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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 (artemether lumefantrine tablets) 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 (artemether lumefantrine tablets) Tablets was studied in active-controlled (366 patients) and non-controlled, open-label trials (1,613 patients). The 6-dose Coartem (artemether lumefantrine tablets) 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 (artemether lumefantrine tablets) 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 (artemether lumefantrine tablets) Tablets appeared similar to that of another antimalarial regimen.

Discontinuation of Coartem (artemether lumefantrine tablets) 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 (artemether lumefantrine tablets) Tablets

Table 2: Adverse Reactions Occurring in 3% or More of Pediatric Patients Treated in Clinical Trials with the 6-dose Regimen of Coartem (artemether lumefantrine tablets) Tablets

Clinically significant adverse reactions reported in adults and/or children treated with the 6-dose regimen of Coartem (artemether lumefantrine tablets) 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 (artemether lumefantrine tablets) 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 including urticaria and angioedema. Serious skin reactions (bullous eruption) have been rarely reported.

Ketoconazole

Concurrent oral administration of ketoconazole, a potent CYP3A4 inhibitor, with a single dose of Coartem (artemether lumefantrine tablets) Tablets resulted in a moderate increase in exposure to artemether, dihydroartemisinin (DHA, metabolite of artemether), and lumefantrine in a study of 15 healthy subjects. No dose adjustment of Coartem (artemether lumefantrine tablets) 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 (artemether lumefantrine tablets) Tablets should be used cautiously with drugs that inhibit CYP3A4 [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 (artemether lumefantrine tablets) 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].

CYP3A4 Metabolism: Hormonal Contraceptives and Anti-Retroviral Drugs

Artemether induces CYP3A4 and both artemether and lumefantrine are metabolized primarily by CYP3A4.

Coartem (artemether lumefantrine tablets) 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 [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Anti-Retroviral drugs (ARTs), such as protease inhibitors and non-nucleoside reverse transcriptase inhibitors, are known to have variable patterns of inhibition, induction or competition for CYP3A4. No formal drug-drug interaction studies between Coartem (artemether lumefantrine tablets) Tablets and ARTs have been performed. However, Coartem (artemether lumefantrine tablets) Tablets should be used cautiously in patients on ARTs as the result may be an increase in lumefantrine concentrations causing QT prolongation or a decrease in concentrations of the ART resulting in loss of efficacy, or a decrease in artemether and/or lumefantrine concentrations resulting in loss of antimalarial efficacy of Coartem Tablets [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

CYP2D6 Substrates

Lumefantrine inhibits CYP2D6 in vitro. Administration of Coartem (artemether lumefantrine tablets) 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 (artemether lumefantrine tablets) 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 (artemether lumefantrine tablets) 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 (artemether lumefantrine tablets) Tablets due to the long elimination half life of lumefantrine and the potential for additive QT effects, [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 5/4/2009
This monograph has been modified to include the generic and brand name in many instances.