both artemether and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with artemether (a CYP3A4 substrate) may result in elevated artemether plasma concentrations. No dosage adjustments are required by the manufacturer, but patients should be monitored for adverse events, including QT prolongation.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with artemether; lumefantrine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Artemether; lumefantrine is associated with prolongation of the QT interval.
    Ketoconazole: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as lumefantrine. Both lumefantrine and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with lumefantrine (a CYP3A4 substrate) results in elevated lumefantrine plasma concentrations. No dosage adjustments are required, but patients should be monitored for adverse events, including QT prolongation. (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong the QT interval and are metabolized by CYP3A4, such as artemether. Both artemether and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with artemether (a CYP3A4 substrate) results in elevated artemether plasma concentrations. No dosage adjustments are required, but patients should be monitored for adverse events, including QT prolongation.
    Lapatinib: (Major) Avoid coadministration of artemether with lapatinib if possible due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct electrolyte abnormalities prior to treatment. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Artemether; lumefantrine is also associated with prolongation of the QT interval. (Major) Avoid coadministration of lumefantrine with lapatinib if possible due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct electrolyte abnormalities prior to treatment. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Artemether; lumefantrine is also associated with prolongation of the QT interval.
    Larotrectinib: (Moderate) Administering artemether with larotrectinib may result in elevated artemether plasma concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation. Artemether is a substrate of CYP3A; larotrectinib is a weak CYP3A inhibitor. (Moderate) Administering lumefantrine with larotrectinib may result in elevated lumefantrine plasma concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation. Lumefantrine is a substrate of CYP3A; larotrectinib is a weak CYP3A inhibitor.
    Lefamulin: (Major) Avoid coadministration of lefamulin with artemether; lumefantrine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Artemether; lumefantrine is associated with prolongation of the QT interval.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with artemether due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Artemether; lumefantrine is also associated with prolongation of the QT interval and should be avoided in combination with other QT prolonging drugs. (Major) Avoid coadministration of lenvatinib with lumefantrine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Artemether; lumefantrine is also associated with prolongation of the QT interval and should be avoided in combination with other QT prolonging drugs.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of artemether; lumefantrine; monitor for potential reduction in efficacy. Lumefantrine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of artemether; lumefantrine; monitor for potential reduction in efficacy. Lumefantrine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Letermovir: (Moderate) A moderate increase in the plasma concentration of artemether may occur if given concurrently with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. No dosage adjustments are required; however, due to the potential for increased concentrations of artemether which could lead to QT prolongation, these drugs should be administered together with caution. Artemether is metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. (Moderate) A moderate increase in the plasma concentration of lumefantrine may occur if given concurrently with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. No dosage adjustments are required; however, due to the potential for increased concentrations of lumefantrine which could lead to QT prolongation, these drugs should be administered together with caution. Lumefantrine is metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Leuprolide: (Major) Avoid coadministration of artemether with leuprolide if possible due to the risk of QT prolongation. Consider ECG monitoring if leuprolide must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with prolongation of the QT interval. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval. (Major) Avoid coadministration of lumefantrine with leuprolide if possible due to the risk of QT prolongation. Consider ECG monitoring if leuprolide must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with prolongation of the QT interval. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including non-oral combination contraceptives, oral contraceptives, and progestin contraceptives (i.e. norethindrone). This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal treatments, including progestin-only contraceptives (e.g., norethindrone). This may be due to a CYP3A4 interaction. Additional use of a non-hormonal method of birth control is recommended when norethindrone is used for birth control. Women receiving norethindrone hormone replacement or contraceptives with artemether; lumefantrine should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. (Major) Avoid coadministration of artemether with leuprolide if possible due to the risk of QT prolongation. Consider ECG monitoring if leuprolide must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with prolongation of the QT interval. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval. (Major) Avoid coadministration of lumefantrine with leuprolide if possible due to the risk of QT prolongation. Consider ECG monitoring if leuprolide must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with prolongation of the QT interval. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
    Levofloxacin: (Major) Concurrent use of artemether; lumefantrine and levofloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if levofloxacin must be used with or after artemether; lumefantrine treatment. Levofloxacin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Additionally, rare cases of TdP have been spontaneously reported during postmarketing surveillance in patients receiving levofloxacin. The administration of artemether; lumefantrine is also associated with prolongation of the QT interval.
    Levonorgestrel: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including progestin contraceptives (i.e. levonorgestrel). Additional use of a non-hormonal method of birth control is recommended.
    Lithium: (Major) Lithium should be avoided with artemether; lumefantrine. Lithium has been associated with QT prolongation. The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment.
    Lofexidine: (Major) Avoid coadministration of lofexidine and artemether; lumefantrine due to the potential for additive QT prolongation and other serious adverse effects. Monitor ECG for QT prolongation and monitor for orthostatic hypotension and bradycardia if coadministration is required. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate that prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes (TdP). Artemether; lumefantrine is a CYP2D6 inhibitor associated with QT interval prolongation. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
    Long-acting beta-agonists: (Moderate) The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. This risk may be more clinically significant with long-acting beta-agonists (i.e., formoterol, arformoterol, indacaterol, olodaterol, salmeterol, umeclidinium; vilanterol) than with short-acting beta-agonists. Beta-agonists should be administered with caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Loperamide: (Major) Loperamide should be avoided in combination with artemether; lumefantrine. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment. In addition, the plasma concentrations of loperamide, a CYP2D6 substrate, may be increased when administered concurrently with lumefantrine, a potent CYP2D6 inhibitor, further increasing the risk of toxicity. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Loperamide; Simethicone: (Major) Loperamide should be avoided in combination with artemether; lumefantrine. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment. In addition, the plasma concentrations of loperamide, a CYP2D6 substrate, may be increased when administered concurrently with lumefantrine, a potent CYP2D6 inhibitor, further increasing the risk of toxicity. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Lopinavir; Ritonavir: (Major) Avoid the concomitant administration of lopinavir; ritonavir and artemether; lumefantrine. Lopinavir; ritonavir is an inhibitor of the CYP3A4 isoenzyme, and both components of artemether; lumefantrine are substrates of CYP3A4. