Lorcaserin Hydrochloride Hemihydrate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [2]
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Overview
Lorcaserin Hydrochloride Hemihydrate is an Antiobesity agent that is FDA approved for the treatment of obesity. Common adverse reactions include ,in non-diabetic patients: headache, dizziness, fatigue, nausea, dry mouth, and constipation; and in diabetic patients are hypoglycemia, headache, back pain, cough, and fatigue.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Obesity
- 10 mg administered orally twice daily.
- Adjunct to a 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 2 diabetes)
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lorcaserin Hydrochloride Hemihydrate in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lorcaserin Hydrochloride Hemihydrate in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Lorcaserin Hydrochloride Hemihydrate FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lorcaserin Hydrochloride Hemihydrate in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lorcaserin Hydrochloride Hemihydrate in pediatric patients.
Contraindications
Warnings
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions
- Lorcaserin hydrochloride 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.
- 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 erotonin syndrome or NMS-like signs and symptoms.
- The safety of lorcaserin hydrochloride 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 lorcaserin hydrochloride 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 lorcaserin hydrochloride 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.
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 hydrochloride 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 hydrochloride 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.
- Lorcaserin hydrochloride 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, lorcaserin hydrochloride should be used with caution in patients with congestive heart failure.
- Lorcaserin hydrochloride 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 a new cardiac murmur while being treated with lorcaserin hydrochloride should be evaluated and discontinuation of lorcaserin hydrochloride should be considered.
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 hydrochloride 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 hydrochloride in clinical trials included confusion, somnolence, and fatigue.
- Since lorcaserin hydrochloride has the potential to impair cognitive function, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that lorcaserin hydrochloride therapy does not affect them adversely.
Psychiatric Disorders
- Events of euphoria, hallucination, and dissociation were seen with lorcaserin hydrochloride at supratherapeutic doses in short-term studies.
- In clinical trials of at least 1-year in duration, 6 patients (0.2%) treated with lorcaserin hydrochloride developed euphoria, as compared with 1 patient (<0.1%) treated with placebo.
- Doses of lorcaserin hydrochloride should not exceed 10 mg twice a day.
- Some drugs that target the central nervous system have been associated with depression or suicidal ideation.
- Patients treated with lorcaserin hydrochloride should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Discontinue lorcaserin hydrochloride in patients who experience suicidal thoughts or behaviors.
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 hydrochloride.
- Lorcaserin hydrochloride has not been studied in combination with insulin.
- Measurement of blood glucose levels prior to starting lorcaserin hydrochloride and during lorcaserin hydrochloride 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 lorcaserin hydrochloride, appropriate changes should be made to the anti-diabetic drug regimen.
Priapism
- 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.
- Lorcaserin hydrochloride 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 hydrochloride and medication indicated for erectile dysfunction (e.g., phosphodiesterase type 5 inhibitors). *Therefore, the combination of lorcaserin hydrochloride 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 hydrochloride and -0.4 bpm in placebo-treated patients without diabetes and -2.0 beats per minute (bpm) in lorcaserin hydrochloride 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 hydrochloride and 3.2% in placebo-treated patients without diabetes and 3.6% in lorcaserin hydrochloride 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 hydrochloride and 0.1% of placebo-treated patients.
- Use with caution in patients with bradycardia or a history of heart block greater than first degree.
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 hydrochloride 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 hydrochloride as compared to 1.2% treated with placebo.
- Consider periodic monitoring of complete blood count during treatment with lorcaserin hydrochloride.
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 lorcaserin hydrochloride-treated patients and 4.8%, 0.8%, and 0.0% of placebo-treated patients, respectively.
- Prolactin should be measured when symptoms and signs of prolactin excess are suspected (e.g., galactorrhea, gynecomastia). There was one patient treated with lorcaserin hydrochloride who developed a prolactinoma during the trial. The relationship of lorcaserin hydrochloride to the prolactinoma in this patient is unknown.
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 lorcaserin hydrochloride is inadequate to determine if lorcaserin hydrochloride increases the risk for pulmonary hypertension.
