Artemether and lumefantrin: Difference between revisions

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|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Artemether and lumefantrin in adult patients.
|fdaLIADAdult====Administration Instructions===
*Coartem Tablets should be taken with food. Patients with acute malaria are frequently averse to food. Patients should be encouraged to resume normal eating as soon as food can be tolerated since this improves absorption of artemether and lumefantrine.
*For patients who are unable to swallow the tablets such as infants and children, Coartem Tablets may be crushed and mixed with a small amount of water (one to two teaspoons) in a clean container for administration immediately prior to use. The container can be rinsed with more water and the contents swallowed by the patient. The crushed tablet preparation should be followed whenever possible by food/drink (e.g., milk, formula, pudding, broth, and porridge).
*In the event of vomiting within 1 to 2 hours of administration, a repeat dose should be taken. If the repeat dose is vomited, the patient should be given an alternative antimalarial for treatment.
 
===Dosage in Adult Patients (>16 years of age)===
*A 3-day treatment schedule with a total of 6 doses is recommended for adult patients with a bodyweight of 35 kg and above:
*Four tablets as a single initial dose, 4 tablets again after 8 hours and then 4 tablets twice daily (morning and evening) for the following two days (total course of 24 tablets).
*For patients weighing less than 35 kg, see '''Dosage in Pediatric Patients'''.
 
===Dosage in Pediatric Patients===
'''A 3-day treatment schedule with a total of 6 doses is recommended as below:'''
*5 kg to less than 15 kg bodyweight: One tablet as an initial dose, 1 tablet again after 8 hours and then 1 tablet twice daily (morning and evening) for the following two days (total course of 6 tablets).
*15 kg to less than 25 kg bodyweight: Two tablets as an initial dose, 2 tablets again after 8 hours and then 2 tablets twice daily (morning and evening) for the following two days (total course of 12 tablets).
*25 kg to less than 35 kg bodyweight: Three tablets as an initial dose, 3 tablets again after 8 hours and then 3 tablets twice daily (morning and evening) for the following two days (total course of 18 tablets).
*35 kg bodyweight and above: Four tablets as a single initial dose, 4 tablets again after 8 hours and then 4 tablets twice daily (morning and evening) for the following two days (total course of 24 tablets).
 
===Dosage in Patients with Hepatic or Renal Impairment===
*No specific pharmacokinetic studies have been carried out in patients with hepatic or renal 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. No specific dose adjustments are needed for patients with mild or moderate hepatic impairment.
*In clinical studies, the adverse event profile did not differ in patients with mild or moderate renal impairment compared to patients with normal renal function. There were few patients with severe renal impairment in clinical studies. There is no significant renal excretion of lumefantrine, artemether and dihydroartemisinin (DHA) in healthy volunteers and while clinical experience in this population is limited, no dose adjustment is recommended.
*Caution should be exercised when administering Coartem Tablets in patients with severe hepatic or renal impairment.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Artemether and Lumefantrin in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Artemether and lumefantrin in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Artemether and lumefantrin in adult patients.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Artemether and lumefantrin in pediatric patients.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Artemether and lumefantrin in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Artemether and lumefantrin in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Artemether and lumefantrin in pediatric patients.
|contraindications=====Hypersensitivity====
|contraindications=====Hypersensitivity====
*Known hypersensitivity to artemether, lumefantrine, or to any of the excipients of Coartem Tablets.
*Known hypersensitivity to artemether, lumefantrine, or to any of the excipients of [[Artemether]]/[[Lumefantrine]] Tablets.


====Strong CYP3A4 Inducers====
====Strong CYP3A4 Inducers====
*Co-administration of strong inducers of [[CYP3A4]] such as [[rifampin]], [[carbamazepine]], [[phenytoin]] and [[St. John's wort]] with Coartem Tablets can result in decreased concentrations of artemether and/or [[lumefantrine]] and loss of [[antimalarial]] efficacy.
*Co-administration of strong inducers of [[CYP3A4]] such as [[rifampin]], [[carbamazepine]], [[phenytoin]] and [[St. John's wort]] with [[Artemether]]/[[Lumefantrine]] Tablets can result in decreased concentrations of artemether and/or [[lumefantrine]] and loss of [[antimalarial]] efficacy.
|warnings=====Prolongation of the QT Interval====
|warnings=====Prolongation of the QT Interval====
Some [[antimalarials]] (e.g., [[halofantrine]], [[quinine]], [[quinidine]]) including Coartem Tablets have been associated with prolongation of the [[QT interval]] on the [[electrocardiogram]].
Some [[antimalarials]] (e.g., [[halofantrine]], [[quinine]], [[quinidine]]) including [[Artemether]]/[[Lumefantrine]] Tablets have been associated with prolongation of the [[QT interval]] on the [[electrocardiogram]].
Coartem Tablets should be avoided in patients:
[[Artemether]]/[[Lumefantrine]] Tablets should be avoided in patients:
*With congenital prolongation of the [[QT interval]] (e.g., [[long QT syndrome]]) or any other clinical condition known to prolong the [[QTc interval]] such as patients with a history of symptomatic [[cardiac arrhythmias]], with clinically relevant bradycardia or with severe cardiac disease.
*With congenital prolongation of the [[QT interval]] (e.g., [[long QT syndrome]]) or any other clinical condition known to prolong the [[QTc interval]] such as patients with a history of symptomatic [[cardiac arrhythmias]], with clinically relevant bradycardia or with severe cardiac disease.
*With a family history of congenital prolongation of the QT interval or [[sudden death]].  
*With a family history of congenital prolongation of the QT interval or [[sudden death]].  
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====Use of QT Prolonging Drugs and Other Antimalarials====
====Use of QT Prolonging Drugs and Other Antimalarials====
*[[Halofantrine]] and Coartem Tablets should not be administered within one month of each other due to the long elimination half-life of lumefantrine (3-6 days) and potential additive effects on the [[QT interval]].  
*[[Halofantrine]] and [[Artemether]]/[[Lumefantrine]] Tablets should not be administered within one month of each other due to the long elimination half-life of lumefantrine (3-6 days) and potential additive effects on the [[QT interval]].  
*[[Antimalarials]] should not be given concomitantly with Coartem Tablets, unless there is no other treatment option, due to limited safety data.
*[[Antimalarials]] should not be given concomitantly with [[Artemether]]/[[Lumefantrine]] Tablets, unless there is no other treatment option, due to limited safety data.
*Drugs that prolong the [[QT interval]], including [[antimalarials]] such as [[quinine]] and [[quinidine]], should be used cautiously following Coartem Tablets, due to the long elimination half-life of [[lumefantrine]] (3-6 days) and the potential for additive effects on the [[QT interval]]; ECG monitoring is advised if use of drugs that prolong the [[QT interval]] is medically required.
*Drugs that prolong the [[QT interval]], including [[antimalarials]] such as [[quinine]] and [[quinidine]], should be used cautiously following [[Artemether]]/[[Lumefantrine]] Tablets, due to the long elimination half-life of [[lumefantrine]] (3-6 days) and the potential for additive effects on the [[QT interval]]; ECG monitoring is advised if use of drugs that prolong the [[QT interval]] is medically required.
*If [[mefloquine]] is administered immediately prior to Coartem Tablets there may be a decreased exposure to [[lumefantrine]], possibly due to a [[mefloquine]]-induced decrease in bile production. Therefore, patients should be monitored for decreased efficacy and food consumption should be encouraged while taking Coartem Tablets.  
*If [[mefloquine]] is administered immediately prior to [[Artemether]]/[[Lumefantrine]] Tablets there may be a decreased exposure to [[lumefantrine]], possibly due to a [[mefloquine]]-induced decrease in bile production. Therefore, patients should be monitored for decreased efficacy and food consumption should be encouraged while taking [[Artemether]]/[[Lumefantrine]] Tablets.  


