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ARTEMETHER/LUMEFANTRINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Artemether/lumefantrine is a combination antimalarial agent with a fixed ratio of 1:6. In vivo and in vitro activity suggests that artemether and lumefantrine, blood schizontocide agents, are active against the erythrocytic stages of Plasmodium falciparum.

Specific Substances

    1) Artemether
    2) Artemisinins
    3) Lumefantrine
    4) CAS 71963-77-4 (Artemether)
    5) CAS 82186-77-4 (Lumefantrine)

Available Forms Sources

    A) FORMS
    1) Tablets are yellow, round and flat and contain 20 mg artemether and 120 mg lumefantrine (Prod Info COARTEM(R) oral tablets, 2009).
    B) SOURCES
    1) Both agents are blood schizontocides with independent modes of action. Artemether is an artemisinin derivative. Artemisinins are extracted from a Chinese medicinal plant, which have potent and rapid activity against the blood stage of P. falciparum and P. vivax. However, artemisinins have a short half-life and are usually combined with a longer-acting antimalarial agent (Prod Info COARTEM(R) oral tablets, 2009; None Listed, 2008). Artemether (half-life 2 hours) is marketed with lumefantrine, a highly lipophilic compound which has a similar structure to halofantrine, which has a half-life of 2 to 3 days (Prod Info COARTEM(R) oral tablets, 2009; None Listed, 2008; Omari et al, 2004).
    C) USES
    1) Artemether/lumefantrine is indicated in the treatment of acute, uncomplicated malaria infections due to Plasmodium falciparum (Prod Info COARTEM(R) oral tablets, 2009). This fixed dose combination was originally developed in China. Artemether acts to rapidly reduce parasitemia, providing symptomatic relief, while lumefantrine can eliminate residual parasites. This combination is considered highly effective against multidrug-resistant P. falciparum (World Health Organization, 2006; Omari et al, 2004).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Artemether/lumefantrine is indicated for the treatment of acute, uncomplicated malaria due to Plasmodium falciparum. This agent is not intended for the prevention of malaria.
    B) PHARMACOLOGY: Each tablet contains a fixed dose combination of artemether, an artemisinin derivative, and lumefantrine, structurally similar to halofantrine, to treat uncomplicated malaria. Both agents are blood schizontocides with independent modes of action. Artemether can rapidly reduce parasitemia providing symptomatic relief, while lumefantrine can eliminate residual parasites to improve therapeutic efficacy. The combination of these agents can delay or avoid the development of resistance.
    C) TOXICOLOGY: Limited data. In animal studies, high doses of lipid soluble artemisinin preparations have produced neurotoxicity.
    D) EPIDEMIOLOGY: At the time of this review, there is no experience with overdose.
    E) WITH THERAPEUTIC USE
    1) COMMON: Headache, anorexia, dizziness, and asthenia are common in adults, while pyrexia, cough, vomiting, anorexia, and headache have been reported frequently in children. Most adverse events are mild and do not require discontinuation of therapy; many adverse events were likely related to the underlying malaria rather than adverse drug events. GENERAL: Other events reported in both adults and children include: malaise, arthralgias, hepatomegaly, splenomegaly, anemia, and rash. QT prolongation may occur with therapy and may be more likely to occur in patients with a history of QT prolongation, receiving concomitant therapy that may prolong QT interval, or disturbances in electrolyte balance.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE ORAL TOXICITY: Toxicity is likely to be an extension of adverse events, including possible QTc prolongation. SEVERE TOXICITY: At the time of this review, there is no experience with overdose.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Pyrexia has been reported with therapeutic use.
    0.2.20) REPRODUCTIVE
    A) Artemether/lumefantrine is classified as FDA pregnancy category C. A systematic review of the safety of artemether/lumefantrine use during pregnancy found that there was no association between the use of artemether/lumefantrine during the second and third trimesters and increased adverse pregnancy outcomes compared with other antimalarials. In a pregnancy study of 500 pregnant women exposed to artemether/lumefantrine, there were no increases in adverse outcomes or teratogenic effects over background rates. In animal studies, an increase in fetal loss and a decrease in live fetuses were observed at doses of about half the highest clinical dose.

