ADVERSE REACTIONS SECTION.

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)] 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 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 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 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 and 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 TabletsAdult patients defined as greater than 16 years of age.System Organ ClassPreferred TermAdultsN 647 (%)Nervous system disordersHeadache360 (56)Dizziness253 (39)Metabolism and nutrition disordersAnorexia260 (40)General disorders and administration site conditionsAsthenia243 (38)Pyrexia159 (25)Chills147 (23)Fatigue111 (17)Malaise20 (3)Musculoskeletal and connective tissue disordersArthralgia219 (34)Myalgia206 (32)Gastrointestinal disordersNausea169 (26)Vomiting113 (17)Abdominal pain112 (17)Diarrhea46 (7)Psychiatric disordersSleep disorder144 (22)Insomnia32 (5)Cardiac disordersPalpitations115 (18)Hepatobiliary disordersHepatomegaly59 (9)Blood and lymphatic system disordersSplenomegaly57 (9)Anemia23 (4)Respiratory, thoracic and mediastinal disordersCough37 (6)Skin and subcutaneous tissue disordersPruritus24 (4)Rash21 (3)Ear and labyrinth disordersVertigo21 (3)Infections and infestationsMalaria18 (3)Nasopharyngitis17 (3)Table 2: Adverse Reactions Occurring in 3% or More of Pediatric Patients Treated in Clinical Trials With the 6-dose Regimen of Coartem TabletsChildren defined as patients less than or equal to 16 years of age.System Organ ClassPreferred TermChildrenN 1332 (%)General disorders and administration site conditionsPyrexia381 (29)Chills72 (5)Asthenia63 (5)Fatigue46 (3)Respiratory, thoracic and mediastinal disordersCough302 (23)Gastrointestinal disordersVomiting242 (18)Abdominal pain112 (8)Diarrhea100 (8)Nausea61 (5)Infections and infestationsPlasmodium falciparum infection224 (17)Rhinitis51 (4)Metabolism and nutrition disordersAnorexia175 (13)Nervous system disordersHeadache168 (13)Dizziness56 (4)Blood and lymphatic system disordersSplenomegaly124 (9)Anemia115 (9)Hepatobiliary disordersHepatomegaly75 (6)InvestigationsAspartate aminotransferase increased51 (4)Musculoskeletal and connective tissue disordersArthralgia39 (3)Myalgia39 (3)Skin and subcutaneous tissue disordersRash38 (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: eosinophiliaEar and Labyrinth Disorders: tinnitusEye Disorders: conjunctivitisGastrointestinal Disorders: constipation, dyspepsia, dysphagia, peptic ulcerGeneral Disorders: gait disturbanceInfections 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 infectionInvestigations: 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 increasedMetabolism and Nutrition Disorders: hypokalemiaMusculoskeletal and Connective Tissue Disorders: back pain Nervous System Disorders: ataxia, clonus, fine motor delay, hyperreflexia, hypoesthesia, nystagmus, tremorPsychiatric Disorders: agitation, mood swingsRenal and Urinary Disorders: hematuria, proteinuriaRespiratory, Thoracic and Mediastinal Disorders: asthma, pharyngo-laryngeal painSkin 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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.. 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Coartem Tablets, fixed dose combination of artemether and lumefantrine in the ratio of 1:6, is an antimalarial agent [see Microbiology (12.4)].. 12.3 Pharmacokinetics. AbsorptionFollowing administration of Coartem Tablets to healthy volunteers and patients with malaria, artemether is absorbed with peak plasma concentrations reached about hours after dosing. Absorption of lumefantrine, highly lipophilic compound, starts after lag-time of up to hours, with peak plasma concentrations about to 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 ConditionsAbbreviations: DHA, dihydroartemisinin; SD, standard deviation; AUC, area under the curve. aMean +- SD Cmax, AUClast, 1/2 and Median Tmax.Study 2102(n 50)Study 2104(n 48)ArtemetherCmax (ng/mL)60.0 +- 32.583.8 +- 59.7Tmax (h)1.502.00AUClast (ng.h/mL)146 +- 72.2259 +- 150t 1/2 (h)1.6 +- 0.72.2 +- 1.9DHACmax (ng/mL)104 +- 35.390.4 +- 48.9Tmax (h)1.762.00AUClast (ng.h/mL)284 +- 83.8285 +- 98.0t 1/2 (h)1.6 +- 0.62.2 +- 1.5LumefantrineCmax (ug/mL)7.38 +- 3.199.80 +- 4.20Tmax (h)6.018.00AUClast (ug.h/mL)158 +- 70.1243 +- 117t 1/2 (h)101 +- 35.6119 +- 51.0Food 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 high-fat meal compared under fasted conditions. Patients should be encouraged to take Coartem Tablets with meal as soon as food can be tolerated [see Dosage and Administration (2.1)].DistributionArtemether 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 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 statistically significant degree. The artemether/DHA area under the curve (AUC) ratio is 1.2 after single dose and 0.3 after doses given over 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)].EliminationArtemether and DHA are cleared from plasma with an elimination half-life of about hours. Lumefantrine is eliminated more slowly, with an elimination half-life of to 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 PopulationsHepatic and Renal ImpairmentNo 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 PatientsThe PK of artemether, DHA, and lumefantrine were obtained in pediatric studies by sparse sampling using population-based approach. PK estimates derived from 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 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 6-dose Regimen of Coartem TabletsAdults1 Pediatric Patients (body weight, kg)2 Drug5 to 1515 to 2525 to 35LumefantrineMean Cmax, range (mcg/mL)5.60-9.04.71-12.6Not AvailableMean AUClast, range (mcg.h/mL)410-561372-699Not AvailableArtemetherMean Cmax +- SD (ng/mL)186 +- 125223 +- 309198 +- 179174 +- 145DihydroartemisininMean Cmax +- SD (ng/mL)101 +- 5854.7 +- 58.979.8 +- 80.565.3 +- 23.6Abbreviations: AUC, area under the curve; DHA, dihydroartemisinin; SD, standard deviation. 1There are total of 181 adults for lumefantrine pharmacokinetic parameters and total of 25 adults for artemether and dihydroartemisinin pharmacokinetic parameters. 