ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reactions in adults (>30%) are headache, anorexia, dizziness, asthenia, arthralgia and myalgia. The most common adverse reactions in children (>12%) are pyrexia, cough, vomiting, anorexia, and headache. (6.2)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 Serious Adverse Reactions. The following serious and otherwise important adverse reactions are discussed in greater detail in other sections of labeling:Hypersensitivity Reactions [see Contraindications (4) and Adverse Reactions (6.3)].. Hypersensitivity Reactions [see Contraindications (4) and Adverse Reactions (6.3)].. 6.2 Clinical Studies 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 1,979 patients including 647 adults (older than 16 years) and 1,332 children (16 years and younger). For the 6-dose regimen, Coartem Tablets was studied in active-controlled (366 patients) and non-controlled, open-label trials (1,613 patients). The 6-dose Coartem Tablets population was patients with malaria between ages months and 71 years: 67% (1,332) were 16 years and younger and 33% (647) were older than 16 years. Males represented 73% and 53% of the adult and pediatric populations, respectively. The majority of adult patients were enrolled in studies in Thailand, while the majority of pediatric patients were enrolled in Africa.Tables and show the most frequently reported adverse reactions (>=3%) in adults and children respectively who received the 6-dose regimen of Coartem Tablets. Adverse reactions collected in clinical trials included signs and symptoms at baseline but only treatment emergent adverse events, defined as events that appeared or worsened after the start of treatment, are presented below. In adults, the most frequently reported adverse reactions were headache, anorexia, dizziness, and asthenia. In children, the adverse reactions were pyrexia, cough, vomiting, anorexia, and headache. Most adverse reactions were mild, did not lead to discontinuation of study medication, and resolved.In limited comparative studies, the adverse reaction profile of Coartem Tablets appeared similar to that of another antimalarial regimen.Discontinuation of Coartem Tablets due to adverse drug reactions occurred in 1.1% of patients treated with the 6-dose regimen overall: 0.2% (1/647) in adults and 1.6% (21/1,332) in children. Table 1: Adverse Reactions Occurring in 3% or More of Adult Patients Treated in Clinical Trials with the 6-dose Regimen of Coartem TabletsSystem 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) Adult patients defined as >16 years of ageTable 2: Adverse Reactions Occurring in 3% or More of Pediatric Patients Treated in Clinical Trials with the 6-dose Regimen of Coartem TabletsSystem Organ ClassPreferred TermChildrenN=1,332 (%)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) Children defined as patients <=16 years of age Clinically significant adverse reactions reported in adults and/or children treated with the 6-dose regimen of Coartem Tablets which occurred in clinical studies at <3% regardless of causality are listed below: Blood and lymphatic system disorders: eosinophilia Ear and labyrinth disorders: tinnitus Eye disorders: conjunctivitis Gastrointestinal disorders: constipation, dyspepsia, dysphagia, peptic ulcer General disorders: gait disturbance Infections and infestations: abscess, acrodermatitis, bronchitis, ear infection, gastroenteritis, helminthic infection, hookworm infection, impetigo, influenza, lower respiratory tract infection, malaria, nasopharyngitis, oral herpes, pneumonia, respiratory tract infection, subcutaneous abscess, upper respiratory tract infection, urinary tract infection Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, hematocrit decreased, lymphocyte morphology abnormal, platelet count decreased, platelet count increased, white blood cell count decreased, white blood cell count increased Metabolism and nutrition disorders: hypokalemia Musculoskeletal and connective tissue disorders: back pain Nervous system disorders: ataxia, clonus, fine motor delay, hyperreflexia, 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. 6.3 Postmarketing Experience. The following adverse reactions have been identified during post-approval 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.. Hypersensitivity reactions: anaphylaxis, urticaria, angioedema, and serious skin reactions (bullous eruption) have been reported.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. Neonatal rats (7 to 21 days old) were more sensitive to the toxic effects of artemether (a component of Coartem Tablets) than older juvenile rats or adults. Mortality and severe clinical signs were observed in neonatal rats at doses which were well tolerated in pups above 22 days old.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisCarcinogenicity studies were not conducted.MutagenesisNo evidence of mutagenicity was detected. The artemether: lumefantrine combination was evaluated using the Salmonella and Escherichia/mammalian-microsome mutagenicity test, the gene mutation test with Chinese hamster cells V79, the cytogenetic test on Chinese hamster cells in vitro, and the rat micronucleus test, in vivo. Impairment of FertilityPregnancy rates were reduced by about one-half in female rats dosed for to weeks with the artemether-lumefantrine combination at 1000 mg/kg (about times the clinical dose based on body surface area comparisons). Male rats dosed for 70 days showed increases in abnormal sperm (87% abnormal) and increased testes weights at 30 mg/kg doses (about one-third the clinical dose). Higher doses (about times the clinical dose) resulted in decreased sperm motility and 100% abnormal sperm cells.