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration with lopinavir; ritonavir may result in additive QT prolongation. Consider ECG monitoring if lopinavir; ritonavir must be used with or after artemether; lumefantrine treatment. (Major) Lopinavir; ritonavir is an inhibitor of the CYP3A4 isoenzyme, and both components of artemether; lumefantrine are substrates of CYP3A4. Furthermore, QT prolongation in patients taking lopinavir; ritonavir has been reported. Lopinavir; ritonavir should be used cautiously with other drugs that prolong the QT interval such as artemether; lumefantrine. Consider ECG monitoring if lopinavir; ritonavir must be used with or after artemether; lumefantrine treatment. (Major) Ritonavir is a substrate, potent inhibitor, and inducer of the CYP3A4 isoenzyme, depending on the activity of the coadministered drug. Both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased or decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation due to increased drug concentrations, or loss of antimalarial activity depending on the artemether; lumefantrine concentrations. Consider ECG monitoring if ritonavir must be used with or after artemether; lumefantrine treatment. (Major) Ritonavir is a substrate, potent inhibitor, and inducer of the CYP3A4 isoenzyme, depending on the activity of the coadministered drug. Both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased or decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation due to increased drug concentrations, or loss of antimalarial activity depending on the artemether; lumefantrine concentrations. Consider ECG monitoring if ritonavir must be used with or after artemether; lumefantrine treatment.
    Lumacaftor; Ivacaftor: (Severe) Concomitant use of lumacaftor; ivacaftor and artemether; lumefantrine is contraindicated. Coadministration is expected to result in subtherapeutic artemether; lumefantrine serum concentrations and a possible reduction in antimalarial activity. Artemether; lumefantrine is primarily metabolized by CYP3A4 and is also a substrate of CYP2B6, CYP2C9, and CYP2C19. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce CYP2B6 and CYP2C19, and induce and/or inhibit CYP2C9.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as artemether; lumefantrine. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Artemether is also associated with prolongation of the QT interval. (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as lumefantrine. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Lumefantrine is also associated with prolongation of the QT interval.
    Maprotiline: (Major) Artemether; lumefantrine is an inhibitor of and maprotiline is partially metabolized by the CYP2D6 isoenzyme; therefore, coadministration may lead to increased maprotiline concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as maprotiline, should be avoided. Consider ECG monitoring if maprotiline must be used with or after artemether; lumefantrine treatment.
    Medroxyprogesterone: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including progestin contraceptives (i.e. medroxyprogesterone). This may be due to a CYP3A4 interaction. Additional use of a non-hormonal method of birth control is recommended.
    Mefloquine: (Major) Mefloquine use immediately prior to lumefantrine treatment may decrease lumefantrine exposure resulting in suboptimal lumefantrine concentrations. Mefloquine causes a reduction in bile production, which is necessary for adequate lumefantrine absorption (see Pharmacokinetics). Sequential oral administration of mefloquine 12 hours prior to initiating the artemether; lumefantrine 6-dose regimen had no statistically significant effects of artemether or on the artemether/dihydroartemisinin (DHA, metabolite of artemether) ratio in 14 healthy volunteers; however, there was a 30% reduction in the Cmax and 40% reduction in the AUC of lumefantrine. Additionally, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, such as mefloquine, coadministration of such drugs may result in additive QT prolongation and should be avoided.
    Meperidine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include artemether; lumefantrine. Additionally, lumefantrine is an inhibitor and promethazine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased promethazine concentrations. Concomitant use warrants caution due to the potential for increased side effects, such as sedation. (Major) The administration of artemether is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Promethazine has been reported to cause QT prolongation. Consider ECG monitoring if co-administration is not avoidable.
    Mephobarbital: (Major) The barbiturates are inducers and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Mesoridazine: (Major) Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, such as mesoridazine, coadministration may result in additive QT prolongation. Concomitant use should be avoided.
    Mestranol; Norethindrone: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including non-oral combination contraceptives, oral contraceptives, and progestin contraceptives (i.e. norethindrone). This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including oral contraceptive. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal treatments, including progestin-only contraceptives (e.g., norethindrone). This may be due to a CYP3A4 interaction. Additional use of a non-hormonal method of birth control is recommended when norethindrone is used for birth control. Women receiving norethindrone hormone replacement or contraceptives with artemether; lumefantrine should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers.
    Methadone: (Major) Artemether; lumefantrine is an inhibitor of and methadone is partially metabolized by the CYP2D6 isoenzyme; therefore, coadministration may lead to increased methadone concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as methadone, should be avoided. Consider ECG monitoring if methadone must be used with or after artemether; lumefantrine treatment.
    Methohexital: (Major) The barbiturates are inducers and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Metoclopramide: (Major) Due to the risk of increased metoclopramide plasma concentrations and extrapyramidal adverse reactions, dose adjustments of oral metoclopramide are recommended when administered in combination with strong CYP2D6 inhibitors. In patients with gastroesophageal reflux receiving a strong CYP2D6 inhibitor or who are known CYP2D6 poor metabolizers (PMs), the recommended dose of metoclopramide is 5 mg PO four times daily or 10 mg PO three times daily. In patients with diabetic gastroparesis receiving a strong CYP2D6 inhibitor or who are known CYP2D6 poor metabolizers (PMs), the recommended dose of metoclopramide is 5 mg PO four times daily times daily. Metoclopramide is a substrate of CYP2D6 and lumefantrine is a strong CYP2D6 inhibitor.
    Metoprolol: (Moderate) Lumefantrine is an inhibitor and metoprolol is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased metoprolol concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Metronidazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include artemether; lumefantrine.
    Mexiletine: (Major) Artemether; lumefantrine is an inhibitor and mexiletine is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased mexiletine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Midostaurin: (Major) Avoid the concomitant use of midostaurin and artemether if possible; both drugs have been reported to increase the QT interval. If use of midostaurin and artemether; lumefantrine is required, consider electrocardiogram monitoring. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin and in patients who received artemether; lumefantrine. (Major) Avoid the concomitant use of midostaurin and artemether; lumefantrine if possible; both drugs have been reported to increase the QT interval. If use of midostaurin and artemether; lumefantrine is required, consider electrocardiogram monitoring. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin and in patients who received artemether; lumefantrine.
    Mifepristone: (Major) Avoid use of mifepristone with artemether; lumefantrine if possible due to increased aremether; lumefantrine exposure and the potential for resultant drug toxicity, including QT prolongation. ECG monitoring is advised if use of drugs that prolong the QT interval is medically required. Both artemether; lumefantrine and mifepristone are associated with QT prolongation. Mifepristone, when used chronically for hormonal conditions such as Cushing's syndrome, is a CYP3A4 inhibitor and is expected to significantly increase the exposure to CYP3A4 substrates, including both artemether and lumefantrine. (Moderate) Avoid use of mifepristone with artemether; lumefantrine if possible due to increased aremether; lumefantrine exposure and the potential for resultant drug toxicity, including QT prolongation. ECG monitoring is advised if use of drugs that prolong the QT interval is medically required. Both artemether; lumefantrine and mifepristone are associated with QT prolongation. Mifepristone, when used chronically for hormonal conditions such as Cushing's syndrome, is a CYP3A4 inhibitor and is expected to significantly increase the exposure to CYP3A4 substrates, including both artemether and lumefantrine.