====Drug Interactions with CYP3A4====
====Drug Interactions with CYP3A4====
*When Coartem Tablets are co-administered with substrates of [[CYP3A4]] it may result in decreased concentrations of the substrate and potential loss of substrate efficacy. When Coartem Tablets are co-administered with an inhibitor of [[CYP3A4]], including grapefruit juice it may result in increased concentrations of [[artemether]] and/or [[lumefantrine]] and potentiate [[QT prolongation]]. When Coartem Tablets are co-administered with inducers of [[CYP3A4]] it may result in decreased concentrations of [[artemether]] and/or [[lumefantrine]] and loss of antimalarial efficacy.
*When [[Artemether]]/[[Lumefantrin]] Tablets are co-administered with substrates of [[CYP3A4]] it may result in decreased concentrations of the substrate and potential loss of substrate efficacy. When [[Artemether]]/[[Lumefantrin]] Tablets are co-administered with an inhibitor of [[CYP3A4]], including grapefruit juice it may result in increased concentrations of [[artemether]] and/or [[lumefantrine]] and potentiate [[QT prolongation]]. When [[Artemether]]/[[Lumefantrin]] Tablets are co-administered with inducers of [[CYP3A4]] it may result in decreased concentrations of [[artemether]] and/or [[lumefantrine]] and loss of antimalarial efficacy.
*Drugs that have a mixed effect on [[CYP3A4]], especially [[antiretroviral]] drugs such as [[HIV]] [[protease inhibitors]] and [[non-nucleoside reverse transcriptase inhibitors]], and those that have an effect on the [[QT interval]] should be used with caution in patients taking Coartem Tablets.
*Drugs that have a mixed effect on [[CYP3A4]], especially [[antiretroviral]] drugs such as [[HIV]] [[protease inhibitors]] and [[non-nucleoside reverse transcriptase inhibitors]], and those that have an effect on the [[QT interval]] should be used with caution in patients taking [[Artemether]]/[[Lumefantrine]] Tablets.
*Coartem Tablets may reduce the effectiveness of [[hormonal contraceptives]]. Therefore, patients using oral, transdermal patch, or other systemic [[hormonal contraceptives]] should be advised to use an additional non-hormonal method of birth control.
*[[Artemether]]/[[Lumefantrine]] Tablets may reduce the effectiveness of [[hormonal contraceptives]]. Therefore, patients using oral, transdermal patch, or other systemic [[hormonal contraceptives]] should be advised to use an additional non-hormonal method of birth control.


====Drug Interactions with CYP2D6====
====Drug Interactions with CYP2D6====
*Administration of Coartem Tablets with drugs that are metabolized by [[CYP2D6]] may significantly increase plasma concentrations of the co-administered drug and increase the risk of adverse effects. Many of the drugs metabolized by [[CYP2D6]] can prolong the [[QT interval]] and should not be administered with Coartem Tablets due to the potential additive effect on the [[QT interval]] (e.g., [[flecainide]], [[imipramine]], [[amitriptyline]], [[clomipramine]]).  
*Administration of [[Artemether]]/[[Lumefantrin]] Tablets with drugs that are metabolized by [[CYP2D6]] may significantly increase plasma concentrations of the co-administered drug and increase the risk of adverse effects. Many of the drugs metabolized by [[CYP2D6]] can prolong the [[QT interval]] and should not be administered with [[Artemether]]/[[Lumefantrine]] Tablets due to the potential additive effect on the [[QT interval]] (e.g., [[flecainide]], [[imipramine]], [[amitriptyline]], [[clomipramine]]).  


====Recrudescence====
====Recrudescence====
*Food enhances absorption of [[artemether]] and [[lumefantrine]] following administration of Coartem Tablets.  
*Food enhances absorption of [[artemether]] and [[lumefantrine]] following administration of [[Artemether]]/[[Lumefantrine]] Tablets.  
*Patients who remain averse to food during treatment should be closely monitored as the risk of recrudescence may be greater. In the event of recrudescent [[P. falciparum]] infection after treatment with Coartem Tablets, patients should be treated with a different antimalarial drug.
*Patients who remain averse to food during treatment should be closely monitored as the risk of recrudescence may be greater. In the event of recrudescent [[P. falciparum]] infection after treatment with [[Artemether]]/[[Lumefantrin]] Tablets, patients should be treated with a different antimalarial drug.


====Hepatic and Renal Impairment====
====Hepatic and Renal Impairment====
*Coartem Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment.  
*[[Artemether]]/[[Lumefantrine]] Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment.  


====Plasmodium vivax Infection====
====Plasmodium vivax Infection====
*Coartem Tablets have been shown in limited data (43 patients) to be effective in treating the [[erythrocytic stage]] of [[P. vivax]] infection. However, [[relapsing malaria]] caused by [[P. vivax]] requires additional treatment with other antimalarial agents to achieve radical cure i.e., eradicate any [[hypnozoites]] forms that may remain dormant in the liver.
*[[Artemether]]/[[Lumefantrine]] Tablets have been shown in limited data (43 patients) to be effective in treating the [[erythrocytic stage]] of [[P. vivax]] infection. However, [[relapsing malaria]] caused by [[P. vivax]] requires additional treatment with other antimalarial agents to achieve radical cure i.e., eradicate any [[hypnozoites]] forms that may remain dormant in the liver.
|clinicalTrials=====Serious Adverse Reactions====
|clinicalTrials=====Serious Adverse Reactions====
The following serious and otherwise important adverse reactions are discussed in greater detail in other sections of labeling:
The following serious and otherwise important adverse reactions are discussed in greater detail in other sections of labeling:
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====Clinical Studies Experience====
====Clinical Studies Experience====
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in practice.
*Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in practice.
 
*The data described below reflect exposure to a 6-dose regimen of [[Artemether]]/[[Lumefantrine]] Tablets in 1,979 patients including 647 adults (older than 16 years) and 1,332 children (16 years and younger). For the 6-dose regimen, [[Artemether]]/[[Lumefantrin]] Tablets was studied in active-controlled (366 patients) and non-controlled, open-label trials (1,613 patients). The 6-dose [[Artemether]]/[[Lumefantrin]] Tablets population was patients with malaria between ages 2 months and 71 years: 67% (1,332) were 16 years and younger and 33% (647) were older than 16 years. Males represented 73% and 53% of the adult and pediatric populations, respectively. The majority of adult patients were enrolled in studies in Thailand, while the majority of pediatric patients were enrolled in Africa.
The data described below reflect exposure to a 6-dose regimen of Coartem Tablets in 1,979 patients including 647 adults (older than 16 years) and 1,332 children (16 years and younger). For the 6-dose regimen, Coartem Tablets was studied in active-controlled (366 patients) and non-controlled, open-label trials (1,613 patients). The 6-dose Coartem Tablets population was patients with malaria between ages 2 months and 71 years: 67% (1,332) were 16 years and younger and 33% (647) were older than 16 years. Males represented 73% and 53% of the adult and pediatric populations, respectively. The majority of adult patients were enrolled in studies in Thailand, while the majority of pediatric patients were enrolled in Africa.
*Tables 1 and 2 show the most frequently reported adverse reactions (вЙ•3%) in adults and children respectively who received the 6-dose regimen of [[Artemether]]/[[Lumefantrin]] Tablets. Adverse reactions collected in clinical trials included signs and symptoms at baseline but only treatment emergent adverse events, defined as events that appeared or worsened after the start of treatment, are presented below. In adults, the most frequently reported adverse reactions were [[headache]], [[anorexia]], [[dizziness]], and [[asthenia]]. In children, the adverse reactions were [[pyrexia]], [[cough]], [[vomiting]], [[anorexia]], and [[headache]]. Most adverse reactions were mild, did not lead to discontinuation of study medication, and resolved.
 
*In limited comparative studies, the adverse reaction profile of [[Artemether]]/[[Lumefantrine]] Tablets appeared similar to that of another antimalarial regimen.
Tables 1 and 2 show the most frequently reported adverse reactions (вЙ•3%) in adults and children respectively who received the 6-dose regimen of Coartem Tablets. Adverse reactions collected in clinical trials included signs and symptoms at baseline but only treatment emergent adverse events, defined as events that appeared or worsened after the start of treatment, are presented below. In adults, the most frequently reported adverse reactions were [[headache]], [[anorexia]], [[dizziness]], and [[asthenia]]. In children, the adverse reactions were [[pyrexia]], [[cough]], [[vomiting]], [[anorexia]], and [[headache]]. Most adverse reactions were mild, did not lead to discontinuation of study medication, and resolved.
*Discontinuation of [[Artemether]]/[[Lumefantrin]] Tablets due to adverse drug reactions occurred in 1.1% of patients treated with the 6-dose regimen overall: 0.2% (1/647) in adults and 1.6% (21/1,332) in children.
 
In limited comparative studies, the adverse reaction profile of Coartem Tablets appeared similar to that of another antimalarial regimen.
 
Discontinuation of Coartem Tablets due to adverse drug reactions occurred in 1.1% of patients treated with the 6-dose regimen overall: 0.2% (1/647) in adults and 1.6% (21/1,332) in children.