Adverse Reactions
Clinical Trials Experience
In the lorcaserin hydrochloride placebo-controlled clinical database of trials of at least one year in duration, of 6888 patients (3451 lorcaserin hydrochloride 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 lorcaserin hydrochloride 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 lorcaserin hydrochloride 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 hydrochloride 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 lorcaserin hydrochloride 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 hydrochloride compared to placebo are summarized in Table 2 (non-diabetic subjects) and Table 3 (subjects with type 2 diabetes mellitus).
Other Adverse Reactions
Serotonin-associated Adverse Reactions
SSRIs, SNRIs, bupropion, tricyclic antidepressants, and MAOIs were excluded from the lorcaserin hydrochloride 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 lorcaserin hydrochloride 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 lorcaserin hydrochloride 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 lorcaserin hydrochloride and serotonin syndrome cannot be excluded on the basis of clinical trial results.
Hypoglycemia in Patients with Type 2 Diabetes
In a clinical trial of patients with type 2 diabetes mellitus, hypoglycemia requiring the assistance of another person occurred in 4 (1.6%) of lorcaserin hydrochloride-treated patients and in 1 (0.4%) placebo-treated patient. Of these 4 lorcaserin hydrochloride-treated patients, all were concomitantly using a sulfonylurea (with or without metformin). Lorcaserin hydrochloride 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 hydrochloride-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 hydrochloride and 0.7% of patients taking placebo.
Psychiatric Disorders
Psychiatric disorders leading to hospitalization or drug withdrawal occurred more frequently in patients treated with lorcaserin hydrochloride (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 hydrochloride (40 and 60 mg) was increased as compared to placebo. In clinical trials of at least 1-year duration in obese patients, euphoria was observed in 0.17% of patients taking lorcaserin hydrochloride 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 hydrochloride-treated vs. 2.4% placebo-treated and suicidal ideation occurred in 0.6% lorcaserin hydrochloride-treated vs. 0.4% placebo-treated patients. 1.3% of lorcaserin hydrochloride 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 lorcaserin hydrochloride 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 hydrochloride 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 hydrochloride-treated patients and 4.8%, 0.8%, and 0.0% of placebo-treated patients, respectively.
Eye disorders
More patients on lorcaserin hydrochloride 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 (6.3% vs. 1.6%). In the population without diabetes, events of blurred vision, dry eye, and visual impairment occurred in lorcaserin hydrochloride-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 lorcaserin hydrochloride-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 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 1 year. At 1 year, 2.4% of patients who received lorcaserin hydrochloride and 2.0% of patients who received placebo developed valvular regurgitation. The relative risk for valvulopathy with lorcaserin hydrochloride is summarized in Table 4. Lorcaserin hydrochloride was not studied in patients with congestive heart failure or hemodynamically-significant valvular heart disease.
Postmarketing Experience
There is limited information regarding Lorcaserin Hydrochloride Hemihydrate Postmarketing Experience in the drug label.
Drug Interactions
Use with Other Agents that Affect Serotonin Pathways
- Based on the mechanism of action of lorcaserin hydrochloride 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.
Cytochrome P450 (2D6) substrates
- Use caution when administering lorcaserin hydrochloride together with drugs that are CYP 2D6 substrates, as lorcaserin hydrochloride can increase exposure of these drugs.
Use in Specific Populations
Pregnancy
- Lorcaserin hydrochloride is contraindicated during pregnancy, because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm.
- Maternal exposure to lorcaserin in late pregnancy in rats resulted in lower body weight in offspring which persisted to adulthood.
- If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard of maternal weight loss to the fetus.
Clinical Considerations
- 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.
Animal Data
- Reproduction studies were performed in pregnant rats and rabbits that were administered lorcaserin during the period of embryofetal organogenesis.
- Plasma exposures up to 44 and 19 times human exposure in 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; pups were indirectly exposed in utero and throughout lactation.
- The highest dose (~44 times human exposure) resulted in stillborns and lower pup viability.
- All doses lowered pup body weight similarly at birth which persisted to adulthood; however, no developmental abnormalities were observed and reproductive performance was not affected at any dose.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lorcaserin Hydrochloride Hemihydrate in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Lorcaserin Hydrochloride Hemihydrate during labor and delivery.