Laboratory Monitoring

    A) Monitor fluid and electrolytes in patients with significant vomiting and/or diarrhea.
    B) Monitor ECG for QT interval prolongation following a significant exposure, or in a patient at risk to develop QT prolongation.
    C) Monitor liver enzymes for transient elevations following a significant overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Patients may require ECG and cardiac monitoring following a significant exposure or patient's at risk (e.g., prior history of QT interval prolongation, coadministration of agents that prolong QT interval).
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive; closely monitor cardiac and neurologic function.
    C) DECONTAMINATION
    1) PREHOSPITAL: Gastrointestinal decontamination generally not necessary.
    2) HOSPITAL: Activated charcoal may be considered in patients with recent, large ingestions who are alert or in whom the airway is protected.
    D) AIRWAY MANAGEMENT
    1) Intubation and mechanical ventilation may be necessary if significant CNS depression develops.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION
    1) Due to the fairly large volume of distribution and high plasma protein binding, enhanced elimination is NOT likely to be beneficial.
    G) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.
    2) ADMISSION CRITERIA: Patients with a deliberate ingestion, demonstrating cardiotoxicity or persistent neurotoxicity should be admitted.
    3) CONSULT CRITERIA: Call a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    H) PITFALLS
    1) When managing a suspected artemether/lumefantrine overdose, the possibility of coingestants should be determined. Coingestion of other agents (including other antimalarials {quinine, quinidine, halofantrine}) may increase the risk of QT prolongation and the potential development of ventricular dysrhythmias.
    I) PHARMACOKINETICS
    1) Peak plasma concentration for this combination medication is approximately 3 hours for artemether and 10 hours for lumefantrine. Artemether/lumefantrine is highly protein bound. Hepatic CYP450 metabolism (artemether primarily by CYP3A4/5 and, to a lesser extent, by CYP2B6, CYP2C9, and CYP2C19.; lumefantrine primarily by CYP3A4). Elimination half-life is approximately 1 hour for artemether; terminal half-life is 3 days for lumefantrine.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may increase QT prolongation.

Range Of Toxicity

    A) At the time of this review, a specific toxic dose has not been established.
    B) THERAPEUTIC: ADULT: 4 tablets as an initial dose, followed by 4 tablets 8 hours later, and then 4 tablets twice daily (morning and evening) for the following 2 days; total course of therapy is 24 tablets. PEDIATRIC: The number of tablets per dose is determined by weight (5 to < 15 kg = 1 tablet; 15 to < 25 kg = 2 tablets; 25 to < 35 kg = 3 tablets and 35 kg and over = 4 tablets). Total course of therapy is 6 doses given over 3 days.

Clinical Effects

Summary Of Exposure

    A) USES: Artemether/lumefantrine is indicated for the treatment of acute, uncomplicated malaria due to Plasmodium falciparum. This agent is not intended for the prevention of malaria.
    B) PHARMACOLOGY: Each tablet contains a fixed dose combination of artemether, an artemisinin derivative, and lumefantrine, structurally similar to halofantrine, to treat uncomplicated malaria. Both agents are blood schizontocides with independent modes of action. Artemether can rapidly reduce parasitemia providing symptomatic relief, while lumefantrine can eliminate residual parasites to improve therapeutic efficacy. The combination of these agents can delay or avoid the development of resistance.
    C) TOXICOLOGY: Limited data. In animal studies, high doses of lipid soluble artemisinin preparations have produced neurotoxicity.
    D) EPIDEMIOLOGY: At the time of this review, there is no experience with overdose.
    E) WITH THERAPEUTIC USE
    1) COMMON: Headache, anorexia, dizziness, and asthenia are common in adults, while pyrexia, cough, vomiting, anorexia, and headache have been reported frequently in children. Most adverse events are mild and do not require discontinuation of therapy; many adverse events were likely related to the underlying malaria rather than adverse drug events. GENERAL: Other events reported in both adults and children include: malaise, arthralgias, hepatomegaly, splenomegaly, anemia, and rash. QT prolongation may occur with therapy and may be more likely to occur in patients with a history of QT prolongation, receiving concomitant therapy that may prolong QT interval, or disturbances in electrolyte balance.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE ORAL TOXICITY: Toxicity is likely to be an extension of adverse events, including possible QTc prolongation. SEVERE TOXICITY: At the time of this review, there is no experience with overdose.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Pyrexia has been reported with therapeutic use.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Pyrexia was reported in 25% of adults and 29% of children (less than 16 years of age) following a 6-dose regimen of artemether/lumefantrine in active controlled and non-controlled, open-label trials (n=647 and n=1332, respectively), and was likely related to underlying malaria infection rather than an adverse drug event (Prod Info COARTEM(R) oral tablets, 2009).

