BELVIQ / BELVIQ XR Film-coated tablet / Extended-release tablet Ref.[10124] Active ingredients: Lorcaserin

5.1 Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions

BELVIQ/BELVIQ XR is a serotonergic drug. The development of a 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. John’s 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 [see 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/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/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/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 [see 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-HT_2B receptor agonist activity. The etiology of the regurgitant valvular disease is thought to be activation of 5-HT_2B receptors on cardiac interstitial cells. At therapeutic concentrations, lorcaserin is selective for 5-HT_2C receptors as compared to 5-HT_2B receptors. In clinical trials of 1-year duration, 2.4% of patients receiving BELVIQ 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 [see Adverse Reactions (6.1) and Clinical Pharmacology (12.1)].

BELVIQ/BELVIQ XR has not been studied in patients with congestive heart failure or hemodynamically-significant valvular heart disease. Preliminary data suggest that 5HT_2B receptors may be overexpressed in congestive heart failure; therefore, BELVIQ/BELVIQ XR should be used with caution in patients with congestive heart failure.

BELVIQ/BELVIQ XR should not be used in combination with serotonergic and dopaminergic drugs that are potent 5-HT_2B 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 a new cardiac murmur while being treated with BELVIQ/BELVIQ XR should be evaluated and discontinuation of BELVIQ/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 BELVIQ 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 BELVIQ in clinical trials included confusion, somnolence, and fatigue [see Adverse Reactions (6.1)].

Since BELVIQ/BELVIQ XR have the potential to impair cognitive function, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that BELVIQ/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 BELVIQ 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, 6 patients (0.2%) treated with BELVIQ developed euphoria, as compared with 1 patient (<0.1%) treated with placebo. Doses should not exceed BELVIQ 10 mg twice daily or BELVIQ XR 20 mg once daily.

Some drugs that target the central nervous system have been associated with depression or suicidal ideation. Patients treated with BELVIQ/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/BELVIQ XR in patients who experience suicidal thoughts or behaviors [see Adverse Reactions (6.1)].

5.5 Potential Risk of Hypoglycemia in Patients with Type 2 Diabetes Mellitus on Anti- diabetic Therapy

Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin and/or insulin secretagogues (e.g., sulfonylureas); hypoglycemia was observed in clinical trials with BELVIQ. BELVIQ/BELVIQ XR has not been studied in combination with insulin. Measurement of blood glucose levels prior to starting BELVIQ/BELVIQ XR and during BELVIQ/BELVIQ XR treatment is recommended in patients with type 2 diabetes. Decreases in medication doses for anti-diabetic medications which are non-glucose-dependent should be considered to mitigate the risk of hypoglycemia. If a patient develops hypoglycemia after starting BELVIQ/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 6 hours in duration) is a potential effect of 5-HT_2C receptor agonism. If not treated promptly, priapism can result in irreversible damage to the erectile tissue. Men who have an erection lasting greater than 4 hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention.

BELVIQ/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 Peyronie’s disease). There is limited experience with the combination of BELVIQ/BELVIQ XR and medication indicated for erectile dysfunction (e.g., phosphodiesterase type 5 inhibitors). Therefore, the combination of BELVIQ/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 BELVIQ and -0.4 bpm in placebo-treated patients without diabetes and -2.0 beats per minute (bpm) in BELVIQ and -0.4 bpm in placebo-treated patients with type 2 diabetes. The incidence of HR less than 50 bpm was 5.3% in BELVIQ and 3.2% in placebo-treated patients without diabetes and 3.6% in BELVIQ and 2.0% in placebo-treated patients with type 2 diabetes. In the combined population, adverse reactions of bradycardia occurred in 0.3% of BELVIQ and 0.1% of placebo-treated patients. Use BELVIQ/BELVIQ XR with caution in patients with bradycardia or a 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 BELVIQ 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 BELVIQ as compared to 1.2% treated with placebo [see Adverse Reactions (6.1)]. Consider periodic monitoring of complete blood count during treatment with BELVIQ/BELVIQ XR.

5.9 Prolactin Elevation

Lorcaserin moderately elevates prolactin levels. In a 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 2 hours after dosing, occurred in 6.7%, 1.7%, and 0.1% of BELVIQ-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 BELVIQ who developed a prolactinoma during the trial. The relationship of BELVIQ/BELVIQ XR 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, a rare but lethal disease. Because of the low incidence of this disease, the clinical trial experience with BELVIQ is inadequate to determine if BELVIQ/BELVIQ XR increases the risk for pulmonary hypertension.