    Mirtazapine: (Major) Artemether; lumefantrine is associated with QT prolongation and should be avoided if possible in combination with other QT prolonging drugs, such as mirtazapine. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. (Major) Artemether; lumefantrine is associated with QT prolongation and should be avoided if possible in combination with other QT prolonging drugs, such as mirtazapine. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Because llumefantrine is a CYP2D6 inhibitor and mirtazapine is partially metabolized by CYP2D6, coadministration may lead to increased mirtazapine concentrations. Monitor for mirtazapine-related side effects such as dizziness, somnolence, xerostomia, and constipation.
    Mitotane: (Severe) Concomitant use of mitotane and artemether is contraindicated. Mitotane is a strong inducer of CYP3A4 and artemether is a substrate of this isoenzyme; therefore, coadministration may lead to decreased artemether concentrations and possible reduction in antimalarial activity. Coadministration of another strong CYP3A4 inducer, rifampin, in 6 HIV and tuberculosis co-infected adults caused reductions in the AUC of artemether, dihydroartemisinin (metabolite of artemether), and lumefantrine by 89%, 85%, and 68%, respectively. (Severe) Concomitant use of mitotane and artemether; lumefantrine is contraindicated. Mitotane is a strong inducer of CYP3A4 and both components of artemether; lumefantrine are substrates of this isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations and possible reduction in antimalarial activity. Coadministration of another strong CYP3A4 inducer, rifampin, in 6 HIV and tuberculosis co-infected adults caused reductions in the AUC of artemether, dihydroartemisinin (metabolite of artemether), and lumefantrine by 89%, 85%, and 68%, respectively.
    Modafinil: (Major) Modafinil is a substrate/inducer and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Moxifloxacin: (Major) Concurrent use of artemether; lumefantrine and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if moxifloxacin must be used with or after artemether; lumefantrine treatment. Moxifloxacin has been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded. Artemether; lumefantrine is also associated with prolongation of the QT interval.
    Nafcillin: (Major) Nafcillin is an inducer and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Nebivolol: (Major) Avoid the concomitant use of nebivolol and artemether; lumefantrine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as lumefantrine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
    Nebivolol; Valsartan: (Major) Avoid the concomitant use of nebivolol and artemether; lumefantrine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as lumefantrine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
    Nefazodone: (Moderate) Nefazodone is a substrate/inhibitor and artemether a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Nefazodone is a substrate/inhibitor and lumefantrine a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Nelfinavir: (Moderate) Nelfinavir is a substrate/inhibitor and artemether a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Nelfinavir is a substrate/inhibitor and lumefantrine a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Artemether; lumefantrine should be used with caution with netupitant; palonosetron. Lumefantrine is an inhibitor of CYP2D6, and palonosetron is a substrate of the CYP2D6 isoenzyme. Coadministration may lead to increased palonosetron concentrations and serotonin-related side effects.
    Nevirapine: (Major) Nevirapine is a substrate/inducer and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Nicardipine: (Moderate) Nicardipine is a substrate/inhibitor and artemether a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Nicardipine is a substrate/inhibitor and lumefantrine a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as artemether; lumefantrine. Additionally, nilotinib is a moderate inhibitor of CYP3A4 and artemether; lumefantrine is a substrate of CYP3A4; administering these drugs together may result in increased artemether; lumefantrine levels. If the use of artemether; lumefantrine is necessary, hold nilotinib therapy. If these drugs are used together, consider an artemether; lumefantrine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Norethindrone: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including non-oral combination contraceptives, oral contraceptives, and progestin contraceptives (i.e. norethindrone). This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended. (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal treatments, including progestin-only contraceptives (e.g., norethindrone). This may be due to a CYP3A4 interaction. Additional use of a non-hormonal method of birth control is recommended when norethindrone is used for birth control. Women receiving norethindrone hormone replacement or contraceptives with artemether; lumefantrine should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers.
    Norfloxacin: (Major) Concurrent use of artemether; lumefantrine and norfloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if norfloxacin must be used with or after artemether; lumefantrine treatment. Administration of artemether; lumefantrine is associated with prolongation of the QT interval. Quinolones have also been associated with QT prolongation and TdP. For norfloxacin specifically, extremely rare cases of TdP were reported during post-marketing surveillance. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Norgestrel: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including progestin contraceptives (i.e. norgestrel). This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended.
    Octreotide: (Major) Concurrent use of octreotide and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if octreotide must be used with or after artemether; lumefantrine treatment. Administration of artemether; lumefantrine is associated with prolongation of the QT interval. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy warranting more cautious monitoring during octreotide administration in higher risk patients with cardiac disease. Since bradycardia is a risk factor for development of TdP, the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Major) Concurrent use of artemether; lumefantrine and ofloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if ofloxacin must be used with or after artemether; lumefantrine treatment. The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Some quinolones, including ofloxacin, have also been associated with QT prolongation. Additionally, post-marketing surveillance for ofloxacin has identified very rare cases of TdP.
    Olanzapine: (Major) Artemether; lumefantrine is an inhibitor and olanzapine is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased olanzapine concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval such as olanzapine should be avoided. Consider ECG monitoring if olanzapine must be used with or after artemether; lumefantrine treatment.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Ritonavir is a substrate, potent inhibitor, and inducer of the CYP3A4 isoenzyme, depending on the activity of the coadministered drug. Both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased or decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation due to increased drug concentrations, or loss of antimalarial activity depending on the artemether; lumefantrine concentrations. Consider ECG monitoring if ritonavir must be used with or after artemether; lumefantrine treatment. (Major) Ritonavir is a substrate, potent inhibitor, and inducer of the CYP3A4 isoenzyme, depending on the activity of the coadministered drug. Both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased or decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation due to increased drug concentrations, or loss of antimalarial activity depending on the artemether; lumefantrine concentrations. Consider ECG monitoring if ritonavir must be used with or after artemether; lumefantrine treatment.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Rifabutin is a substrate/inducer and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Ondansetron: (Major) Avoid coadministration due to the potential for QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Artemether; lumefantrine is associated with prolongation of the QT interval.
