Included as part of the "PRECAUTIONS" Section
Serotonin Syndrome Or Neuroleptic Malignant Syndrome (NMS)-Like Reactions
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].
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 [see ADVERSE REACTIONS and DRUG INTERACTIONS].
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 [see ADVERSE REACTIONS and CLINICAL PHARMACOLOGY].
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 5HT2B 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 XR should be evaluated and discontinuation of BELVIQ XR should be considered.
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].
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 INFORMATION].
Events of euphoria, hallucination, and dissociation were seen with lorcaserin at supratherapeutic doses in short-term studies [see ADVERSE REACTIONS , DRUG INTERACTIONS and OVERDOSE]. In clinical trials of at least 1-year in duration, 6 patients (0.2%) treated with lorcaserin developed euphoria, as compared with 1 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 [see ADVERSE REACTIONS].
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 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 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 XR, appropriate changes should be made to the anti-diabetic drug regimen [see ADVERSE REACTIONS].
Priapism (painful erections greater than 6 hours in duration) is a 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 4 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 Peyronie's disease). There is limited experience with the combination of lorcaserin and medication indicated for erectile dysfunction (e.g., phosphodiesterase type 5 inhibitors). Therefore, the combination of BELVIQ XR and these medications should be used with caution.
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 2 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 2 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 a history of heart block greater than first degree.
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 [see ADVERSE REACTIONS]. Consider periodic monitoring of complete blood count during treatment with BELVIQ XR.
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 lorcaserin-treated patients and 4.8%, 0.8%, and 0.0% of placebo-treated patients, respectively [see ADVERSE REACTIONS]. 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 a prolactinoma during the trial. The relationship of lorcaserin to the prolactinoma in this patient is unknown.
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 lorcaserin is inadequate to determine if BELVIQ XR increases the risk for pulmonary hypertension.
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 a 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. John’s 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 4 hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention.
- Pregnancy: Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider with a known or suspected pregnancy [see CONTRAINDICATIONS, Use In Specific Populations].
- Lactation: Advise women to avoid use of BELVIQ XR while breastfeeding [see Use In Specific Populations].
- 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.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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.
The carcinogenic potential of lorcaserin was assessed in two-year carcinogenicity studies in mice and rats. CD1 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 8 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 4 weeks prior to and through the mating period, and females were dosed for 2 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.
Use In Specific Populations
BELVIQ XR is contraindicated during pregnancy, because weight loss offers no potential 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 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 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.
Disease-associated Maternal and/or Embryofetal Risk
A 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.
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 20mg clinical dose 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 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.
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 XR is not recommended while breastfeeding.
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.
In lorcaserin clinical trials, a 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 a higher incidence of renal impairment, use of BELVIQ XR in the elderly should be made on the basis of renal function [see Renal Impairment and CLINICAL PHARMACOLOGY]. Elderly patients with normal renal function should require no dose adjustment.
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 [see CLINICAL PHARMACOLOGY].
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 [see CLINICAL PHARMACOLOGY].