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)]

In the BELVIQ placebo-controlled clinical database of trials of at least one year in duration, of 6888 patients (3451 BELVIQ 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 2 diabetics), a total of 1969 patients were exposed to BELVIQ 10 mg twice daily for 1 year and 426 patients were exposed for 2 years.

In clinical trials of at least one year in duration, 8.6% of patients treated with BELVIQ 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 BELVIQ 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 a 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 BELVIQ 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 BELVIQ compared to placebo are summarized in Table 2 (non-diabetic subjects) and Table 3 (subjects with type 2 diabetes mellitus).

Table 2. Adverse Reactions Reported by Greater Than or Equal to 2% of BELVIQ Patients and More Commonly than with Placebo in Patients without Diabetes Mellitus:

Table 3. Adverse Reactions Reported by Greater Than or Equal to 2% of BELVIQ Patients and More Commonly than with Placebo in Patients with Type 2 Diabetes Mellitus:

Other Adverse Reactions

Serotonin-associated Adverse Reactions

SSRIs, SNRIs, bupropion, tricyclic antidepressants, and MAOIs were excluded from the BELVIQ trials. Triptans and dextromethorphan were permitted: 2% and 15%, respectively, of patients without diabetes and 1% and 12%, respectively, of patients with type 2 diabetes experienced concomitant use at some point during the trials. Two patients treated with BELVIQ in the clinical program experienced a 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 BELVIQ and placebo during clinical trials of at least 1 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 a very low incidence, an association between BELVIQ/BELVIQ XR and serotonin syndrome cannot be excluded on the basis of clinical trial results [see Warnings and Precautions (5.1)].

Hypoglycemia in Patients with Type 2 Diabetes

In a clinical trial of patients with type 2 diabetes mellitus, severe hypoglycemia (requiring the assistance of another person, requiring intravenous glucose, or hospitalization) occurred in 4 (1.6%) of BELVIQ-treated patients and in 1 (0.4%) placebo-treated patient. Of these 4 BELVIQ-treated patients, all were concomitantly using a sulfonylurea (with or without metformin). BELVIQ/BELVIQ XR 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%) BELVIQ-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 BELVIQ and 0.7% of patients taking placebo.

Psychiatric Disorders

Psychiatric disorders leading to hospitalization or drug withdrawal occurred more frequently in patients treated with BELVIQ (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 BELVIQ (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 BELVIQ 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% BELVIQ-treated vs. 2.4% placebo-treated and suicidal ideation occurred in 0.6% BELVIQ-treated vs. 0.4% placebo-treated patients. 1.3% of BELVIQ patients vs. 0.6% of placebo patients discontinued drug due to depression-, mood-, or suicidal ideation-related events.

Laboratory Abnormalities

Lymphocyte 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 BELVIQ 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 BELVIQ 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 BELVIQ-treated patients and 4.8%, 0.8%, and 0.0% of placebo-treated patients, respectively.

Eye disorders

More patients on BELVIQ reported an eye disorder than patients on placebo in clinical trials of patients without diabetes (4.5% vs. 3.0%) and with type 2 diabetes (5.9% vs. 1.6%). In the population without diabetes, events of blurred vision, dry eye, and visual impairment occurred in BELVIQ-treated patients at an incidence greater than that of placebo. In the population with type 2 diabetes, visual disorders, conjunctival infections, irritations, and inflammations, ocular sensation disorders, and cataract conditions occurred in BELVIQ-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 BELVIQ. 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 1 year. At 1 year, 2.4% of patients who received BELVIQ and 2.0% of patients who received placebo developed valvular regurgitation. The relative risk for valvulopathy with BELVIQ is summarized in Table 4. BELVIQ/BELVIQ XR was not studied in patients with congestive heart failure or hemodynamically-significant valvular heart disease [see Warnings and Precautions (5.2)].

