Artemether And Lumefantrine

1 INDICATIONS AND USAGE Coartem Tablets are 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. 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.

2 DOSAGE AND ADMINISTRATION Coartem Tablets should be taken with food. ( 2.1 , 5.2 ) Tablets may be crushed and mixed with 1 to 2 teaspoons of water immediately prior to administration to patients, including children. ( 2.1 ) Coartem Tablets should be administered over 3 days for a total of 6 doses: an initial dose, second dose after 8 hours, and then twice-daily (morning and evening) for the following 2 days. ( 2.2 , 2.3 ) The adult dosage for patients with bodyweight of 35 kg and above is 4 tablets per dose for a total of 6 doses. ( 2.2 ) The number of tablets per dose for children is determined by bodyweight, as shown in the chart below. ( 2.3 ) Tablets per dose by bodyweight; total of 6 doses over 3 days 5 to < 15 kg 1 tablet 15 to < 25 kg 2 tablets 25 to < 35 kg 3 tablets 35 kg and over 4 tablets 2.1 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 (1 to 2 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 after administration, a repeat dose should be taken. If the repeat dose is vomited, the patient should be given an alternative antimalarial for treatment. 2.2 Dosage in Adult Patients (greater than 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 2 days (total course of 24 tablets). For patients weighing less than 35 kg, [see Dosage and Administration (2.3)] . 2.3 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 2 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 2 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 2 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 2 days (total course of 24 tablets). 2.4 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 (5.6)] .

6 ADVERSE REACTIONS The following serious and otherwise important adverse reactions are discussed in greater detail in other sections of 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.

12.3 Pharmacokinetics Absorption Following administration of Coartem Tablets to healthy volunteers and patients with malaria, artemether is absorbed with peak plasma concentrations reached about 2 hours after dosing. Absorption of lumefantrine, a highly lipophilic compound, starts after a lag-time of up to 2 hours, with peak plasma concentrations about 6 to 8 hours after administration. The single dose (4 tablets) pharmacokinetic parameters for artemether, DHA, an active antimalarial metabolite of artemether, and lumefantrine in adult Caucasian healthy volunteers are given in Table 3. Multiple dose data after the 6-dose regimen of Coartem Tablets in adult malaria patients are given in Table 4. Table 3: Single Dose Pharmacokinetic Parametersa for Artemether, Dihydroartemisinin, and Lumefantrine Under-Fed Conditions Abbreviations: DHA, dihydroartemisinin; SD, standard deviation; AUC, area under the curve. a Mean ± SD C max , AUC last , t ½ and Median T max . Study 2102 (n = 50) Study 2104 (n = 48) Artemether C max (ng/mL) 60.0 ± 32.5 83.8 ± 59.7 T max (h) 1.50 2.00 AUC last (ng·h/mL) 146 ± 72.2 259 ± 150 t ½ (h) 1.6 ± 0.7 2.2 ± 1.9 DHA C max (ng/mL) 104 ± 35.3 90.4 ± 48.9 T max (h) 1.76 2.00 AUC last (ng·h/mL) 284 ± 83.8 285 ± 98.0 t ½ (h) 1.6 ± 0.6 2.2 ± 1.5 Lumefantrine C max (µg/mL) 7.38 ± 3.19 9.80 ± 4.20 T max (h) 6.01 8.00 AUC last (µg·h/mL) 158 ± 70.1 243 ± 117 t ½ (h) 101 ± 35.6 119 ± 51.0 Food enhances the absorption of both artemether and lumefantrine. In healthy volunteers, the relative bioavailability of artemether was increased between 2- to 3-fold, and that of lumefantrine 16-fold when Coartem Tablets were taken after a high-fat meal compared under fasted conditions. Patients should be encouraged to take Coartem Tablets with a meal as soon as food can be tolerated [see Dosage and Administration (2.1)] . Distribution Artemether and lumefantrine are both highly bound to human serum proteins in vitro (95.4% and 99.7%, respectively). Dihydroartemisinin (DHA) is also bound to human serum proteins (47% to 76%). Protein binding to human plasma proteins is linear. Biotransformation In human liver microsomes and recombinant CYP450 enzymes, the metabolism of artemether was catalyzed predominantly by CYP3A4/5. Dihydroartemisinin (DHA) is