Artemether/Lumefantrine
Artemisinin-based combination therapy (ACT)
What it is used for
acute, uncomplicated malaria infections due to Plasmodium falciparum (P. falciparum) in patients 2 months of age and older with a bodyweight of 5 kg and above. Coartem Tablets have been shown to be effective in geographical regions where resistance to chloroquine has been reported [see Clinical Studies (14.1)] . Limitations of Use : Coartem Tablets are not approved for patients with severe or complicated P. falciparum malaria. Coartem Tablets are not approved for the prevention of malaria. Coartem Tablets are a combination of artemether and lumefantrine, both antimalarials, indicated for treatment of acute, uncomplicated malaria infections due to Plasmodium falciparum (P. falciparum) in patients 2 months of age and older with a bodyweight of 5 kg and above. ( 1 ) Coartem Tablets have been shown to be effective in geographical regions where resistance to chloroquine has been reported. ( 1 ) Limitations of Use: ( 1 ) Coartem Tablets are not approved for patients with severe or complicated P. falciparum malaria . Coartem Tablets are not approved for the prevention of malaria.
Warnings
prolongation, those with hypokalemia or hypomagnesemia, and those taking other drugs that prolong the QT interval. ( 5.1 , 12.6 ) Halofantrine and Coartem Tablets should not be administered within one month of each other due to potential additive effects on the QT interval. ( 5.1 , 5.2 , 12.3 ) Antimalarials should not be given concomitantly, unless there is no other treatment option, due to limited safety data. ( 5.2 ) QT prolonging drugs, including quinine and quinidine, should be used cautiously following Coartem Tablets. ( 5.1 , 5.2 , 7.7 , 12.3 ) Substrates, inhibitors, or inducers of CYP3A4, including antiretroviral medications, should be used cautiously with Coartem Tablets, due to a potential loss of efficacy of the concomitant drug or additive QT prolongation. ( 5.3 , 7.2 , 7.3 ) 5.1 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 (ECG). Coartem 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 a family history of congenital prolongation of the QT interval or sudden death. With known disturbances of electrolyte balance, e.g., hypokalemia or hypomagnesemia. Receiving other medications that prolong the QT interval, such as Class IA (quinidine, procainamide, disopyramide), or Class III (amiodarone, sotalol) antiarrhythmic agents; antipsychotics (pimozide, ziprasidone); antidepressants; certain antibiotics (macrolide antibiotics, fluoroquinolone antibiotics, imidazole, and triazole antifungal agents) [see Clinical Pharmacology (12.6)] . Receiving medications that are metabolized by the cytochrome enzyme CYP2D6, which also have cardiac effects (e.g., flecainide, imipramine, amitriptyline, clomipramine) [see Warnings and Precautions (5.4), Drug Interactions (7.6), and Clinical Pharmacology (12.3)] . 5.2 Use of QT Prolonging Drugs and Other Antimalarials Halofantrine and Coartem Tablets should not be administered within 1 month of each other due to the long elimination half-life of lumefantrine (3 to 6 days) and potential additive effects on the QT interval [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)] . Antimalarials should not be given concomitantly with Coartem 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 to 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 [see Warnings and Precautions (5.1), Drug Interactions (7.7), and Clinical Pharmacology (12.3)] . 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 [see Dosage and Administration (2.1), Drug Interactions (7.4), and Clinical Pharmacology (12.3)] . 5.3 Drug Interactions With CYP3A4 When Coartem Tablets are coadministered with substrates of CYP3A4, it may result in decreased concentrations of the substrate and potential loss of substrate efficacy. When Coartem Tablets are coadministered 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 coadministered with inducers of CYP3A4, it may result in decreased concentrations of artemether and/or lumefantrine and loss of antimalarial efficacy [see Contraindications (4) and Drug Interactions (7)] . 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 [see Drug Interactions (7.3, 7.7)] . Coartem Tablets may reduce the effectiveness of hormonal contraceptives. Therefore, patients using hormonal contraceptives should be advised to use an alternative non-hormonal contraceptive method or add a barrier method of contraception during treatment with Coartem [see Drug Interactions (7.5)] . 5.4 Drug Interactions With CYP2D6 Administration of Coartem Tablets with drugs that are metabolized by CYP2D6 may significantly increase plasma concentrations of the coadministered 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) [see Warnings and Precautions (5.1), Drug Interactions (7.6), and Clinical Pharmacology (12.3)] . 5.5 Recrudescence Food enhances absorption of artemether and lumefantrine following administration of Coartem Tablets. Patients who remain averse to food during treatment should be closely monitored as the risk of recrudescence may be greater [see Dosage and Administration (2.1)] . In the event of recrudescent P. falciparum infection after treatment with Coartem Tablets, patients should be treated with a different antimalarial drug. 5.6 Hepatic and Renal Impairment Coartem Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment [see Dosage and Administration (2.4)] . 5.7 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.
