Coartem Drug Information

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% were 16 years and younger and 33% 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 Dizziness 253 Metabolism and nutrition disorders Anorexia 260 General disorders and administration site conditions Asthenia 243 Pyrexia 159 Chills 147 Fatigue 111 Malaise 20 Musculoskeletal and connective tissue disorders Arthralgia 219 Myalgia 206 Gastrointestinal disorders Nausea 169 Vomiting 113 Abdominal pain 112 Diarrhea 46 Psychiatric disorders Sleep disorder 144 Insomnia 32 Cardiac disorders Palpitations 115 Hepatobiliary disorders Hepatomegaly 59 Blood and lymphatic system disorders Splenomegaly 57 Anemia 23 Respiratory, thoracic and mediastinal disorders Cough 37 Skin and subcutaneous tissue disorders Pruritus 24 Rash 21 Ear and labyrinth disorders Vertigo 21 Infections and infestations Malaria 18 Nasopharyngitis 17 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 Chills 72 Asthenia 63 Fatigue 46 Respiratory, thoracic and mediastinal disorders Cough 302 Gastrointestinal disorders Vomiting 242 Abdominal pain 112 Diarrhea 100 Nausea 61 Infections and infestations Plasmodium falciparum infection 224 Rhinitis 51 Metabolism and nutrition disorders Anorexia 175 Nervous system disorders Headache 168 Dizziness 56 Blood and lymphatic system disorders Splenomegaly 124 Anemia 115 Hepatobiliary disorders Hepatomegaly 75 Investigations Aspartate aminotransferase increased 51 Musculoskeletal and connective tissue disorders Arthralgia 39 Myalgia 39 Skin and subcutaneous tissue disorders Rash 38 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

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.

Rifampin Oral administration of rifampin, a strong

CYP3A4 inducer, with Coartem Tablets resulted in significant decreases in exposure to artemether, 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 .

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 .

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 . 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 .

Prior Use of Mefloquine

Administration of 3 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 .

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 CYP3A4. Therefore, Coartem Tablets may potentially reduce the effectiveness of hormonal contraceptives. Patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method or add a barrier method of contraception during treatment with Coartem .

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 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) .

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 .

Interaction With Drugs That are Known to Prolong the QT Interval Coartem

Tablets are to be used with caution when coadministered 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 .

Pregnancy Risk Summary Published data from clinical studies and pharmacovigilance data have not established an association with artemether/lumefantrine use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Malaria during and after pregnancy increases the risk for adverse pregnancy and neonatal outcomes, including maternal anemia, severe malaria, spontaneous abortion, stillbirths, preterm delivery, low birth weight, intrauterine growth restriction, congenital malaria, and maternal and neonatal mortality. Data Human Data While available studies cannot definitively establish the absence of risk, a meta-analysis of observational studies including over 500 artemether-lumefantrine exposed women in their first trimester of pregnancy, data from observational, and open label studies including more than 1200 pregnant women in their second- or third trimester exposed to artemether-lumefantrine compared to other antimalarials, and pharmacovigilance data have not demonstrated an increase in major birth defects, miscarriage, or adverse maternal or fetal outcomes. Published epidemiologic studies have important methodological limitations which hinder interpretation of data, including inability to control for confounders, such as underlying maternal disease, and maternal use of concomitant medications and missing information on the dose and duration of use.

Animal Data Pregnant rats dosed orally during the period of organogenesis at 50 mg/kg/day artemether-lumefantrine combination (corresponding to 7 mg/kg/day artemether or higher, a dose of less than half the maximum recommended human dose (MRHD) of 1120 mg artemether-lumefantrine per day (based on body surface area (BSA) comparisons), showed increases in fetal loss, early resorptions, and postimplantation loss. No adverse effects were observed in animals dosed at 25 mg/kg/day artemether-lumefantrine (corresponding to 3.6 mg/kg/day of artemether), about one-third the MRHD (based on BSA comparison). Similarly, oral dosing in pregnant rabbits during organogenesis (GD 7 through GD 19) at 175 mg/kg/day, (corresponding to 25 mg/kg/day artemether) about 3 times the MRHD (based on BSA comparisons) resulted in abortions, preimplantation loss, post implantation loss and decreases in the number of live fetuses. No adverse reproductive effects were detected in rabbits at 105 mg/kg/day artemether-lumefantrine (corresponding to 15 mg/kg/day artemether), about 2 times the MRHD. Artemether and other artemisinins are associated with maternal toxicity and embryotoxicity and malformations in animals at clinically relevant exposures; however, lumefantrine doses as high as 1000 mg/kg/day, showed no evidence to suggest maternal, embryo- or fetotoxicity or teratogenicity in rats and rabbits.

The relevance of the findings from the animal reproductive studies to human risk is unclear.

Pediatric Use The safety and effectiveness of Coartem Tablets have been established in pediatric patients aged 2 months and older with a bodyweight of 5 kg and above for the treatment of acute, uncomplicated malaria . The safety and effectiveness of Coartem Tablets have not been established in pediatric patients younger than 2 months old or who weigh less than 5 kg. Pediatric patients from non-endemic countries were not included in clinical trials.

Hypersensitivity Known hypersensitivity to artemether, lumefantrine, or to any of the excipients of Coartem Tablets . Strong CYP3A4 Inducers Coadministration 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 . Known hypersensitivity to artemether, lumefantrine, or to any of the excipients. Coadministration of strong inducers of CYP3A4 such as rifampin, carbamazepine, phenytoin, and St.

John’s wort with Coartem Tablets.

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.