[[file:Artemether AR.png|none|400px]]
[[file:Artemether AR.png|none|400px]]


Clinically significant adverse reactions reported in adults and/or children treated with the 6-dose regimen of Coartem Tablets which occurred in clinical studies at <3% regardless of causality are listed below:
'''Clinically significant adverse reactions reported in adults and/or children treated with the 6-dose regimen of [[Artemether]]/[[Lumefantrine]] Tablets which occurred in clinical studies at <3% regardless of causality are listed below:'''
 
*Blood and lymphatic system disorders: [[eosinophilia]]
*Blood and lymphatic system disorders: [[eosinophilia]]
*Ear and labyrinth disorders: [[tinnitus]]
*Ear and labyrinth disorders: [[tinnitus]]
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*Respiratory, thoracic and mediastinal disorders: [[asthma]], [[pharyngo-laryngeal pain]]
*Respiratory, thoracic and mediastinal disorders: [[asthma]], [[pharyngo-laryngeal pain]]
*Skin and subcutaneous tissue disorders: [[urticaria]]
*Skin and subcutaneous tissue disorders: [[urticaria]]
|postmarketing=The following adverse reactions have been identified during post-approval use of Coartem Tablets. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
|postmarketing=<i>The following adverse reactions have been identified during post-approval use of [[Artemether]]/[[Lumefantrin]] Tablets. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.</i>
*Hypersensitivity reactions including urticaria and angioedema. Serious skin reactions (bullous eruption) have been rarely reported.
*Hypersensitivity reactions including urticaria and angioedema. Serious skin reactions (bullous eruption) have been rarely reported.
|drugInteractions=====Rifampin====
|drugInteractions=====Rifampin====
Oral administration of [[rifampin]], a strong [[CYP3A4]] inducer, with Coartem Tablets resulted in significant decreases in exposure to artemether, dihydroartemisinin (DHA, metabolite of artemether) and [[lumefantrine]] by 89%, 85% and 68%, respectively, when compared to exposure values after Coartem Tablets alone. Concomitant use of strong inducers of [[CYP3A4]] such as [[rifampin]], [[carbamazepine]], [[phenytoin]] and [[St. John's wort]] is contraindicated with Coartem Tablets.
*Oral administration of [[rifampin]], a strong [[CYP3A4]] inducer, with [[Artemether]]/[[Lumefantrin]] Tablets resulted in significant decreases in exposure to artemether, dihydroartemisinin (DHA, metabolite of artemether) and [[lumefantrine]] by 89%, 85% and 68%, respectively, when compared to exposure values after [[Artemether]]/[[Lumefantrin]] Tablets alone. Concomitant use of strong inducers of [[CYP3A4]] such as [[rifampin]], [[carbamazepine]], [[phenytoin]] and [[St. John's wort]] is contraindicated with [[Artemether]]/[[Lumefantrin]] Tablets.


====Ketoconazole====
====Ketoconazole====
Concurrent oral administration of [[ketoconazole]], a potent [[CYP3A4]] inhibitor, with a single dose of Coartem Tablets resulted in a moderate increase in exposure to artemether, DHA, and lumefantrine in a study of 15 healthy subjects. No dose adjustment of Coartem Tablets is necessary when administered with [[ketoconazole]] or other potent [[CYP3A4]] inhibitors. However, due to the potential for increased concentrations of lumefantrine which could lead to [[QT prolongation]], Coartem Tablets should be used cautiously with drugs that inhibit [[CYP3A4]].  
*Concurrent oral administration of [[ketoconazole]], a potent [[CYP3A4]] inhibitor, with a single dose of [[Artemether]]/[[Lumefantrine]] Tablets resulted in a moderate increase in exposure to artemether, DHA, and lumefantrine in a study of 15 healthy subjects. No dose adjustment of [[Artemether]]/[[Lumefantrine]] Tablets is necessary when administered with [[ketoconazole]] or other potent [[CYP3A4]] inhibitors. However, due to the potential for increased concentrations of lumefantrine which could lead to [[QT prolongation]], [[Artemether]]/[[Lumefantrine]] Tablets should be used cautiously with drugs that inhibit [[CYP3A4]].  


====Antiretroviral Drugs====
====Antiretroviral Drugs====
Both artemether and [[lumefantrine]] are metabolized by [[CYP3A4]]. [[Antiretroviral drugs]], such as [[protease inhibitors]] and [[non-nucleoside reverse transcriptase inhibitors]], are known to have variable patterns of inhibition, induction or competition for [[CYP3A4]]. Therefore, the effects of antiretroviral drugs on the exposure to artemether, DHA, and [[lumefantrine]] are also variable [see Clinical Pharmacology (12.3)]. Coartem Tablets should be used cautiously in patients on antiretroviral drugs because decreased artemether, DHA, and/or [[lumefantrine]] concentrations may result in a decrease of antimalarial efficacy of Coartem Tablets, and increased lumefantrine concentrations may cause [[QT prolongation]].  
*Both artemether and [[lumefantrine]] are metabolized by [[CYP3A4]]. [[Antiretroviral drugs]], such as [[protease inhibitors]] and [[non-nucleoside reverse transcriptase inhibitors]], are known to have variable patterns of inhibition, induction or competition for [[CYP3A4]]. Therefore, the effects of antiretroviral drugs on the exposure to artemether, DHA, and [[lumefantrine]] are also variable. [[Artemether]]/[[Lumefantrine]] Tablets should be used cautiously in patients on antiretroviral drugs because decreased artemether, DHA, and/or [[lumefantrine]] concentrations may result in a decrease of antimalarial efficacy of [[Artemether]]/[[Lumefantrine]] Tablets, and increased lumefantrine concentrations may cause [[QT prolongation]].  


====Prior Use of Mefloquine====
====Prior Use of Mefloquine====
Administration of three doses of [[mefloquine]] followed 12 hours later by a 6-dose regimen of Coartem Tablets in 14 healthy volunteers demonstrated no effect of [[mefloquine]] on plasma concentrations of artemether or the artemether/DHA ratio. However, exposure to [[lumefantrine]] was reduced, possibly due to lower absorption secondary to a [[mefloquine]]-induced decrease in bile production. Patients should be monitored for decreased efficacy and food consumption should be encouraged with administration of Coartem Tablets.
*Administration of three doses of [[mefloquine]] followed 12 hours later by a 6-dose regimen of [[Artemether]]/[[Lumefantrine]] Tablets in 14 healthy volunteers demonstrated no effect of [[mefloquine]] on plasma concentrations of artemether or the artemether/DHA ratio. However, exposure to [[lumefantrine]] was reduced, possibly due to lower absorption secondary to a [[mefloquine]]-induced decrease in bile production. Patients should be monitored for decreased efficacy and food consumption should be encouraged with administration of [[Artemether]]/[[Lumefantrine]] Tablets.


====Hormonal Contraceptives====
====Hormonal Contraceptives====
In vitro, the metabolism of [[ethinyl estradiol]] and [[levonorgestrel]] was not induced by artemether, DHA, or [[lumefantrine]]. However, artemether has been reported to weakly induce, in humans, the activity of [[CYP2C19]], [[CYP2B6]], and [[CYP3A]]. Therefore, Coartem Tablets may potentially reduce the effectiveness of [[hormonal contraceptives]]. Patients using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to use an additional non-hormonal method of birth control.
*In vitro, the metabolism of [[ethinyl estradiol]] and [[levonorgestrel]] was not induced by artemether, DHA, or [[lumefantrine]]. However, artemether has been reported to weakly induce, in humans, the activity of [[CYP2C19]], [[CYP2B6]], and [[CYP3A]]. Therefore, [[Artemether]]/[[Lumefantrine]] Tablets may potentially reduce the effectiveness of [[hormonal contraceptives]]. Patients using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to use an additional non-hormonal method of birth control.


====CYP2D6 Substrates====
====CYP2D6 Substrates====
Lumefantrine inhibits [[CYP2D6]] in vitro. Administration of Coartem Tablets with drugs that are metabolized by [[CYP2D6]] may significantly increase plasma concentrations of the co-administered drug and increase the risk of adverse effects. Many of the drugs metabolized by [[CYP2D6]] can prolong the [[QT interval]] and should not be administered with Coartem Tablets due to the potential additive effect on the [[QT interval]] (e.g., [[flecainide]], [[imipramine]], [[amitriptyline]], [[clomipramine]])
*Lumefantrine inhibits [[CYP2D6]] in vitro. Administration of [[Artemether]]/[[Lumefantrine]] Tablets with drugs that are metabolized by [[CYP2D6]] may significantly increase plasma concentrations of the co-administered drug and increase the risk of adverse effects. Many of the drugs metabolized by [[CYP2D6]] can prolong the [[QT interval]] and should not be administered with [[Artemether]]/[[Lumefantrine]] Tablets due to the potential additive effect on the [[QT interval]] (e.g., [[flecainide]], [[imipramine]], [[amitriptyline]], [[clomipramine]])