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 Clinical Pharmacology (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, dihydroartemisinin (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 (DHA), and Lumefantrine under Fed ConditionsStudy 2102(n=50)Study 2104(n=48)ArtemetherCmax (ng/mL)60.0 +- 32.583.8 +- 59.7tmax (h)1.502.00AUClast (ngh/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 (ngh/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 (ugh/mL)158 +- 70.1243 +- 117t 1/2 (h)101 +- 35.6119 +- 51.0aMean +- SD Cmax, AUClast, 1/2 and Median tmax 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 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 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 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. Hepatic 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 mg/kg body weight basis in pediatric patients (>=5 to <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)2Drug5 to <1515 to <2525 to <35LumefantrineMean Cmax, range (mcg/mL)5.60 9.04.71 12.6Not AvailableMean AUClast, range (mcgh/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 +- 23.61 There are total of 181 adults for lumefantrine pharmacokinetic parameters and total of 25 adults for artemether and dihydroartemisinin pharmacokinetic parameters. There are 477 children for the lumefantrine pharmacokinetic parameters; for artemether and dihydroartemisinin pharmacokinetic parameters there are 55, 29, and children for the to <15, 15 to <25 and the 25 to <35 kg groups, respectively.Geriatric PatientsNo specific pharmacokinetic studies have been performed in patients older than 65 years of age.Drug InteractionsRifampin (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, 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 area under the curve (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 CYP3A. 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 Action Coartem Tablets, fixed ratio of 1:6 parts of artemether and lumefantrine, respectively, is an antimalarial agent. Artemether is rapidly metabolized into an active metabolite dihydroartemisinin (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 VivoArtemether and lumefantrine are active against the erythrocytic stages of Plasmodium falciparum. Drug ResistanceStrains 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. The clinical relevance of such an effect is 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 CI: 11 msec). There was concentration-dependent increase in QTcF for lumefantrine.In clinical trials conducted in children, no patient had QTcF >500 msec. Over 5% of patients had an increase in QTcF of over 60 msec.In clinical trials conducted in adults, QTcF prolongation of >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 (>=5kg 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 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 >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 parasite clearance time (PCT) and fever clearance time (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]Lumefantrine 45/51 (88.2)36 hours [12, 60]48 hours [42, 60]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 >37.5C at baseline only 495% CI (Coartem Tablets artemether) on 28-day cure rate: 37.8%, 66.0% 5P-value comparing Coartem Tablets to lumefantrine on parasite clearance time (PCT) and fever clearance time (FCT): <0.001 6P-value comparing Coartem Tablets to lumefantrine on parasite clearance time (PCT): <0.001 and on fever clearance time (FCT): <0.05Results 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 >=2 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 >=2 years received Coartem Tablets. In study 5, total 164 adults and children >=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 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 >=37.5oC.Study was conducted in Africa in 452 infants and children, aged months to 12 years, weighing kg to <35 kg, with fever (>=37.5C axillary or >=38C rectally) or history of fever in the preceding 24 hours. Results of 28-day cure rate, median parasite clearance time (PCT), and fever clearance time (FCT) for Studies to are reported in Table 6.Table 6: Clinical Efficacy of 6-dose Regimen of Coartem Tablets Study No. Region/ages28-day cure rate1 n/N (%) patientsMedian FCT2[25th, 75th percentile]Median PCT[25th, 75th percentile]mITT3EvaluableStudy Thailand, ages - 62 years 96/118 (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 - 63 years 130/149 (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 years 148/164 (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 Europe/Columbia, ages 16 66 years 120/162 (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 years 268/310 (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 years 374/452 (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)1 Efficacy cure rate based on blood smear microscopy For patients who had body temperature >37.5C at baseline only In mITT analysis, patients whose status was uncertain were classified as treatment failures. Early 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 Late 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 Other includes withdrawn due to protocol violation or non-compliance, received additional medication after day 7, withdrew consent, missing day or 28 assessmentIn 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 population1Evaluable 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)1 In mITT analysis, patients whose status was uncertain were classified as treatment failures. Efficacy cure rate based on blood smear microscopy Coartem Tablets administered as crushed tabletsThe 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 >37.5C at baseline).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. HypersensitivityKnown hypersensitivity to artemether, lumefantrine, or to any of the excipients of Coartem Tablets [see Adverse Reactions (6.3)]. Strong CYP3A4 InducersCoadministration of strong inducers of CYP3A4 such as rifampin, carbamazepine, phenytoin, and St. Johns wort with Coartem Tablets can result in decreased concentrations of artemether and/or lumefantrine and loss of antimalarial efficacy [see Warnings and Precautions (5.3), Drug Interactions (7.1), and Clinical Pharmacology (12.3)].. Known hypersensitivity to artemether, lumefantrine, or to any of the excipients of Coartem Tablets [see Adverse Reactions (6.3)]. Coadministration of strong inducers of CYP3A4 such as rifampin, carbamazepine, phenytoin, and St. Johns wort with Coartem Tablets can result in decreased concentrations of artemether and/or lumefantrine and loss of antimalarial efficacy [see Warnings and Precautions (5.3), Drug Interactions (7.1), and Clinical Pharmacology (12.3)].. Known hypersensitivity to artemether, lumefantrine, or to any of the excipients. (4)Coadministration of strong inducers of CYP3A4 such as rifampin, carbamazepine, phenytoin, and St. Johns wort with Coartem Tablets. (4, 7.1, 12.3). Known hypersensitivity to artemether, lumefantrine, or to any of the excipients. (4). Coadministration of strong inducers of CYP3A4 such as rifampin, carbamazepine, phenytoin, and St. Johns wort with Coartem Tablets. (4, 7.1, 12.3).