Heent

    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) HEARING LOSS
    a) In a prospective study of 150 adults who received artemether/lumefantrine for uncomplicated malaria (6-dose regimen administered twice daily over 3 days), hearing thresholds were measured at several frequencies at the time of employment and following therapy. The findings suggested a subtle association between artemether/lumefantrine treatment and irreversible negative hearing threshold changes. Although the exact mechanism is unknown, artemisinins are known to be neurotoxic when given parenterally in laboratory animals and may be linked to ototoxicity. In addition, lumefantrine, a phenanthrene methanol derivative of quinine (which is known to be ototoxic), may have role in the development of ototoxicity. The authors suggest a possible additive or synergistic effect of the two agents (Toovey, 2006). Other studies have not reported any signs or symptoms of ototoxicity related to artemether/lumefantrine therapy (Abdulla et al, 2008).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) QT interval prolongation has been associated with some antimalarial agents (eg, halofantrine, quinine, quinidine), including artemether/lumefantrine. Patients at risk to develop QT interval prolongation (eg, congenital QT prolongation, family history, electrolyte disturbances, and coadministration of other agents they may potentially prolong the QT interval) should not receive artemether/lumefantrine. Concomitant therapy with other antimalarial agents is also not recommended (Prod Info COARTEM(R) oral tablets, 2009).
    b) No significant adverse cardiovascular events have been observed in malaria patients treated with fixed artemether/lumefantrine in available studies. Increases in the QTc interval and modest ST-elevations have occurred in some patients, although these changes were not clinically significant and were more likely related to malaria or recovery from malaria (Bindschedler et al, 2000; van Vugt et al, 1999; Looareesuwan et al, 1999; von Seidlein et al, 1997).
    c) In a prospective study of 165 non-immune patients with acute, uncomplicated P. falciparum malaria or mixed infection who were treated with 6-dose regimen of artemether/lumefantrine, no clinically relevant changes in mean or median QTc (using either Bazett's or Friedericia's formula) interval were observed. Most patients had QTc increases of less than 30 ms from baseline, and no patient had an absolute QTc value of great than 500 ms. One patient did have an increase of 71 ms from baseline (from 331 to 402 ms), but developed only mild symptoms of vertigo (Hatz et al, 2008).
    B) PALPITATIONS
    1) WITH THERAPEUTIC USE
    a) Palpitations were reported in 18% (n=115) of adults greater than 16 years of age following a 6-dose regimen of artemether/lumefantrine in active-controlled and non-controlled, open-label trials (n=647) (Prod Info COARTEM(R) oral tablets, 2009).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) COUGH
    1) WITH THERAPEUTIC USE
    a) Cough was reported in 6% of adults and 23% of children (less than 16 years of age) following a 6-dose regimen of artemether/lumefantrine in active controlled and non-controlled, open-label trials (n=647 and n=1332, respectively) (Prod Info COARTEM(R) oral tablets, 2009).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache was reported in 56% of adults and 13% of children (less than 16 years of age) following a 6-dose regimen of artemether/lumefantrine in active controlled and non-controlled, open-label trials (n=647 and n=1332, respectively) (Prod Info COARTEM(R) oral tablets, 2009).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness was reported in 39% of adults and 4% of children (less than 16 years of age) following a 6-dose regimen of artemether/lumefantrine in active controlled and non-controlled, open-label trials (n=647 and n=1332, respectively) (Prod Info COARTEM(R) oral tablets, 2009). In a prospective study, dizziness and other common adverse events were thought to be related to malaria infection (Hatz et al, 2008).