an active metabolite of artemether. The metabolism of artemether was also catalyzed to a lesser extent by CYP2B6, CYP2C9 and CYP2C19. In vitro studies with artemether at therapeutic concentrations revealed no significant inhibition of the metabolic activities of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11. In vitro studies with artemether, DHA, and lumefantrine at therapeutic concentrations revealed no significant induction of the metabolic activities of CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, or CYP3A5. During repeated administration of Coartem Tablets, systemic exposure of artemether decreased significantly, while concentrations of DHA increased, although not to a statistically significant degree. The artemether/DHA area under the curve (AUC) ratio is 1.2 after a single dose and 0.3 after 6 doses given over 3 days. This suggests that there was induction of enzymes responsible for the metabolism of artemether. In human liver microsomes and in recombinant CYP450 enzymes, lumefantrine was metabolized mainly by CYP3A4 to desbutyl-lumefantrine. The systemic exposure to the metabolite desbutyl-lumefantrine was less than 1% of the exposure to the parent compound. In vitro , lumefantrine significantly inhibits the activity of CYP2D6 at therapeutic plasma concentrations. Caution is recommended when combining Coartem Tablets with substrates, inhibitors, or inducers of CYP3A4, especially antiretroviral drugs and those that prolong the QT interval (e.g., macrolide antibiotics, pimozide) [see Contraindications (4), Warnings and Precautions (5.1, 5.2, 5.3), and Drug Interactions (7)] . Coadministration of Coartem Tablets with CYP2D6 substrates may result in increased plasma concentrations of the CYP2D6 substrate and increase the risk of adverse reactions. In addition, 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, 5.4) and Drug Interactions (7.6)] . Elimination Artemether and DHA are cleared from plasma with an elimination half-life of about 2 hours. Lumefantrine is eliminated more slowly, with an elimination half-life of 3 to 6 days in healthy volunteers and in patients with falciparum malaria. Demographic characteristics such as sex and weight appear to have no clinically relevant effects on the pharmacokinetics of artemether and lumefantrine. In 16 healthy volunteers, neither lumefantrine nor artemether was found in the urine after administration of Coartem Tablets, and urinary excretion of DHA amounted to less than 0.01% of the artemether dose. Specific Populations Hepatic and Renal Impairment No specific pharmacokinetic studies have been performed in patients with either hepatic or renal impairment. There is no significant renal excretion of lumefantrine, artemether, and DHA in healthy volunteers and while clinical experience in this population is limited, no dose adjustment in renal impairment is recommended [see Dosage and Administration (2.4)] . Pediatric Patients The PK of artemether, DHA, and lumefantrine were obtained in 2 pediatric studies by sparse sampling using a population-based approach. PK estimates derived from a composite plasma concentration profile for artemether, DHA, and lumefantrine are provided in Table 4. Systemic exposure to artemether, DHA, and lumefantrine, when dosed on an mg/kg body weight basis in pediatric patients (greater than or equal to 5 to less than 35 kg body weight), is comparable to that of the recommended dosing regimen in adult patients. Table 4: Summary of Pharmacokinetic Parameters for Lumefantrine, Artemether, and DHA in Pediatric and Adult Patients With Malaria Following Administration of a 6-dose Regimen of Coartem Tablets Adults 1 Pediatric Patients (body weight, kg) 2 Drug 5 to < 15 15 to < 25 25 to < 35 Lumefantrine Mean C max , range (mcg/mL) 5.60-9.0 4.71–12.6 Not Available Mean AUC last , range (mcg·h/mL) 410-561 372–699 Not Available Artemether Mean C max ± SD (ng/mL) 186 ± 125 223 ± 309 198 ± 179 174 ± 145 Dihydroartemisinin Mean C max ± SD (ng/mL) 101 ± 58 54.7 ± 58.9 79.8 ± 80.5 65.3 ± 23.6 Abbreviations: AUC, area under the curve; DHA, dihydroartemisinin; SD, standard deviation. 1 There are a total of 181 adults for lumefantrine pharmacokinetic parameters and a total of 25 adults for artemether and dihydroartemisinin pharmacokinetic parameters. 