DESCRIPTION SECTION.

11 DESCRIPTION. Coartem Tablets contain fixed combination of antimalarial active ingredients, artemether, an artemisinin derivative, and lumefantrine. Both components are blood schizontocides. The chemical name of artemether is (3R,5aS,6R,8aS,9R,10S,12R,12aR)-10-methoxy-3,6,9-trimethyldecahydro-3,12-epoxypyrano[4,3-j]-1,2-benzodioxepine. Artemether is white, crystalline powder that is freely soluble in acetone, soluble in methanol and ethanol, and practically insoluble in water. It has the empirical formula C16H26O5 with molecular weight of 298.4, and the following structural formula:The chemical name of lumefantrine is (1RS)-2-(dibutylamino)-1-(9Z)-2,7-dichloro-9-[(4-chlorophenyl)methylene]-9H-fluorene-4-ylethanol. Lumefantrine is yellow, crystalline powder that is freely soluble in N,N-dimethylformamide, chloroform, and ethyl acetate; soluble in dichloromethane; slightly soluble in ethanol and methanol; and insoluble in water. It has the empirical formula C30H32Cl3NO with molecular weight of 528.9, and the following structural formula: Coartem Tablets are for oral administration. Each Coartem Tablet contains 20 mg of artemether and 120 mg lumefantrine. The inactive ingredients are colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, and polysorbate 80.. Artemether structural formula. Lumefantrine structural formula.

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 of 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 (>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 in Pediatric Patients (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)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Coartem Tablets contain 20 mg of artemether and 120 mg of lumefantrine. Coartem Tablets are supplied as yellow, round, flat tablets with beveled edges and scored on one side. Tablets are imprinted with N/C on one side and CG on the other side.. Tablets are scored and contain 20 mg artemether and 120 mg lumefantrine. (3).