2There are 477 children for the lumefantrine pharmacokinetic parameters; for artemether and dihydroartemisinin pharmacokinetic parameters there are 55, 29, and children for the to less than 15, 15 to less than 25 and the 25 to less than 35 kg groups, respectively.Geriatric PatientsNo specific pharmacokinetic studies have been performed in patients older than 65 years of age.Drug Interaction StudiesRifampin (strong CYP3A4 inducer)Oral administration of rifampin (600 mg daily), strong CYP3A4 inducer, with Coartem Tablets (6-dose regimen over days) in 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. Johns wort is contraindicated with Coartem Tablets [see Contraindications (4)]. Ketoconazole (potent CYP3A4 inhibitor)Concurrent oral administration of ketoconazole (400 mg on day followed by 200 mg on Days 2, 3, 4, and 5) with Coartem Tablets (single-dose of tablets of 20 mg artemether/120 mg lumefantrine per tablet) with 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)].AntimalarialsThe oral administration of mefloquine in 14 healthy volunteers administered as doses of 500 mg, 250 mg, and 250 mg, followed 12 hours later by Coartem Tablets (6 doses of 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 30% reduction in Cmax and 40% reduction in AUC of lumefantrine, possibly due to lower absorption secondary to mefloquine-induced decrease in bile production.Intravenous administration of single dose of quinine (10 mg/kg bodyweight) concurrent with the last dose of 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 DrugsThe 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 days), resulted in 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 days), resulted in 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 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 ContraceptivesNo 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)]. 12.4 Microbiology. Mechanism of ActionCoartem Tablets, fixed ratio of 1:6 parts of artemether and lumefantrine, respectively, is an antimalarial agent. Artemether is rapidly metabolized into an active metabolite DHA. The antimalarial activity of artemether and DHA has been attributed to endoperoxide moiety. The exact mechanism by which lumefantrine exerts its antimalarial effect is not well defined. Available data suggest lumefantrine inhibits the formation of -hematin by forming complex with hemin. Both artemether and lumefantrine were shown to inhibit nucleic acid and protein synthesis. Activity In Vitro and In Vivo Artemether and lumefantrine are active against the erythrocytic stages of P. falciparum. Drug ResistanceThere is potential for development of resistance to artemether and lumefantrine. Strains of P. falciparum with moderate decrease in susceptibility to artemether or lumefantrine alone can be selected in vitro or in vivo, but not maintained in the case of artemether. Alterations in some genetic regions of P. falciparum [multidrug resistant (pfmdr1), chloroquine resistance transporter (pfcrt), and kelch 13 (K13)] based on in vitro testing and/or identification of isolates in endemic areas where artemether/lumefantrine treatment was administered, have been reported. The clinical relevance of these findings are not known.. 12.6 Effects on the Electrocardiogram. In healthy adult volunteer parallel-group study including placebo and moxifloxacin control-group (n 42 per group), the administration of the 6-dose regimen of Coartem Tablets was associated with prolongation of QTcF (Fridericia). Following administration of 6-dose regimen of Coartem Tablets consisting of tablets per dose (total of tablets of 80 mg artemether/480 mg lumefantrine) taken with food, the maximum mean change from baseline and placebo adjusted QTcF was 7.5 msec (1-sided 95% upper confidence interval: 11 msec). There was concentration-dependent increase in QTcF for lumefantrine.In clinical trials conducted in children, no patient had QTcF greater than 500 msec. Over 5% of patients had an increase in QTcF of over 60 msec.In clinical trials conducted in adults, QTcF prolongation of greater than 500 msec was reported in (0.3%) patients. Over 6% of adults had QTcF increase of over 60 msec from baseline.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Treatment of Acute, Uncomplicated P. falciparum Malaria. The efficacy of Coartem Tablets was evaluated for the treatment of acute, uncomplicated malaria caused by P. falciparum in HIV negative patients in clinical studies. Uncomplicated malaria was defined as symptomatic P. falciparum malaria without signs and symptoms of severe malaria or evidence of vital organ dysfunction. Baseline parasite density ranged from 500/mcL to 200,000/mcL (0.01% to 4% parastextia) in the majority of patients. Studies were conducted in partially immune and non-immune adults and children (greater than or equal to kg body weight) with uncomplicated malaria in China, Thailand, sub-Saharan Africa, Europe, and South America. Patients who had clinical features of severe malaria, severe cardiac, renal, or hepatic impairment were excluded.The studies include two 4-dose studies assessing the efficacy of the components of the regimen, study comparing 4-dose versus 6-dose regimen, and additional 6-dose regimen studies.Coartem Tablets were administered at 0, 8, 24, and 48 hours in the 4-dose regimen, and at 0, 8, 24, 36, 48, and 60 hours in the 6-dose regimen. Efficacy endpoints consisted of:28-day cure rate, defined as clearance of asexual parasites (the erythrocytic stage) within days without recrudescence by Day 28parasite clearance time (PCT), defined as time from first dose until first total and continued disappearance of asexual parasite which continues for further 48 hoursfever clearance time (FCT), defined as time from first dose until the first time body temperature fell below 37.5C and remained below 37.5C for at least further 48 hours (only for patients with temperature greater than 37.5C at baseline)The modified intent-to-treat (mITT) population includes all patients with malaria diagnosis confirmation who received at least dose of study drug. Evaluable patients generally are all patients who had Day and Day 28 parasitological assessment or experienced treatment failure by Day 28.Studies and 2: The studies, which assessed the efficacy of Coartem Tablets (4 doses of tablets of 20 mg artemether/120 mg lumefantrine) compared to each component alone, were randomized, double-blind, comparative, single center, conducted in China. The efficacy results (Table 5) support that the combination of artemether and lumefantrine in Coartem Tablets had significantly higher 28-day cure rate compared to artemether and had significantly faster PCT and FCT compared to lumefantrine.Table 5: Clinical Efficacy of Coartem Tablets Versus Components (mITT Population)1 Study No.Region/patient ages28-day cure rate2n/N (%) patientsMedian FCT3[25th, 75th percentile]Median PCT[25th, 75th percentile]Study 1China, ages 13 to 57 yearsCoartem Tablets 50/51 (98.0)24 hours [9, 48]30 hours [24, 36]Artemether4 24/52 (46.2)21 hours [12, 30]30 hours [24, 33]Lumefantrine5 47/52 (90.4)60 hours [36, 78]54 hours [45, 66]Study 2China, ages 12 to 65 yearsCoartem Tablets50/52 (96.2)21 hours [6, 33]30 hours [24, 36]Lumefantrine6 45/51 (88.2)36 hours [12, 60]48 hours [42, 60]Abbreviations: FCT, fever clearance time; mITT, modified intent-to-treat; PCT, parasite clearance time. 1In mITT analysis, patients whose status was uncertain were classified as treatment failures. 2Efficacy cure rate based on blood smear microscopy. 3For patients who had body temperature greater than 37.5C at baseline only. 495% Confidence Interval (Coartem Tablets-artemether) on 28-day cure rate: 37.8%, 66.0%. 5P-value comparing Coartem Tablets to lumefantrine on PCT and FCT: 0.001. 