Drug: Coartem
Coartem Tablets contain a fixed combination of two antimalarial active ingredients, artemether, an artemisinin derivative, and lumefantrine. Both components are blood schizontocides. The chemical name of artemether is (3R,5aS,6R,8aS,9R,10S,12R,12aR)-10-methoxy-3,6,9-trimethyldecahydro-3,12-epoxypyrano[4,3-j]-1,2benzodioxepine. Artemether is a white, crystalline powder that is freely soluble in acetone, soluble in methanol and ethanol, and practically insoluble in water. It has the empirical formula C16H26O5 with a molecular weight of 298.4, and the following structural formula: The chemical name of lumefantrine is (1RS)-2-(dibutylamino)-1-{(9Z)-2,7-dichloro-9-[(4chlorophenyl)methylene]-9H-fluorene-4-yl}ethanol. Lumefantrine is a yellow, crystalline powder that is freely soluble in N,N-dimethylformamide, chloroform, and ethyl acetate; soluble in dichloromethane; slightly soluble in ethanol and methanol; and insoluble in water. It has the empirical formula C30H32Cl3NO with a molecular weight of 528.9, and the following structural formula: Coartem Tablets are for oral administration. Each Coartem Tablet contains 20 mg of artemether and 120 mg lumefantrine. The inactive ingredients are colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, and polysorbate 80.
Source: http://www.rxlist.com
Serious Adverse Reactions The following serious and otherwise important adverse reactions are discussed in greater detail in other sections of labeling:
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) * Adult patients defined as > 16 years of age Table 2: Adverse Reactions Occurring in 3% or More of Pediatric Patients Treated in Clinical Trials with the 6-dose Regimen of Coartem Tablets
System Organ Class Preferred Term Children*
N=1,332 (%) 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) * Children defined as patients ≤ 16 years of age 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: 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, hookworm 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, hypoaesthesia, 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 Postmarketing Experience 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.
- Hypersensitivity Reactions [see CONTRAINDICATIONS and Postmarketing Experience].
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) * Adult patients defined as > 16 years of age Table 2: Adverse Reactions Occurring in 3% or More of Pediatric Patients Treated in Clinical Trials with the 6-dose Regimen of Coartem Tablets
System Organ Class Preferred Term Children*
N=1,332 (%) 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) * Children defined as patients ≤ 16 years of age 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: 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, hookworm 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, hypoaesthesia, 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 Postmarketing Experience 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.
- Hypersensitivity reactions including urticaria and angioedema. Serious skin reactions (bullous eruption) have been rarely reported.
Source: http://www.rxlist.com
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 [see WARNINGS AND PRECAUTIONS].
Source: http://www.rxlist.com
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 [see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY]. 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 [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. 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]. 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 [see WARNINGS AND PRECAUTIONS]. 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 [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. 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 [see WARNINGS AND PRECAUTIONSand CLINICAL PHARMACOLOGY]. 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) [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. 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 [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. 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 [see WARNINGS AND PRECAUTIONS]. Read the Coartem Drug Interactions Center for a complete guide to possible interactions Learn More »
Source: http://www.rxlist.com
Coartem (artemether/lumefantrine) Tablets are indicated for treatment of acute, uncomplicated malaria infections due to Plasmodium falciparum in patients of 5 kg bodyweight and above. Coartem Tablets have been shown to be effective in geographical regions where resistance to chloroquine has been reported [see Clinical Studies]. 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.
Source: http://www.rxlist.com
Hypersensitivity
This monograph has been modified to include the generic and brand name in many instances.
- Known hypersensitivity to artemether, lumefantrine, or to any of the excipients of Coartem Tablets [see ADVERSE REACTIONS].
- 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 [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].
This monograph has been modified to include the generic and brand name in many instances.
Source: http://www.rxlist.com
There is no information on overdoses of Coartem 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.
Source: http://www.rxlist.com
Dosage Forms And Strengths Coartem Tablets contain 20 mg of artemether and 120 mg of lumefantrine. Coartem Tablets are supplied as 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 side. 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 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in tight container (USP). Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936. Revised: Apr 2013 Last reviewed on RxList: 5/28/2013
This monograph has been modified to include the generic and brand name in many instances.
This monograph has been modified to include the generic and brand name in many instances.
Source: http://www.rxlist.com
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. Coartem Tablets should be avoided in patients:
This monograph has been modified to include the generic and brand name in many instances.
- 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); certain non-sedating antihistaminics (terfenadine, astemizole), or cisapride [see CLINICAL PHARMACOLOGY].
- receiving medications that are metabolized by the cytochrome enzyme CYP2D6 which also have cardiac effects (e.g., flecainide, imipramine, amitriptyline, clomipramine) [see DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].
- Instruct patients to take Coartem Tablets with food. Patients who do not have an adequate intake of food are at risk for recrudescence of malaria.
- Patients hypersensitive to artemether, lumefantrine, or to any of the excipients should not receive Coartem Tablets.
- Instruct patients to inform their physician of any personal or family history of QT prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or recent myocardial ischemia.
- Instruct patients to inform their physician if they are taking any 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); certain non-sedating antihistamines (terfenadine, astemizole), or cisapride.
- Instruct patients to notify their physicians if they have any symptoms of prolongation of the QT interval, including prolonged heart palpitations or a loss of consciousness.
- Instruct patients to avoid medications that are metabolized by the cytochrome enzyme CYP2D6 while receiving Coartem Tablets since these drugs also have cardiac effects (e.g., flecainide, imipramine, amitriptyline, clomipramine).
- Inform patients that based on animal data, Coartem Tablets administered during pregnancy may result in fetal loss. Fetal defects have been reported when artemisinins are administered to animals.
- Halofantrine and Coartem Tablets should not be administered within one month of each other due to 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.
- QT prolonging drugs, including quinine and quinidine, should be used cautiously following Coartem Tablets due to the long elimination half-life of lumefantrine and the potential for additive effects on the QT interval.
- Closely monitor food intake in patients who received mefloquine immediately prior to treatment with Coartem Tablets.
- Use Coartem Tablets cautiously in patients receiving other drugs that are substrates, inhibitors or inducers of CYP3A4, including grapefruit juice, especially those that prolong the QT interval or are anti-retroviral drugs.
- Co-administration of strong inducers of CYP3A4 such as rifampin, carbamazine, phenytoin and St. John's wort is contraindicated with Coartem 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.
- Inform patients that Coartem Tablets can cause hypersensitivity reactions. Instruct patients to discontinue the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (e.g., swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.
This monograph has been modified to include the generic and brand name in many instances.
Source: http://www.rxlist.com
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