Nursing Mothers
- It is not known whether lorcaserin hydrochloride is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
- The safety and effectiveness of lorcaserin hydrochloride in pediatric patients below the age of 18 have not been established and the use of lorcaserin hydrochloride is not recommended in pediatric patients.
Geriatic Use
- In the lorcaserin hydrochloride clinical trials, a total of 135 (2.5%) of the patients were 65 years of age and older.
- Clinical studies of lorcaserin hydrochloride 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 lorcaserin hydrochloride in the elderly should be made on the basis of renal function. *Elderly patients with normal renal function should require no dose adjustment.
Gender
- No dosage adjustment based on gender is necessary. Gender did not meaningfully affect the pharmacokinetics of lorcaserin.
Race
- No dosage adjustment based on race is necessary. Race did not meaningfully affect the pharmacokinetics of lorcaserin.
Renal Impairment
- No dose adjustment of lorcaserin hydrochloride is required in patients with mild renal impairment.
- Use lorcaserin hydrochloride with caution in patients with moderate renal impairment.
- Use of lorcaserin hydrochloride in patients with severe renal impairment or end stage renal disease is not recommended.
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.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lorcaserin Hydrochloride Hemihydrate in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Lorcaserin Hydrochloride Hemihydrate in patients who are immunocompromised.
Administration and Monitoring
Administration
- Oral
- Can be taken with or without food.
Monitoring
- Monitor for depression or suicidal thoughts.
- Consider periodic monitoring of complete blood count during treatment with lorcaserin hydrochloride.
IV Compatibility
There is limited information regarding the compatibility of Lorcaserin Hydrochloride Hemihydrate and IV administrations.
Overdosage
- No experience with overdose of lorcaserin hydrochloride is available.
- In clinical studies that used doses that were higher than the recommended dose, the most frequent adverse reactions associated with lorcaserin hydrochloride were headache, nausea, abdominal discomfort, and dizziness. Single 40- and 60-mg doses of lorcaserin hydrochloride caused euphoria, altered mood, and hallucination in some subjects.
- Treatment of overdose should consist of lorcaserin hydrochloride discontinuation and general supportive measures in the management of overdosage.
- Lorcaserin hydrochloride is not eliminated to a therapeutically significant degree by hemodialysis.
Pharmacology
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| Clinical data | |
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| Trade names | lorcaserin hydrochloride |
| [[Regulation of therapeutic goods |Template:Engvar data]] |
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| Routes of administration | Oral |
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| Pharmacokinetic data | |
| Protein binding | 70% |
| Metabolism | Hepatic (extensive) |
| Elimination half-life | 11 hours |
| Excretion | Renal (92.3%), Faecal (2.2%) |
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| ChEMBL | |
| E number | {{#property:P628}} |
| ECHA InfoCard | {{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value). |
| Chemical and physical data | |
| Formula | C11H14ClN |
| Molar mass | 195.688 g/mol |
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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.
Structure
Its chemical name is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride hemihydrate. The empirical formula is C11H15Cl2N·0.5H2O, and the molecular weight of the hemihydrate form is 241.16 g/mol.
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Pharmacodynamics
Cardiac Electrophysiology
The effect of multiple oral doses of lorcaserin 15 mg and 40 mg once daily on QTc interval was evaluated in a randomized, placebo- and active- (moxifloxacin 400 mg) controlled four-treatment arm parallel thorough QT study in 244 healthy subjects. In a 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.
Pharmacokinetics
Absorption
Lorcaserin is absorbed from the gastrointestinal tract with peak plasma concentration occurring 1.5 - 2 hours after oral dosing. The absolute bioavailability of lorcaserin has not been determined. Lorcaserin has a plasma half life of ~11 hours; steady state is reached within 3 days after twice daily dosing, and accumulation is estimated to be approximately 70%.
Effect of Food
Twelve adult volunteers (6 men and 6 women) were given a single 10 mg oral dose of lorcaserin hydrochloride in a fasted state and after administration of a high fat (approximately 50% of total caloric content of the meal) and high-calorie (approximately 800-1000 calories) meal. The Cmax increased approximately 9% and exposure (AUC) increased approximately 5% under fed conditions. Tmax was delayed approximately 1 hour in the fed state. Lorcaserin hydrochloride can be administered with or without food.