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, dihydroartemisinin (DHA, metabolite of artemether) and lumefantrine by 89%, 85% and 68%, respectively, when compared to exposure values after Coartem Tablets alone. Concomitant use of strong inducers of CYP3A4 such as rifampin, carbamazepine, phenytoin, and St. 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 CYP3A. Therefore, Coartem Tablets may potentially reduce the effectiveness of hormonal contraceptives. Patients using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to use an additional non-hormonal method of birth control [see Warnings and Precautions (5.3) 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)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of Coartem Tablets did not include sufficient numbers of subjects aged 65 years and over to determine 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Coartem (artemether/lumefantrine) Tablets20 mg/120 mg Tablets yellow, round flat tablets with beveled edges and scored on one side. Tablets are imprinted with N/C on one side and CG on the other.Bottle of 24 NDC 0078-0568-45Store at 25oC (77oF); excursions permitted to 15oC to 30oC (59oF to 86oF) [see USP Controlled Room Temperature].Dispense in tight container (USP).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Coartem (artemether/lumefantrine) Tablets are indicated for treatment of acute, uncomplicated malaria infections due to Plasmodium falciparum in patients of kg bodyweight 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 not approved for patients with severe or complicated P. falciparum malaria. Coartem Tablets are not approved for the prevention of malaria.. Coartem (artemether and lumefantrine) Tablets are indicated for treatment of acute, uncomplicated malaria infections due to Plasmodium falciparum in patients of kg bodyweight and above. (1) Coartem Tablets have been shown to be effective in geographical regions where resistance to chloroquine has been reported. (1) Coartem Tablets should not be used to treat severe malaria or to prevent malaria. (1). Coartem (artemether and lumefantrine) Tablets are indicated for treatment of acute, uncomplicated malaria infections due to Plasmodium falciparum in patients of kg bodyweight and above. (1) Coartem Tablets have been shown to be effective in geographical regions where resistance to chloroquine has been reported. (1) Coartem Tablets should not be used to treat severe malaria or to prevent malaria. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise patients to read the FDA-Approved Patient Labeling.Information for Safe UseInstruct patients to take Coartem Tablets with food. Patients who do not have an adequate intake of food are at risk for recrudescence of malaria. Patients with known hypersensitivity to artemether, lumefantrine, or to any of the excipients should not receive Coartem Tablets. 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. 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). 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. Instruct 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). Inform patients that based on animal data, Coartem Tablets administered during pregnancy may result in fetal loss. Fetal defects have been reported when artemisinins are administered to animals. Halofantrine 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. QT 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. Closely monitor food intake in patients who received mefloquine immediately prior to treatment with Coartem Tablets. Use 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. Coartem Tablets may reduce the effectiveness of hormonal contraceptives. Therefore, patients using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to use an additional non-hormonal method of birth control. Inform 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. T2015-44March 2015. Instruct patients to take Coartem Tablets with food. Patients who do not have an adequate intake of food are at risk for recrudescence of malaria. Patients with known hypersensitivity to artemether, lumefantrine, or to any of the excipients should not receive Coartem Tablets. 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. 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). 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. Instruct 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). Inform patients that based on animal data, Coartem Tablets administered during pregnancy may result in fetal loss. Fetal defects have been reported when artemisinins are administered to animals. Halofantrine 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. QT 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. Closely monitor food intake in patients who received mefloquine immediately prior to treatment with Coartem Tablets. Use 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. Coartem Tablets may reduce the effectiveness of hormonal contraceptives. Therefore, patients using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to use an additional non-hormonal method of birth control. Inform 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.

MECHANISM OF ACTION SECTION.

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 Clinical Pharmacology (12.4)].