Table 4. Incidence of FDA-Defined Valvulopathy at Week 52 by Treatment Group¹:

¹ Patients without valvulopathy at baseline who received study medication and had a postbaseline echocardiogram; ITT-intention-to-treat; LOCF-last observation carried forward

The following adverse reactions have been identified during post approval use. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: drug hypersensitivity

7.1 Use with Other Agents that Affect Serotonin Pathways

Based on the mechanism of action of BELVIQ/BELVIQ XR and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, but not limited to, triptans, monoamine oxidase inhibitors (MAOIs, including linezolid, an antibiotic which is a reversible non-selective MAOI), selective serotonin reuptake inhibitors (SSRIs), selective serotonin- norepinephrine reuptake inhibitors (SNRIs), dextromethorphan, tricyclic antidepressants (TCAs), bupropion, lithium, tramadol, tryptophan, and St. John’s Wort [see Warnings and Precautions (5.1)].

7.2 Cytochrome P450 (2D6) substrates

Use caution when administering BELVIQ/BELVIQ XR together with drugs that are CYP 2D6 substrates, as BELVIQ/BELVIQ XR can increase exposure of these drugs [see Clinical Pharmacology (12.3)].

Risk Summary

BELVIQ/BELVIQ XR is contraindicated during pregnancy, because weight loss offers no benefit to a pregnant woman and may result in fetal harm [see Clinical Considerations]. Limited data on lorcaserin use in pregnant women are not sufficient to determine a 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 clinical dose of 20 mg daily, 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 a 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 Considerations

Disease-associated maternal and/or embryofetal risk

Appropriate weight gain based on pre-pregnancy weight 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.

Data

Animal Data

Reproduction 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 clinical dose of 20 mg daily in pregnant rats and rabbits, respectively, did not reveal evidence of teratogenicity or embryolethality with lorcaserin hydrochloride.

In a pre- and postnatal development study, maternal rats were dosed from gestation through post-natal day 21 at 5, 15, and 50 mg/kg lorcaserin hydrochloride; pups were indirectly exposed in utero and throughout lactation. Stillborns and lower pup viability was observed at 50 mg/kg, or 44 times the clinical dose of 20 mg daily, 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.

Risk Summary

There 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 a breastfed infant, advise women that use of BELVIQ/BELVIQ XR is not recommended while breastfeeding.

The safety and effectiveness of BELVIQ/BELVIQ XR in pediatric patients below the age of 18 have not been established and the use of BELVIQ/BELVIQ XR is not recommended in pediatric patients.

In the BELVIQ clinical trials, a total of 135 (2.5%) of the patients were 65 years of age and older. Clinical studies of BELVIQ 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 a higher incidence of renal impairment, use of BELVIQ/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.

No dose adjustment of BELVIQ/BELVIQ XR is required in patients with mild renal impairment. Use BELVIQ/BELVIQ XR with caution in patients with moderate renal impairment. Use of BELVIQ/BELVIQ XR in patients with severe renal impairment or end stage renal disease is not recommended [see Clinical Pharmacology (12.3)].

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 BELVIQ/BELVIQ XR with caution in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

BELVIQ/BELVIQ XR is listed in Schedule IV of the Controlled Substances Act.

In a human abuse potential study in recreational drug abusers, supratherapeutic oral doses of BELVIQ (40 and 60 mg) produced up to two- to six-fold increases on measures of “High”, “Good Drug Effects”, “Hallucinations” and “Sedation” compared to placebo. These responses were similar to those produced by oral administration of the positive control drugs, zolpidem (15 and 30 mg) and ketamine (100 mg). In this study, the incidence of the adverse reaction of euphoria following lorcaserin administration (40 and 60 mg; 19%) is similar to the incidence following zolpidem administration (13-16%), but less than the incidence following ketamine administration (50%). The duration of euphoria following lorcaserin administration persisted longer (>9 hours) than that following zolpidem (1.5 hours) or ketamine (2.5 hours) administration.

Overall, in short-term studies with healthy individuals, the rate of euphoria following oral administration of lorcaserin was 16% following 40 mg (n = 11 of 70) and 19% following 60 mg (n = 6 of 31). However, in clinical studies with obese patients with durations of 4 weeks to 2 years, the incidence of euphoria and hallucinations following oral doses of lorcaserin up to 40 mg was low (<1.0%).

There are no data from well-conducted animal or human studies that evaluate whether lorcaserin can induce physical dependence, as evidenced by a withdrawal syndrome. However, the ability of lorcaserin to produce hallucinations, euphoria, and positive subjective responses at supratherapeutic doses suggests that lorcaserin may produce psychic dependence.