    Oritavancin: (Moderate) Coadministration may decrease the exposure and potential efficacy of lumefantrine. Lumefantrine is metabolized by CYP3A4. Oritavancin weakly induces CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of lack of efficacy. (Moderate) Coadministration of oritavancin and artemether; lumefantrine may result in increases or decreases in artemether exposure and may increase side effects or decrease efficacy of artemether. Artemether is primarily metabolized by CYP3A4/5, but is also metabolized by CYP2C19 and CYP2C9. Oritavancin weakly induces CYP3A4, while weakly inhibiting CYP2C19 and CYP2C9. If these drugs are administered concurrently, monitor the patient for signs of toxicity or lack of efficacy.
    Osimertinib: (Major) Avoid coadministration of artemether with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Artemether is also associated with prolongation of the QT interval. Concomitant use may increase the risk of QT prolongation. (Major) Avoid coadministration of lumefantrine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Artemether is also associated with prolongation of the QT interval. Concomitant use may increase the risk of QT prolongation.
    Oxaliplatin: (Major) Avoid coadministration of oxaliplatin and artemether if possible due to the risk of QT prolongation. If unavoidable, monitor ECGs and electrolytes periodically during therapy; correct electrolyte abnormalities prior to administration of oxaliplatin. The administration of artemether; lumefantrine is associated with prolongation of the QT interval. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in post-marketing experience. (Major) Avoid coadministration of oxaliplatin and lumefantrine if possible due to the risk of QT prolongation. If unavoidable, monitor ECGs and electrolytes periodically during therapy; correct electrolyte abnormalities prior to administration of oxaliplatin. The administration of artemether; lumefantrine is associated with prolongation of the QT interval. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in post-marketing experience.
    Oxcarbazepine: (Major) Oxcarbazepine is an inducer and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Paliperidone: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Artemether; lumefantrine is associated with prolongation of the QT interval and should be avoided in combination with other QT prolonging drugs. However, if coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. Consider ECG monitoring if paliperidone must be used with or after artemether; lumefantrine treatment.
    Palonosetron: (Major) Artemether; lumefantrine should be used with caution with netupitant; palonosetron. Lumefantrine is an inhibitor of CYP2D6, and palonosetron is a substrate of the CYP2D6 isoenzyme. Coadministration may lead to increased palonosetron concentrations and serotonin-related side effects.
    Panobinostat: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include artemether; lumefantrine.
    Pasireotide: (Major) Coadministration of artemether; lumefantrine and pasireotide may have additive effects on the prolongation of the QT interval. The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Consider ECG monitoring if pasireotide must be used with or after artemether; lumefantrine treatment.
    Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib and artemether; lumefantrine have been reported to prolong the QT interval. If pazopanib and artemether; lumefantrine must be continued, closely monitor the patient for QT interval prolongation. Consider ECG monitoring if pazopanib must be used with or after artemether; lumefantrine treatment. In addition, pazopanib is a weak inhibitor of CYP3A4 and a substrate for CYP2D6, while artemether; lumefantrine is a CYP3A4 substrate and inhibitor of CYP2D6. Coadministration may cause an increase in systemic concentrations of both drugs. Use caution when concurrent administration of artemether; lumefantrine and pazopanib is necessary.
    Penicillamine: (Severe) Antimalarials have adverse reactions similar to those of penicillamine. Concomitant use is contraindicated because of the increased risk of developing severe hematologic and renal toxicity.
    Pentamidine: (Major) Pentamidine has been associated with QT prolongation. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with pentamidine include artemether; lumefantrine. Consider ECG monitoring if pentamidine must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine.is an inhibitor and pentamidine is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased pentamidine concentrations and drug toxicity.
    Pentobarbital: (Major) The barbiturates are inducers and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Perphenazine: (Minor) Artemether; lumefantrine is an inhibitor of and perphenazine is partially metabolized by the CYP2D6 isoenzyme; therefore, coadministration may lead to increased perphenazine concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as perphenazine, should be avoided. Consider ECG monitoring if perphenazine must be used with or after artemether; lumefantrine treatment.
    Perphenazine; Amitriptyline: (Minor) Artemether; lumefantrine is an inhibitor of and perphenazine is partially metabolized by the CYP2D6 isoenzyme; therefore, coadministration may lead to increased perphenazine concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as perphenazine, should be avoided. Consider ECG monitoring if perphenazine must be used with or after artemether; lumefantrine treatment.
    Phenobarbital: (Major) The barbiturates are inducers and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Phenylephrine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include artemether; lumefantrine. Additionally, lumefantrine is an inhibitor and promethazine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased promethazine concentrations. Concomitant use warrants caution due to the potential for increased side effects, such as sedation. (Major) The administration of artemether is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Promethazine has been reported to cause QT prolongation. Consider ECG monitoring if co-administration is not avoidable.
    Phenytoin: (Severe) Concomitant use of phenytoin and artemether; lumefantrine is contraindicated. Phenytoin is an inducer of CYP3A4 and both components of artemether; lumefantrine are substrates of this isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations and possible reduction in antimalarial activity.
    Pimavanserin: (Major) Pimavanserin should be avoided in combination with artemether; lumefantrine. Pimavanserin may cause QT prolongation. The administration of artemether; lumefantrine is also associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment.
    Pimozide: (Severe) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of lumefantrine with pimozide is contraindicated.
    Pitolisant: (Major) Avoid coadministration of pitolisant with artemether; lumefantrine as concurrent use may increase the risk of QT prolongation. Consider ECG monitoring if pitolisant must be used with or after artemether; lumefantrine treatment. Pitolisant prolongs the QT interval. Artemether; lumefantrine is associated with prolongation of the QT interval.
    Posaconazole: (Severe) The concurrent use of posaconazole and artemether; lumefantrine is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of both artemether and lumefantrine. These drugs used in combination may result in elevated artemether; lumefantrine plasma concentrations, causing an increased risk for artemether; lumefantrine-related adverse events, such as QT prolongation. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as artemether; lumefantrine. (Severe) The concurrent use of posaconazole and artemether; lumefantrine is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of both artemether and lumefantrine. These drugs used in combination may result in elevated artemether; lumefantrine plasma concentrations, causing an increased risk for artemether; lumefantrine-related adverse events, such as QT prolongation. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as artemether; lumefantrine.
    Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include artemether; lumefantrine. (Moderate) Other antimalarial agents, such as primaquine, should not be given with artemether unless there is no other treatment option because limited safety data are available.
    Primidone: (Major) The barbiturates are inducers and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Procainamide: (Major) Procainamide is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Consider ECG monitoring if procainamide must be used with or after artemether; lumefantrine treatment.