6P-value comparing Coartem Tablets to lumefantrine on PCT: 0.001 and on FCT: 0.05.Results of 4-dose studies conducted in areas with high resistance such as Thailand during 1995-96 showed lower efficacy results than the above studies. Therefore, Study was conducted.Study 3: Study was randomized, double-blind, 2-center study conducted in Thailand in adults and children (aged greater than or equal to years), which compared the 4-dose regimen (administered over 48 hours) of Coartem Tablets to 6-dose regimen (administered over 60 hours). Twenty-eight day cure rate in mITT subjects was 81% (96/118) for the Coartem Tablets 6-dose arm as compared to 71% (85/120) in the 4-dose arm. Studies 4, 5, 6, 7, and 8: In these studies, Coartem Tablets were administered as the 6-dose regimen. In study 4, total of 150 adults and children aged greater than or equal to years received Coartem Tablets. In study 5, total 164 adults and children greater than or equal to 12 years received Coartem Tablets. Both studies were conducted in Thailand.Study was study of 165 non-immune adults residing in regions non-endemic for malaria (Europe and Colombia) who contracted acute uncomplicated P. falciparum malaria when traveling in endemic regions.Study was conducted in Africa in 310 infants and children aged months to years, weighing kg to 25 kg, with an axillary temperature greater than or equal to 37.5oC.Study was conducted in Africa in 452 infants and children, aged months to 12 years, weighing kg to less than 35 kg, with fever (greater than or equal to 37.5C axillary or greater than or equal to 38C rectally) or history of fever in the preceding 24 hours.Results of 28-day cure rate, median PCT, and FCT for Studies to are reported in Table 6.Table 6: Clinical Efficacy of 6-dose Regimen of Coartem TabletsStudy No. Region/ages28-day cure rate1 n/N (%) PatientsMedian FCT2[25th, 75th percentile]Median PCT[25th, 75th percentile]mITT3EvaluableStudy Thailand, ages 3-62 years96/118 (81.4)93/96 (96.9)35 hours[20, 46]44 hours[22, 47]Early failure4 00Late failure5 (3.4)3 (3.1)Lost to follow-up18 (15.3)Other6 0Study Thailand, ages 2-63 years130/149 (87.2)130/134 (97.0)22 hours[19, 44]NAEarly failure4 00Late failure5 (2.7)4 (3.0)Lost to follow-up13 (8.7)Other6 (1.3)Study Thailand, ages 12-71 years148/164 (90.2)148/155 (95.5)29 hours[8, 51]29 hours [18, 40]Early failure4 00Late failure5 (4.3)7 (4.5)Lost to follow-up9 (5.5)Other6 0Study 6Europe/Columbia, ages 16-66 years120/162 (74.1)119/124 (96.0)37 hours[18, 44]42 hours [34, 63]Early failure4 (3.7)1 (0.8)Late failure5 (1.9)3 (2.4)Lost to follow-up17 (10.5)Other6 16 (9.9)1 (0.8)Study Africa, ages months-9 years268/310 (86.5)267/300 (89.0)8 hours[8, 24]24 hours [24, 36]Early failure4 (0.6)0Late failure5 34 (11.0)33 (11.0)Lost to follow-up2 (0.6)Other6 (1.3)Study Africa, ages months-12 years374/452 (82.7)370/419 (88.3)8 hours[8, 23]35 hours[24, 36]Early failure4 13 (2.9)0Late failure5 49 (10.8)49 (11.7)Lost to follow-up6 (1.3)Other6 10 (2.2)Abbreviations: FCT, fever clearance time; mITT, modified intent-to-treat; PCT, parasite clearance time; NULL, not applicable. 1Efficacy cure rate based on blood smear microscopy. 2For patients who had body temperature greater than 37.5C at baseline only. 3In mITT analysis, patients whose status was uncertain were classified as treatment failures. 4Early failures were usually defined as patients withdrawn for unsatisfactory therapeutic effect within the first days or because they received another antimalarial medication within the first days. 5Late failures were defined as patients achieving parasite clearance within days but having parasite reappearance including recrudescence or new infection during the 28-day follow-up period. 6Other includes withdrawn due to protocol violation or non-compliance, received additional medication after day 7, withdrew consent, missing day or 28 assessment.In all studies, patients signs and symptoms of malaria resolved when parasites were cleared.In studies conducted in areas with high transmission rates, such as Africa, reappearance of P. falciparum parasites may be due to recrudescence or new infection.The efficacy by body weight category for studies and is summarized in Table 7. Table 7: Clinical Efficacy by Weight for Pediatric StudiesStudy No.Age categoryCoartem Tablets 6-dose RegimenmITT Population1 Evaluable PopulationMedian PCT[25th, 75th percentile]28-day cure rate2n/N (%) patients28-day cure rate2n/N (%) patientsStudy 75 to 10 kg24 [24, 36]133/154 (86.4)133/149 (89.3)10 to 15 kg35 [24, 36]94/110 (85.5)94/107 (87.9)15 to 25 kg24 [24, 36]41/46 (89.1)40/44 (90.9)Study 835 to 10 kg36 [24, 36]61/83 (73.5)61/69 (88.4)10 to 15 kg35 [24, 36]160/190 (84.2)157/179 (87.7)15 to 25 kg35 [24, 36]123/145 (84.8)123/140 (87.9)25 to 35 kg26 [24, 36]30/34 (88.2)29/31 (93.5)Abbreviations: mITT, modified intent-to-treat; PCT, parasite clearance time. 1In mITT analysis, patients whose status was uncertain were classified as treatment failures. 2Efficacy cure rate based on blood smear microscopy. 3Coartem Tablets administered as crushed tablets.The efficacy of Coartem Tablets for the treatment P. falciparum infections mixed with P. vivax was assessed in small number of patients. Coartem Tablets are only active against the erythrocytic phase of P. vivax malaria. Of the 43 patients with mixed infections at baseline, all cleared their parastextia within 48 hours. However, parasite relapse occurred commonly (14/43; 33%). Relapsing malaria caused by P. vivax requires additional treatment with other antimalarial agents to achieve radical cure i.e., eradicate any hypnozoite forms that may remain dormant in the liver.. 28-day cure rate, defined as clearance of asexual parasites (the erythrocytic stage) within days without recrudescence by Day 28. parasite clearance time (PCT), defined as time from first dose until first total and continued disappearance of asexual parasite which continues for further 48 hours. fever clearance time (FCT), defined as time from first dose until the first time body temperature fell below 37.5C and remained below 37.5C for at least further 48 hours (only for patients with temperature greater than 37.5C at baseline).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Coartem Tablets should be taken with food. (2.1, 5.2) Tablets may be crushed and mixed with to teaspoons of water immediately prior to administration to patients, including children. (2.1) Coartem Tablets should be administered over days for total of doses: an initial dose, second dose after hours, and then twice-daily (morning and evening) for the following days. (2.2, 2.3) The adult dosage for patients with bodyweight of 35 kg and above is tablets per dose for total of 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 doses over days5 to 15 kg1 tablet15 to 25 kg2 tablets25 to 35 kg3 tablets35 kg and over4 tablets. Coartem Tablets should be taken with food. (2.1, 5.2) Tablets may be crushed and mixed with to teaspoons of water immediately prior to administration to patients, including children. (2.1) Coartem Tablets should be administered over days for total of doses: an initial dose, second dose after hours, and then twice-daily (morning and evening) for the following days. (2.2, 2.3) The adult dosage for patients with bodyweight of 35 kg and above is tablets per dose for total of doses. (2.2) The number of tablets per dose for children is determined by bodyweight, as shown in the chart below. (2.3). 