====Sequential Use of Quinine====
====Sequential Use of Quinine====
A single dose of intravenous [[quinine]] (10 mg/kg bodyweight) concurrent with the final dose of a 6-dose regimen of Coartem Tablets demonstrated no effect of intravenous [[quinine]] on the systemic exposure of DHA or [[lumefantrine]]. [[Quinine]] exposure was also not altered. Exposure to artemether was decreased. This decrease in artemether exposure is not thought to be clinically significant. However, [[quinine]] and other drugs that prolong the [[QT interval]] should be used cautiously following treatment with Coartem Tablets due to the long elimination half-life of [[lumefantrine]] and the potential for additive [[QT effects]]; ECG monitoring is advised if use of drugs that prolong the [[QT interval]] is medically required.
*A single dose of intravenous [[quinine]] (10 mg/kg bodyweight) concurrent with the final dose of a 6-dose regimen of [[Artemether]]/[[Lumefantrin]] Tablets demonstrated no effect of intravenous [[quinine]] on the systemic exposure of DHA or [[lumefantrine]]. [[Quinine]] exposure was also not altered. Exposure to artemether was decreased. This decrease in artemether exposure is not thought to be clinically significant. However, [[quinine]] and other drugs that prolong the [[QT interval]] should be used cautiously following treatment with [[Artemether]]/[[Lumefantrine]] Tablets due to the long elimination half-life of [[lumefantrine]] and the potential for additive [[QT effects]]; ECG monitoring is advised if use of drugs that prolong the [[QT interval]] is medically required.


====Interaction with Drugs that are Known to Prolong the QT Interval====
====Interaction with Drugs that are Known to Prolong the QT Interval====
Coartem is to be used with caution when co-administered with drugs that may cause prolonged [[QT interval]] such as [[antiarrhythmics]] of classes IA and III, [[neuroleptics]] and [[antidepressant agents]], certain [[antibiotics]] including some agents of the following classes: [[macrolides]], [[fluoroquinolones]], [[imidazole]], and [[triazole]] [[antifungal agents]].
*[[Artemether]]/[[Lumefantrine]] is to be used with caution when co-administered with drugs that may cause prolonged [[QT interval]] such as [[antiarrhythmics]] of classes IA and III, [[neuroleptics]] and [[antidepressant agents]], certain [[antibiotics]] including some agents of the following classes: [[macrolides]], [[fluoroquinolones]], [[imidazole]], and [[triazole]] [[antifungal agents]].
|FDAPregCat=C
|useInPregnancyFDA=*Safety data from an observational pregnancy study of approximately 500 pregnant women who were exposed to [[Artemether]]/[[Lumefantrine]] Tablets (including a third of patients who were exposed in the first trimester), and published data of over 1,000 pregnant patients who were exposed to artemisinin derivatives, did not show an increase in adverse pregnancy outcomes or teratogenic effects over background rate.
*The efficacy of [[Artemether]]/[[Lumefantrine]] Tablets in the treatment of acute, uncomplicated malaria in pregnant women has not been established.
*[[Artemether]]/[[Lumefantrine]] Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
*Pregnant rats dosed during the period of organogenesis at or higher than a dose of about half the highest clinical dose of 1120 mg artemether-lumefantrine per day (based on body surface area comparisons), showed increases in fetal loss, early resorptions and post implantation loss. No adverse effects were observed in animals dosed at about one-third the highest clinical dose. Similarly, dosing in pregnant rabbits at about three times the clinical dose (based on body surface area comparisons) resulted in abortions, preimplantation loss, post implantation loss and decreases in the number of live fetuses. No adverse reproductive effects were detected in rabbits at two times the clinical dose. Embryo-fetal loss is a significant reproductive toxicity. Other artemisinins are known to be embryotoxic in animals. However, because metabolic profiles in animals and humans are dissimilar, artemether exposures in animals may not be predictive of human exposures [see Nonclinical Toxicology (13.2)]. These data cannot rule out an increased risk for early pregnancy loss or fetal defects in humans.
|useInNursing=*It is not known whether artemether or lumefantrine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when [[Artemether]]/[[Lumefantrine]] Tablets are administered to a nursing woman. Animal data suggest both artemether and lumefantrine are excreted into breast milk. The benefits of breastfeeding to mother and infant should be weighed against potential risk from infant exposure to artemether and lumefantrine through breast milk.
|useInPed=*The safety and effectiveness of [[Artemether]]/[[Lumefantrine]] Tablets have been established for the treatment of acute, uncomplicated malaria in studies involving pediatric patients weighing 5 kg or more [see Clinical Studies (14.1)]. The safety and efficacy have not been established in pediatric patients who weigh less than 5 kg. Children from non-endemic countries were not included in clinical trials.
|useInGeri=*Clinical studies of [[Artemether]]/[[Lumefantrine]] Tablets did not include sufficient numbers of subjects aged 65 years and over to determine they respond differently from younger subjects. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing [[Artemether]]/[[Lumefantrine]] Tablets.
|useInRenalImpair=*No specific pharmacokinetic studies have been performed in patients with either hepatic or renal impairment. [[Artemether]]/[[Lumefantrine]] Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment. Based on the pharmacokinetic data in 16 healthy subjects showing no or insignificant renal excretion of lumefantrine, artemether and DHA, no dose adjustment for the use of [[Artemether]]/[[Lumefantrine]] in patients with renal impairment is advised. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment [see Dosage and Administration (2.4) and Warnings and Precautions (5.6)].
|useInHepaticImpair=*No specific pharmacokinetic studies have been performed in patients with either hepatic or renal impairment. [[Artemether]]/[[Lumefantrine]] Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment. Based on the pharmacokinetic data in 16 healthy subjects showing no or insignificant renal excretion of lumefantrine, artemether and DHA, no dose adjustment for the use of [[Artemether]]/[[Lumefantrine]] in patients with renal impairment is advised. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment [see Dosage and Administration (2.4) and Warnings and Precautions (5.6)].
|overdose=*There is no information on overdoses of [[Artemether]]/[[Lumefantrine]] Tablets higher than the doses recommended for treatment.
*In cases of suspected overdosage, symptomatic and supportive therapy, which would include ECG and blood electrolyte monitoring, should be given as appropriate.
|drugBox={{Drugbox2
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 457818137
| IUPAC_name =  (3''R'',5a''S'',6''R'',8a''S'',9''R'',10''S'',12''R'',12a''R'')-10-methoxy-3,6,9-trimethyldecahydro-12''H''-3,12-epoxy[1,2]dioxepino[4,3-''i'']-2-benzopyran
| image = Artemether Structure.png
 
<!--Clinical data-->
| tradename = 
| Drugs.com = {{drugs.com|international|artemether}}
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = C
| pregnancy_category = 
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| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = POM
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_status = 
| routes_of_administration = Oral
 
<!--Pharmacokinetic data-->
| bioavailability = 
| protein_bound = 
| metabolism = 
| elimination_half-life = 
| excretion =
 
<!--Identifiers-->
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 71963-77-4
| ATC_prefix = P01
| ATC_suffix = BE02
| ATC_supplemental = 
| PubChem = 68911
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB06697
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 62138
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = C7D6T3H22J
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D02483
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 195280
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1237051
 
<!--Chemical data-->
| chemical_formula = 
| C=16 | H=26 | O=5
| molecular_weight = 298.374 g/mol
| smiles = C[C@@H]1CC[C@@H]3C42OO[C@](C)(CC[C@@H]12)O[C@H]4O[C@H](OC)[C@@H]3C
| InChI = 1/C16H26O5/c1-9-5-6-12-10(2)13(17-4)18-14-16(12)11(9)7-8-15(3,19-14)20-21-16/h9-14H,5-8H2,1-4H3/t9-,10-,11+,12+,13+,14-,15-,16?/m1/s1
| InChIKey = SXYIRMFQILZOAM-LJXHFVHTBB
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C16H26O5/c1-9-5-6-12-10(2)13(17-4)18-14-16(12)11(9)7-8-15(3,19-14)20-21-16/h9-14H,5-8H2,1-4H3/t9-,10-,11+,12+,13+,14-,15-,16-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = SXYIRMFQILZOAM-HVNFFKDJSA-N
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|mechAction=*[[Artemether]]/[[Lumefantrin]] Tablets, a fixed dose combination of artemether and lumefantrine in the ratio of 1:6, is an antimalarial agent. Artemether is rapidly metabolized into an active metabolite dihydroartemisinin (DHA). The antimalarial activity of artemether and DHA has been attributed to endoperoxide moiety. The exact mechanism by which lumefantrine, exerts its antimalarial effect is not well defined. Available data suggest lumefantrine inhibits the formation of ќ≤-hematin by forming a complex with hemin. Both artemether and lumefantrine were shown to inhibit nucleic acid and protein synthesis.
|structure='''Artemether has the empirical formula C16H26O5 with a molecular weight of 298.4, and the following structural formula:'''
 
[[file:Artemether Structure.png|none|200px]]
 
'''[[Lumefantrin]] has the empirical formula C30H32Cl3NO with a molecular weight of 528.9, and the following structural formula:'''
 
[[file:Lumefantrine Structure.png|none|200px]]
|PK=====Absorption====
*Following administration of [[Artemether]]/[[Lumefantrine]] Tablets to healthy volunteers and patients with [[malaria]], artemether is absorbed with peak plasma concentrations reached about 2 hours after dosing. Absorption of [[lumefantrine]], a highly [[lipophilic]] compound, starts after a lag-time of up to 2 hours, with peak plasma concentrations about 6 to 8 hours after administration. The single dose (4 tablets) pharmacokinetic parameters for artemether, dihydroartemisinin (DHA), an active [[antimalarial]] metabolite of artemether, and lumefantrine in adult Caucasian healthy volunteers are given in Table 3. Multiple dose data after the 6-dose regimen of [[Artemether]]/[[Lumefantrine]] Tablets in adult malaria patients are given in Table 4.
 