    Prochlorperazine: (Minor) Concurrent use of prochlorperazine and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If coadministration is considered necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. Consider ECG monitoring if prochlorperazine must be used with or after artemether; lumefantrine treatment. Administration of artemether; lumefantrine is associated with prolongation of the QT interval. Phenothiazines, such as prochlorperazine, have also been reported to prolong the QT interval.
    Progesterone: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including progestin contraceptives (i.e.progesterone). This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended.
    Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include artemether; lumefantrine. Additionally, lumefantrine is an inhibitor and promethazine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased promethazine concentrations. Concomitant use warrants caution due to the potential for increased side effects, such as sedation. (Major) The administration of artemether is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Promethazine has been reported to cause QT prolongation. Consider ECG monitoring if co-administration is not avoidable.
    Propafenone: (Major) Artemether; lumefantrine is an inhibitor and propafenone is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased propafenone concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as propafenone, should be avoided. Consider ECG monitoring if propafenone must be used with or after artemether; lumefantrine treatment.
    Propoxyphene: (Moderate) Lumefantrine is an inhibitor and propoxyphene is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased propoxyphene concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Propranolol: (Moderate) Lumefantrine is an inhibitor and propranolol is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased propranolol concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Pyrimethamine: (Moderate) Other antimalarial agents, such as pyrimethamine, should not be given with artemether; lumefantrine unless there is no other treatment option because limited safety data are available.
    Pyrimethamine; Sulfadoxine: (Moderate) Other antimalarial agents, such as pyrimethamine, should not be given with artemether; lumefantrine unless there is no other treatment option because limited safety data are available.
    Quetiapine: (Major) Concurrent use of quetiapine and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if quetiapine must be used with or after artemether; lumefantrine treatment. Administration of artemether; lumefantrine is associated with prolongation of the QT interval. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances.
    Quinine: (Major) Concurrent use of quinine and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if quinine must be used with or after artemether; lumefantrine treatment. Quinine has been associated with prolongation of the QT interval and rare cases of TdP. Administration of artemether; lumefantrine is also associated with prolongation of the QT interval. Further, concentrations of both drugs may be elevated with concomitant use. Artemether; lumefantrine is an inhibitor and quinine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased quinine concentrations. Additionally, artemether; lumefantrine is a substrate and quinine is a substrate/inhibitor of the CYP3A4 isoenzyme; therefore, concomitant use may lead to increased concentrations.
    Rabies Vaccine: (Major) If administered concurrently, antimalarials can impair the immunologic response to the rabies vaccine, thereby, decreasing its protective effect. If possible, administration of antimalarials should be avoided during use of the rabies vaccine for postexposure prophylaxis. When antimalarials must be administered to persons also receiving the rabies vaccine for postexposure prophylaxis, a serum rabies antibody titer should be obtained on day 14 (day of the 4th vaccination) to ensure an acceptable antibody response has been induced.
    Ranolazine: (Major) Artemether; lumefantrine is an inhibitor and ranolazine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased ranolazine concentrations. Additionally, artemether; lumefantrine is a substrate and ranolazine is an inhibitor of the CYP3A4 isoenzyme; therefore, concomitant use may lead to increased artemether; lumefantrine concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval such as ranolazine should be avoided. Consider ECG monitoring if ranolazine must be used with or after artemether; lumefantrine treatment.
    Ribociclib: (Major) Avoid coadministration of ribociclib with artemether due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of artemether may also be increased resulting in an increase in artemether-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Artemether is a CYP3A4 substrate that has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased artemether exposure by 2.3-fold. (Major) Avoid coadministration of ribociclib with lumefantrine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of lumefantrine may also be increased resulting in increase in lumefantrine-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Lumefantrine is a CYP3A4 substrate that is also associated with prolongation of the QT interval. Concomitant use may increase the risk for QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased lumefantrine exposure by 1.6-fold.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with artemether due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of artemether may also be increased resulting in an increase in artemether-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Artemether is a CYP3A4 substrate that has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased artemether exposure by 2.3-fold. (Major) Avoid coadministration of ribociclib with lumefantrine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of lumefantrine may also be increased resulting in increase in lumefantrine-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Lumefantrine is a CYP3A4 substrate that is also associated with prolongation of the QT interval. Concomitant use may increase the risk for QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased lumefantrine exposure by 1.6-fold.
    Rifabutin: (Major) Rifabutin is a substrate/inducer and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Rifampin: (Severe) Concomitant use of rifampin and artemether; lumefantrine is contraindicated. Rifampin is a potent inducer of CYP3A4 and both components of artemether; lumefantrine are substrates of this isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations and possible reduction in antimalarial activity. Coadministration in 6 HIV and tuberculosis co-infected adults caused reductions in the AUC of artemether, dihydroartemisinin (metabolite of artemether), and lumefantrine by 89%, 85%, and 68%, respectively.
    Rifapentine: (Severe) Concomitant use of rifapentine and artemether; lumefantrine is contraindicated. Rifapentine is a potent inducer of CYP3A4 and both components of artemether; lumefantrine are substrates of this isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations and possible reduction in antimalarial activity.
    Rilpivirine: (Major) Concurrent use of rilpivirine and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if rilpivirine must be used with or after artemether; lumefantrine treatment. Administration of artemether; lumefantrine is associated with prolongation of the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as artemether. In addition to avoiding drug interactions, the potential for torsade de pointes (TdP) can be reduced by avoiding the use of QT prolonging drugs in patients at substantial risk for TdP. Consider ECG monitoring if rilpivirine must be used with or after artemether; lumefantrine treatment.
    Risperidone: (Major) Concomitant use of drugs with a possible risk of QT prolongation and torsade de pointes, including artemether; lumefantrine and risperidone, should be avoided if possible. Consider ECG monitoring if risperidone must be used with artemether; lumefantrine.
    Ritonavir: (Major) Ritonavir is a substrate, potent inhibitor, and inducer of the CYP3A4 isoenzyme, depending on the activity of the coadministered drug. Both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased or decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation due to increased drug concentrations, or loss of antimalarial activity depending on the artemether; lumefantrine concentrations. Consider ECG monitoring if ritonavir must be used with or after artemether; lumefantrine treatment. (Major) Ritonavir is a substrate, potent inhibitor, and inducer of the CYP3A4 isoenzyme, depending on the activity of the coadministered drug. Both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased or decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation due to increased drug concentrations, or loss of antimalarial activity depending on the artemether; lumefantrine concentrations. Consider ECG monitoring if ritonavir must be used with or after artemether; lumefantrine treatment.