    C) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Ataxia, clonus, fine motor delay, hyperreflexia, hypoaesthesia, nystagmus and tremor have been reported infrequently in both adults and children (less than 16 years of age) following a 6-dose regimen of artemether/lumefantrine in active controlled and non-controlled, open-label trials (n=647 and n=1332, respectively) (Prod Info COARTEM(R) oral tablets, 2009).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea was reported in 26% of adults and 5% of children (less than 16 years of age) following a 6-dose regimen of artemether/lumefantrine in active controlled and non-controlled, open-label trials (n=647 and n=1332, respectively). In the same studies, abdominal pain occurred in 17% of adults and 8% of children (Prod Info COARTEM(R) oral tablets, 2009). In a prospective study, gastrointestinal symptoms and other common adverse events were thought to be related to malaria infection (Hatz et al, 2008).
    B) VOMITING
    1) WITH THERAPEUTIC USE
    a) Vomiting was reported in 17% of adults and 18% of children (less than 16 years of age) following a 6-dose regimen of artemether/lumefantrine in active controlled and non-controlled, open-label trials (n=647 and n=1332, respectively) (Prod Info COARTEM(R) oral tablets, 2009).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea was reported in 7% of adults and 8% of children (less than 16 years of age) following a 6-dose regimen of artemether/lumefantrine in active controlled and non-controlled, open-label trials (n=647 and n=1332, respectively) (Prod Info COARTEM(R) oral tablets, 2009).
    D) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia was reported in 40% of adults and 13% of children (less than 16 years of age) following a 6-dose regimen of artemether/lumefantrine in active controlled and non-controlled, open-label trials (n=647 and n=1332, respectively) (Prod Info COARTEM(R) oral tablets, 2009).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) JAUNDICE
    1) WITH THERAPEUTIC USE
    a) In a randomized clinical trial to determine the efficacy of artemether/lumefantrine as compared to sulfadoxine-pyrimethamine, 21.7% of artmether/lumefantrine-treated patients (n=104/485) developed jaundice, as compared to 10.7% (n=51/486) treated with sulfadoxine-pyrimethamine (Mulenga et al, 2006). In this study, adverse events did not result in an interruption or discontinuation of therapy.
    B) LARGE LIVER
    1) WITH THERAPEUTIC USE
    a) Hepatomegaly was reported in 9% of adults and 6% of children (less than 16 years of age) following a 6-dose regimen of artemether/lumefantrine in active controlled and non-controlled, open-label trials (n=647 and n=1332, respectively) (Prod Info COARTEM(R) oral tablets, 2009).
    C) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) In a prospective study of 165 nonimmune patients with acute, uncomplicated P. falciparum malaria or mixed infection who were treated with a 6-dose regimen of artemether/lumefantrine, 9 patients developed elevated transaminase or bilirubin concentrations. In most cases, laboratory analyses were within normal range by Day 28. An increase in SGPT (up to 2.5 times the upper limit of normal) was also observed in one case (Hatz et al, 2008).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) Splenomegaly was reported in 9% of both adults and children (less than 16 years of age) following a 6-dose regimen of artemether/lumefantrine in active controlled and non-controlled, open-label trials (n=647 and n=1332, respectively). In the same studies, anemia occurred in 4% of adults and 9% of children (Prod Info COARTEM(R) oral tablets, 2009).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) In a prospective study of 165 nonimmune patients with acute, uncomplicated P. falciparum malaria or mixed infection who were treated with a 6-dose regimen of artemether/lumefantrine, 4 patients developed anemia. Of those patients, one developed microcytic anemia and thrombocytopenia. By Day 28, laboratory results (ie, hemoglobin, hematocrit and platelet count) were normal in all patients (Hatz et al, 2008).
    C) AUTOIMMUNE HEMOLYTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Autoimmune hemolytic anemia was associated with the use of artemether/lumefantrine therapy in a 57-year-old man with history of multiple episodes of P. falciparum malaria attacks and blackwater fever complicated by autoimmune hemolytic anemia due to halofantrine therapy. Anemia and thrombocytopenia were observed 24 hours after taking 8 tablets. Blood count showed normochromic, normocytic, regenerative severe anemia (hemoglobin 4 g/dL). The patient recovered completely with supportive care (Merat et al, 2003). The authors suggested that the severe anemia observed was likely due to an immunoallergy response to lumefantrine.

