ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in labeling:Serotonin Syndrome or NMS-like Reactions [see Warnings and Precautions (5.1)] Valvular Heart Disease [see Warnings and Precautions (5.2)] Cognitive Impairment [see Warnings and Precautions (5.3)] Psychiatric Disorders [see Warnings and Precautions (5.4)] Hypoglycemia [see Warnings and Precautions (5.5)] Heart Rate Decreases [see Warnings and Precautions (5.7)] Hematological Changes [see Warnings and Precautions (5.8)] Prolactin Elevation [see Warnings and Precautions (5.9)]. Serotonin Syndrome or NMS-like Reactions [see Warnings and Precautions (5.1)] Valvular Heart Disease [see Warnings and Precautions (5.2)] Cognitive Impairment [see Warnings and Precautions (5.3)] Psychiatric Disorders [see Warnings and Precautions (5.4)] Hypoglycemia [see Warnings and Precautions (5.5)] Heart Rate Decreases [see Warnings and Precautions (5.7)] Hematological Changes [see Warnings and Precautions (5.8)] Prolactin Elevation [see Warnings and Precautions (5.9)]. Most common adverse reactions (greater than 5%) in non-diabetic patients are headache, dizziness, fatigue, nausea, dry mouth, and constipation, and in diabetic patients are hypoglycemia, headache, back pain, cough, and fatigue. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at 1-888-274-2378 or FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.. 6.1 Clinical Trials Experience In the lorcaserin placebo-controlled clinical database of trials of at least one year in duration, of 6888 patients (3451 lorcaserin vs. 3437 placebo; age range 18-66 years, 79.3% women, 66.6% Caucasians, 19.2% Blacks, 11.8% Hispanics, 2.4% other, 7.4% type diabetics), total of 1969 patients were exposed to immediate-release lorcaserin hydrochloride 10 mg twice daily for year and 426 patients were exposed for years. In clinical trials of at least one year in duration, 8.6% of patients treated with lorcaserin prematurely discontinued treatment due to adverse reactions, compared with 6.7% of placebo-treated patients. The most common adverse reactions leading to discontinuation more often among lorcaserin-treated patients than placebo were headache (1.3% vs. 0.8%), depression (0.9% vs. 0.5%) and dizziness (0.7% vs. 0.2%). Most Common Adverse Reactions 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 rates observed in practice. The most common adverse reactions for non-diabetic patients (greater than 5% and more commonly than placebo) treated with lorcaserin compared to placebo were headache, dizziness, fatigue, nausea, dry mouth, and constipation. The most common adverse reactions for diabetic patients were hypoglycemia, headache, back pain, cough, and fatigue. Adverse reactions that were reported by greater than or equal to 2% of patients and were more frequently reported by patients taking lorcaserin compared to placebo are summarized in Table (non-diabetic subjects) and Table (subjects with type diabetes mellitus). Table 2. Adverse Reactions Reported by Greater Than or Equal to 2% of Lorcaserin Patients and More Commonly than with Placebo in Patients without Diabetes MellitusAdverse ReactionNumber of patients (%)LorcaserinN=3195PlaceboN=3185Gastrointestinal DisordersNausea264 (8.3)170 (5.3)Diarrhea207 (6.5)179 (5.6)Constipation186 (5.8)125 (3.9)Dry mouth169 (5.3)74 (2.3)Vomiting122 (3.8)83 (2.6)General Disorders And Administration Site ConditionsFatigue229 (7.2)114 (3.6)Infections And InfestationsUpper respiratory tract infection439 (13.7)391 (12.3)Nasopharyngitis414 (13.0)381 (12.0)Urinary tract infection207 (6.5)171 (5.4)Musculoskeletal And Connective Tissue DisordersBack pain201 (6.3)178 (5.6)Musculoskeletal pain65 (2.0)43 (1.4)Nervous System DisordersHeadache537 (16.8)321 (10.1)Dizziness270 (8.5)122 (3.8)Respiratory, Thoracic And Mediastinal DisordersCough136 (4.3)109 (3.4)Oropharyngeal pain111 (3.5)80 (2.5)Sinus congestion93 (2.9)78 (2.4)Skin And Subcutaneous Tissue DisordersRash67 (2.1)58 (1.8) Immediate-release lorcaserin hydrochloride, 10 mg twice dailyTable 3. Adverse Reactions Reported by Greater Than or Equal to 2% of Lorcaserin Patients and More Commonly than with Placebo in Patients with Type Diabetes MellitusNumber of patients (%) Adverse ReactionLorcaserinN=256PlaceboN=252Gastrointestinal DisordersNausea24 (9.4)20 (7.9)Toothache7 (2.7)0General Disorders And Administration Site ConditionsFatigue19 (7.4)10 (4.0)Peripheral edema 12 (4.7)6 (2.4)Immune System DisordersSeasonal allergy8 (3.1)2 (0.8)Infections And InfestationsNasopharyngitis29 (11.3)25 (9.9)Urinary tract infection23 (9.0)15 (6.0)Gastroenteritis8 (3.1)5 (2.0)Metabolism And Nutrition DisordersHypoglycemia75 (29.3)53 (21.0)Worsening of diabetes mellitus7 (2.7)2 (0.8)Decreased appetite6 (2.3)1 (0.4)Musculoskeletal And Connective Tissue DisordersBack pain30 (11.7)20 (7.9)Muscle spasms12 (4.7)9 (3.6)Nervous System DisordersHeadache37 (14.5)18 (7.1)Dizziness18 (7.0)16 (6.3)Psychiatric DisordersAnxiety9 (3.5)8 (3.2)Insomnia9 (3.5)6 (2.4)Stress7 (2.7)3 (1.2)Depression6 (2.3)5 (2.0)Respiratory, Thoracic And Mediastinal DisordersCough21 (8.2)11 (4.4)Vascular DisordersHypertension13 (5.1)8 (3.2) Immediate-release lorcaserin hydrochloride, 10 mg twice dailyOther Adverse ReactionsSerotonin-associated Adverse Reactions SSRIs, SNRIs, bupropion, tricyclic antidepressants, and MAOIs were excluded from the lorcaserin trials. Triptans and dextromethorphan were permitted: 2% and 15%, respectively, of patients without diabetes and 1% and 12%, respectively, of patients with type diabetes experienced concomitant use at some point during the trials. Two patients treated with lorcaserin in the clinical program experienced constellation of symptoms and signs consistent with serotonergic excess, including one patient on concomitant dextromethorphan who reported an event of serotonin syndrome. Some symptoms of possible serotonergic etiology that are included in the criteria for serotonin syndrome were reported by patients treated with lorcaserin and placebo during clinical trials of at least year in duration. In both groups, chills were the most frequent of these events (1.0% vs. 0.2%, respectively), followed by tremor (0.3% vs. 0.2%), confusional state (0.2% vs. less than 0.1%), disorientation (0.1% vs. 0.1%) and hyperhidrosis (0.1% vs. 0.2%). Because serotonin syndrome has very low incidence, an association between BELVIQ XR and serotonin syndrome cannot be excluded on the basis of clinical trial results [s ee Warnings and Precautions (5.1)]. Hypoglycemia in Patients with Type Diabetes In clinical trial of patients with type diabetes mellitus, severe hypoglycemia (requiring the assistance of another person, requiring intravenous glucose, or hospitalization) occurred in (1.6%) of lorcaserin-treated patients and in (0.4%) placebo-treated patient. Of these lorcaserin-treated patients, all were concomitantly using sulfonylurea (with or without metformin). Lorcaserin has not been studied in patients taking insulin. Hypoglycemia defined as blood sugar less than or equal to 65 mg/dL and with symptoms occurred in 19 (7.4%) lorcaserin-treated patients and 16 (6.3%) placebo-treated patients. Cognitive Impairment In clinical trials of at least 1-year duration, adverse reactions related to cognitive impairment (e.g., difficulty with concentration/attention, difficulty with memory, and confusion) occurred in 2.3% of patients taking lorcaserin and 0.7% of patients taking placebo.Psychiatric DisordersPsychiatric disorders leading to hospitalization or drug withdrawal occurred more frequently in patients treated with lorcaserin (2.2%) as compared to placebo (1.1%) in non-diabetic patients.Euphoria. In short-term studies with healthy individuals, the incidence of euphoric mood following supratherapeutic doses of lorcaserin (40 and 60 mg) was increased as compared to placebo [see Drug Abuse and Dependence (9.2)]. In clinical trials of at least 1-year duration in obese patients, euphoria was observed in 0.17% of patients taking lorcaserin and 0.03% taking placebo.Depression and Suicidality. In trials of at least one year in duration, reports of depression/mood problems occurred in 2.6% lorcaserin-treated vs. 2.4% placebo-treated and suicidal ideation occurred in 0.6% lorcaserin-treated vs. 0.4% placebo-treated patients. 