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of Action Coartem Tablets, fixed ratio of 1:6 parts of artemether and lumefantrine, respectively, is an antimalarial agent. Artemether is rapidly metabolized into an active metabolite dihydroartemisinin (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 VivoArtemether and lumefantrine are active against the erythrocytic stages of Plasmodium falciparum. Drug ResistanceStrains 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. The clinical relevance of such an effect is not known.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisCarcinogenicity studies were not conducted.MutagenesisNo evidence of mutagenicity was detected. The artemether: lumefantrine combination was evaluated using the Salmonella and Escherichia/mammalian-microsome mutagenicity test, the gene mutation test with Chinese hamster cells V79, the cytogenetic test on Chinese hamster cells in vitro, and the rat micronucleus test, in vivo. Impairment of FertilityPregnancy rates were reduced by about one-half in female rats dosed for to weeks with the artemether-lumefantrine combination at 1000 mg/kg (about times the clinical dose based on body surface area comparisons). Male rats dosed for 70 days showed increases in abnormal sperm (87% abnormal) and increased testes weights at 30 mg/kg doses (about one-third the clinical dose). Higher doses (about times the clinical dose) resulted in decreased sperm motility and 100% abnormal sperm cells.. 13.2 Animal Toxicology and/or Pharmacology. Neonatal rats (7 to 21 days old) were more sensitive to the toxic effects of artemether (a component of Coartem Tablets) than older juvenile rats or adults. Mortality and severe clinical signs were observed in neonatal rats at doses which were well tolerated in pups above 22 days old.

NURSING MOTHERS SECTION.

8.3 Nursing Mothers. It is not known whether artemether or lumefantrine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Coartem Tablets are administered to nursing woman. Animal data suggest both artemether and lumefantrine are excreted into breast milk. The benefits of breastfeeding to mother and infant should be weighed against potential risk from infant exposure to artemether and lumefantrine through breast milk.

OVERDOSAGE SECTION.

10 OVERDOSAGE. There is no information on overdoses of Coartem Tablets higher than the doses recommended for treatment.In cases of suspected overdosage, symptomatic and supportive therapy, which would include ECG and blood electrolyte monitoring, should be given as appropriate.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 20/120 mg Tablet Bottle Label. Austin/Travis Co. Health Human Services Dept.1000 Toyath St Austin, TX 78703 512-972-6206 Coartem20/120 mg24 Date: Name:Dr. First day, tablet by mouth every hours for doses, then tabletevery 12 hours on days and 02/2018 F0171W1 Coartem 20/120 mg tabs 24 NDC 76413-154-24 Batch: 08231704Lot: F0171W1Exp: 02/2018NOVARTIS Federal law prohibits the transfer of this drug to any other person than the patient for whom prescribed. PRINCIPAL DISPLAY PANEL 20/120 mg Tablet Bottle Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of Coartem Tablets have been established for the treatment of acute, uncomplicated malaria in studies involving pediatric patients weighing kg or more [see Clinical Studies (14.1)]. The safety and efficacy have not been established in pediatric patients who weigh less than kg. Children from non-endemic countries were not included in clinical trials.

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, dihydroartemisinin (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 (DHA), and Lumefantrine under Fed ConditionsStudy 2102(n=50)Study 2104(n=48)ArtemetherCmax (ng/mL)60.0 +- 32.583.8 +- 59.7tmax (h)1.502.00AUClast (ngh/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 (ngh/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 (ugh/mL)158 +- 70.1243 +- 117t 1/2 (h)101 +- 35.6119 +- 51.0aMean +- SD Cmax, AUClast, 1/2 and Median tmax 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 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 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 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. Hepatic 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 mg/kg body weight basis in pediatric patients (>=5 to <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)2Drug5 to <1515 to <2525 to <35LumefantrineMean Cmax, range (mcg/mL)5.60 9.04.71 12.6Not AvailableMean AUClast, range (mcgh/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 +- 23.61 There are total of 181 adults for lumefantrine pharmacokinetic parameters and total of 25 adults for artemether and dihydroartemisinin pharmacokinetic parameters. There are 477 children for the lumefantrine pharmacokinetic parameters; for artemether and dihydroartemisinin pharmacokinetic parameters there are 55, 29, and children for the to <15, 15 to <25 and the 25 to <35 kg groups, respectively.Geriatric PatientsNo specific pharmacokinetic studies have been performed in patients older than 65 years of age.Drug InteractionsRifampin (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, 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 area under the curve (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 CYP3A. 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. Pregnancy Category Safety data from an observational pregnancy study of approximately 500 pregnant women who were exposed to Coartem Tablets (including third of patients who were exposed in the first trimester), and published data of over 1,000 pregnant patients who were exposed to artemisinin derivatives, did not show an increase in adverse pregnancy outcomes or teratogenic effects over background rate. The efficacy of Coartem Tablets in the treatment of acute, uncomplicated malaria in pregnant women has not been established.Coartem Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant rats dosed during the period of organogenesis at or higher than dose of about half the highest clinical dose of 1120 mg artemether-lumefantrine per day (based on body surface area comparisons), showed increases in fetal loss, early resorptions and post implantation loss. No adverse effects were observed in animals dosed at about one-third the highest clinical dose. Similarly, dosing in pregnant rabbits at about times the clinical dose (based on body surface area 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 times the clinical dose. Embryo-fetal loss is significant reproductive toxicity. Other artemisinins are known to be embryotoxic in animals. However, because metabolic profiles in animals and humans are dissimilar, artemether exposures in animals may not be predictive of human exposures [see Nonclinical Toxicology (13.2)]. These data cannot rule out an increased risk for early pregnancy loss or fetal defects in humans.