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 small amount of water (1 to teaspoons) in 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 to hours after administration, 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). 3-day treatment schedule with total of doses is recommended for adult patients with bodyweight of 35 kg and above:Four tablets as single initial dose, tablets again after hours, and then tablets twice-daily (morning and evening) for the following 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. 3-day treatment schedule with total of doses is recommended as below:5 kg to less than 15 kg bodyweight: One tablet as an initial dose, tablet again after hours, and then tablet twice daily (morning and evening) for the following days (total course of tablets).15 kg to less than 25 kg bodyweight: Two tablets as an initial dose, tablets again after hours, and then tablets twice daily (morning and evening) for the following days (total course of 12 tablets).25 kg to less than 35 kg bodyweight: Three tablets as an initial dose, tablets again after hours, and then tablets twice daily (morning and evening) for the following days (total course of 18 tablets).35 kg bodyweight and above: Four tablets as single initial dose, tablets again after hours, and then tablets twice daily (morning and evening) for the following 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)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. CYP3A4 Inducers: Potential for loss of antimalarial efficacy. (4, 5.3, 7.1, 12.3)CYP3A4 Inhibitors: Use cautiously due to potential for QT prolongation. (5.3, 7.2, 12.3)Antiretrovirals: Use cautiously due to potential for QT prolongation, loss of antiviral efficacy, or loss of antimalarial efficacy of Coartem Tablets. (5.3, 7.3, 12.3)Mefloquine: If used immediately before treatment, monitor for decreased efficacy of Coartem Tablets and encourage food consumption. (2.1, 7.4, 12.3)Hormonal Contraceptives: Effectiveness may be reduced; use an additional method of birth control. (5.3, 7.5, 12.3)CYP2D6 Substrates: Monitor for adverse reactions and potential QT prolongation. (5.1, 5.4, 7.6). CYP3A4 Inducers: Potential for loss of antimalarial efficacy. (4, 5.3, 7.1, 12.3). CYP3A4 Inhibitors: Use cautiously due to potential for QT prolongation. (5.3, 7.2, 12.3). Antiretrovirals: Use cautiously due to potential for QT prolongation, loss of antiviral efficacy, or loss of antimalarial efficacy of Coartem Tablets. (5.3, 7.3, 12.3). Mefloquine: If used immediately before treatment, monitor for decreased efficacy of Coartem Tablets and encourage food consumption. (2.1, 7.4, 12.3). Hormonal Contraceptives: Effectiveness may be reduced; use an additional method of birth control. (5.3, 7.5, 12.3). CYP2D6 Substrates: Monitor for adverse reactions and potential QT prolongation. (5.1, 5.4, 7.6). 7.1 Rifampin. Oral administration of rifampin, 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. Johns wort is contraindicated with Coartem Tablets [see Contraindications (4) and Clinical Pharmacology (12.3)].. 7.2 Ketoconazole. Concurrent oral administration of ketoconazole, potent CYP3A4 inhibitor, with single dose of Coartem Tablets resulted in moderate increase in exposure to artemether, DHA, and lumefantrine in 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 (5.1, 5.3) and Clinical Pharmacology (12.3)].. 7.3 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 (12.3)]. Coartem Tablets should be used cautiously in patients on antiretroviral drugs because decreased artemether, DHA, and/or lumefantrine concentrations may result in decrease of antimalarial efficacy of Coartem Tablets, and increased lumefantrine concentrations may cause QT prolongation [see Warnings and Precautions (5.3)]. 7.4 Prior Use of Mefloquine. Administration of doses of mefloquine followed 12 hours later by 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 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 (5.2) and Clinical Pharmacology (12.3)].. 7.5 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 barrier method of contraception during treatment with Coartem [see Warnings and Precautions (5.3), Use in Specific Populations (8.3) and Clinical Pharmacology (12.3)].. 7.6 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) [see Warnings and Precautions (5.1, 5.4) and Clinical Pharmacology (12.3)].. 7.7 Sequential Use of Quinine. single dose of intravenous quinine (10 mg/kg bodyweight) concurrent with the final dose of 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 (5.2) and Clinical Pharmacology (12.3)].. 7.8 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 [see Warnings and Precautions (5.1, 5.2)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise patients to read the FDA-Approved Patient Labeling (Patient Information).Administration InstructionsInstruct patients to take Coartem Tablets with food. Patients who do not have an adequate intake of food are at risk for recrudescence of malaria [see Dosage and Administration (2.1)].HypersensitivityPatients with known hypersensitivity to artemether, lumefantrine, or to any of the excipients should not receive Coartem Tablets [see Contraindications (4)].Prolongation of the QT IntervalInstruct 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 [see Warnings and Precautions (5.1)].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) [see Warnings and Precautions (5.1)]. Instruct patients to notify their physicians if they have any symptoms of prolongation of the QT interval, including prolonged heart palpitations or loss of consciousness [see Warnings and Precautions (5.1)]. Drug Interactions With CYP2D6Instruct 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) [see Warnings and Precautions (5.4)].ContraceptionAdvise patients that use of Coartem may reduce the efficacy of hormonal contraceptives. Advise patients using hormonal contraceptive to use an alternative non-hormonal contraceptive method or add barrier method of contraception during treatment with Coartem [see Drug Interactions (7.5) and Use in Specific Populations (8.3)].Use of QT Prolonging Drugs and Other AntimalarialsHalofantrine and Coartem Tablets should not be administered within 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 [see Warnings and Precautions (5.2)].Sequential Use of QuinineQT 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. ECG monitoring is advised if use of drugs that prolong the QT interval is medically required [see Drug Interactions (7.7)].Prior Use of MefloquineClosely monitor food intake in patients who received mefloquine immediately prior to treatment with Coartem Tablets [see Drug Interactions (7.4)].Drug Interactions With CYP3A4Use 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 antiretroviral drugs. Coadministration of strong inducers of CYP3A4 such as rifampin, carbamazepine, phenytoin, and St. Johns wort is contraindicated with Coartem Tablets [see Warnings and Precautions (5.3)].Hypersensitivity ReactionsInform patients that Coartem Tablets can cause hypersensitivity reactions. Instruct patients to discontinue the drug at the first sign of skin rash, hives or other skin reactions, 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 [see Contraindications (4)].T2019-88. 