1.3% of lorcaserin patients vs. 0.6% of placebo patients discontinued drug due to depression-, mood-, or suicidal ideation-related events.Laboratory AbnormalitiesLymphocyte and Neutrophil Counts. In clinical trials of at least 1-year duration, lymphocyte counts were below the lower limit of normal in 12.2% of patients taking lorcaserin and 9.0% taking placebo, and neutrophil counts were low in 5.6% and 4.3%, respectively.Hemoglobin. In clinical trials of at least 1-year duration, 10.4% of patients taking lorcaserin and 9.3% taking placebo had hemoglobin below the lower limit of normal at some point during the trials.Prolactin. In clinical trials, elevations of prolactin greater than the upper limit of normal, two times the upper limit of normal, and five times the upper limit of normal, occurred in 6.7%, 1.7%, and 0.1% of lorcaserin-treated patients and 4.8%, 0.8%, and 0.0% of placebo-treated patients, respectively. Eye disorders More patients on lorcaserin reported an eye disorder than patients on placebo in clinical trials of patients without diabetes (4.5% vs. 3.0%) and with type diabetes (5.9% vs. 1.6%). In the population without diabetes, events of blurred vision, dry eye, and visual impairment occurred in lorcaserin-treated patients at an incidence greater than that of placebo. In the population with type diabetes, visual disorders, conjunctival infections, irritations, and inflammations, ocular sensation disorders, and cataract conditions occurred in lorcaserin-treated patients at an incidence greater than placebo. Echocardiographic Safety Assessments The possible occurrence of regurgitant cardiac valve disease was prospectively evaluated in 7794 patients in three clinical trials of at least one year in duration, 3451 of whom took immediate-release lorcaserin hydrochloride 10 mg twice daily. The primary echocardiographic safety parameter was the proportion of patients who developed echocardiographic criteria of mild or greater aortic insufficiency and/or moderate or greater mitral insufficiency from baseline to year. At year, 2.4% of patients who received lorcaserin and 2.0% of patients who received placebo developed valvular regurgitation. The relative risk for valvulopathy with lorcaserin is summarized in Table 4. Lorcaserin was not studied in patients with congestive heart failure or hemodynamically-significant valvular heart disease [s ee Warnings and Precautions (5.2)]. Table 4. Incidence of FDA-Defined Valvulopathy at Week 52 by Treatment Group1 Study 1Study 2Study 3LorcaserinN=1278PlaceboN=1191LorcaserinN=1208PlaceboN=1153LorcaserinN=210PlaceboN=209FDA-defined Valvulopathy, (%)34 (2.7)28 (2.4)24 (2.0)23 (2.0)6 (2.9)1 (0.5)Relative Risk (95% CI)1.13 (0.69, 1.85)1.00 (0.57, 1.75)5.97 (0.73, 49.17)Pooled RR (95% CI)1.16 (0.81, 1.67)Patients without valvulopathy at baseline who received study medication and had post-baseline echocardiogram; ITT-intention-to-treat; LOCF-last observation carried forward Immediate-release lorcaserin hydrochloride, 10 mg twice daily. Patients without valvulopathy at baseline who received study medication and had post-baseline echocardiogram; ITT-intention-to-treat; LOCF-last observation carried forward Immediate-release lorcaserin hydrochloride, 10 mg twice daily. 6.2 Post-Marketing Experience. The following adverse reactions have been identified during post approval use of lorcaserin. Because these reactions 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.Immune System Disorders: drug hypersensitivity.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Mutagenesis Lorcaserin was not mutagenic in an in vitro bacterial mutation assay (Ames test), was not clastogenic in an in vitro chromosome aberration assay in Chinese hamster ovary cells, and was not genotoxic in an in vivo micronucleus assay in rat bone marrow. Carcinogenesis The carcinogenic potential of lorcaserin was assessed in two-year carcinogenicity studies in mice and rats. CD-1 mice received doses of 5, 25 and 50 mg/kg. There were no treatment-related increases in the incidence of any tumor in mice at doses that produced plasma exposure in males and females of and 4-times the daily human clinical dose, respectively. In the rat carcinogenicity study, male and female Sprague-Dawley rats received 10, 30, and 100 mg/kg lorcaserin hydrochloride. In females, mammary adenocarcinoma increased at 100 mg/kg, which was associated with plasma exposures that were 87-times the daily human clinical dose. The incidence of mammary fibroadenoma was increased in female rats at all doses with no safety margin to the clinical dose. The increases in adenocarcinomas and fibroadenomas may be associated with lorcaserin-induced changes in prolactin homeostasis in rats. The relevance of the increased incidence of mammary adenocarcinomas and fibroadenomas in rats to humans is unknown.In male rats, treatment-related neoplastic changes were observed in the subcutis (fibroadenoma, Schwannoma), the skin (squamous cell carcinoma), mammary gland (adenocarcinoma and fibroadenoma), and the brain (astrocytoma) at greater than or equal to 30 mg/kg (plasma exposure 17-times human clinical dose). At higher exposure, liver adenoma and thyroid follicular cell adenoma were increased but were considered secondary to liver enzyme induction in rats and are not considered relevant to humans. Human brain exposure (AUC24h,ss) to lorcaserin at the clinical dose is estimated to be 70-fold lower than brain exposure in rats at the dose at which no increased incidence of astrocytoma was observed. Excluding the liver and thyroid tumors, these neoplastic findings in male rats are of unknown relevance to humans. Impairment of Fertility Potential effects on fertility were assessed in Sprague-Dawley rats in which males were dosed with lorcaserin hydrochloride for weeks prior to and through the mating period, and females were dosed for weeks prior to mating and through gestation day 7. Lorcaserin had no effects on fertility in rats at exposures up to 29 times the human clinical dose.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lorcaserin is believed to decrease food consumption and promote satiety by selectively activating 5-HT2C receptors on anorexigenic pro-opiomelanocortin neurons located in the hypothalamus. The exact mechanism of action is not known.Lorcaserin at the recommended daily dose selectively interacts with 5-HT2C receptors as compared to 5-HT2A and 5-HT2B receptors (see Table 5), other 5-HT receptor subtypes, the 5-HT receptor transporter, and 5-HT reuptake sites. Table 5. Lorcaserin Potency (EC50) and Binding Affinity (Ki) to Human 5-HT2A, 5-HT2B, and 5-HT2C Receptor Subtypes Serotonin Receptor SubtypeEC50, nMKi, nM5HT2C 39135HT2B 23801475HT2A 55392. 12.2 Pharmacodynamics Cardiac Electrophysiology. The effect of multiple oral doses of immediate-release lorcaserin hydrochloride 15 mg and 40 mg once daily on QTc interval was evaluated in randomized, placebo- and active- (moxifloxacin 400 mg) controlled four-treatment arm parallel thorough QT study in 244 healthy subjects. In study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 ms, the threshold for regulatory concern. 12.3 Pharmacokinetics Absorption In an open label, randomized, crossover clinical trial, single dose and steady state pharmacokinetics of BELVIQ XR 20 mg administered once daily were compared with immediate-release lorcaserin hydrochloride 10 mg tablet administered twice daily under fasted conditions in 34 healthy subjects. At steady state, the time to reach peak plasma concentrations of lorcaserin (tmax) following BELVIQ XR 20 mg once daily was approximately 10 hours compared with 1.5 hours for immediate-release lorcaserin hydrochloride 10 mg tablet twice daily. single dose administration of BELVIQ XR 20 mg resulted in comparable total plasma exposure (AUC0-), but approximately 25% lower peak exposures (Cmax) relative to two doses of immediate-release tablets administered 12 hours apart. At steady state, however, both Cmax,ss and area under the plasma concentration versus time curve (AUC0-24,ss) of BELVIQ XR 20 mg administered once daily were bioequivalent to immediate-release lorcaserin hydrochloride 10 mg tablets administered twice daily under fasted conditions. Effect of Food. Intake of high fat, high calorie breakfast before single 20 mg oral dose of BELVIQ XR resulted in approximately 46% increase in Cmax and 17% increase in AUC0- but no change in tmax. At steady state, however, there was no significant food effect on the rate or extent of absorption of BELVIQ XR. Distribution Lorcaserin distributes to the cerebrospinal fluid and central nervous system in humans. Lorcaserin is moderately bound (~70%) to human plasma proteins. Metabolism Lorcaserin is extensively metabolized in the liver by multiple enzymatic pathways. After oral administration of lorcaserin, the major circulating metabolite is lorcaserin sulfamate (M1), with plasma Cmax that exceeds lorcaserin Cmax by 1- to 5-fold. N-carbamoyl glucuronide lorcaserin (M5) is the major metabolite in urine; M1 is minor metabolite in urine, representing approximately 3% of dose. Other minor metabolites excreted in urine were identified as glucuronide or sulfate conjugates of oxidative metabolites. The principal metabolites exert no pharmacological activity at serotonin receptors. Elimination Lorcaserin is extensively metabolized by the liver and the metabolites are excreted in the urine. In human mass balance study in which healthy subjects ingested radiolabeled lorcaserin, 94.5% of radiolabeled material was recovered, with 92.3% and 2.2% recovered from urine and feces, respectively. The plasma half-life of BELVIQ XR is approximately 12 hours. Specific Populations Renal Impairment. The