SPL PATIENT PACKAGE INSERT SECTION.

FDA-Approved Patient LabelingPatient InformationCoartem(R) (co-AR-tem)(artemether and lumefantrine)TabletsRead this patient information 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 in adults and children who weigh at least 11 pounds (5 kg). Who should not take CoartemDo not take Coartem if you are allergic to any of the ingredients. See the end of this leaflet for complete list of ingredients in Coartem. Do not take Coartem if you are taking rifampin (medicine to treat leprosy or tuberculosis), certain medicines used to treat epilepsy (such as carbamazepine, phenytoin), or St. Johns wort (Hypericum perforatum, medicinal plant or extract of this medicinal plant).What should tell my healthcare provider before taking CoartemBefore you take Coartem, tell your healthcare provider about all 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 are planning to become pregnant. Coartem may increase your risk for loss of pregnancy. Fetal defects have been reported when artemisinins are administered to animals. Talk to your healthcare provider before taking Coartem. are breastfeeding. It is not known if Coartem passes into your breast milk. You and your doctor will decide the best way to feed your baby if you take Coartem.Tell your doctor about all the medicines you take, including prescription and non-prescription 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 doctor 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) medicines to treat HIV-infection hormonal methods of birth control (for example, birth control pills or patch). If you are taking hormonal birth control medicine, you should also use an additional method of birth control.Ask your healthcare provider if you are not sure if your medicine is that is listed above. Know the medicines you take. Keep list of your medicines with you to show your healthcare providers 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. If you weigh less than 77 pounds (35 kg), your healthcare provider will tell you how many tablets to take for each dose. full course of treatment is doses of Coartem taken over days: Day 1: take dose; 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 eveningTake Coartem for days even if you are feeling better.Every dose of Coartem should be taken with food, 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. Coartem may be crushed and mixed with to teaspoons of water in clean container. If you vomit within hour of 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 you vomited any of your doses of Coartem you are not able to eat you get flu-like symptoms (chills, fever, muscle pains, or headaches) again after you have finished your treatment with Coartem. you 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), and in people who take medicines to control heartbeats. Allergic reactions. Symptoms of an allergic reaction include: rash, hives, fast heartbeat, trouble swallowing or breathing, swelling of lips, tongue, face, tightness of the throat, or trouble speaking. If you have serious allergic reaction, stop taking Coartem and get emergency medical help right away. The most common side effects in adults are: headache feeling dizzy feeling weak loss of appetite muscle and joint pain or stiffness feeling tired chills fever The most common side effects in children are: fever cough vomiting headache loss of appetiteThese 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 between 59oF to 86oF (15oC to 30oC). 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 leaflets. 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. For more information call 1-855-262-7836. What are the ingredients in CoartemActive ingredients include: artemether, lumefantrineInactive ingredients include: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polysorbate 80Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936(C) NovartisT2015-45March 2015. 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 are planning to become pregnant. Coartem may increase your risk for loss of pregnancy. Fetal defects have been reported when artemisinins are administered to animals. Talk to your healthcare provider before taking Coartem. are breastfeeding. It is not known if Coartem passes into your breast milk. You and your doctor will decide the best way to feed your baby if you take 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) medicines to treat HIV-infection hormonal methods of birth control (for example, birth control pills or patch). If you are taking hormonal birth control medicine, you should also use an additional method of birth control.. Take Coartem exactly as prescribed. If you weigh 77 pounds (35 kg) or more, dose of Coartem is tablets. If you weigh less than 77 pounds (35 kg), your healthcare provider will tell you how many tablets to take for each dose. A full course of treatment is doses of Coartem taken over days: Day 1: take dose; 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 evening. Every dose of Coartem should be taken with food, 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. Coartem may be crushed and mixed with to teaspoons of water in clean container. If you vomit within hour of 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 you vomited any of your doses of Coartem you are not able to eat you get flu-like symptoms (chills, fever, muscle pains, or headaches) again after you have finished your treatment with Coartem. 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), and in people who take medicines to control heartbeats. Allergic reactions. Symptoms of an allergic reaction include: rash, hives, fast heartbeat, trouble swallowing or breathing, swelling of lips, tongue, face, tightness of the throat, or trouble speaking. If you have serious allergic reaction, stop taking Coartem and get emergency medical help right away. headache feeling dizzy feeling weak loss of appetite muscle and joint pain or stiffness feeling tired chills fever fever cough vomiting headache loss of appetite.