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 [see Warnings and Precautions (5.1)].. 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) [see Warnings and Precautions (5.1)]. Instruct patients to notify their physicians if they have any symptoms of prolongation of the QT interval, including prolonged heart palpitations or loss of consciousness [see Warnings and Precautions (5.1)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionFollowing administration of Coartem Tablets to healthy volunteers and patients with malaria, artemether is absorbed with peak plasma concentrations reached about hours after dosing. Absorption of lumefantrine, highly lipophilic compound, starts after lag-time of up to hours, with peak plasma concentrations about to 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 ConditionsAbbreviations: DHA, dihydroartemisinin; SD, standard deviation; AUC, area under the curve. aMean +- SD Cmax, AUClast, 1/2 and Median Tmax.Study 2102(n 50)Study 2104(n 48)ArtemetherCmax (ng/mL)60.0 +- 32.583.8 +- 59.7Tmax (h)1.502.00AUClast (ng.h/mL)146 +- 72.2259 +- 150t 1/2 (h)1.6 +- 0.72.2 +- 1.9DHACmax (ng/mL)104 +- 35.390.4 +- 48.9Tmax (h)1.762.00AUClast (ng.h/mL)284 +- 83.8285 +- 98.0t 1/2 (h)1.6 +- 0.62.2 +- 1.5LumefantrineCmax (ug/mL)7.38 +- 3.199.80 +- 4.20Tmax (h)6.018.00AUClast (ug.h/mL)158 +- 70.1243 +- 117t 1/2 (h)101 +- 35.6119 +- 51.0Food 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 high-fat meal compared under fasted conditions. Patients should be encouraged to take Coartem Tablets with meal as soon as food can be tolerated [see Dosage and Administration (2.1)].DistributionArtemether 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 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 statistically significant degree. The artemether/DHA area under the curve (AUC) ratio is 1.2 after single dose and 0.3 after doses given over 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)].EliminationArtemether and DHA are cleared from plasma with an elimination half-life of about hours. Lumefantrine is eliminated more slowly, with an elimination half-life of to 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 PopulationsHepatic and Renal ImpairmentNo 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 PatientsThe PK of artemether, DHA, and lumefantrine were obtained in pediatric studies by sparse sampling using population-based approach. PK estimates derived from 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 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 6-dose Regimen of Coartem TabletsAdults1 Pediatric Patients (body weight, kg)2 Drug5 to 1515 to 2525 to 35LumefantrineMean Cmax, range (mcg/mL)5.60-9.04.71-12.6Not AvailableMean AUClast, range (mcg.h/mL)410-561372-699Not AvailableArtemetherMean Cmax +- SD (ng/mL)186 +- 125223 +- 309198 +- 179174 +- 145DihydroartemisininMean Cmax +- SD (ng/mL)101 +- 5854.7 +- 58.979.8 +- 80.565.3 +- 23.6Abbreviations: AUC, area under the curve; DHA, dihydroartemisinin; SD, standard deviation. 1There are total of 181 adults for lumefantrine pharmacokinetic parameters and total of 25 adults for artemether and dihydroartemisinin pharmacokinetic parameters. 2There are 477 children for the lumefantrine pharmacokinetic parameters; for artemether and dihydroartemisinin pharmacokinetic parameters there are 55, 29, and children for the to less than 15, 15 to less than 25 and the 25 to less than 35 kg groups, respectively.Geriatric PatientsNo specific pharmacokinetic studies have been performed in patients older than 65 years of age.Drug Interaction StudiesRifampin (strong CYP3A4 inducer)Oral administration of rifampin (600 mg daily), strong CYP3A4 inducer, with Coartem Tablets (6-dose regimen over days) in 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. Johns wort is contraindicated with Coartem Tablets [see Contraindications (4)]. Ketoconazole (potent CYP3A4 inhibitor)Concurrent oral administration of ketoconazole (400 mg on day followed by 200 mg on Days 2, 3, 4, and 5) with Coartem Tablets (single-dose of tablets of 20 mg artemether/120 mg lumefantrine per tablet) with 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)].AntimalarialsThe oral administration of mefloquine in 14 healthy volunteers administered as doses of 500 mg, 250 mg, and 250 mg, followed 12 hours later by Coartem Tablets (6 doses of 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 30% reduction in Cmax and 40% reduction in AUC of lumefantrine, possibly due to lower absorption secondary to mefloquine-induced decrease in bile production.Intravenous administration of single dose of quinine (10 mg/kg bodyweight) concurrent with the last dose of 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 DrugsThe 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 days), resulted in 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 days), resulted in 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 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 ContraceptivesNo 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)].

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryPublished 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 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 ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskMalaria 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.DataHuman DataWhile available studies cannot definitively establish the absence of risk, 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 DataPregnant rats dosed orally during the period of organogenesis [gestational days (GD) through 17] at 50 mg/kg/day artemether-lumefantrine combination (corresponding to mg/kg/day artemether or higher, 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 through GD 19) at 175 mg/kg/day, (corresponding to 25 mg/kg/day artemether) about 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 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.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: August 2019Patient InformationCoartem(R) (co-AR-tem)(artemether and lumefantrine)tablets, for oral useRead this Patient Information leaflet before you start taking Coartem. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.What is CoartemCoartem is prescription medicine used to treat uncomplicated malaria caused by the parasite Plasmodium falciparum (P. falciparum) in people months of age and older who weigh at least 11 pounds (5 kg).Coartem is not approved to: Treat severe or complicated P. falciparum malariaPrevent malaria It is not known if Coartem is safe and effective in children who weigh less than 11 pounds (5 kg). Who should not take CoartemDo not take Coartem if you:are allergic to artemether, lumefantrine, or any of the ingredients in Coartem. See the end of this Patient Information leaflet for complete list of ingredients in Coartem. Symptoms of serious allergic reaction with Coartem can include: rash, hives, fast heartbeat, trouble swallowing or breathing, swelling of lips, tongue, face, tightness of the throat, or trouble speaking. If you have any of these symptoms of serious allergic reaction while taking Coartem, stop taking Coartem and get emergency medical help right away.are taking rifampin (medicine used to treat leprosy or tuberculosis), carbamazepine or phenytoin (medicines used to treat epilepsy), or St. Johns wort (Hypericum perforatum, medicinal plant or extract of this medicinal plant).What should tell my healthcare provider before taking CoartemBefore taking Coartem, tell your healthcare provider about all of your medical conditions, including if you:have heart disease or family history of heart problems or heart disease. have liver or kidney problems. have recently taken other medicines used to treat malaria. are pregnant or plan to become pregnant. Treatment of malaria is important because it can be serious disease for pregnant woman and her unborn baby. are taking hormonal contraceptives (such as birth control pills). Coartem may affect how well hormonal contraceptives work and may cause them to not work as well. Females who are able to become pregnant should use another effective non-hormonal form of birth control or an additional barrier method of birth control (such as male condoms) during treatment with Coartem. Talk with your healthcare provider if you have questions about birth control methods that may be right for you during this time.are breastfeeding or plan to breastfeed. It is not known if Coartem passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking Coartem.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Coartem and other medicines may affect each other causing side effects. Coartem may affect the way other medicines work and other medicines may affect how Coartem works.Especially tell your healthcare provider if you take:any other medicines to treat or prevent malaria medicines for your heart antipsychotic medicines antidepressants medicines for seizures or trigeminal neuralgia (facial nerve pain) antibiotics (including medicines to treat tuberculosis) antifungal medicines (such as itraconazole, ketoconazole, and fluconazole)medicines to treat HIV-infection hormonal methods of birth control. See What should tell my healthcare provider before taking CoartemAsk your healthcare provider if you are not sure if your medicine is listed above. Know the medicines you take. Keep list of your medicines with you and show it to your healthcare provider and pharmacist when you get new medicine.How should take CoartemTake Coartem exactly as prescribed. If you weigh 77 pounds (35 kg) or more, dose of Coartem is tablets. full course of treatment is doses (24 tablets) of Coartem taken over days: Day 1: take dose, then hours later take doseDay 2: take dose in the morning, dose in the eveningDay 3: take dose in the morning, dose in the eveningImportant: Take the full course of treatment with Coartem for all days even if you are feeling better. If you weigh less than 77 pounds (35 kg), your healthcare provider will tell you how many tablets to take for each dose.Each dose of Coartem should be taken with food or drink, such as milk, infant formula, pudding, porridge, or broth. It is important for you to eat as soon as you can so that your malaria will go away and not get worse. Do not drink grapefruit juice while you take Coartem. Drinking grapefruit juice during treatment with Coartem can cause you to have too much medicine in your blood.If you are not able to swallow Coartem tablets, Coartem may be crushed and mixed with to teaspoons of water in clean container. If any medicine remains, you can add more water to the container and drink right away.If you vomit within to hours after taking Coartem, you should take another dose of Coartem. If you vomit the second dose, tell your healthcare provider. different medicine may need to be prescribed for you.Tell your healthcare provider right away if:your malaria does not get better or you get flu-like symptoms such as chills, fever, muscle pains, or headaches again after you finish treatment with Coartemyou vomit any doses of Coartemyou are not able to eatyou have any change in the way your heart beats or loss of consciousness (fainting) What are the possible side effects of CoartemCoartem can cause serious side effects, including:A heart problem called QT prolongation that can cause an abnormal heartbeat can happen in people who take Coartem. The chance of this happening is higher in people with family history of prolonged QT interval, low potassium (hypokalemia) or low magnesium (hypomagnesemia), and in people who take certain medicines including medicine to control heartbeats.The most common side effects of Coartem in adults include:headachenot wanting to eatdizzinessfeverweakness or lack of energyjoint painmuscle pain, tenderness and weaknessThe most common side effects of Coartem in children include:fevercoughvomitingnot wanting to eatheadacheThese are not all the possible side effects of Coartem. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store CoartemStore Coartem at room temperature between 68F to 77F (20C to 25C).Store Coartem in the original container and keep the container tightly closed.Keep Coartem and all medicines out of the reach of children.General information about the safe and effective use of Coartem.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use Coartem for condition for which it was not prescribed. Do not give Coartem to other people, even if they have the same symptoms that you have. It may harm them.This Patient Information leaflet summarizes the most important information about Coartem. If you would like more information about Coartem talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Coartem that is written for health professionals.What are the ingredients in CoartemActive ingredients: artemether, lumefantrineInactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, and polysorbate 80Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936(C) NovartisT2019-89For more information about Coartem, call 1-855-262-7836 or go to http://www.coartem.us.com. Treat severe or complicated P. falciparum malaria. Prevent malaria. are allergic to artemether, lumefantrine, or any of the ingredients in Coartem. See the end of this Patient Information leaflet for complete list of ingredients in Coartem. Symptoms of serious allergic reaction with Coartem can include: rash, hives, fast heartbeat, trouble swallowing or breathing, swelling of lips, tongue, face, tightness of the throat, or trouble speaking. If you have any of these symptoms of serious allergic