pharmacokinetics of lorcaserin was studied in patients with varying degrees of renal function following administration of immediate-release lorcaserin. Creatinine clearance (CLcr) was calculated by Cockcroft-Gault equation based on ideal body weight (IBW). Impaired renal function decreased Cmax of lorcaserin, with no change in AUC. Exposure of lorcaserin sulfamate metabolite (M1) was increased in patients with impaired renal function by approximately 1.7-fold in mild (CLcr 50-80 mL/min), 2.3-fold in moderate (CLcr 30-50 mL/min) and 10.5-fold in severe renal impairment (CLcr <30 mL/min) compared to normal subjects (CLcr >80 mL/min). Exposure of the N-carbamoyl-glucuronide metabolite (M5) was increased in patients with impaired renal function by approximately 1.5-fold in mild (CLcr 50-80 mL/min), 2.5-fold in moderate (CLcr 30-50 mL/min) and 5.1-fold in severe renal impairment (CLcr <30 mL/min) compared to normal subjects (CLcr >80 mL/min). The terminal half-life of M1 is prolonged by 26%, 96%, and 508% in mild, moderate, and severe renal impairment, respectively. The terminal half-life of M5 is prolonged by 0%, 26%, and 22% in mild, moderate, and severe renal impairment, respectively. The metabolites M1 and M5 accumulate in patients with severely impaired renal function. Approximately 18% of metabolite M5 in the body was cleared from the body during standard 4-hour hemodialysis procedure. Lorcaserin and M1 were not cleared by hemodialysis. Lorcaserin is not recommended for patients with severe renal impairment (CLcr <30 mL/min) or patients with end stage renal disease [s ee Use in Specific Populations (8.6)].Estimate Ideal Body Weight (IBW) in (kg) Males: IBW 50 kg 2.3 kg for each inch over feet. Females: IBW 45.5 kg 2.3 kg for each inch over feet. The Cockcroft-Gault calculation using the IBW:female:GFR (mL/min) 0.85 (140-age) ideal body weight (kg) 72 serum creatinine (mg/dL)male:GFR (mL/min) (140-age) ideal body weight (kg) 72 serum creatinine (mg/dL)Hepatic Impairment. The pharmacokinetics of lorcaserin was evaluated in patients with hepatic impairment and subjects with normal hepatic function following administration of immediate-release lorcaserin. Lorcaserin Cmax was 7.8% and 14.3% lower, in subjects with mild (Child-Pugh score 5-6) and moderate (Child-Pugh score 7-9) hepatic impairment, respectively, than that in subjects with normal hepatic function. The half-life of lorcaserin is prolonged by 59% to 19 hours in patients with moderate hepatic impairment. Lorcaserin exposure (AUC) is approximately 22% and 30% higher in patients with mild and moderate hepatic impairment, respectively. Dose adjustment is not required for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on lorcaserin was not evaluated [s ee Use in Specific Populations (8.7)].Gender. No dosage adjustment based on gender is necessary. Gender did not meaningfully affect the pharmacokinetics of lorcaserin.Geriatric. No dosage adjustment is required based on age alone. In clinical trial of 12 healthy elderly (age greater than 65 years) subjects and 12 matched adult patients who were administered immediate-release lorcaserin, exposure (AUC and Cmax) of lorcaserin was equivalent in the two groups. Cmax was approximately 18% lower in the elderly group, and Tmax was increased from hours to 2.5 hours in the elderly group as compared to the non-elderly adult group. Race. No dosage adjustment based on race is necessary. Race did not meaningfully affect the pharmacokinetics of lorcaserin. Drug-Drug InteractionsLorcaserin inhibits CYP 2D6-mediated metabolism. In clinical trial in 21 CYP 2D6 extensive metabolizers, concomitant administration of tablets of immediate-release lorcaserin hydrochloride (10 mg twice daily for days) increased dextromethorphan peak concentrations (Cmax) by approximately 76% and exposure (AUC) by approximately 2-fold [see Drug Interactions (7.2)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES The safety and efficacy of lorcaserin for chronic weight management in conjunction with reduced caloric intake and increased physical activity were evaluated in randomized, double-blind, placebo-controlled trials with durations ranging from 52 to 104 weeks. Two trials in adults without type diabetes mellitus (Study and Study 2) and one study in adults with type diabetes mellitus (Study 3) evaluated the effect of immediate-release lorcaserin hydrochloride 10 mg twice daily. The primary efficacy parameter in these studies was weight loss at year, which was assessed by percent of patients achieving greater than or equal to 5% weight loss, percent of patients achieving greater than or equal to 10% weight loss, and mean weight change. All patients received one-on-one instruction for reduced-calorie diet and exercise counseling that began with the first dose of study medication and continued every four weeks throughout the trial. Study was 2-year study that enrolled 3182 patients who were obese (BMI 30-45 kg/m2), or who were overweight (BMI 27-29.9 kg/m2) and had at least one weight-related comorbid condition such as hypertension or dyslipidemia. In Year 2, placebo patients were continued on placebo and lorcaserin patients were re-randomized in 2:1 ratio to continue lorcaserin or to switch to placebo. The mean age was 44 (range 18-65); 83.5% were women. Sixty-seven percent were Caucasian, 19% were African American and 12% were Hispanic. Mean baseline body weight was 100.0 kg and mean BMI was 36.2 kg/m2. Study was 1-year study that enrolled 4008 patients who were obese (BMI 30-45 kg/m2) or were overweight (BMI 27-29.9 kg/m2) with at least one comorbid condition such as hypertension or dyslipidemia. The mean age was 44 (range 18-65); 80% were women. Sixty-seven percent were Caucasian, 20% were African American and 11% were Hispanic. Mean baseline body weight was 100.2 kg and mean BMI was 35.9 kg/m2. Study was 1-year study that enrolled 604 adult patients with BMI greater than or equal to 27 kg/m2 and inadequately controlled type diabetes (HbA1c range 7-10%) being treated with metformin and/or sulfonylurea. Mean age was 53 (range 21-65); 54% were women. Sixty-one percent were Caucasian, 21% African American and 14% were Hispanic. Mean BMI was 36 kg/m2 and mean HbA1C was 8.1%. substantial percentage of randomized subjects withdrew from each study prior to week 52: 50% in Study 1, 45% in Study and 36% in Study 3. One-Year Weight Management in Patients without Diabetes Mellitus Weight loss at year in Studies and is presented in Table 6. The pooled data are reflective of the individual study results.Statistically significantly greater weight loss was achieved with lorcaserin compared to placebo at week 52. The Year placebo-adjusted weight loss achieved in patients treated with lorcaserin was 3.3 kg by ITT/LOCF analysis. The time course of weight loss with lorcaserin and placebo through week 52 is depicted in Figure 1.Patients who did not lose at least 5% of baseline body weight by week 12 were unlikely to achieve at least 5% weight loss at week 52.Table 6. Weight Loss at Year in Studies and Combined LorcaserinN=3098PlaceboN=3038Weight (kg) Baseline mean (SD)100.4 (15.7)100.2 (15.9) Change from baseline (adjusted mean1) (SE)-5.8 (0.1)-2.5 (0.1) Difference from placebo (adjusted mean1) (95% CI)-3.3 (-3.6, -2.9) Percent change from baseline (adjusted mean1) (SE)-5.8 (0.1)-2.5 (0.1) Difference from placebo (adjusted mean1) (95% CI)-3.3 -3.6, -3.0)% of Patients losing greater than or equal to 5% body weight47.122.6 Difference from placebo (95% CI)24.5 (22.2, 26.8)% of Patients losing greater than or equal to 10% body weight22.48.7 Difference from placebo (95% CI)13.8 (12.0, 15.5)SD=Standard Deviation; SE=Standard Error; CI=Confidence IntervalIntent to Treat Population using last observation carried forward method; All patients who received study medication and had post-baseline body weight. Forty-four percent (44%) of patients in lorcaserin and 51% in placebo dropped out before the 52-week endpoint.1Least squares means adjusted for baseline value, treatment, study and treatment by study interaction.p<0.001 compared to placebo. Type error was controlled across the three endpoints. Immediate-release lorcaserin hydrochloride 10 mg twice dailyFigure 1. Longitudinal Weight Change (kg) in Completer Population: Studies and Two-Year Weight Management in Patients without Diabetes Mellitus The safety and efficacy of lorcaserin for weight management during years of treatment were evaluated in Study 1. Of the 3182 patients who were randomized in Year 1, 1553 (48.8%) were randomized in Year 2. Patients in all three Year patient groups (lorcaserin Year 1/ lorcaserin Year 2, lorcaserin Year 1/placebo Year 2, and placebo Year 1/placebo Year 2) regained weight in Year but remained below their Year mean baseline weight (Figure 2). Figure 2. Body Weight Changes during Study in the Completers Population Effect of orcaserin on Cardiometabolic Parameters and Anthropometry Changes in lipids, fasting glucose, fasting