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash was reported in 3% of both adults and children (less than 16 years of age) following a 6-dose regimen of artemether/lumefantrine in active controlled and non-controlled, open-label trials (n=647 and n=1332, respectively) (Prod Info COARTEM(R) oral tablets, 2009).
    B) URTICARIA
    1) WITH THERAPEUTIC USE
    a) Pruritus was reported in 4% of adults following a 6-dose regimen of artemether/lumefantrine in active controlled and non-controlled, open-label trials (n=647) (Prod Info COARTEM(R) oral tablets, 2009).
    C) BULLOUS ERUPTION
    1) WITH THERAPEUTIC USE
    a) In postmarketing experience, bullous eruptions have been rarely reported with therapeutic use of artemether/lumefantrine (Prod Info COARTEM(R) oral tablets, 2009).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgia was reported in 34% of adults and 3% of children (less than 16 years of age) following a 6-dose regimen of artemether/lumefantrine in active controlled and non-controlled, open-label trials (n=647 and n=1332, respectively) (Prod Info COARTEM(R) oral tablets, 2009).
    B) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgia was reported in 32% of adults and 3% of children (less than 16 years of age) following a 6-dose regimen of artemether/lumefantrine in active controlled and non-controlled, open-label trials (n=647 and n=1332, respectively) (Prod Info COARTEM(R) oral tablets, 2009).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) In postmarketing experience, hypersensitivity reactions (includes urticaria and angioedema) have been reported with therapeutic use of artemether/lumefantrine (Prod Info COARTEM(R) oral tablets, 2009).
    b) CASE REPORT - A 9-year-old boy (37 kg), with a prior history of malaria and treated with quinine and artesunate without any adverse effects, was treated for suspected malaria with artemether/lumefantrine. He developed severe coughing episodes (occurred 4.5 to 7 hours after administration) and bilateral eyelid edema after 2 doses. Following the third dose, an increase in bilateral eyelid edema and slight puffiness of the cheeks was observed. Therapy was discontinued. Loratadine was begun with gradual improvement of facial edema over the next 2 days. The patient recovered completely (Krippner & Staples, 2003).

Reproductive

    3.20.1) SUMMARY
    A) Artemether/lumefantrine is classified as FDA pregnancy category C. A systematic review of the safety of artemether/lumefantrine use during pregnancy found that there was no association between the use of artemether/lumefantrine during the second and third trimesters and increased adverse pregnancy outcomes compared with other antimalarials. In a pregnancy study of 500 pregnant women exposed to artemether/lumefantrine, there were no increases in adverse outcomes or teratogenic effects over background rates. In animal studies, an increase in fetal loss and a decrease in live fetuses were observed at doses of about half the highest clinical dose.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) In an observational study of approximately 500 pregnant women who received artemether/lumefantrine therapy (including a third of patients who were exposed during the first trimester), there was no increase in teratogenic effects over background rates. In addition, published data on over 1000 pregnant women receiving artemisinin derivatives did not reveal any increase in adverse outcomes (Prod Info Coartem(R) oral tablets, 2013).
    2) A systematic review of the safety of artemether/lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria during pregnancy found that there was no association between the use of artemether/lumefantrine during the second and third trimesters and increased adverse pregnancy outcomes compared with other antimalarials. As part of the review, 16 publications (including randomized clinical trials, observational trials, and previous systematic reviews) were identified that included reports of artemether or artemether/lumefantrine exposure during pregnancy. Overall, there were 1103 reports of artemether/lumefantrine use during pregnancy, including 890 second/third trimester exposures, 212 first trimester exposures, and 1 case where the trimester was not identified. Use of artemether/lumefantrine during the second and third trimesters was not associated with an increased risk of spontaneous abortion, stillbirth or congenital defects when compared with quinine, sulfadoxine/pyrimethamine, or artesunate (Manyando et al, 2012).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified artemether/lumefantrine as FDA pregnancy category C. It is recommended that the fixed-dose combination or artemether/lumefantrine should be administered only if the potential benefit to the mother justifies the potential risk to the fetus (Prod Info Coartem(R) oral tablets, 2013).
    B) ANIMAL STUDIES
    1) RATS, RABBITS: Increase in fetal loss, early resorptions, and post implantation losses were noted in studies of pregnant rats exposed during organogenesis to doses of at least 560 mg/day (half of the highest clinical dose). However, no adverse effects were observed at about one-third the highest clinical dose. Similarly, abortions, preimplantation loss, post implantation loss and decreases in the number of live fetuses occurred with exposures of about 3 times the clinical dose in pregnant rabbits, whereas exposures at 2 times the clinical dose produced no adverse reproductive effects (Prod Info Coartem(R) oral tablets, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is not known if artemether or lumefantrine are excreted in human milk. Data suggests that artemether and lumefantrine are excreted into breast milk in animals. Because many drugs are excreted into human milk, caution should be used when artemether/lumefantrine is administered to a nursing mother. The benefits to the mother should be weighed against the potential risk to the fetus with use of this combination in nursing mothers (Prod Info Coartem(R) oral tablets, 2013).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor fluid and electrolytes in patients with significant vomiting and/or diarrhea.
    B) Monitor ECG for QT interval prolongation following a significant exposure, or in a patient at risk to develop QT prolongation.
    C) Monitor liver enzymes for transient elevations following a significant overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who develop cardiotoxicity or persistent neurotoxicity should be admitted.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Call a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.