reaction while taking Coartem, stop taking Coartem and get emergency medical help right away.. are taking rifampin (medicine used to treat leprosy or tuberculosis), carbamazepine or phenytoin (medicines used to treat epilepsy), or St. Johns wort (Hypericum perforatum, medicinal plant or extract of this medicinal plant).. have heart disease or family history of heart problems or heart disease. have liver or kidney problems. have recently taken other medicines used to treat malaria. are pregnant or plan to become pregnant. Treatment of malaria is important because it can be serious disease for pregnant woman and her unborn baby. are taking hormonal contraceptives (such as birth control pills). Coartem may affect how well hormonal contraceptives work and may cause them to not work as well. Females who are able to become pregnant should use another effective non-hormonal form of birth control or an additional barrier method of birth control (such as male condoms) during treatment with Coartem. Talk with your healthcare provider if you have questions about birth control methods that may be right for you during this time.. are breastfeeding or plan to breastfeed. It is not known if Coartem passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking Coartem.. any other medicines to treat or prevent malaria medicines for your heart antipsychotic medicines antidepressants medicines for seizures or trigeminal neuralgia (facial nerve pain) antibiotics (including medicines to treat tuberculosis) antifungal medicines (such as itraconazole, ketoconazole, and fluconazole). medicines to treat HIV-infection hormonal methods of birth control. See What should tell my healthcare provider before taking Coartem. Take Coartem exactly as prescribed. If you weigh 77 pounds (35 kg) or more, dose of Coartem is tablets. full course of treatment is doses (24 tablets) of Coartem taken over days: Day 1: take dose, then hours later take doseDay 2: take dose in the morning, dose in the eveningDay 3: take dose in the morning, dose in the eveningImportant: Take the full course of treatment with Coartem for all days even if you are feeling better. Day 1: take dose, then hours later take dose. Day 2: take dose in the morning, dose in the evening. Day 3: take dose in the morning, dose in the eveningImportant: Take the full course of treatment with Coartem for all days even if you are feeling better.. If you weigh less than 77 pounds (35 kg), your healthcare provider will tell you how many tablets to take for each dose.. Each dose of Coartem should be taken with food or drink, such as milk, infant formula, pudding, porridge, or broth. It is important for you to eat as soon as you can so that your malaria will go away and not get worse. Do not drink grapefruit juice while you take Coartem. Drinking grapefruit juice during treatment with Coartem can cause you to have too much medicine in your blood.. If you are not able to swallow Coartem tablets, Coartem may be crushed and mixed with to teaspoons of water in clean container. If any medicine remains, you can add more water to the container and drink right away.. If you vomit within to hours after taking Coartem, you should take another dose of Coartem. If you vomit the second dose, tell your healthcare provider. different medicine may need to be prescribed for you.. your malaria does not get better or you get flu-like symptoms such as chills, fever, muscle pains, or headaches again after you finish treatment with Coartem. you vomit any doses of Coartem. you are not able to eat. you have any change in the way your heart beats or loss of consciousness (fainting) A heart problem called QT prolongation that can cause an abnormal heartbeat can happen in people who take Coartem. The chance of this happening is higher in people with family history of prolonged QT interval, low potassium (hypokalemia) or low magnesium (hypomagnesemia), and in people who take certain medicines including medicine to control heartbeats.. headache. not wanting to eat. dizziness. fever. weakness or lack of energy. joint pain. muscle pain, tenderness and weakness. fever. cough. vomiting. not wanting to eat. headache. Store Coartem at room temperature between 68F to 77F (20C to 25C).. Store Coartem in the original container and keep the container tightly closed.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryPublished 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 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 ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskMalaria 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.DataHuman DataWhile available studies cannot definitively establish the absence of risk, 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 DataPregnant rats dosed orally during the period of organogenesis [gestational days (GD) through 17] at 50 mg/kg/day artemether-lumefantrine combination (corresponding to mg/kg/day artemether or higher, 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 through GD 19) at 175 mg/kg/day, (corresponding to 25 mg/kg/day artemether) about 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 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.. 8.2 Lactation. Risk SummaryThere are no data on the presence of artemether or lumefantrine in human milk, the effects on the breastfed infant or the effects on milk production. Artemether and lumefantrine are transferred into rat milk. When drug is transferred into animal milk, it is likely that the drug will also be transferred into human milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Coartem and any potential adverse effects on the breastfed infant from Coartem or from the underlying maternal condition.. 8.3 Females and Males of Reproductive Potential. ContraceptionUse of Coartem may reduce the efficacy of hormonal contraceptives. Advise patients using hormonal contraceptives to use an alternative non-hormonal contraceptive method or add barrier method of contraception during treatment with Coartem [see Drug Interactions (7.5)].InfertilityIn animal fertility studies, administration of repeated doses of artemether-lumefantrine combination to female rats (for to weeks) resulted in pregnancy rates that were reduced by one half. In male rats dosed for approximately months with artemether-lumefantrine combination, abnormal sperm cells, decreased sperm motility, and increased testes weight were observed [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. The safety and effectiveness of Coartem Tablets have been established in pediatric patients aged months and older with bodyweight of kg and above for the treatment of acute, uncomplicated malaria [see Clinical Studies (14.1)]. The safety and effectiveness of Coartem Tablets have not been established in pediatric patients younger than months old or who weigh less than kg. Pediatric patients from non-endemic countries were not included in clinical trials.. 8.5 Geriatric Use. Clinical studies of Coartem Tablets did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing Coartem Tablets.. 