    Romidepsin: (Major) Concurrent use of romidepsin and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If these drugs must be coadministered, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Both romidepsin and artemether; lumefantrine are associated with prolongation of the QT interval.
    Saquinavir: (Severe) The concurrent use of saquinavir boosted with ritonavir and artemether; lumefantrine should be avoided if possible due to the potential for life threatening arrhythmias such as torsades de pointes TdP). Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of both components of artemether; lumefantrine. During coadministration, elevated serum concentrations of artemether; lumefantrine can occur; thus, caution is warrented due to the potential for increased side effects, including QT prolongation. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as artemether; lumefantrine. If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring. (Major) The concurrent use of saquinavir boosted with ritonavir and artemether; lumefantrine should be avoided if possible due to the potential for life threatening arrhythmias such as torsades de pointes (TdP). Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of both components of artemether; lumefantrine. During coadministration, elevated serum concentrations of artemether; lumefantrine can occur; thus, caution is warrented due to the potential for increased side effects, including QT prolongation. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as artemether; lumefantrine. If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring (see Saquinavir Contraindications).
    Secobarbital: (Major) The barbiturates are inducers and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Segesterone Acetate; Ethinyl Estradiol: (Major) Although no formal drug interaction studies have been performed, the manufacturer states that artemether; lumefantrine may reduce the effectiveness of hormonal contraceptives, including oral contraceptives. This may be due to a CYP3A4 interaction. Artemether; lumefantrine is a substrate and ethinyl estradiol is a substrate/inhibitor of the CYP3A4 isoenzyme. Additional use of a non-hormonal method of birth control is recommended.
    Sertraline: (Major) Avoid coadministration of artemether; lumefantrine with sertraline due to the potential for additive QT prolongation. Consider ECG monitoring if sertraline must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with prolongation of the QT interval. QTc prolongation and torsade de pointes (TdP) have been reported during postmarketing use of sertraline; most cases had confounding risk factors. The risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure).
    Short-acting beta-agonists: (Minor) The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. This risk may be more clinically significant with long-acting beta-agonists (i.e., formoterol, arformoterol, indacaterol, olodaterol, salmeterol, umeclidinium; vilanterol) than with short-acting beta-agonists. Beta-agonists should be administered with caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Simeprevir: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of artemether; lumefantrine, which is a CYP3A4 substrate. Monitor patients for adverse effects of artemether; lumefantrine, such as QT prolongation.
    Siponimod: (Major) Avoid coadministration of siponimod and artemether; lumefantrine due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Artemether; lumefantrine is associated with QT interval prolongation.
    Solifenacin: (Major) Solifenacin should be avoided with artemether; lumefantrine. Solifenacin has been associated with dose-dependent prolongation of the QT interval. Torsades de pointes (TdP) has been reported with post-marketing use, although causality was not determined. The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Consider ECG monitoring if solifenacin must be used with or after artemether; lumefantrine treatment.
    Sorafenib: (Major) Avoid coadministration of artemether with sorafenib due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Artemether; lumefantrine is associated with prolongation of the QT interval. Sorafenib has also been associated with QT prolongation. (Major) Avoid coadministration of lumefantrine with sorafenib due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Artemether; lumefantrine is associated with prolongation of the QT interval. Sorafenib has also been associated with QT prolongation.
    Sotalol: (Major) Sotalol administration is associated with QT prolongation and torsades de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment. The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Consider ECG monitoring if sotalol must be used with or after artemether; lumefantrine treatment.
    Sparfloxacin: (Major) Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, such as sparfloxacin, coadministration may result in additive QT prolongation. Concomitant use should be avoided.
    St. John's Wort, Hypericum perforatum: (Severe) Concomitant use of St. John's wort, Hypericum perforatum and artemether; lumefantrine is contraindicated. St. John's wort is an inducer of CYP3A4 and both components of artemether; lumefantrine are substrates of this isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations and possible reduction in antimalarial activity.
    Sunitinib: (Major) Avoid coadministration of artemether with sunitinib due to the risk of QT prolongation. If concomitant use is unavoidable, consider ECG monitoring. Sunitinib can cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including torsades de points (TdP). Artemether; lumefantrine is also associated with prolongation of the QT interval. (Major) Avoid coadministration of lumefantrine with sunitinib due to the risk of QT prolongation. If concomitant use is unavoidable, consider ECG monitoring. Sunitinib can cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including torsades de points (TdP). Artemether; lumefantrine is also associated with prolongation of the QT interval.
    Tacrolimus: (Major) Concurrent use of tacrolimus and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If tacrolimus must be coadministered with substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, such as artemether; lumefantrine, consider reducing the tacrolimus dose, closely monitor tacrolimus whole blood concentrations, and monitor for QT prolongation. Consider ECG monitoring if tacrolimus must be used with or after artemether; lumefantrine treatment.
    Tamoxifen: (Major) Avoid coadministration of tamoxifen with artemether due to an increased risk of QT prolongation. Consider ECG monitoring if tamoxifen must be used with or after artemether treatment. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Artemether; lumefantrine is also associated with prolongation of the QT interval. Concomitant use may increase the risk of QT prolongation.
    Tamsulosin: (Moderate) Use caution when administering tamsulosin with a strong CYP2D6 inhibitor such as artemether; lumefantrine. Tamsulosin is extensively metabolized by CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP2D6 inhibitor resulted in increases in tamsulosin exposure. If concomitant use in necessary, monitor patient closely for increased side effects.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering artemether with telaprevir due to an increased potential for artemether-related adverse events. If artemether dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of artemether. Artemether is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated artemether plasma concentrations.
    Telavancin: (Major) Concurrent use of telavancin and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if telavancin must be used with or after artemether; lumefantrine treatment. Both telavancin and artemether; lumefantrine are associated with prolongation of the QT interval.
    Telithromycin: (Major) Concurrent use of telithromycin and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if telithromycin must be used with or after artemether; lumefantrine treatment. Telithromycin is associated with QT prolongation and TdP and is a strong inhibitor of the CYP3A4 isoenzyme. Coadministration with other drugs that prolong the QT interval and are CYP3A4 substrates, such as artemether; lumefantrine, may result in increased concentrations of those drugs and an increased risk of adverse reactions, such as QT prolongation.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and artemether is necessary, as the systemic exposure of artemether may be decreased resulting in reduced antimalarial efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of artemether; consider increasing the dose of artemether if necessary. Artemether is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. (Moderate) Use caution if coadministration of telotristat ethyl and lumefantrine is necessary, as the systemic exposure of lumefantrine may be decreased resulting in reduced antimalarial efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of lumefantrine; consider increasing the dose of lumefantrine if necessary. Lumefantrine is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Tetrabenazine: (Major) Artemether; lumefantrine is an inhibitor and tetrabenazine is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased tetrabenazine concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval such as tetrabenazine should be avoided. Consider ECG monitoring if tetrabenazine must be used with or after artemether; lumefantrine treatment.