Monitoring

    A) Monitor fluid and electrolytes in patients with significant vomiting and/or diarrhea.
    B) Monitor ECG for QT interval prolongation following a significant exposure, or in a patient at risk to develop QT prolongation.
    C) Monitor liver enzymes for transient elevations following a significant overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not necessary.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment of artemether/lumefantrine overdose is symptomatic and supportive.
    B) MONITORING OF PATIENT
    1) Monitor fluid and electrolytes in cases of severe vomiting and diarrhea.
    2) Liver function tests should be monitored in symptomatic patients.
    3) Monitor ECG for QT interval prolongation or ECG abnormalities.
    C) PROLONGED QT INTERVAL
    1) Therapeutic doses of lumefantrine may cause prolongation of the QT interval. At the time of this review, there have been no reports of ventricular dysrhythmias or torsades de pointes. Other agents, including other antimalarials, should be used cautiously with artemether/lumefantrine because of the potential additive effects on QT interval and the prolonged half-life (3 to 6 days) of lumefantrine (Prod Info COARTEM(R) oral tablets, 2009).
    2) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    3) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    4) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    5) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    6) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    7) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    8) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

Enhanced Elimination

    A) SUMMARY
    1) Due to the fairly large volume of distribution and high plasma protein binding, enhanced elimination is NOT likely to be beneficial.

Range Of Toxicity

Summary

    A) At the time of this review, a specific toxic dose has not been established.
    B) THERAPEUTIC: ADULT: 4 tablets as an initial dose, followed by 4 tablets 8 hours later, and then 4 tablets twice daily (morning and evening) for the following 2 days; total course of therapy is 24 tablets. PEDIATRIC: The number of tablets per dose is determined by weight (5 to < 15 kg = 1 tablet; 15 to < 25 kg = 2 tablets; 25 to < 35 kg = 3 tablets and 35 kg and over = 4 tablets). Total course of therapy is 6 doses given over 3 days.