insulin, waist circumference, heart rate, and blood pressure with lorcaserin are shown in Table 7. In substudy of 154 patients conducted as part of Study 2, DEXA analysis showed 9.9% reduction in fat mass from baseline of 44.5 kg in patients treated with lorcaserin compared to 4.6% reduction from baseline of 45.0 kg in patients treated with placebo. The placebo-adjusted reduction in fat mass achieved on lorcaserin was -5.3%. Reductions in lean body mass were 1.9% and 0.3% from baseline values of 48.0 kg and 51.0 kg, respectively, for lorcaserin- and placebo-treated patients.Table 7. Mean Changes in Cardiometabolic Parameters and Waist Circumference in Year of Studies and 2Lorcaserin+-N=3096PlaceboN=3039Lorcaserin minus Placebo (LSMean)Baseline mg/dL% change from Baseline(LSMean1)Baselinemg/dL% change from Baseline(LSMean)Total Cholesterol194.4 -0.9194.8 0.4-1.2 LDL Cholesterol114.3 1.6 114.12.9-1.3 HDL Cholesterol53.2 1.8 53.50.61.2 Triglycerides135.4 -5.3137.0-0.5-4.8 Baseline change from Baseline(LSMean)Baseline change from Baseline(LSMean)Lorcaserin minus Placebo (LSMean)Systolic blood pressure (mmHg)121.4 -1.8121.5-1.0-0.7 Diastolic blood pressure (mmHg)77.4 -1.6 77.7-1.0-0.6 Heart Rate (bpm)69.5-1.269.5-0.4-0.8 Fasting glucose (mg/dL)92.1 -0.292.40.6-0.8 Fasting insulin2 (uIU/mL)15.9-3.315.8-1.3-2.1 Waist Circumference (cm)109.3-6.5109.6-4.0-2.5 Least squares means adjusted for baseline value, treatment, study and treatment by study interaction2 Measured in Study only (n=1538) Statistically significant versus placebo based on the pre-specified gatekeeping method for controlling Type error in key secondary endpoints. +-Immediate-release lorcaserin hydrochloride 10 mg twice daily One-Year Weight Management in Patients with Type Diabetes Mellitus Weight loss among patients with type diabetes mellitus who were treated with lorcaserin was statistically significantly greater than that among patients treated with placebo (Table 8). Table 8. Weight Loss at Year in Study (Type Diabetes Mellitus)LorcaserinN=251PlaceboN=248Weight loss (kg) Baseline mean (SD)103.5 (17.2)102.3 (18.0) Change from baseline (adjusted mean1) (SE)-4.7 (0.4)-1.6 (0.4) Difference from placebo (adjusted mean1) (95% CI)-3.1 (-4.0, -2.2) Percent change from baseline (adjusted mean1) (SE)-4.5 (0.4)-1.5 (0.4) Difference from placebo (adjusted mean1) (95% CI)-3.1 (-3.9, -2.2)% of Patients losing greater than or equal to 5% body weight37.516.1 Difference from placebo (95% CI)21.3 (13.8, 28.9)% of Patients losing greater than or equal to 10% body weight16.34.4 Difference from placebo (95% CI)11.9 (6.7, 17.1)SD=Standard Deviation; SE=Standard Error; CI=Confidence IntervalIntent to Treat Population using last observation carried forward method; All patients who received study medication and had post-baseline body weight. Thirty-four percent (34%) of patients in lorcaserin and 38% in placebo dropped out before the 52-week endpoint.1Least squares means adjusted for baseline value, baseline HbA1c stratum and prior antihyperglycemic medication stratum.Immediate-release lorcaserin hydrochloride 10 mg twice dailyp<0.001 compared to placebo. Type error was controlled across the three endpoints. Effect of orcaserin on Cardiometabolic Parameters and Anthropometry in Patients with Type Diabetes Mellitus Patients in Study were taking either metformin and/or sulfonylurea at study start, and had inadequate glycemic control (HbA1c range 7-10%). Changes in HbA1c and fasting glucose with lorcaserin use are shown in Table 9. Table 9. Mean Changes in Cardiometabolic Parameters and Waist Circumference in Patients with Type Diabetes MellitusLorcaserin+-N=256PlaceboN=252Lorcaserin minus Placebo (LSMean)BaselineChange from Baseline(LSMean1)BaselineChange from Baseline(LSMean)HbA1C (%)8.1-0.98.0-0.4-0.5 Fasting glucose (mg/dL)163.3-27.4160.0-11.9-15.5 Systolic blood pressure (mmHg)126.6-0.8126.5-0.90.1 Diastolic blood pressure (mmHg)77.9-1.178.7-0.7-0.4 Heart Rate (bpm)72.3-2.072.7-0.4-1.6 Waist Circumference (cm)115.8-5.5113.5-3.3-2.2Baseline% Change from Baseline(LSMean)Baseline% Change from Baseline(LSMean)Lorcaserin minus Placebo (LSMean)Total Cholesterol (mg/dL)173.5-0.7172.0-0.1-0.5 LDL Cholesterol (mg/dL)95.04.294.65.0-0.8 HDL Cholesterol (mg/dL)45.35.245.71.63.6 Triglycerides (mg/dL)172.1-10.7163.5-4.8-5.9 Intent to Treat Population using last observation carried forward method; All patients who received study medication and had post-baseline measurement. Statistically significant versus placebo based on the pre-specified gatekeeping method for controlling Type error in key secondary endpoints. 1Least squares means adjusted for baseline value, baseline HbA1c stratum and prior antihyperglycemic medication stratum.+-Immediate-release lorcaserin hydrochloride 10 mg twice daily. Least squares means adjusted for baseline value, treatment, study and treatment by study interaction. Measured in Study only (n=1538) Statistically significant versus placebo based on the pre-specified gatekeeping method for controlling Type error in key secondary endpoints. Figure 1.Longitudinal Weight Change (kg) in Completer Population: Studies and 2. Figure 2.Body Weight Changes during Study in the Completers Population.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE BELVIQ XR (lorcaserin hydrochloride) extended-release tablet is indicated as an adjunct to reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of:30 kg/m2 or greater (obese), or 27 kg/m2 or greater (overweight) in the presence of at least one weight related comorbid condition (e.g., hypertension, dyslipidemia, type diabetes) [s ee Dosage and Administration (2)]Limitations of Use:The safety and efficacy of coadministration of BELVIQ XR with other products intended for weight loss including prescription drugs (e.g., phentermine), over-the-counter drugs, and herbal preparations have not been established. The effect of BELVIQ XR on cardiovascular morbidity and mortality has not been established.. 30 kg/m2 or greater (obese), or 27 kg/m2 or greater (overweight) in the presence of at least one weight related comorbid condition (e.g., hypertension, dyslipidemia, type diabetes) The safety and efficacy of coadministration of BELVIQ XR with other products intended for weight loss including prescription drugs (e.g., phentermine), over-the-counter drugs, and herbal preparations have not been established. The effect of BELVIQ XR on cardiovascular morbidity and mortality has not been established.. BELVIQ XR is serotonin 2C receptor agonist indicated as an adjunct to reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of:30 kg/m2 or greater (obese) (1) or 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid condition, (e.g., hypertension, dyslipidemia, type diabetes) (1)Limitations of Use:The safety and efficacy of coadministration with other products for weight loss have not been established (1) The effect of BELVIQ XR on cardiovascular morbidity and mortality has not been established (1). 30 kg/m2 or greater (obese) (1) or 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid condition, (e.g., hypertension, dyslipidemia, type diabetes) (1). The safety and efficacy of coadministration with other products for weight loss have not been established (1) The effect of BELVIQ XR on cardiovascular morbidity and mortality has not been established (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). BELVIQ XR is indicated for chronic weight management only in conjunction with reduced-calorie diet and increased physical activity. Patients should be instructed to discontinue use of BELVIQ XR if they have not achieved 5% weight loss by 12 weeks of treatment. Patients should be informed of the possibility of serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions with the combined use of BELVIQ XR with other serotonergic drugs, including selective serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs), triptans, drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors [MAOIs]), dietary supplements such as St. Johns Wort and tryptophan, tramadol, or antipsychotics or other dopamine antagonists. Patients who develop signs or symptoms of valvular heart disease, including dyspnea or dependent edema should seek medical attention. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that BELVIQ XR therapy does not affect them adversely. Patients should be instructed to seek medical attention in the event of emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Patients should be cautioned not to increase their dose of BELVIQ XR. Men who have an erection lasting greater than hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention. Pregnancy: Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider with known or suspected pregnancy see Contraindications (4) Use in Specific Populations (8.1) ]. Lactation: Advise women to avoid use of BELVIQ XR while breastfeeding [see Use in Specific Populations (8.2) ]. Patients should tell their healthcare provider about all the medications, nutritional supplements and vitamins (including any weight loss products) that they may take while taking BELVIQ XR.BELVIQ XR is registered trademark of Arena Pharmaceuticals GmbH, Zofingen, Switzerland Manufactured by Arena Pharmaceuticals GmbH, Untere Bruhlstrasse 4, CH-4800, Zofingen, Switzerland Distributed by Eisai Inc., Woodcliff Lake, NJ 07677. BELVIQ XR is indicated for chronic weight management only in conjunction with reduced-calorie diet and increased physical activity. Patients should be instructed to discontinue use of BELVIQ XR if they have not achieved 5% weight loss by 12 weeks of treatment. Patients should be informed of the possibility of serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions with the combined use of BELVIQ XR with other serotonergic drugs, including selective serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs), triptans, drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors [MAOIs]), dietary supplements such as St. Johns Wort and tryptophan, tramadol, or antipsychotics or other dopamine antagonists. Patients who develop signs or symptoms of valvular heart disease, including dyspnea or dependent edema should seek medical attention. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that BELVIQ XR therapy does not affect them adversely. Patients should be instructed to seek medical attention in the event of emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Patients should be cautioned not to increase their dose of BELVIQ XR. Men who have an erection lasting greater than hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention. Pregnancy: Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider with known or suspected pregnancy see Contraindications (4) Use in Specific Populations (8.1) ]. Lactation: Advise women to avoid use of BELVIQ XR while breastfeeding [see Use in Specific Populations (8.2) ]. Patients should tell their healthcare provider about all the medications, nutritional supplements and vitamins (including any weight loss products) that they may take while taking BELVIQ XR.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Mutagenesis Lorcaserin was not mutagenic in an in vitro bacterial mutation assay (Ames test), was not clastogenic in an in vitro chromosome aberration assay in Chinese hamster ovary cells, and was not genotoxic in an in vivo micronucleus assay in rat bone marrow. Carcinogenesis The carcinogenic potential of lorcaserin was assessed in two-year carcinogenicity studies in mice and rats. CD-1 mice received doses of 5, 25 and 50 mg/kg. There were no treatment-related increases in the incidence of any tumor in mice at doses that produced plasma exposure in males and females of and 4-times the daily human clinical dose, respectively. In the rat carcinogenicity study, male and female Sprague-Dawley rats received 10, 30, and 100 mg/kg lorcaserin hydrochloride. In females, mammary adenocarcinoma increased at 100 mg/kg, which was associated with plasma exposures that were 87-times the daily human clinical dose. The incidence of mammary fibroadenoma was increased in female rats at all doses with no safety margin to the clinical dose. The increases in adenocarcinomas and fibroadenomas may be associated with lorcaserin-induced changes in prolactin homeostasis in rats. The relevance of the increased incidence of mammary adenocarcinomas and fibroadenomas in rats to humans is unknown.In male rats, treatment-related neoplastic changes were observed in the subcutis (fibroadenoma, Schwannoma), the skin (squamous cell carcinoma), mammary gland (adenocarcinoma and fibroadenoma), and the brain (astrocytoma) at greater than or equal to 30 mg/kg (plasma exposure 17-times human clinical dose). At higher exposure, liver adenoma and thyroid follicular cell adenoma were increased but were considered secondary to liver enzyme induction in rats and are not considered relevant to humans. Human brain exposure (AUC24h,ss) to lorcaserin at the clinical dose is estimated to be 70-fold lower than brain exposure in rats at the dose at which no increased incidence of astrocytoma was observed. Excluding the liver and thyroid tumors, these neoplastic findings in male rats are of unknown relevance to humans. Impairment of Fertility Potential effects on fertility were assessed in Sprague-Dawley rats in which males were dosed with lorcaserin hydrochloride for weeks prior to and through the mating period, and females were dosed for weeks prior to mating and through gestation day 7. Lorcaserin had no effects on fertility in rats at exposures up to 29 times the human clinical dose.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Absorption In an open label, randomized, crossover clinical trial, single dose and steady state pharmacokinetics of BELVIQ XR 20 mg administered once daily were compared with immediate-release lorcaserin hydrochloride 10 mg tablet administered twice daily under fasted conditions in 34 healthy subjects. At steady state, the time to reach peak plasma concentrations of lorcaserin (tmax) following BELVIQ XR 20 mg once daily was approximately 10 hours compared with 1.5 hours for immediate-release lorcaserin hydrochloride 10 mg tablet twice daily. single dose administration of BELVIQ XR 20 mg resulted in comparable total plasma exposure (AUC0-), but approximately 25% lower peak exposures (Cmax) relative to two doses of immediate-release tablets administered 12 hours apart. At steady state, however, both Cmax,ss and area under the plasma concentration versus time curve (AUC0-24,ss) of BELVIQ XR 20 mg administered once daily were bioequivalent to immediate-release lorcaserin hydrochloride 10 mg tablets administered twice daily under fasted conditions. Effect of Food. Intake of high fat, high calorie breakfast before single 20 mg oral dose of BELVIQ XR resulted in approximately 46% increase in Cmax and 17% increase in AUC0- but no change in tmax. At steady state, however, there was no significant food effect on the rate or extent of absorption of BELVIQ XR. Distribution Lorcaserin distributes to the cerebrospinal fluid and central nervous system in humans. Lorcaserin is moderately bound (~70%) to human plasma proteins. Metabolism Lorcaserin is extensively metabolized in the liver by multiple enzymatic pathways. After oral administration of lorcaserin, the major circulating metabolite is lorcaserin sulfamate (M1), with plasma Cmax that exceeds lorcaserin Cmax by 1- to 5-fold. N-carbamoyl glucuronide lorcaserin (M5) is the major metabolite in urine; M1 is minor metabolite in urine, representing approximately 3% of dose. Other minor metabolites excreted in urine were identified as glucuronide or sulfate conjugates of oxidative metabolites. The principal metabolites exert no pharmacological activity at serotonin receptors. Elimination Lorcaserin is extensively metabolized by the liver and the metabolites are excreted in the urine. In human mass balance study in which healthy subjects ingested radiolabeled lorcaserin, 94.5% of radiolabeled material was recovered, with 92.3% and 2.2% recovered from urine and feces, respectively. The plasma half-life of BELVIQ XR is approximately 12 hours. Specific Populations Renal Impairment. The pharmacokinetics of lorcaserin was studied in patients with varying degrees of renal function following administration of immediate-release lorcaserin. Creatinine clearance (CLcr) was calculated by Cockcroft-Gault equation based on ideal body weight (IBW). Impaired renal function decreased Cmax of lorcaserin, with no change in AUC. Exposure of lorcaserin sulfamate metabolite (M1) was increased in patients with impaired renal function by approximately 1.7-fold in mild (CLcr 50-80 mL/min), 2.3-fold in moderate (CLcr 30-50 mL/min) and 10.5-fold in severe renal impairment (CLcr <30 mL/min) compared to normal subjects (CLcr >80 mL/min). Exposure of the N-carbamoyl-glucuronide metabolite (M5) was increased in patients with impaired renal function by approximately 1.5-fold in mild (CLcr 50-80 mL/min), 2.5-fold in moderate (CLcr 30-50 mL/min) and 5.1-fold in severe renal impairment (CLcr <30 mL/min) compared to normal subjects (CLcr >80 mL/min). The terminal half-life of M1 is prolonged by 26%, 96%, and 508% in mild, moderate, and severe renal impairment, respectively. The terminal half-life of M5 is prolonged by 0%, 26%, and 22% in mild, moderate, and severe renal impairment, respectively. The metabolites M1 and M5 accumulate in patients with severely impaired renal function. Approximately 18% of metabolite M5 in the body was cleared from the body during standard 4-hour hemodialysis procedure. Lorcaserin and M1 were not cleared by hemodialysis. Lorcaserin is not recommended for patients with severe renal impairment (CLcr <30 mL/min) or patients with end stage renal disease [s ee Use in Specific Populations (8.6)].Estimate Ideal Body Weight (IBW) in (kg) Males: IBW 50 kg 2.3 kg for each inch over feet. Females: IBW 45.5 kg 2.3 kg for each inch over feet. The Cockcroft-Gault