[[file:Rtemether PK1.png|none|400px]]
 
*Food enhances the absorption of both artemether and [[lumefantrine]]. In healthy volunteers, the relative bioavailability of artemether was increased between two- to three-fold, and that of lumefantrine sixteen-fold when [[Artemether]]/[[Lumefantrine]] Tablets were taken after a high-fat meal compared under fasted conditions. Patients should be encouraged to take [[Artemether]]/[[Lumefantrine]] Tablets with a meal as soon as food can be tolerated.
 
====Distribution====
*Artemether and lumefantrine are both highly bound to human serum proteins in vitro (95.4% and 99.7%, respectively). Dihydroartemisinin is also bound to human serum proteins (47% to 76%). Protein binding to human plasma proteins is linear.
 
====Biotransformation====
*In human [[liver microsomes]] and recombinant [[CYP450]] enzymes, the metabolism of artemether was catalyzed predominantly by [[CYP3A4]]/[[CYP3A5]]. Dihydroartemisinin (DHA) is an active metabolite of artemether. The metabolism of artemether was also catalyzed to a lesser extent by [[CYP2B6]], [[CYP2C9]] and [[CYP2C19]]. In vitro studies with artemether at therapeutic concentrations revealed no significant inhibition of the metabolic activities of [[CYP1A2]], [[CYP2A6]], [[CYP2C9]], [[CYP2C19]], [[CYP2D6]], [[CYP2E1]], [[CYP3A4]]/[[CYP3A5]], and [[CYP4A9]]/[[CYP3A11]]. In vitro studies with artemether, DHA, and [[lumefantrine]] at therapeutic concentrations revealed no significant induction of the metabolic activities of [[CYP1A1]], [[CYP1A2]], [[CYP2B6]], [[CYP2C8]], [[CYP2C9]], [[CYP2C19]], [[CYP3A4]], or [[CYP3A5]].
*During repeated administration of [[Artemether]]/[[Lumefantrin]] Tablets, systemic exposure of artemether decreased significantly, while concentrations of DHA increased, although not to a statistically significant degree. The artemether/DHA AUC ratio is 1.2 after a single dose and 0.3 after 6 doses given over 3 days. This suggests that there was induction of enzymes responsible for the metabolism of artemether.
*In human [[liver microsomes]] and in recombinant [[CYP450]] enzymes, [[lumefantrine]] was metabolized mainly by [[CYP3A4]] to desbutyl-lumefantrine. The systemic exposure to the metabolite desbutyl-lumefantrine was less than 1% of the exposure to the parent compound. In vitro, [[lumefantrine]] significantly inhibits the activity of [[CYP2D6]] at therapeutic plasma concentrations.
*Caution is recommended when combining [[Artemether]]/[[Lumefantrin]] Tablets with substrates, inhibitors, or inducers of [[CYP3A4]], especially [[antiretroviral]] drugs and those that prolong the [[QT interval]] (e.g., [[macrolide]] antibiotics, [[pimozide]]).
*Co-administration of [[Artemether]]/[[Lumefantrin]] Tablets with [[CYP2D6]] substrates may result in increased plasma concentrations of the [[CYP2D6]] substrate and increase the risk of adverse reactions. In addition, many of the drugs metabolized by [[CYP2D6]] can prolong the [[QT interval]] and should not be administered with [[Artemether]]/[[Lumefantrin]] Tablets due to the potential additive effect on the [[QT interval]] (e.g., [[flecainide]], [[imipramine]], [[amitriptyline]], [[clomipramine]]).
 
====Elimination====
*Artemether and DHA are cleared from plasma with an elimination half-life of about 2 hours. [[Lumefantrine]] is eliminated more slowly, with an elimination half-life of 3-6 days in healthy volunteers and in patients with [[falciparum]] [[malaria]]. Demographic characteristics such as sex and weight appear to have no clinically relevant effects on the pharmacokinetics of artemether and [[lumefantrine]].
*In 16 healthy volunteers, neither lumefantrine nor artemether was found in the urine after administration of [[Artemether]]/[[Lumefantrin]]  and urinary excretion of DHA amounted to less than 0.01% of the artemether dose.
 
===Pharmacokinetics in Special Population===
 
====Hepatic and Renal Impairment====
*No specific pharmacokinetic studies have been performed in patients with either hepatic or renal impairment.
*There is no significant renal excretion of lumefantrine, artemether and DHA in healthy volunteers and while clinical experience in this population is limited, no dose adjustment in renal impairment is recommended.
 
====Pediatric Patients=====
*The PK of artemether, DHA, and lumefantrine were obtained in two pediatric studies by sparse sampling using a population based approach. PK estimates derived from a composite plasma concentration profile for artemether, DHA, and lumefantrine are provided in Table 4.
*Systemic exposure to artemether, DHA, and lumefantrine, when dosed on a mg/kg body weight basis in pediatric patients (вЙ•5 to <35 kg body weight), is comparable to that of the recommended dosing regimen in adult patients.
 
[[file:Artemether PK2.png|none|300px]]
 
====Geriatric Patients====
*No specific pharmacokinetic studies have been performed in patients older than 65 years of age.
|nonClinToxic====Carcinogenesis, Mutagenesis, Impairment of Fertility===
 
====Carcinogenesis====
*Carcinogenicity studies were not conducted.
 
====Mutagenesis====
*No evidence of mutagenicity was detected. The artemether: lumefantrine combination was evaluated using the [[Salmonella]] and [[Escherichia]]/mammalian-microsome mutagenicity test, the gene mutation test with Chinese hamster cells V79, the cytogenetic test on Chinese hamster cells in vitro, and the rat micronucleus test, in vivo.
 
====Impairment of Fertility====
*Pregnancy rates were reduced by about one half in female rats dosed for 2 to 4 weeks with the artemether-lumefantrine combination at 1000 mg/kg (about 9 times the clinical dose based on body surface area comparisons).
*Male rats dosed for 70 days showed increases in abnormal sperm (87% abnormal) and increased testes weights at 30 mg/kg doses (about one third the clinical dose). Higher doses (about 9 times the clinical dose) resulted in decreased sperm motility and 100% abnormal sperm cells.
 
===Animal Toxicology and/or Pharmacology===
*Neonatal rats (7-21 days old) were more sensitive to the toxic effects of artemether (a component of [[Artemether]]/[[Lumefantrin]]  than older juvenile rats or adults. Mortality and severe clinical signs were observed in neonatal rats at doses which were well tolerated in pups above 22 days old.
|clinicalStudies====Treatment of Acute, Uncomplicated P. falciparum Malaria===
*The efficacy of [[Artemether]]/[[Lumefantrin]] Tablets was evaluated for the treatment of acute, uncomplicated [[malaria]] caused by [[P. falciparum]] in [[HIV]] negative patients in 8 clinical studies. Uncomplicated [[malaria]] was defined as symptomatic [[P. falciparum]] [[malaria]] without signs and symptoms of severe [[malaria]] or evidence of vital [[organ dysfunction]]. Baseline [[parasite]] density ranged from 500/µL - 200,000/µL (0.01% to 4% parasitemia) in the majority of patients. Studies were conducted in partially immune and non-immune adults and children (вЙ•5kg body weight) with uncomplicated malaria in China, Thailand, sub-Saharan Africa, Europe, and South America. Patients who had clinical features of severe malaria, severe cardiac, renal, or hepatic impairment were excluded.
*The studies include two 4-dose studies assessing the efficacy of the components of the regimen, a study comparing a 4-dose versus a 6-dose regimen, and 5 additional 6-dose regimen studies.
*[[Artemether]]/[[Lumefantrin]] Tablets were administered at 0, 8, 24, and 48 hours in the 4-dose regimen, and at 0, 8, 24, 36, 48, and 60 hours in the 6-dose regimen. Efficacy endpoints consisted of:
**28 day cure rate, defined as clearance of asexual parasites (the erythrocytic stage) within 7 days without recrudescence by day 28
**[[Parasite clearance time]] ([[PCT]]), defined as time from first dose until first total and continued disappearance of asexual parasite which continues for a further 48 hours
**[[Fever clearance time]] ([[FCT]]), defined as time from first dose until the first time body temperature fell below 37.5°C and remained below 37.5°C for at least a further 48 hours (only for patients with temperature >37.5°C at baseline)
 