SPL UNCLASSIFIED SECTION.

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 of administration, repeat dose should be taken. If the repeat dose is vomited, the patient should be given an alternative antimalarial for treatment.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may increase fetal loss. (8.1)Nursing Mothers: Use caution when administering to nursing woman. (8.3)Pediatric Use: Studied in children months of age and older with bodyweight of kg and greater. (8.4)Geriatric Use: Not studied in geriatric patients. (8.5). Pregnancy: Based on animal data, may increase fetal loss. (8.1). Nursing Mothers: Use caution when administering to nursing woman. (8.3). Pediatric Use: Studied in children months of age and older with bodyweight of kg and greater. (8.4). Geriatric Use: Not studied in geriatric patients. (8.5). 8.1 Pregnancy. Pregnancy Category Safety data from an observational pregnancy study of approximately 500 pregnant women who were exposed to Coartem Tablets (including third of patients who were exposed in the first trimester), and published data of over 1,000 pregnant patients who were exposed to artemisinin derivatives, did not show an increase in adverse pregnancy outcomes or teratogenic effects over background rate. The efficacy of Coartem Tablets in the treatment of acute, uncomplicated malaria in pregnant women has not been established.Coartem Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant rats dosed during the period of organogenesis at or higher than dose of about half the highest clinical dose of 1120 mg artemether-lumefantrine per day (based on body surface area comparisons), showed increases in fetal loss, early resorptions and post implantation loss. No adverse effects were observed in animals dosed at about one-third the highest clinical dose. Similarly, dosing in pregnant rabbits at about times the clinical dose (based on body surface area 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 times the clinical dose. Embryo-fetal loss is significant reproductive toxicity. Other artemisinins are known to be embryotoxic in animals. However, because metabolic profiles in animals and humans are dissimilar, artemether exposures in animals may not be predictive of human exposures [see Nonclinical Toxicology (13.2)]. These data cannot rule out an increased risk for early pregnancy loss or fetal defects in humans. 8.3 Nursing Mothers. It is not known whether artemether or lumefantrine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Coartem Tablets are administered to nursing woman. Animal data suggest both artemether and lumefantrine are excreted into breast milk. The benefits of breastfeeding to mother and infant should be weighed against potential risk from infant exposure to artemether and lumefantrine through breast milk. 8.4 Pediatric Use. The safety and effectiveness of Coartem Tablets have been established for the treatment of acute, uncomplicated malaria in studies involving pediatric patients weighing kg or more [see Clinical Studies (14.1)]. The safety and efficacy have not been established in pediatric patients who weigh less than kg. Children 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 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. 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 oral, transdermal patch, or other systemic hormonal contraceptives should be advised to use an additional non-hormonal method of birth control [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.