calculation using the IBW:female:GFR (mL/min) 0.85 (140-age) ideal body weight (kg) 72 serum creatinine (mg/dL)male:GFR (mL/min) (140-age) ideal body weight (kg) 72 serum creatinine (mg/dL)Hepatic Impairment. The pharmacokinetics of lorcaserin was evaluated in patients with hepatic impairment and subjects with normal hepatic function following administration of immediate-release lorcaserin. Lorcaserin Cmax was 7.8% and 14.3% lower, in subjects with mild (Child-Pugh score 5-6) and moderate (Child-Pugh score 7-9) hepatic impairment, respectively, than that in subjects with normal hepatic function. The half-life of lorcaserin is prolonged by 59% to 19 hours in patients with moderate hepatic impairment. Lorcaserin exposure (AUC) is approximately 22% and 30% higher in patients with mild and moderate hepatic impairment, respectively. Dose adjustment is not required for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on lorcaserin was not evaluated [s ee Use in Specific Populations (8.7)].Gender. No dosage adjustment based on gender is necessary. Gender did not meaningfully affect the pharmacokinetics of lorcaserin.Geriatric. No dosage adjustment is required based on age alone. In clinical trial of 12 healthy elderly (age greater than 65 years) subjects and 12 matched adult patients who were administered immediate-release lorcaserin, exposure (AUC and Cmax) of lorcaserin was equivalent in the two groups. Cmax was approximately 18% lower in the elderly group, and Tmax was increased from hours to 2.5 hours in the elderly group as compared to the non-elderly adult group. Race. No dosage adjustment based on race is necessary. Race did not meaningfully affect the pharmacokinetics of lorcaserin. Drug-Drug InteractionsLorcaserin inhibits CYP 2D6-mediated metabolism. In clinical trial in 21 CYP 2D6 extensive metabolizers, concomitant administration of tablets of immediate-release lorcaserin hydrochloride (10 mg twice daily for days) increased dextromethorphan peak concentrations (Cmax) by approximately 76% and exposure (AUC) by approximately 2-fold [see Drug Interactions (7.2)].

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONBELVIQ XR(R) (BEL-VEEK EKS-ARE)(lorcaserin hydrochloride)Extended Release TabletsWhat is BELVIQ XRBELVIQ XR is prescription medicine that may help some obese adults or overweight adults who also have weight related medical problems lose weight and keep the weight off.BELVIQ XR should be used with reduced calorie diet and increased physical activity.It is not known if BELVIQ XR is safe and effective when taken with other prescription, over-the-counter, or herbal weight loss products.It is not known if BELVIQ XR changes your risk of heart problems or stroke or of death due to heart problems or stroke.It is not known if BELVIQ XR is safe when taken with some other medicines that treat depression, migraines, mental problems, or the common cold (serotonergic or antidopaminergic agents).It is not known if BELVIQ XR is safe and effective in children under 18 years old.BELVIQ XR is federally controlled substance (CIV) because it contains lorcaserin hydrochloride and may be abused or lead to drug dependence. Keep your BELVIQ XR in safe place, to protect it from theft. Never give your BELVIQ XR to anyone else, because it may cause harm to them. Selling or giving away this medicine is against the law.Do not take BELVIQ XR if you: are pregnant or planning to become pregnant. BELVIQ XR may harm your unborn baby. are allergic to lorcaserin hydrochloride or any of the ingredients in BELVIQ XR. See the end of this leaflet for complete list of ingredients in BELVIQ XR.Before you take BELVIQ XR, tell your healthcare provider about all of your medical conditions, including if you: have or have had heart problems including: congestive heart failure heart valve problems slow heart beat or heart block have diabetes have condition such as sickle cell anemia, multiple myeloma, or leukemia have deformed penis, Peyronies disease, or ever had an erection that lasted more than hours have kidney problems have liver problems are pregnant or plan to become pregnant. are breastfeeding or plan to breastfeed. It is not known if BELVIQ XR passes into your breast milk. You and your healthcare provider should decide if you will take BELVIQ XR or breastfeed. You should not do both.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. BELVIQ XR may affect the way other medicines work, and other medicines may affect how BELVIQ XR works. Especially tell your healthcare provider if you take medicines for depression, migraines or other medical conditions such as: triptans, used to treat migraine headache medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, selective serotonin uptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), or antipsychotics cabergoline linezolid, an antibiotic tramadol dextromethorphan, an over-the-counter medicine used to treat the common cold or cough over-the-counter supplements such as tryptophan or St. Johns Wort medicines to treat erectile dysfunctionAsk your healthcare provider or pharmacist for list of these medicines, if you are not sure.Know all the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine. How should take BELVIQ XRo Take BELVIQ XR exactly as your healthcare provider tells you to take it.o Your healthcare provider will tell you how much BELVIQ XR to take and when to take it. Take tablet time each day. Do not increase your dose of BELVIQ XR. BELVIQ XR can be taken with or without food. Take the whole tablet. Do not chew, crush, or divide the tablet.o Your healthcare provider should start you on diet and exercise program when you start taking BELVIQ XR. Stay on this program while you are taking BELVIQ XR.o Your healthcare provider should tell you to stop taking BELVIQ XR if you do not lose certain amount of weight within the first 12 weeks of treatment. If you take too much BELVIQ XR or overdose, call your healthcare provider or go to the nearest emergency room right away. What should avoid while taking BELVIQ XRo Do not drive car or operate heavy machinery until you know how BELVIQ XR affects you. BELVIQ XR can slow your thinking. What are the possible side effects of BELVIQ XRBELVIQ XR may cause serious side effects, including: Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions. BELVIQ XR and certain medicines for depression, migraine, the common cold, or other medical problems may affect each other causing serious or life-threatening side effects. Call your healthcare provider right away if you start to have any of the following symptoms while taking BELVIQ XR: mental changes such as agitation, hallucinations, confusion, or other changes in mental status coordination problems, uncontrolled muscle spasms, or muscle twitching (overactive reflexes) restlessness racing or fast heart beat, high or low blood pressure sweating or fever nausea, vomiting, or diarrhea muscle rigidity (stiff muscles) Valvular heart disease. Some people taking medicines like BELVIQ XR have had problems with the valves in their heart. Call your healthcare provider right away if you have any of the following symptoms while taking BELVIQ XR: trouble breathing swelling of the arms, legs, ankles, or feet dizziness, fatigue, or weakness that will not go away fast or irregular heartbeat Changes in your attention or memory. Mental problems. Taking BELVIQ XR in high doses may cause psychiatric problems such as: hallucinations feeling high or in very good mood (euphoria) feelings of standing next to yourself or out of your body (disassociation) Depression or thoughts of suicide. You should pay attention to any mental changes, especially sudden changes, in your mood, behaviors, thoughts, or feelings. Call your healthcare provider right away if you have any mental changes that are new, worse, or worry you.Low blood sugar (hypoglycemia) in people with type diabetes mellitus who also take medicines used to treat type diabetes mellitus. Weight loss can cause low blood sugar in people with type diabetes mellitus who also take medicines used to treat type diabetes mellitus (such as insulin or sulfonylureas). You should check your blood sugar before you start taking BELVIQ XR and while you take BELVIQ XR.Painful erections (priapism). The medicine in BELVIQ XR can cause painful erections that last more than hours. If you have an erection lasting more than hours whether it is painful or not, stop using BELVIQ XR and call your healthcare provider or go to the nearest emergency room right away.Slow heart beat. BELVIQ XR may cause your heart to beat slower. Tell your healthcare provider if you have history of your heart beating slow or heart block. Decreases in your blood cell count. BELVIQ XR may cause your red and white blood cell count to decrease. Your healthcare provider may do tests to check your blood cell count while you are taking BELVIQ XR. Increase in prolactin. The medicine in BELVIQ XR may increase the amount of certain hormone your body makes called prolactin. Tell your healthcare provider if your breasts begin to make milk or milky discharge or if you are male and your breasts begin to increase in size. The most common side effects of BELVIQ XR include: headache nausea cough dizziness dry mouth low blood sugar (hypoglycemia) in patients with diabetes fatigue constipation back pain These are not all the possible side effects of BELVIQ XR. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store BELVIQ XRStore BELVIQ XR at room temperature between 59F to 86F (15C to 30C). Safely throw away medicine that is out of date or no longer needed. Keep BELVIQ XR and all medicines out of the reach of children. General information about the safe and effective use of BELVIQ XR.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use BELVIQ XR for condition for which it was not prescribed. Do not give BELVIQ XR to other people, even if they have the same symptoms you have. It may harm them. This Patient Information leaflet summarizes the most important information about BELVIQ XR. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about BELVIQ XR that is written for health professionals. What are the ingredients in BELVIQ XRActive ingredient: lorcaserin hydrochlorideInactive ingredients: microcrystalline cellulose NF; mannitol USP; hypromellose 2208 USP; ethylcellulose dispersion Type NF; hypromellose 2910 USP; colloidal silicon dioxide NF; polyvinyl alcohol USP; polyethylene glycol NF; titanium dioxide USP; talc USP; FD&C yellow 6/sunset yellow FCF; aluminum lake; iron oxide yellow NF; iron oxide red NF; and magnesium stearate NFManufactured by: Manufactured by Arena Pharmaceuticals GmbH, Untere Brhlstrasse 4, CH-4800, Zofingen, Switzerland Distributed by Eisai Inc., Woodcliff Lake, NJ 07677For more information, go to www.BELVIQXR.com or call 1-888-274-2378. This Patient Information has been approved by the U.S. Food and Drug Administration Issued: July 2016. Depression or thoughts of suicide. You should pay attention to any mental changes, especially sudden changes, in your mood, behaviors, thoughts, or feelings. Call your healthcare provider right away if you have any mental changes that are new, worse, or worry you.. Low blood sugar (hypoglycemia) in people with type diabetes mellitus who also take medicines used to treat type diabetes mellitus. Weight loss can cause low blood sugar in people with type diabetes mellitus who also take medicines used to treat type diabetes mellitus (such as insulin or sulfonylureas). You should check your blood sugar before you start taking BELVIQ XR and while you take BELVIQ XR.. Painful erections (priapism). The medicine in BELVIQ XR can cause painful erections that last more than hours. If you have an erection lasting more than hours whether it is painful or not, stop using BELVIQ XR and call your healthcare provider or go to the nearest emergency room right away.. Slow heart beat. BELVIQ XR may cause your heart to beat slower. Tell your healthcare provider if you have history of your heart beating slow or heart block. Decreases in your blood cell count. BELVIQ XR may cause your red and white blood cell count to decrease. Your healthcare provider may do tests to check your blood cell count while you are taking BELVIQ XR. Increase in prolactin. The medicine in BELVIQ XR may increase the amount of certain hormone your body makes called prolactin. Tell your healthcare provider if your breasts begin to make milk or milky discharge or if you are male and your breasts begin to increase in size.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS Lactation: Belviq XR is not recommended when breastfeeding. (8.2) Pediatric Use: Safety and effectiveness not established and use not recommended. (8.4). Lactation: Belviq XR is not recommended when breastfeeding. (8.2) Pediatric Use: Safety and effectiveness not established and use not recommended. (8.4). 8.1 Pregnancy Risk SummaryBELVIQ XR is contraindicated during pregnancy, because weight loss offers no potential benefit to pregnant woman and may result in fetal harm [see Clinical Considerations . Limited data on lorcaserin use in pregnant women are not sufficient to determine drug-associated risk of major congenital malformations or miscarriage. No adverse developmental effects were observed when lorcaserin was administered to pregnant rats and rabbits during organogenesis at exposures up to 44- and 19-times the 20mg/day clinical dose, respectively. In rats, maternal exposure to lorcaserin in late pregnancy resulted in lower body weight in offspring which persisted to adulthood [see Data . Advise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage of clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical ConsiderationsDisease-associated maternal and/or embryofetal riskA minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy.DataAnimal DataReproduction studies were performed in pregnant rats and rabbits that were administered lorcaserin hydrochloride during the period of embryofetal organogenesis. Plasma exposures up to 44 and 19 times the 20mg clinical dose in pregnant rats and rabbits, respectively, did not reveal evidence of teratogenicity or embryolethality with lorcaserin hydrochloride.In pre- and postnatal development study, maternal rats were dosed from gestation through post-natal day 21 at 5, 15, and 50mg/kg lorcaserin hydrochloride; pups were indirectly exposed in utero and throughout lactation. Stillborns and lower pup viability was observed at 50mg/kg, or 44 times the 20mg clinical dose, based on AUC. All other doses lowered pup body weight similarly at birth which persisted to adulthood; however, no developmental abnormalities were observed and reproductive performance was not affected.. 8.2 Lactation Risk SummaryThere are no data on the presence of lorcaserin in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infant, advise women that use of BELVIQ XR is not recommended while breastfeeding. 8.4 Pediatric Use The safety and effectiveness of BELVIQ XR in pediatric patients below the age of 18 have not been established and the use of BELVIQ XR is not recommended in pediatric patients.. 8.5 Geriatric Use In lorcaserin clinical trials, total of 135 (2.5%) of the patients were 65 years of age and older. Clinical studies of lorcaserin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects, but greater sensitivity of some older individuals cannot be ruled out.Since elderly patients have higher incidence of renal impairment, use of BELVIQ XR in the elderly should be made on the basis of renal function [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Elderly patients with normal renal function should require no dose adjustment. 8.6 Renal Impairment No dose adjustment of BELVIQ XR is required in patients with mild renal impairment. Use BELVIQ XR with caution in patients with moderate renal impairment. Use of BELVIQ XR in patients with severe renal impairment or end stage renal disease is not recommended [s ee Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment Dose adjustment is not required for patients with mild hepatic impairment (Child-Pugh score 5-6) to moderate hepatic impairment (Child-Pugh score 7-9). The effect of severe hepatic impairment on lorcaserin was not evaluated. Use lorcaserin with caution in patients with severe hepatic impairment [s ee Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions: The safety of coadministration with other serotonergic or antidopaminergic agents has not been established. Manage with immediate BELVIQ XR discontinuation and provide supportive treatment. (5.1) Valvular heart disease: If signs or symptoms develop consider BELVIQ XR discontinuation and evaluate the patient for possible valvulopathy. (5.2) Cognitive Impairment: May cause disturbances in attention or memory. Caution with use of hazardous machinery when starting BELVIQ XR treatment. (5.3) Psychiatric Disorders, including euphoria and dissociation: Do not exceed recommended dose of 20 mg per day. (5.4) Monitor for depression or suicidal thoughts. Discontinue if symptoms develop. (5.4) Use of Antidiabetic Medications: weight loss may cause hypoglycemia. Monitor blood glucose. Lorcaserin has not been studied in patients taking insulin. (5.5) Priapism: Patients should seek emergency treatment if an erection lasts >4 hours. Use BELVIQ XR with caution in patients predisposed to priapism. (5.6) Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions: The safety of coadministration with other serotonergic or antidopaminergic agents has not been established. Manage with immediate BELVIQ XR discontinuation and provide supportive treatment. (5.1) Valvular heart disease: If signs or symptoms develop consider BELVIQ XR discontinuation and evaluate the patient for possible valvulopathy. (5.2) Cognitive Impairment: May cause disturbances in attention or memory. Caution with use of hazardous machinery when starting BELVIQ XR treatment. (5.3) Psychiatric Disorders, including euphoria and dissociation: Do not exceed recommended dose of 20 mg per day. (5.4) Monitor for depression or suicidal thoughts. Discontinue if symptoms develop. (5.4) Use of Antidiabetic Medications: weight loss may cause hypoglycemia. Monitor blood glucose. Lorcaserin has not been studied in patients taking insulin. (5.5) Priapism: Patients should seek emergency treatment if an erection lasts >4 hours. Use BELVIQ XR with caution in patients predisposed to priapism. (5.6) 5.1 Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions BELVIQ XR is serotonergic drug. The development of potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported during use of serotonergic drugs, including, but not limited to, selective serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), bupropion, triptans, dietary supplements such as St. Johns Wort and tryptophan, drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors [MAOIs]), dextromethorphan, lithium, tramadol, antipsychotics or other dopamine antagonists, particularly when used in combination [s ee Drug Interactions (7.1)]. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. The safety of BELVIQ XR when coadministered with other serotonergic or antidopaminergic agents, including antipsychotics, or drugs that impair metabolism of serotonin, including MAOIs, has not been systematically evaluated and has not been established. If concomitant administration of BELVIQ XR with an agent that affects the serotonergic neurotransmitter system is clinically warranted, extreme caution and careful observation of the patient is advised, particularly during treatment initiation and dose increases. Treatment with BELVIQ XR and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated [s ee Adverse Reactions (6.1) and Drug Interactions (7.1)]. 5.2 Valvular Heart Disease Regurgitant cardiac valvular disease, primarily affecting the mitral and/or aortic valves, has been reported in patients who took serotonergic drugs with 5-HT2B receptor agonist activity. The etiology of the regurgitant valvular disease is thought to be activation of 5-HT2B receptors on cardiac interstitial cells. At therapeutic concentrations, lorcaserin is selective for 5-HT2C receptors as compared to 5-HT2B receptors. In clinical trials of 1-year duration, 2.4% of patients receiving lorcaserin and 2.0% of patients receiving placebo developed echocardiographic criteria for valvular regurgitation at one year (mild or greater aortic regurgitation and/or moderate or greater mitral regurgitation): none of these patients was symptomatic [s ee Adverse Reactions (6.1) and Clinical Pharmacology (12.1)]. Lorcaserin has not been studied in patients with congestive heart failure or hemodynamically-significant valvular heart disease. Preliminary data suggest that 5HT2B receptors may be overexpressed in congestive heart failure; therefore, BELVIQ XR should be used with caution in patients with congestive heart failure. BELVIQ XR should not be used in combination with serotonergic and dopaminergic drugs that are potent 5-HT2B receptor agonists and are known to increase the risk for cardiac valvulopathy (e.g., cabergoline).Patients who develop signs or symptoms of valvular heart disease, including dyspnea, dependent edema, congestive heart failure, or new cardiac murmur while being treated with BELVIQ XR should be evaluated and discontinuation of BELVIQ XR should be considered. 5.3 Cognitive Impairment In clinical trials of at least one year in duration, impairments in attention and memory were reported adverse reactions associated with 1.9% of patients treated with lorcaserin and 0.5% of patients treated with placebo, and led to discontinuation in 0.3% and 0.1% of these patients, respectively. Other reported adverse reactions associated with lorcaserin in clinical trials included confusion, somnolence, and fatigue [see Adverse Reactions (6.1)].Since BELVIQ XR has the potential to impair cognitive function, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that BELVIQ XR therapy does not affect them adversely [see Patient Counseling Information (17)].. 5.4 Psychiatric Disorders Events of euphoria, hallucination, and dissociation were seen with lorcaserin at supratherapeutic doses in short-term studies [see Adverse Reactions (6.1) Drug Abuse and Dependence (9.2) and Overdosage (10)]. In clinical trials of at least 1-year in duration, patients (0.2%) treated with lorcaserin developed euphoria, as compared with patient (<0.1%) treated with placebo. Doses of BELVIQ XR should not exceed 20 mg once daily.Some drugs that target the central nervous system have been associated with depression or suicidal ideation. Patients treated with BELVIQ XR should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue BELVIQ XR in patients who experience suicidal thoughts or behaviors [s ee Adverse Reactions (6.1)].. 5.5 Potential Risk of Hypoglycemia in Patients with Type Diabetes Mellitus on Anti-diabetic Therapy Weight loss may increase the risk of hypoglycemia in patients with type diabetes mellitus treated with insulin and/or insulin secretagogues (e.g., sulfonylureas); hypoglycemia was observed in clinical trials with lorcaserin. Lorcaserin has not been studied in combination with insulin. Measurement of blood glucose levels prior to starting BELVIQ XR and during BELVIQ XR treatment is recommended in patients with type diabetes. Decreases in medication doses for anti-diabetic medications which are non-glucose-dependent should be considered to mitigate the risk of hypoglycemia. If patient develops hypoglycemia after starting BELVIQ XR, appropriate changes should be made to the anti-diabetic drug regimen [see Adverse Reactions (6.1)].. 5.6 Priapism Priapism (painful erections greater than hours in duration) is potential effect of 5-HT2C receptor agonism. If not treated promptly, priapism can result in irreversible damage to the erectile tissue. Men who have an erection lasting greater than hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention.BELVIQ XR should be used with caution in men who have conditions that might predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia), or in men with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronies disease). There is limited experience with the combination of lorcaserin and medication indicated for erectile dysfunction (e.g., phosphodiesterase type inhibitors). Therefore, the combination of BELVIQ XR and these medications should be used with caution. 5.7 Heart Rate Decreases In clinical trials of at least 1-year in duration, the mean change in heart rate (HR) was -1.2 beats per minute (bpm) in lorcaserin and -0.4 bpm in placebo-treated patients without diabetes and -2.0 beats per minute (bpm) in lorcaserin and -0.4 bpm in placebo-treated patients with type diabetes. The incidence of HR less than 50 bpm was 5.3% in lorcaserin and 3.2% in placebo-treated patients without diabetes and 3.6% in lorcaserin and 2.0% in placebo-treated patients with type diabetes. In the combined population, adverse reactions of bradycardia occurred in 0.3% of lorcaserin and 0.1% of placebo-treated patients. Use with caution in patients with bradycardia or history of heart block greater than first degree.. 5.8 Hematological Changes In clinical trials of at least one year in duration, adverse reactions of decreases in white blood cell count (including leukopenia, lymphopenia, neutropenia, and decreased white cell count) were reported in 0.4% of patients treated with lorcaserin as compared to 0.2% of patients treated with placebo. Adverse reactions of decreases in red blood cell count (including anemia and decreases in hemoglobin and hematocrit) were reported by 1.3% of patients treated with lorcaserin as compared to 1.2% treated with placebo [s ee Adverse Reactions (6.1)]. Consider periodic monitoring of complete blood count during treatment with BELVIQ XR.. 5.9 Prolactin Elevation Lorcaserin moderately elevates prolactin levels. In subset of placebo-controlled clinical trials of at least one year in duration, elevations of prolactin greater than the upper limit of normal, two times the upper limit of normal, and five times the upper limit of normal, measured both before and hours after dosing, occurred in 6.7%, 1.7%, and 0.1% of lorcaserin-treated patients and 4.8%, 0.8%, and 0.0% of placebo-treated patients, respectively [see Adverse Reactions (6.1)]. Prolactin should be measured when symptoms and signs of prolactin excess are suspected (e.g., galactorrhea, gynecomastia). There was one patient treated with lorcaserin who developed prolactinoma during the trial. The relationship of lorcaserin to the prolactinoma in this patient is unknown.. 5.10 Pulmonary Hypertension Certain centrally-acting weight loss agents that act on the serotonin system have been associated with pulmonary hypertension, rare but lethal disease. Because of the low incidence of this disease, the clinical trial experience with lorcaserin is inadequate to determine if BELVIQ XR increases the risk for pulmonary hypertension.