Therapeutic Dose

    7.2.1) ADULT
    A) ACUTE, UNCOMPLICATED MALARIA
    1) 35 KG OR MORE: Recommended oral dose is 4 tablets as a single initial dose, then 4 tablets as a single dose 8 hours later, then 4 tablets twice daily for 2 days (total of 24 tablets/course of therapy) (Prod Info Coartem(R) oral tablets, 2013).
    2) LESS THAN 35 KG: Refer to pediatric dosing.
    7.2.2) PEDIATRIC
    A) ACUTE, UNCOMPLICATED MALARIA
    1) 5 KG TO LESS THAN 15 KG: Recommended oral initial dose is 1 tablet, followed by 1 tablet after 8 hours, then 1 tablet twice daily for 2 days (total of 6 tablets/course of therapy) (Prod Info Coartem(R) oral tablets, 2013).
    2) 15 KG TO LESS THAN 25 KG: Recommended oral dose is 2 tablets as a single initial dose, then 2 tablets as a single dose 8 hours later, then 2 tablets twice daily for 2 days (total of 12 tablets/course of therapy)(Prod Info Coartem(R) oral tablets, 2013).
    3) 25 KG TO LESS THAN 35 KG: Recommended oral dose is 3 tablets as a single initial dose, then 3 tablets as a single dose 8 hours later, then 3 tablets twice daily for 2 days (total of 18 tablets/course of therapy) (Prod Info Coartem(R) oral tablets, 2013).
    4) 35 KG AND ABOVE: Recommended dose is 4 tablets as a single initial dose, then 4 tablets as a single dose 8 hours later, then 4 tablets twice daily for 2 days (total of 24 tablets/course of therapy) (Prod Info Coartem(R) oral tablets, 2013).
    5) DISPERSIBLE FORMULATION: In a non-randomized, non-inferiority study conducted among children (weighing 5-35 kg) with uncomplicated Plasmodium falciparum malaria, a sweetened cherry-flavored dispersible formulation which contained the same amount of artemether and lumefantrine as commercial crushed tablets was found to be similar in both efficacy and safety to the standard formulation (Abdulla et al, 2008).

Minimum Lethal Exposure

    A) At the time of this review, there is no data available to determine a minimum lethal exposure (Prod Info COARTEM(R) oral tablets, 2009).

Maximum Tolerated Exposure

    A) At the time of this review, there is no data available to determine a maximum tolerated exposure (Prod Info COARTEM(R) oral tablets, 2009).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Artemether/lumefantrine is produced as a 1:6 fixed dose combination. Both artemether and lumefantrine inhibit nucleic acid and protein synthesis. The antimalarial effect of artemether is due to the effects of the endoperoxide moiety of artemether and dihydroartemisinin, an active metabolite. Lumefantrine, a member of the aryl aminoalcohol group of antimalarials, inhibits beta-hematin formation by binding to hemin; however, the exact antimalarial mechanism of lumefantrine is unknown. It is a racemic fluorine derivative that was developed in China (Prod Info COARTEM(R) oral tablets, 2009; World Health Organization, 2006).