    Thiopental: (Major) The barbiturates are inducers and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Thioridazine: (Severe) The concomitant use of artemether; lumefantrine and thioridazine is contraindicated. Artemether; lumefantrine is an inhibitor and thioridazine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased thioridazine concentrations. Furthermore, thioridazine is contraindicated with CYP2D6 inhibitors due to the potential for QT prolongation. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Timolol: (Moderate) Lumefantrine is an inhibitor and timolol is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased timolol concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Tipranavir: (Moderate) Tipranavir is a substrate and a potent inhibitor and artemether a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Tipranavir is a substrate and a potent inhibitor and lumefantrine a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Tolterodine: (Major) Artemether; lumefantrine is an inhibitor and tolterodine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased tolterodine concentrations. Concomitant use warrants caution due to the potential for increased side effects. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as tolterodine, should be avoided. Consider ECG monitoring if tolterodine must be used with or after artemether; lumefantrine treatment.
    Toremifene: (Major) Avoid coadministration of artemether with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Artemether; lumefantrine is also associated with prolongation of the QT interval. (Major) Avoid coadministration of lumefantrine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Artemether; lumefantrine is also associated with prolongation of the QT interval.
    Tramadol: (Moderate) Lumefantrine is an inhibitor and tramadol is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased tramadol concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Trazodone: (Major) Avoid coadministration of trazodone and artemether; lumefantrine. The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Consider ECG monitoring if trazodone must be used with or after artemether; lumefantrine treatment.
    Tricyclic antidepressants: (Major) Artemether; lumefantrine is an inhibitor and the tricyclic antidepressants are substrates of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased tricyclic antidepressant concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval such as tricyclic antidepressants should be avoided. Consider ECG monitoring if tricyclic antidepressants must be used with or after artemether; lumefantrine treatment.
    Trifluoperazine: (Minor) Concurrent use of trifluoperazine and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if trifluoperazine must be used with or after artemether; lumefantrine treatment. Trifluoperazine, a phenothiazine, is associated with a possible risk for QT prolongation. Administration of artemether; lumefantrine is also associated with prolongation of the QT interval.
    Triptorelin: (Major) Avoid coadministration of artemether with triptorelin if possible due to the risk of QT prolongation. Consider ECG monitoring if triptorelin must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with prolongation of the QT interval. Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval. (Major) Avoid coadministration of lumefantrine with triptorelin if possible due to the risk of QT prolongation. Consider ECG monitoring if triptorelin must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with prolongation of the QT interval. Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval.
    Valbenazine: (Major) Consider reducing the dose of valbenazine, based on tolerability, during co-administration with a strong CYP2D6 inhibitor, such as lumefantrine. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, concentrations of the active metabolite of valbenazine may be higher in patients taking a strong CYP2D6 inhibitor and QT prolongation may become clinically significant.
    Vandetanib: (Major) Avoid coadministration of vandetanib with artemether; lumefantrine due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Artemether; lumefantrine is also associated with prolongation of the QT interval.
    Vardenafil: (Major) Concurrent use of vardenafil and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if vardenafil must be used with or after artemether; lumefantrine treatment. Administration of artemether; lumefantrine is associated with prolongation of the QT interval. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil have also produced increases in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction).
    Vemurafenib: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as artemether; lumefantrine, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, artemether is a substrate of CYP2C9 and 3A4, while lumefantrine is a substrate of CYP3A4. Vemurafenib is a CYP2C9 inhibitor and CYP3A4 substrate/inducer. Altered concentrations of artemether; lumefantrine may increase side effects or decrease the potency of the antimicrobial effect. Caution is warranted with coadministration.
    Venlafaxine: (Major) Artemether; lumefantrine is an inhibitor of and venlafaxine is metabolized by the CYP2D6 isoenzyme; therefore, coadministration may lead to increased venlafaxine concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as venlafaxine, should be avoided. Consider ECG monitoring if venlafaxine must be used with or after artemether; lumefantrine treatment.
    Voriconazole: (Major) Avoid coadministration of voriconazole with artemether due to an increased risk for QT prolongation and torsade de pointes (TdP). If coadministration cannot be avoided, consider ECG monitoring. Systemic exposure of artemether may also be increased resulting in an increase in artemether-related adverse reactions. Voriconazole is a strong CYP3A4 inhibitor that has been associated with rare cases of torsade de pointes, cardiac arrest, and sudden death. Artemether is a CYP3A4 substrate that has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased artemether exposure by 2.3-fold. (Major) Avoid coadministration of voriconazole with lumefantrine due to an increased risk for QT prolongation and torsade de pointes (TdP). If coadministration cannot be avoided, consider ECG monitoring. Systemic exposure of lumefantrine may also be increased resulting in an increase in lumefantrine-related adverse reactions. Voriconazole is a strong CYP3A4 inhibitor that has been associated with rare cases of torsade de pointes, cardiac arrest, and sudden death. lumefantrine is a CYP3A4 substrate that has also been associated with QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased lumefantrine exposure by 1.6-fold. No dosage adjustments are required by the manufacturer, but patients should be monitored for adverse events, including QT prolongation.
    Vorinostat: (Major) The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, such as vorinostat, coadministration may result in additive QT prolongation and should be avoided. Consider ECG monitoring if vorinostat must be used with or after artemether; lumefantrine treatment.
    Vortioxetine: (Major) Concurrent use of lumefantrine and vortioxetine may result in increased plasma concentrations of vortioxetine due to CYP2D6 inhibition by artemether; lumefantrine. Because the primary isoenzyme involved in the metabolim of vortioxetine is CYP2D6, the manufacturer recommends a reduction in the vortioxetine dose by one-half during co-administration with strong inhibitors of CYP2D6. The vortioxetine dose should be increased to the original level when the CYP2D6 inhibitor is discontinued.
    Zafirlukast: (Moderate) Zafirlukast is a inhibitor and artemether a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Zafirlukast is a inhibitor and lumefantrine a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Ziprasidone: (Major) Concomitant use of ziprasidone and artemether; lumefantrine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Artemether; lumefantrine is associated with prolongation of the QT interval and should be avoided in combination with other QT prolonging drugs. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment.