<i>The modified intent to treat (mITT) population includes all patients with malaria diagnosis confirmation who received at least one dose of study drug. Evaluable patients generally are all patients who had a day 7 and a day 28 parasitological assessment or experienced treatment failure by day 28.</i>
 
*Studies 1 and 2: The two studies which assessed the efficacy of [[Artemether]]/[[Lumefantrine]] Tablets (4 doses of 4 tablets of 20 mg artemether/120 mg lumefantrine) compared to each component alone were randomized, double-blind, comparative, single center, conducted in China. The efficacy results (Table 5) support that the combination of artemether and lumefantrine in [[Artemether]]/[[Lumefantrin]] Tablets had a significantly higher 28-day cure rate compared to artemether and had a significantly faster parasite clearance time (PCT) and fever clearance time (FCT) compared to lumefantrine.
 
[[file:Artemether CS1.png|none|300px]]
 
*Results of 4-dose studies conducted in areas with high resistance such as Thailand during 1995-96 showed lower efficacy results than the above studies. Therefore, Study 3 was conducted.
 
'''Study 3''': Study 3 was a randomized, double-blind, two-center study conducted in Thailand in adults and children (aged вЙ•2 years), which compared the 4-dose regimen (administered over 48 hours) of [[Artemether]]/[[Lumefantrine]] Tablets to a 6-dose regimen (administered over 60 hours). Twenty-eight day cure rate in mITT subjects was 81% (96/118) for the [[Artemether]]/[[Lumefantrine]] Tablets 6-dose arm as compared to 71% (85/120) in the 4-dose arm.
 
'''Studies 4, 5, 6, 7, and 8''': In these studies, [[Artemether]]/[[Lumefantrine]] Tablets were administered as the 6-dose regimen.
*In study 4, a total of 150 adults and children aged вЙ•2 years received [[Artemether]]/[[Lumefantrine]] Tablets. In study 5, a total 164 adults and children вЙ•12 years received [[Artemether]]/[[Lumefantrine]] Tablets. Both studies were conducted in Thailand.
*Study 6 was a study of 165 non-immune adults residing in regions non-endemic for malaria (Europe and Colombia) who contracted acute uncomplicated falciparum malaria when traveling in endemic regions.
*Study 7 was conducted in Africa in 310 infants and children aged 2 months to 9 years, weighing 5 kg to 25 kg, with an axillary temperature вЙ•37.5ºC.
*Study 8 was conducted in Africa in 452 infants and children, aged 3 months to 12 years, weighing 5 kg to <35 kg, with fever (вЙ•37.5°C axillary or вЙ•38°C rectally) or history of fever in the preceding 24 hours.
 
*Results of 28-day cure rate, median parasite clearance time (PCT), and fever clearance time (FCT) for Studies 3 to 8 are reported in Table 6.
 
[[file:Artemether CS2.png|none|400px]]
 
*In all studies, patients’ signs and symptoms of malaria resolved when parasites were cleared.
*In studies conducted in areas with high transmission rates, such as Africa, reappearance of P. falciparum parasites may be due to recrudescence or a new infection.
 
'''The efficacy by body weight category for studies 7 and 8 is summarized in Table 7. '''
 
[[file:Artemether CS3.png|none|400px]]
|howSupplied=====[[Artemether]]/[[Lumefantrine]] (artemether/lumefantrine) Tablets====
20 mg/120 mg Tablets - yellow, round flat tablets with beveled edges and scored on one side. Tablets are imprinted with N/C on one side and CG on the other.
*Bottle of 24: NDC 0078-0568-45
|storage=Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF)
|packLabel=[[file:Artemether Package.png|none|200px]]
[[file:Artemether Appearance.png|none|400px]]
|alcohol=Alcohol-Artemether and lumefantrin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|alcohol=Alcohol-Artemether and lumefantrin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=*[[Coartem]]
}}
}}

Latest revision as of 18:40, 27 February 2015

Artemether and lumefantrin
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]

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Overview

Artemether and lumefantrin is an antimanlaric that is FDA approved for the treatment of acute, uncomplicated malaria infections due to Plasmodium falciparum in patients of 5 kg bodyweight and above. Common adverse reactions include headache, anorexia, dizziness, asthenia, arthralgia and myalgia.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Administration Instructions

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

Dosage in Adult Patients (>16 years of age)

  • A 3-day treatment schedule with a total of 6 doses is recommended for adult patients with a bodyweight of 35 kg and above:
  • Four tablets as a single initial dose, 4 tablets again after 8 hours and then 4 tablets twice daily (morning and evening) for the following two days (total course of 24 tablets).
  • For patients weighing less than 35 kg, see Dosage in Pediatric Patients.

Dosage in Pediatric Patients

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

  • 5 kg to less than 15 kg bodyweight: One tablet as an initial dose, 1 tablet again after 8 hours and then 1 tablet twice daily (morning and evening) for the following two days (total course of 6 tablets).
  • 15 kg to less than 25 kg bodyweight: Two tablets as an initial dose, 2 tablets again after 8 hours and then 2 tablets twice daily (morning and evening) for the following two days (total course of 12 tablets).
  • 25 kg to less than 35 kg bodyweight: Three tablets as an initial dose, 3 tablets again after 8 hours and then 3 tablets twice daily (morning and evening) for the following two days (total course of 18 tablets).
  • 35 kg bodyweight and above: Four tablets as a single initial dose, 4 tablets again after 8 hours and then 4 tablets twice daily (morning and evening) for the following two days (total course of 24 tablets).

Dosage in Patients with Hepatic or Renal Impairment

  • No specific pharmacokinetic studies have been carried out in patients with hepatic or renal 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. No specific dose adjustments are needed for patients with mild or moderate hepatic impairment.
  • In clinical studies, the adverse event profile did not differ in patients with mild or moderate renal impairment compared to patients with normal renal function. There were few patients with severe renal impairment in clinical studies. There is no significant renal excretion of lumefantrine, artemether and dihydroartemisinin (DHA) in healthy volunteers and while clinical experience in this population is limited, no dose adjustment is recommended.
  • Caution should be exercised when administering Coartem Tablets in patients with severe hepatic or renal impairment.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Artemether and Lumefantrin in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Artemether and lumefantrin in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Artemether and lumefantrin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Artemether and lumefantrin in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Artemether and lumefantrin in pediatric patients.

Contraindications

Hypersensitivity

  • Known hypersensitivity to artemether, lumefantrine, or to any of the excipients of Artemether/Lumefantrine Tablets.

Strong CYP3A4 Inducers

Warnings

Prolongation of the QT Interval

Some antimalarials (e.g., halofantrine, quinine, quinidine) including Artemether/Lumefantrine Tablets have been associated with prolongation of the QT interval on the electrocardiogram. Artemether/Lumefantrine Tablets should be avoided in patients:

Use of QT Prolonging Drugs and Other Antimalarials

Drug Interactions with CYP3A4

Drug Interactions with CYP2D6

Recrudescence

  • Food enhances absorption of artemether and lumefantrine following administration of Artemether/Lumefantrine Tablets.
  • Patients who remain averse to food during treatment should be closely monitored as the risk of recrudescence may be greater. In the event of recrudescent P. falciparum infection after treatment with Artemether/Lumefantrin Tablets, patients should be treated with a different antimalarial drug.

Hepatic and Renal Impairment

  • Artemether/Lumefantrine Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment.