8.6 Hepatic and Renal Impairment. No specific pharmacokinetic studies have been performed in patients with either hepatic or renal impairment. Coartem Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment. Based on the pharmacokinetic data in 16 healthy subjects showing no or insignificant renal excretion of lumefantrine, artemether, and DHA, no dose adjustment for the use of Coartem Tablets in patients with renal impairment is advised. No dosage adjustment is necessary in patients with mild-to-moderate hepatic impairment [see Dosage and Administration (2.4) and Warnings and Precautions (5.6)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Avoid use in patients with known QT prolongation, those with hypokalemia or hypomagnesemia, and those taking other drugs that prolong the QT interval. (5.1, 12.6) Halofantrine and Coartem Tablets should not be administered within one month of each other due to potential additive effects on the QT interval. (5.1, 5.2, 12.3) Antimalarials should not be given concomitantly, unless there is no other treatment option, due to limited safety data. (5.2) QT prolonging drugs, including quinine and quinidine, should be used cautiously following Coartem Tablets. (5.1, 5.2, 7.7, 12.3) Substrates, inhibitors, or inducers of CYP3A4, including antiretroviral medications, should be used cautiously with Coartem Tablets, due to potential loss of efficacy of the concomitant drug or additive QT prolongation. (5.3, 7.2, 7.3). Avoid use in patients with known QT prolongation, those with hypokalemia or hypomagnesemia, and those taking other drugs that prolong the QT interval. (5.1, 12.6) Halofantrine and Coartem Tablets should not be administered within one month of each other due to potential additive effects on the QT interval. (5.1, 5.2, 12.3) Antimalarials should not be given concomitantly, unless there is no other treatment option, due to limited safety data. (5.2) QT prolonging drugs, including quinine and quinidine, should be used cautiously following Coartem Tablets. (5.1, 5.2, 7.7, 12.3) Substrates, inhibitors, or inducers of CYP3A4, including antiretroviral medications, should be used cautiously with Coartem Tablets, due to potential loss of efficacy of the concomitant drug or additive QT prolongation. (5.3, 7.2, 7.3). 5.1 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 (ECG).Coartem Tablets should be avoided in patients: 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 history of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease.With 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) [see Clinical Pharmacology (12.6)].Receiving medications that are metabolized by the cytochrome enzyme CYP2D6, which also have cardiac effects (e.g., flecainide, imipramine, amitriptyline, clomipramine) [see Warnings and Precautions (5.4), Drug Interactions (7.6), and Clinical Pharmacology (12.3)].. 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 history of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease.. With 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) [see Clinical Pharmacology (12.6)].. Receiving medications that are metabolized by the cytochrome enzyme CYP2D6, which also have cardiac effects (e.g., flecainide, imipramine, amitriptyline, clomipramine) [see Warnings and Precautions (5.4), Drug Interactions (7.6), and Clinical Pharmacology (12.3)].. 5.2 Use of QT Prolonging Drugs and Other Antimalarials. Halofantrine and Coartem Tablets should not be administered within month of each other due to the long elimination half-life of lumefantrine (3 to days) and potential additive effects on the QT interval [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].Antimalarials should not be given concomitantly with Coartem Tablets, unless there is no other treatment option, due to limited safety data.Drugs that prolong the QT interval, including antimalarials such as quinine and quinidine, should be used cautiously following Coartem Tablets, due to the long elimination half-life of lumefantrine (3 to days) and the potential for additive effects on the QT interval; ECG monitoring is advised if use of drugs that prolong the QT interval is medically required [see Warnings and Precautions (5.1), Drug Interactions (7.7), and Clinical Pharmacology (12.3)]. If mefloquine is administered immediately prior to Coartem Tablets, there may be decreased exposure to lumefantrine, possibly due to mefloquine-induced decrease in bile production. Therefore, patients should be monitored for decreased efficacy and food consumption should be encouraged while taking Coartem Tablets [see Dosage and Administration (2.1), Drug Interactions (7.4), and Clinical Pharmacology (12.3)].. 5.3 Drug Interactions With CYP3A4 When Coartem Tablets are coadministered with substrates of CYP3A4, it may result in decreased concentrations of the substrate and potential loss of substrate efficacy. When Coartem Tablets are coadministered with an inhibitor of CYP3A4, including grapefruit juice, it may result in increased concentrations of artemether and/or lumefantrine and potentiate QT prolongation. When Coartem Tablets are coadministered with inducers of CYP3A4, it may result in decreased concentrations of artemether and/or lumefantrine and loss of antimalarial efficacy [see Contraindications (4) and Drug Interactions (7)].Drugs that have mixed effect on CYP3A4, especially antiretroviral drugs such as HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, and those that have an effect on the QT interval should be used with caution in patients taking Coartem Tablets [see Drug Interactions (7.3, 7.7)].Coartem Tablets may reduce the effectiveness of hormonal contraceptives. Therefore, patients using hormonal contraceptives should be advised to use an alternative non-hormonal contraceptive method or add barrier method of contraception during treatment with Coartem [see Drug Interactions (7.5)].. 5.4 Drug Interactions With CYP2D6. 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) [see Warnings and Precautions (5.1), Drug Interactions (7.6), and Clinical Pharmacology (12.3)].. 5.5 Recrudescence. Food enhances absorption of artemether and lumefantrine following administration of Coartem Tablets. Patients who remain averse to food during treatment should be closely monitored as the risk of recrudescence may be greater [see Dosage and Administration (2.1)].In the event of recrudescent P. falciparum infection after treatment with Coartem Tablets, patients should be treated with different antimalarial drug.. 5.6 Hepatic and Renal Impairment. Coartem Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment [see Dosage and Administration (2.4)].. 5.7 Plasmodium vivax Infection. Coartem Tablets have been shown in limited data (43 patients) to be effective in treating the erythrocytic stage of P. vivax infection. However, relapsing malaria caused by P. vivax requires additional treatment with other antimalarial agents to achieve radical cure i.e., eradicate any hypnozoites forms that may remain dormant in the liver.