    PREGNANCY AND LACTATION

    Pregnancy

    A meta-analysis of observational studies that included over 500 first trimester exposures, observational and open-label studies that included more than 1,200 second and third-trimester exposures, and pharmacovigilance data have not established an association with artemether; lumefantrine use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes.[35401] Guidelines suggest artemether; lumefantrine may be used for the treatment of malaria in the second and third trimesters of pregnancy as well as in the first trimester of pregnancy if no other treatment options are available.[64059] Malaria during and after pregnancy increases the risk for adverse pregnancy and neonatal outcomes, including maternal anemia, severe malaria, spontaneous abortion, stillbirths, preterm delivery, low birth weight, intrauterine growth restriction, congenital malaria, and maternal and neonatal mortality.[35401]

    There are no data on the presence of artemether or lumefantrine in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for artemether; lumefantrine and any potential adverse effects on the breast-fed infant from artemether; lumefantrine or the underlying maternal condition.[35401] Guidelines do not recommend artemether; lumefantrine for the treatment of malaria in women breast-feeding an infant weighing less than 5 kg. In general, very small amounts of antimalarial drugs are excreted in the breast milk. Because the quantity of antimalarial drugs transferred in breast milk is insufficient to provide adequate protection against malaria, an infant who requires chemoprophylaxis must receive the recommended dosages of antimalarial drugs.[63990] Tablets can be crushed and administered in breast milk to enhance absorption in small children.[48457]

    MECHANISM OF ACTION

    Artemether and lumefantrine are blood schizonticides; however, the exact mechanisms of action are unclear. Artemether and lumefantrine are active against the erythrocytic stages of Plasmodium falciparum and Plasmodium vivax. Both artemether and lumefantrine have been shown to inhibit nucleic acid and protein synthesis. In studies with mixed infections, data indicate that there is rapid clearance of most Plasmodium species from the blood; however, there is no effect on hypnozoites, the liver dormant forms of P. vivax or P. ovale.
     
    The antimalarial activity of artemether may involve free radical damage to membrane systems in the parasite during the asexual developmental states. The release of these free radicals may be catalyzed by intraparasitic iron and/or heme. Spectrophotometric studies have shown disruption of the porphyrin ring, likely due to oxidative degradation. Artemether is mostly converted to dihydroartemisinin (DHA), which is an active metabolite that is more effective than the parent drug. A portion of the antimalarial activity of artemether and DHA may result from the production of free radicals resulting from the iron-catalyzed cleavage of the artemisinin endoperoxide bridge in the parasite food vacuole. However, nonspecific oxidative damage may not fully explain the antimalarial effect of the artemisinin class ; other intraparasitic targets may be affected by the theoretical production of carbon-centered free radicals, rather than oxygen free radicals. Additionally, there is gametocytocidal activity that may reduce the rate of gametocyte carriers after successful treatment.
     
    The mechanism of lumefantrine is less clear; however, available data suggest that it may inhibit the formation of beta-hematin by forming a complex with hemin. This may inhibit the parasite's ability to detoxify free heme, which is a necessary step after the parasite's degradation of human hemoglobin.
     
    Artemether has a rapid onset to control parasitemia and fever; however, the recrudescence rate is high (more than 40%), which is likely due to the drug's short half-life. Combining artemether with lumefantrine (a long-acting agent) increases the cure rate compared to artemether monotherapy. The 28-day cure rate for the 6-dose artemether; lumefantrine regimen was 74.1% to 90.2% in clinical trials.
     
    In population pharmacokinetic/pharmacodynamic modeling, the area under the curve (AUC) was identified as the key parameter influencing the 28-day cure rate.
     
    Strains of P. falciparum with a moderate decrease in susceptibility to artemether or lumefantrine alone can be selected in vitro or in vivo, but not maintained in the case of artemether. Alterations in some genetic regions of P. falciparum [multidrug resistant 1 (pfmdr1), chloroquine resistance transporter (pfcrt), and kelch 13 (K13)] have been reported. The clinical relevance of these findings is not known.

    PHARMACOKINETICS

    Artemether; lumefantrine is administered orally as a fixed dose tablet.
    Artemether: Artemether is highly bound to human serum proteins in vitro (95.4%), and its active metabolite, dihydroartemisinin (DHA), is bound to human serum proteins to a lesser extent (47—76%). Protein binding to human plasma proteins is linear. Artemether is rapidly eliminated from plasma with a half-life of 2—3 hours. The main route of metabolism is via the CYP3A4/5 isoenzymes. The biologically active metabolite, DHA, is formed primarily via CYP3A4/5 with lesser contributions from CYP2B6, CYP2C9, and CYP2C19. In vitro studies showed no significant inhibition of the following CYP isoenzymes: CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, CYP4A9/11. After repeated artemether; lumefantrine administration, systemic exposure to artemether significantly decreased, while DHA concentrations increased. The artemether/DHA AUC ratio was 1.2 after one dose, but 0.3 after all 6 doses, suggesting possible induction of the CYP3A4/5. Urinary excretion studies have not been conducted in humans. In animals, no unchanged artemether was excreted in urine, but multiple metabolites were detected.
    Lumefantrine: Lumefantrine is highly lipophilic. Lumefantrine is highly bound to human serum proteins in vitro (99.7%). The protein binding to human plasma proteins is linear. The half-life of lumefantrine is 3—6 days. Due to this slow elimination, lumefantrine exposure increases after each dose of artemether; lumefantrine and reaches a peak on day 3 of therapy. Lumefantrine is N-debutylated; it is mainly catalyzed by the CYP3A4 isoenzyme to desbutyl-lumefantrine. In animal studies, glucuronidation of lumefantrine takes place directly after oxidative biotransformation. In vitro, lumefantrine significantly inhibits the CYP2D6 isoenzyme at therapeutic concentrations. Lumefantrine is not eliminated renally; however, unchanged drug has been noted in the feces. Some metabolites are excreted with bile, though they appear to be hydrolyzed in the gut, releasing lumefantrine.

    Oral Route

    Artemether: After oral administration of artemether; lumefantrine, artemether is rapidly absorbed, reaching a peak plasma concentration in approximately 2 hours. Food (a standard FDA high-fat breakfast) enhances absorption and bioavailability of artemether 2- to 3-fold compared to fasted conditions. The active metabolite, dihydroartemisinin (DHA), also reaches a peak plasma concentration approximately 2 hours after administration. After administration of the 6-dose regimen, the artemether mean Cmax is 186 ng/mL (+/- 125 ng/mL) and the DHA mean Cmax is 101 ng/mL (+/- 58 ng/mL) in adults.
    Lumefantrine: Lumefantrine is highly lipophilic. The absorption is slower and starts after a lag-time of up to 2 hours, reaching a peak plasma concentration approximately 6—8 hours after administration. Food (a standard FDA high-fat breakfast) enhances absorption and bioavailability of lumefantrine 16-fold as compared to fasted conditions. After administration of the 6-dose regimen, the lumefantrine mean Cmax is 5.6—9 mcg/mL and the mean AUC is 410—561 mcg x hour/mL in adults.