warnings and cautions
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/BELVIQ XR discontinuation and provide supportive treatment. ( 5.1 ) Valvular heart disease: If signs or symptoms develop consider BELVIQ/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/BELVIQ XR treatment. ( 5.3 ) Psychiatric Disorders, including euphoria and dissociation: Do not exceed recommended dose of BELVIQ 10 mg twice daily or BELVIQ XR 20 mg once daily. ( 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. BELVIQ/BELVIQ XR has not been studied in patients taking insulin. ( 5.5 ) Priapism: Patients should seek emergency treatment if an erection lasts >4 hours. Use BELVIQ/BELVIQ XR with caution in patients predisposed to priapism. ( 5.6 ) 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 [ s e e 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 2 B receptor agonist activity. The etiology of the regurgitant valvular disease is thought to be activation of 5-HT 2 B receptors on cardiac interstitial cells. At therapeutic concentrations, lorcaserin is selective for 5-HT 2 C receptors as compared to 5-HT 2 B 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 [ s e e 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 2 B 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 [ se e Adverse Reactions ( 6.1 ), Drug Abus e 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 2 C 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.