2 There are 477 children for the lumefantrine pharmacokinetic parameters; for artemether and dihydroartemisinin pharmacokinetic parameters there are 55, 29, and 8 children for the 5 to less than 15, 15 to less than 25 and the 25 to less than 35 kg groups, respectively. Geriatric Patients No specific pharmacokinetic studies have been performed in patients older than 65 years of age. Drug Interaction Studies Rifampin (strong CYP3A4 inducer) Oral administration of rifampin (600 mg daily), a strong CYP3A4 inducer, with Coartem Tablets (6-dose regimen over 3 days) in 6 HIV-1 and tuberculosis co-infected adults without malaria resulted in significant decreases in exposure, in terms of AUC, to artemether, DHA 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 (4)] . Ketoconazole (potent CYP3A4 inhibitor) Concurrent oral administration of ketoconazole (400 mg on day 1 followed by 200 mg on Days 2, 3, 4, and 5) with Coartem Tablets (single-dose of 4 tablets of 20 mg artemether/120 mg lumefantrine per tablet) with a meal led to an increase in exposure, in terms of AUC, of artemether (2.3-fold), DHA (1.5-fold), and lumefantrine (1.6-fold) in 13 healthy subjects. The pharmacokinetics of ketoconazole was not evaluated. Based on this study, dose adjustment of Coartem Tablets is considered unnecessary when administered with ketoconazole or other 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 other drugs that inhibit CYP3A4 (e.g., antiretroviral drugs, macrolide antibiotics, antidepressants, imidazole antifungal agents) [see Warnings and Precautions (5.1, 5.3)] . Antimalarials The oral administration of mefloquine in 14 healthy volunteers administered as 3 doses of 500 mg, 250 mg, and 250 mg, followed 12 hours later by Coartem Tablets (6 doses of 4 tablets of 20 mg artemether/120 mg lumefantrine per tablet), had no effect on plasma concentrations of artemether or the artemether/DHA ratio. In the same study, there was a 30% reduction in C max and 40% reduction in AUC of lumefantrine, possibly due to lower absorption secondary to a mefloquine-induced decrease in bile production. Intravenous administration of a single dose of quinine (10 mg/kg bodyweight) concurrent with the last dose of a 6-dose regimen of Coartem Tablets had no effect on systemic exposure of DHA, lumefantrine, or quinine in 14 healthy volunteers. Mean AUC of artemether were 46% lower when administered with quinine compared to Coartem Tablets alone. This decrease in artemether exposure is not thought to be clinically significant. However, quinine should be used cautiously in patients following treatment with Coartem Tablets due to the long elimination half-life of lumefantrine and the potential for additive effects on the QT interval; ECG monitoring is advised if use of quinine is medically required [see Warnings and Precautions (5.2)] . Antiretroviral Drugs The oral administration of lopinavir/ritonavir (400 mg/100 mg twice daily for 26 days) in 10 healthy volunteers coadministered with Coartem Tablets (6-dose regimen over 3 days), resulted in a decrease in systemic exposures, in terms of AUC, to artemether and DHA by approximately 40%, but an increase in exposure to lumefantrine by approximately 2.3-fold. The oral administration of efavirenz (600 mg once daily for 26 days) in 12 healthy volunteers coadministered with Coartem Tablets (6-dose regimen over 3 days), resulted in a decrease in exposures to artemether, DHA, and lumefantrine by approximately 50%, 45%, and 20%, respectively. Exposures to lopinavir/ritonavir and efavirenz were not significantly affected by concomitant use of Coartem Tablets. Coartem Tablets should be used cautiously in patients on antiretroviral drugs such as HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors 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 (5.3) and Drug Interactions (7.3)] . Hormonal Contraceptives No clinical drug-drug interaction studies between Coartem Tablets and hormonal contraceptives have been performed. In vitro studies revealed that 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, coadministration of Coartem Tablets may potentially reduce the effectiveness of hormonal contraceptives [see Warnings and Precautions (5.3) and Drug Interactions (7.5)] .