Plasmodium vivax Infection

Adverse Reactions

Clinical Trials Experience

Serious Adverse Reactions

The following serious and otherwise important adverse reactions are discussed in greater detail in other sections of labeling:

Clinical Studies Experience

  • Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in practice.
  • The data described below reflect exposure to a 6-dose regimen of Artemether/Lumefantrine Tablets in 1,979 patients including 647 adults (older than 16 years) and 1,332 children (16 years and younger). For the 6-dose regimen, Artemether/Lumefantrin Tablets was studied in active-controlled (366 patients) and non-controlled, open-label trials (1,613 patients). The 6-dose Artemether/Lumefantrin Tablets population was patients with malaria between ages 2 months and 71 years: 67% (1,332) were 16 years and younger and 33% (647) were older than 16 years. Males represented 73% and 53% of the adult and pediatric populations, respectively. The majority of adult patients were enrolled in studies in Thailand, while the majority of pediatric patients were enrolled in Africa.
  • Tables 1 and 2 show the most frequently reported adverse reactions (вЙ•3%) in adults and children respectively who received the 6-dose regimen of Artemether/Lumefantrin Tablets. Adverse reactions collected in clinical trials included signs and symptoms at baseline but only treatment emergent adverse events, defined as events that appeared or worsened after the start of treatment, are presented below. In adults, the most frequently reported adverse reactions were headache, anorexia, dizziness, and asthenia. In children, the adverse reactions were pyrexia, cough, vomiting, anorexia, and headache. Most adverse reactions were mild, did not lead to discontinuation of study medication, and resolved.
  • In limited comparative studies, the adverse reaction profile of Artemether/Lumefantrine Tablets appeared similar to that of another antimalarial regimen.
  • Discontinuation of Artemether/Lumefantrin Tablets due to adverse drug reactions occurred in 1.1% of patients treated with the 6-dose regimen overall: 0.2% (1/647) in adults and 1.6% (21/1,332) in children.

Clinically significant adverse reactions reported in adults and/or children treated with the 6-dose regimen of Artemether/Lumefantrine Tablets which occurred in clinical studies at <3% regardless of causality are listed below:

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Artemether/Lumefantrin Tablets. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  • Hypersensitivity reactions including urticaria and angioedema. Serious skin reactions (bullous eruption) have been rarely reported.

Drug Interactions

Rifampin

Ketoconazole

Antiretroviral Drugs

Prior Use of Mefloquine

  • Administration of three doses of mefloquine followed 12 hours later by a 6-dose regimen of Artemether/Lumefantrine Tablets in 14 healthy volunteers demonstrated no effect of mefloquine on plasma concentrations of artemether or the artemether/DHA ratio. However, exposure to lumefantrine was reduced, possibly due to lower absorption secondary to a mefloquine-induced decrease in bile production. Patients should be monitored for decreased efficacy and food consumption should be encouraged with administration of Artemether/Lumefantrine Tablets.

Hormonal Contraceptives

CYP2D6 Substrates

Sequential Use of Quinine

  • A single dose of intravenous quinine (10 mg/kg bodyweight) concurrent with the final dose of a 6-dose regimen of Artemether/Lumefantrin Tablets demonstrated no effect of intravenous quinine on the systemic exposure of DHA or lumefantrine. Quinine exposure was also not altered. Exposure to artemether was decreased. This decrease in artemether exposure is not thought to be clinically significant. However, quinine and other drugs that prolong the QT interval should be used cautiously following treatment with Artemether/Lumefantrine Tablets due to the long elimination half-life of lumefantrine and the potential for additive QT effects; ECG monitoring is advised if use of drugs that prolong the QT interval is medically required.

Interaction with Drugs that are Known to Prolong the QT Interval

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C

  • Safety data from an observational pregnancy study of approximately 500 pregnant women who were exposed to Artemether/Lumefantrine Tablets (including a third of patients who were exposed in the first trimester), and published data of over 1,000 pregnant patients who were exposed to artemisinin derivatives, did not show an increase in adverse pregnancy outcomes or teratogenic effects over background rate.
  • The efficacy of Artemether/Lumefantrine Tablets in the treatment of acute, uncomplicated malaria in pregnant women has not been established.
  • Artemether/Lumefantrine Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
  • Pregnant rats dosed during the period of organogenesis at or higher than a dose of about half the highest clinical dose of 1120 mg artemether-lumefantrine per day (based on body surface area comparisons), showed increases in fetal loss, early resorptions and post implantation loss. No adverse effects were observed in animals dosed at about one-third the highest clinical dose. Similarly, dosing in pregnant rabbits at about three times the clinical dose (based on body surface area comparisons) resulted in abortions, preimplantation loss, post implantation loss and decreases in the number of live fetuses. No adverse reproductive effects were detected in rabbits at two times the clinical dose. Embryo-fetal loss is a significant reproductive toxicity. Other artemisinins are known to be embryotoxic in animals. However, because metabolic profiles in animals and humans are dissimilar, artemether exposures in animals may not be predictive of human exposures [see Nonclinical Toxicology (13.2)]. These data cannot rule out an increased risk for early pregnancy loss or fetal defects in humans.


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Artemether and lumefantrin in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Artemether and lumefantrin during labor and delivery.

Nursing Mothers

  • It is not known whether artemether or lumefantrine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Artemether/Lumefantrine Tablets are administered to a nursing woman. Animal data suggest both artemether and lumefantrine are excreted into breast milk. The benefits of breastfeeding to mother and infant should be weighed against potential risk from infant exposure to artemether and lumefantrine through breast milk.

Pediatric Use

  • The safety and effectiveness of Artemether/Lumefantrine Tablets have been established for the treatment of acute, uncomplicated malaria in studies involving pediatric patients weighing 5 kg or more [see Clinical Studies (14.1)]. The safety and efficacy have not been established in pediatric patients who weigh less than 5 kg. Children from non-endemic countries were not included in clinical trials.

Geriatic Use

  • Clinical studies of Artemether/Lumefantrine Tablets did not include sufficient numbers of subjects aged 65 years and over to determine they respond differently from younger subjects. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing Artemether/Lumefantrine Tablets.

Gender

There is no FDA guidance on the use of Artemether and lumefantrin with respect to specific gender populations.

Race

There is no FDA guidance on the use of Artemether and lumefantrin with respect to specific racial populations.

Renal Impairment

  • No specific pharmacokinetic studies have been performed in patients with either hepatic or renal impairment. Artemether/Lumefantrine Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment. Based on the pharmacokinetic data in 16 healthy subjects showing no or insignificant renal excretion of lumefantrine, artemether and DHA, no dose adjustment for the use of Artemether/Lumefantrine in patients with renal impairment is advised. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment [see Dosage and Administration (2.4) and Warnings and Precautions (5.6)].

Hepatic Impairment

  • No specific pharmacokinetic studies have been performed in patients with either hepatic or renal impairment. Artemether/Lumefantrine Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment. Based on the pharmacokinetic data in 16 healthy subjects showing no or insignificant renal excretion of lumefantrine, artemether and DHA, no dose adjustment for the use of Artemether/Lumefantrine in patients with renal impairment is advised. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment [see Dosage and Administration (2.4) and Warnings and Precautions (5.6)].

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Artemether and lumefantrin in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Artemether and lumefantrin in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Artemether and lumefantrin Administration in the drug label.

Monitoring

There is limited information regarding Artemether and lumefantrin Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Artemether and lumefantrin and IV administrations.

Overdosage

  • There is no information on overdoses of Artemether/Lumefantrine Tablets higher than the doses recommended for treatment.
  • In cases of suspected overdosage, symptomatic and supportive therapy, which would include ECG and blood electrolyte monitoring, should be given as appropriate.

Pharmacology

Template:Px
Artemether and lumefantrin
Systematic (IUPAC) name
(3R,5aS,6R,8aS,9R,10S,12R,12aR)-10-methoxy-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]-2-benzopyran
Identifiers
CAS number 71963-77-4
ATC code P01BE02
PubChem 68911
DrugBank DB06697
Chemical data
Formula Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox 
Mol. mass 298.374 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability ?
Metabolism ?
Half life ?
Excretion ?
Therapeutic considerations
Pregnancy cat.

C(US)

Legal status

POM(UK)

Routes Oral

Mechanism of Action

  • Artemether/Lumefantrin Tablets, a fixed dose combination of artemether and lumefantrine in the ratio of 1:6, is an antimalarial agent. Artemether is rapidly metabolized into an active metabolite dihydroartemisinin (DHA). The antimalarial activity of artemether and DHA has been attributed to endoperoxide moiety. The exact mechanism by which lumefantrine, exerts its antimalarial effect is not well defined. Available data suggest lumefantrine inhibits the formation of ќ≤-hematin by forming a complex with hemin. Both artemether and lumefantrine were shown to inhibit nucleic acid and protein synthesis.

Structure

Artemether has the empirical formula C16H26O5 with a molecular weight of 298.4, and the following structural formula:

Lumefantrin has the empirical formula C30H32Cl3NO with a molecular weight of 528.9, and the following structural formula:

Pharmacodynamics

There is limited information regarding Artemether and lumefantrin Pharmacodynamics in the drug label.