References

General Bibliography

    1) Abdulla S , Sagara I , Borrmann S , et al: Efficacy and safety of artemether-lumefantrine dispersible tablets compared with crushed commercial tablets in African infants and children with uncomplicated malaria: a randomised, single-blind, multicentre trial. Lancet 2008; 372(9652):1819-1827.
    2) American Heart Association: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005; 112(24 Suppl):IV 1-203. Available from URL: http://circ.ahajournals.org/content/vol112/24_suppl/. As accessed 12/14/2005.
    3) Bindschedler M , Lefevre G , Ezzet F , et al: Cardiac effects of co-artemether (artemether/lumefantrine) and mefloquine given alone or in combination to healthy volunteers. Eur J Clin Pharmacol 2000; 56(5):375-381.
    4) Charlton NP , Lawrence DT , Brady WJ , et al: Termination of drug-induced torsades de pointes with overdrive pacing. Am J Emerg Med 2010; 28(1):95-102.
    5) Drew BJ, Ackerman MJ, Funk M, et al: Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2010; 55(9):934-947.
    6) Hatz C , Soto J , Nothdurft HD , et al: Treatment of acute uncomplicated falciparum malaria with artemether-lumefantrine in nonimmune populations: a safety, efficacy, and pharmacokinetic study. Am J Trop Med Hyg 2008; 78(2):241-247.
    7) Keren A, Tzivoni D, & Gavish D: Etiology, warning signs and therapy of torsade de pointes: a study of 10 patients. Circulation 1981; 64:1167-1174.
    8) Khan IA & Gowda RM: Novel therapeutics for treatment of long-QT syndrome and torsade de pointes. Int J Cardiol 2004; 95(1):1-6.
    9) Krippner R & Staples J : Suspected allergy to artemether-lumefantrine treatment of malaria. J Travel Med 2003; 10(5):303-305.
    10) Link MS, Berkow LC, Kudenchuk PJ, et al: Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S444-S464.
    11) Looareesuwan S, Wilairatana P, Chokejindachai W, et al: A randomized, double-blind, comparative trial of a new oral combination of artemether and benflumetol (CGP 56697) with mefloquine in the treatment of acute Plasmodium falciparum malaria in Thailand. Am J Trop Med 1999; 60(2):238-243.
    12) Manyando C, Kayentao K, D'Alessandro U, et al: A systematic review of the safety and efficacy of artemether-lumefantrine against uncomplicated Plasmodium falciparum malaria during pregnancy. Malar J 2012; 11(1):141-.
    13) Merat S , Lambert E , Vincenti-Rouquette I , et al: Case report: combination artemether-lumefantrine and haemolytic anaemia following a malarial attack. Trans R Soc Trop Med Hyg 2003; 97(4):433-434.
    14) Mulenga M, VangGeertruyden JP, Mwananyanda L, et al: Safety and efficacy of lumefantrine-artemether (Coartem) for the treatment of uncomplicated Plasmodium falciparum malaria in Zambian adults. MalarJ 2006; 5:73.
    15) Na-Bangchang K, Karbwang J, Tasanor U, et al: Pharmacokinetics of benflumetol given as a fixed combination artemether-benflumetol (CGP 56697) in Thai patients with uncomplicated falciparum malaria. Int J Clin Pharm Res 1999; 19(2):41-46.
    16) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    17) None Listed : Artemether + lumefantrine: new drug. An alternative to atovaquone + proguanil. Prescrire Int 2008; 17(94):54-56.
    18) Omari AA , Gamble C , & Garner P : Artemether-lumefantrine for uncomplicated malaria: a systematic review. Trop Med Int Health 2004; 9(2):192-199.
    19) Perticone F, Ceravolo R, & Cuccurullo O: Prolonged magnesium sulfate infusion in the treatment of ventricular tachycardia in acquired long QT syndrome. Clin Drug Inverst 1997; 13:229-236.
    20) Product Information: COARTEM(R) oral tablets, artemether lumefantrine oral tablets. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2009.
    21) Product Information: Coartem(R) oral tablets, artemether lumefantrine oral tablets. Novartis Pharmaceuticals Corporation (per FDA), East Hanover, NJ, 2013.
    22) Product Information: Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, isoproterenol HCl intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection. Hospira, Inc. (per FDA), Lake Forest, IL, 2013.
    23) Product Information: magnesium sulfate heptahydrate IV, IM injection, solution, magnesium sulfate heptahydrate IV, IM injection, solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2009.
    24) Smith WM & Gallagher JJ: "Les torsades de pointes": an unusual ventricular arrhythmia. Ann Intern Med 1980; 93:578-584.
    25) Toovey S : Effects of weight, age, and time on artemether-lumefantrine associated ototoxicity and evidence of irreversibility. Travel Med Infect Dis 2006; 4(2):71-76.
    26) World Health Organization: Guidelines for the treatment of malaria. World Health Organization. Geneva, Switzerland. 2006. Available from URL: http://www.helid.desastres.net/gsdl2/tmp/export/who/s13418e.pdf. As accessed 2009-04-20.
    27) van Agtmael MA, Cheng-Qi S, Qing JX, et al: Multiple dose pharmacokinetics of artemether in Chinese patients with uncomplicated falciparum malaria. Int J Antimicrob Agents 1999a; 12:151-158.
    28) van Vugt M, Wilairatana P, Gemperli B, et al: Efficacy of six doses of artemether-lumefantrine (benflumetol) in multidrug-resistant Plasmodium falciparum malaria. Am J Trop Med Hyg 1999; 60(6):936-942.
    29) von Seidlein L, Jaffar S, Pinder M, et al: Treatment of African children with uncomplicated falciparum malaria with a new antimalarial drug, CGP 56697. J Infect Dis 1997; 176:1113-1116.