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Serious Adverse Reactions
The following serious and otherwise important adverse reactions are discussed in greater detail in other sections of labeling:
- Hypersensitivity Reactions [see CONTRAINDICATIONS and Postmarketing 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.
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 ( ≥ 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% (21/1,332) 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
|System Organ Class||Preferred Term||Adults*
|Nervous system disorders||Headache||360 (56)|
|Metabolism and nutrition disorders||Anorexia||260 (40)|
|General disorders and administration site conditions||Asthenia||243 (38)|
|Musculoskeletal and connective tissue disorders||Arthralgia||219 (34)|
|Gastrointestinal disorders||Nausea||169 (26)|
|Abdominal pain||112 (17)|
|Psychiatric disorders||Sleep disorder||144 (22)|
|Cardiac disorders||Palpitations||115 (18)|
|Hepatobiliary disorders||Hepatomegaly||59 (9)|
|Blood and lymphatic system disorders||Splenomegaly||57(9)|
|Respiratory, thoracic and mediastinal disorders||Cough||37 (6)|
|Skin and subcutaneous tissue disorders||Pruritus||24 (4)|
|Ear and labyrinth disorders||Vertigo||21 (3)|
|Infections and infestations||Malaria||18(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*
|General disorders and administration site conditions||Pyrexia||381 (29)|
|Respiratory, thoracic and mediastinal disorders||Cough||302 (23)|
|Abdominal pain||112 (8)|
|Infections and infestations||Plasmodium falciparum infection||224 (17)|
|Metabolism and nutrition disorders||Anorexia||175 (13)|
|Nervous system disorders||Headache||168 (13)|
|Blood and lymphatic system disorders||Splenomegaly||124 (9)|
|Hepatobiliary disorders||Hepatomegaly||75 (6)|
|Investigations||Aspartate aminotransferase increased||51 (4)|
|Musculoskeletal and connective tissue disorders||Arthralgia||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
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
Psychiatric disorders: agitation, mood swings
Respiratory, thoracic and mediastinal disorders: asthma, pharyngo-laryngeal pain
Skin and subcutaneous tissue disorders: urticaria
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.
Read the Coartem (artemether lumefantrine tablets) Side Effects Center for a complete guide to possible side effects
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].
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].
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].
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].
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
Last reviewed on RxList: 5/28/2013
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