Pharmacokinetics

Absorption

  • Following administration of Artemether/Lumefantrine Tablets to healthy volunteers and patients with malaria, artemether is absorbed with peak plasma concentrations reached about 2 hours after dosing. Absorption of lumefantrine, a highly lipophilic compound, starts after a lag-time of up to 2 hours, with peak plasma concentrations about 6 to 8 hours after administration. The single dose (4 tablets) pharmacokinetic parameters for artemether, dihydroartemisinin (DHA), an active antimalarial metabolite of artemether, and lumefantrine in adult Caucasian healthy volunteers are given in Table 3. Multiple dose data after the 6-dose regimen of Artemether/Lumefantrine Tablets in adult malaria patients are given in Table 4.
  • Food enhances the absorption of both artemether and lumefantrine. In healthy volunteers, the relative bioavailability of artemether was increased between two- to three-fold, and that of lumefantrine sixteen-fold when Artemether/Lumefantrine Tablets were taken after a high-fat meal compared under fasted conditions. Patients should be encouraged to take Artemether/Lumefantrine Tablets with a meal as soon as food can be tolerated.

Distribution

  • Artemether and lumefantrine are both highly bound to human serum proteins in vitro (95.4% and 99.7%, respectively). Dihydroartemisinin is also bound to human serum proteins (47% to 76%). Protein binding to human plasma proteins is linear.

Biotransformation

Elimination

  • Artemether and DHA are cleared from plasma with an elimination half-life of about 2 hours. Lumefantrine is eliminated more slowly, with an elimination half-life of 3-6 days in healthy volunteers and in patients with falciparum malaria. Demographic characteristics such as sex and weight appear to have no clinically relevant effects on the pharmacokinetics of artemether and lumefantrine.
  • In 16 healthy volunteers, neither lumefantrine nor artemether was found in the urine after administration of Artemether/Lumefantrin and urinary excretion of DHA amounted to less than 0.01% of the artemether dose.

Pharmacokinetics in Special Population

Hepatic and Renal Impairment

  • No specific pharmacokinetic studies have been performed in patients with either hepatic or renal impairment.
  • There is no significant renal excretion of lumefantrine, artemether and DHA in healthy volunteers and while clinical experience in this population is limited, no dose adjustment in renal impairment is recommended.

Pediatric Patients=

  • The PK of artemether, DHA, and lumefantrine were obtained in two pediatric studies by sparse sampling using a population based approach. PK estimates derived from a composite plasma concentration profile for artemether, DHA, and lumefantrine are provided in Table 4.
  • Systemic exposure to artemether, DHA, and lumefantrine, when dosed on a mg/kg body weight basis in pediatric patients (вЙ•5 to <35 kg body weight), is comparable to that of the recommended dosing regimen in adult patients.

Geriatric Patients

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

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

  • Carcinogenicity studies were not conducted.

Mutagenesis

  • No evidence of mutagenicity was detected. The artemether: lumefantrine combination was evaluated using the Salmonella and Escherichia/mammalian-microsome mutagenicity test, the gene mutation test with Chinese hamster cells V79, the cytogenetic test on Chinese hamster cells in vitro, and the rat micronucleus test, in vivo.

Impairment of Fertility

  • Pregnancy rates were reduced by about one half in female rats dosed for 2 to 4 weeks with the artemether-lumefantrine combination at 1000 mg/kg (about 9 times the clinical dose based on body surface area comparisons).
  • Male rats dosed for 70 days showed increases in abnormal sperm (87% abnormal) and increased testes weights at 30 mg/kg doses (about one third the clinical dose). Higher doses (about 9 times the clinical dose) resulted in decreased sperm motility and 100% abnormal sperm cells.

Animal Toxicology and/or Pharmacology

  • Neonatal rats (7-21 days old) were more sensitive to the toxic effects of artemether (a component of Artemether/Lumefantrin than older juvenile rats or adults. Mortality and severe clinical signs were observed in neonatal rats at doses which were well tolerated in pups above 22 days old.

Clinical Studies

Treatment of Acute, Uncomplicated P. falciparum Malaria

  • The efficacy of Artemether/Lumefantrin Tablets was evaluated for the treatment of acute, uncomplicated malaria caused by P. falciparum in HIV negative patients in 8 clinical studies. Uncomplicated malaria was defined as symptomatic P. falciparum malaria without signs and symptoms of severe malaria or evidence of vital organ dysfunction. Baseline parasite density ranged from 500/µL - 200,000/µL (0.01% to 4% parasitemia) in the majority of patients. Studies were conducted in partially immune and non-immune adults and children (вЙ•5kg body weight) with uncomplicated malaria in China, Thailand, sub-Saharan Africa, Europe, and South America. Patients who had clinical features of severe malaria, severe cardiac, renal, or hepatic impairment were excluded.
  • The studies include two 4-dose studies assessing the efficacy of the components of the regimen, a study comparing a 4-dose versus a 6-dose regimen, and 5 additional 6-dose regimen studies.
  • Artemether/Lumefantrin Tablets were administered at 0, 8, 24, and 48 hours in the 4-dose regimen, and at 0, 8, 24, 36, 48, and 60 hours in the 6-dose regimen. Efficacy endpoints consisted of:
    • 28 day cure rate, defined as clearance of asexual parasites (the erythrocytic stage) within 7 days without recrudescence by day 28
    • Parasite clearance time (PCT), defined as time from first dose until first total and continued disappearance of asexual parasite which continues for a further 48 hours
    • Fever clearance time (FCT), defined as time from first dose until the first time body temperature fell below 37.5°C and remained below 37.5°C for at least a further 48 hours (only for patients with temperature >37.5°C at baseline)

The modified intent to treat (mITT) population includes all patients with malaria diagnosis confirmation who received at least one dose of study drug. Evaluable patients generally are all patients who had a day 7 and a day 28 parasitological assessment or experienced treatment failure by day 28.

  • Studies 1 and 2: The two studies which assessed the efficacy of Artemether/Lumefantrine Tablets (4 doses of 4 tablets of 20 mg artemether/120 mg lumefantrine) compared to each component alone were randomized, double-blind, comparative, single center, conducted in China. The efficacy results (Table 5) support that the combination of artemether and lumefantrine in Artemether/Lumefantrin Tablets had a significantly higher 28-day cure rate compared to artemether and had a significantly faster parasite clearance time (PCT) and fever clearance time (FCT) compared to lumefantrine.
  • Results of 4-dose studies conducted in areas with high resistance such as Thailand during 1995-96 showed lower efficacy results than the above studies. Therefore, Study 3 was conducted.

Study 3: Study 3 was a randomized, double-blind, two-center study conducted in Thailand in adults and children (aged вЙ•2 years), which compared the 4-dose regimen (administered over 48 hours) of Artemether/Lumefantrine Tablets to a 6-dose regimen (administered over 60 hours). Twenty-eight day cure rate in mITT subjects was 81% (96/118) for the Artemether/Lumefantrine Tablets 6-dose arm as compared to 71% (85/120) in the 4-dose arm.

Studies 4, 5, 6, 7, and 8: In these studies, Artemether/Lumefantrine Tablets were administered as the 6-dose regimen.

  • In study 4, a total of 150 adults and children aged вЙ•2 years received Artemether/Lumefantrine Tablets. In study 5, a total 164 adults and children вЙ•12 years received Artemether/Lumefantrine Tablets. Both studies were conducted in Thailand.
  • Study 6 was a study of 165 non-immune adults residing in regions non-endemic for malaria (Europe and Colombia) who contracted acute uncomplicated falciparum malaria when traveling in endemic regions.
  • Study 7 was conducted in Africa in 310 infants and children aged 2 months to 9 years, weighing 5 kg to 25 kg, with an axillary temperature вЙ•37.5ºC.
  • Study 8 was conducted in Africa in 452 infants and children, aged 3 months to 12 years, weighing 5 kg to <35 kg, with fever (вЙ•37.5°C axillary or вЙ•38°C rectally) or history of fever in the preceding 24 hours.
  • Results of 28-day cure rate, median parasite clearance time (PCT), and fever clearance time (FCT) for Studies 3 to 8 are reported in Table 6.
  • In all studies, patients’ signs and symptoms of malaria resolved when parasites were cleared.
  • In studies conducted in areas with high transmission rates, such as Africa, reappearance of P. falciparum parasites may be due to recrudescence or a new infection.

The efficacy by body weight category for studies 7 and 8 is summarized in Table 7.

How Supplied

Artemether/Lumefantrine (artemether/lumefantrine) Tablets

20 mg/120 mg Tablets - yellow, round flat tablets with beveled edges and scored on one side. Tablets are imprinted with N/C on one side and CG on the other.

  • Bottle of 24: NDC 0078-0568-45

Storage

Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF)

Images

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Patient Counseling Information

There is limited information regarding Artemether and lumefantrin Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Artemether and lumefantrin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

There is limited information regarding Artemether and lumefantrin Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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