Possible side effects
labeling: Hypersensitivity Reactions [see Contraindications (4)] Prolongation of the QT Interval [see Warnings and Precautions (5.1)] Use of QT Prolonging Drugs and Other Antimalarials [see Warnings and Precautions (5.2)] Drug Interactions with CYP3A4 [see Warnings and Precautions (5.3)] Drug Interactions with CYP2D6 [see Warnings and Precautions (5.4)] The most common adverse reactions in adults (greater than 30%) are headache, anorexia, dizziness, asthenia, arthralgia, and myalgia. The most common adverse reactions in children (greater than 12%) are pyrexia, cough, vomiting, anorexia, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials 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 Coartem Tablets in 1979 patients including 647 adults (older than 16 years) and 1332 children (16 years and younger). For the 6-dose regimen, Coartem Tablets was studied in active-controlled (366 patients) and noncontrolled, open-label trials (1613 patients). The 6-dose Coartem Tablets population was patients with malaria between ages 2 months and 71 years: 67% (1332) 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 (greater than or equal to 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. 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% (21/1332) in children. Table 1: Adverse Reactions Occurring in 3% or More of Adult Patients Treated in Clinical Trials With the 6-dose Regimen of Coartem Tablets *Adult patients defined as greater than 16 years of age. System Organ Class Preferred Term Adults* N = 647 (%) Nervous system disorders Headache 360 (56) Dizziness 253 (39) Metabolism and nutrition disorders Anorexia 260 (40) General disorders and administration site conditions Asthenia 243 (38) Pyrexia 159 (25) Chills 147 (23) Fatigue 111 (17) Malaise 20 (3) Musculoskeletal and connective tissue disorders Arthralgia 219 (34) Myalgia 206 (32) Gastrointestinal disorders Nausea 169 (26) Vomiting 113 (17) Abdominal pain 112 (17) Diarrhea 46 (7) Psychiatric disorders Sleep disorder 144 (22) Insomnia 32 (5) Cardiac disorders Palpitations 115 (18) Hepatobiliary disorders Hepatomegaly 59 (9) Blood and lymphatic system disorders Splenomegaly 57 (9) Anemia 23 (4) Respiratory, thoracic and mediastinal disorders Cough 37 (6) Skin and subcutaneous tissue disorders Pruritus 24 (4) Rash 21 (3) Ear and labyrinth disorders Vertigo 21 (3) Infections and infestations Malaria 18 (3) Nasopharyngitis 17 (3) Table 2: Adverse Reactions Occurring in 3% or More of Pediatric Patients Treated in Clinical Trials With the 6-dose Regimen of Coartem Tablets *Children defined as patients less than or equal to 16 years of age. System Organ Class Preferred Term Children* N = 1332 (%) General disorders and administration site conditions Pyrexia 381 (29) Chills 72 (5) Asthenia 63 (5) Fatigue 46 (3) Respiratory, thoracic and mediastinal disorders Cough 302 (23) Gastrointestinal disorders Vomiting 242 (18) Abdominal pain 112 (8) Diarrhea 100 (8) Nausea 61 (5) Infections and infestations Plasmodium falciparum infection 224 (17) Rhinitis 51 (4) Metabolism and nutrition disorders Anorexia 175 (13) Nervous system disorders Headache 168 (13) Dizziness 56 (4) Blood and lymphatic system disorders Splenomegaly 124 (9) Anemia 115 (9) Hepatobiliary disorders Hepatomegaly 75 (6) Investigations Aspartate aminotransferase increased 51 (4) Musculoskeletal and connective tissue disorders Arthralgia 39 (3) Myalgia 39 (3) Skin and subcutaneous tissue disorders Rash 38 (3) 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 less than 3% regardless of causality are listed below: Blood and Lymphatic System Disorders: eosinophilia Ear and Labyrinth Disorders: tinnitus Eye Disorders: conjunctivitis Gastrointestinal Disorders: constipation, dyspepsia, dysphagia, peptic ulcer General Disorders: gait disturbance Infections and Infestations: abscess, acrodermatitis, bronchitis, ear infection, gastroenteritis, helminthic infection, hook-worm infection, impetigo, influenza, lower respiratory tract infection, malaria, nasopharyngitis, oral herpes, pneumonia, respiratory tract infection, subcutaneous abscess, upper respiratory tract infection, urinary tract infection Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, hematocrit decreased, lymphocyte morphology abnormal, platelet count decreased, platelet count increased, white blood cell count decreased, white blood cell count increased Metabolism and Nutrition Disorders: hypokalemia Musculoskeletal and Connective Tissue Disorders: back pain Nervous System Disorders: ataxia, clonus, fine motor delay, hyperreflexia, hypoesthesia, nystagmus, tremor Psychiatric Disorders: agitation, mood swings Renal and Urinary Disorders: hematuria, proteinuria Respiratory, Thoracic and Mediastinal Disorders: asthma, pharyngo-laryngeal pain Skin and Subcutaneous Tissue Disorders: urticaria 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval 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. Hypersensitivity Reactions: anaphylaxis, urticaria, angioedema, and serious skin reactions (bullous eruption) have been reported. Blood and Lymphatic System Disorders: Cases of delayed hemolytic anemia have been reported following treatment with artemether-lumefantrine, mostly when used for treatment of severe malaria in patients initially treated with IV/parenteral artesunate. Coartem Tablets should not be used to treat severe malaria as it is not an approved indication.
Storage
16 HOW SUPPLIED/STORAGE AND HANDLING Coartem (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 Store at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature] . Dispense in tight container (USP).
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