Distribution
Lorcaserin distributes to the cerebrospinal fluid and central nervous system in humans. Lorcaserin hydrochloride 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 hydrochloride, the major circulating metabolite is lorcaserin sulfamate (M1), with a plasma Cmax that exceeds lorcaserin Cmax by 1- to 5-fold. N-carbamoyl glucuronide lorcaserin (M5) is the major metabolite in urine; M1 is a 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 a 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.
Specific Populations
Renal Impairment
The disposition of lorcaserin was studied in patients with varying degrees of renal function. Creatinine clearance (CLcr) was calculated by Cockgroft-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 a 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.
Hepatic Impairment
The disposition of lorcaserin was evaluated in patients with hepatic impairment and subjects with normal hepatic function. 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.
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 a clinical trial of 12 healthy elderly (age greater than 65 years) subjects and 12 matched adult patients, lorcaserin exposure (AUC and Cmax) was equivalent in the two groups. Cmax was approximately 18% lower in the elderly group, and Tmax was increased from 2 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 Interactions
Lorcaserin inhibits CYP 2D6-mediated metabolism. In a clinical trial in 21 CYP 2D6 extensive metabolizers, concomitant administration of lorcaserin (10 mg BID for 4 days) increased dextromethorphan peak concentrations (Cmax) by approximately 76% and exposure (AUC) by approximately 2-fold.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Mutagenesis
- Lorcaserin hydrochloride 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 hydrochloride 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 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 hydrochloride-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 hydrochloride had no effects on fertility in rats at exposures up to 29 times the human clinical dose.
Clinical Studies
- The safety and efficacy of lorcaserin hydrochloride for chronic weight management in conjunction with reduced caloric intake and increased physical activity were evaluated in 3 randomized, double-blind, placebo-controlled trials with durations ranging from 52 to 104 weeks.
- Two trials in adults without type 2 diabetes mellitus (Study 1 and Study 2) and one study in adults with type 2 diabetes mellitus (Study 3) evaluated the effect of lorcaserin hydrochloride 10 mg twice daily.
- The primary efficacy parameter in these studies was weight loss at 1 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 a reduced-calorie diet and exercise counseling that began with the first dose of study medication and continued every four weeks throughout the trial.
- Study 1 was a 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 hydrochloride patients were re-randomized in a 2:1 ratio to continue lorcaserin hydrochloride 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 2 was a 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 3 was a 1-year study that enrolled 604 adult patients with BMI greater than or equal to 27 kg/m2 and inadequately controlled type 2 diabetes (HbA1c range 7-10%) being treated with metformin and/or a 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%.
- A substantial percentage of randomized subjects withdrew from each study prior to week 52: 50% in Study 1, 45% in Study 2 and 36% in Study 3.
One-Year Weight Management in Patients without Diabetes Mellitus
- Weight loss at 1 year in Studies 1 and 2 is presented in Table 6.
- The pooled data are reflective of the individual study results.
- Statistically significantly greater weight loss was achieved with lorcaserin hydrochloride compared to placebo at week 52. The Year 1 placebo-adjusted weight loss achieved in patients treated with lorcaserin hydrochloride was 3.3 kg by ITT/LOCF analysis. The time course of weight loss with lorcaserin hydrochloride 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.
Effect of lorcaserin hydrochloride on Cardiometabolic Parameters and Anthropometry
- Changes in lipids, fasting glucose, fasting insulin, waist circumference, heart rate, and blood pressure with lorcaserin hydrochloride are shown in Table 7.
- In a substudy of 154 patients conducted as part of Study 2, DEXA analysis showed a 9.9% reduction in fat mass from a baseline of 45.0 kg in patients treated with lorcaserin hydrochloride compared to a 4.6% reduction from a baseline of 44.5 kg in patients treated with placebo.
- The placebo-adjusted reduction in fat mass achieved on lorcaserin hydrochloride 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 hydrochloride- and placebo-treated patients.
One-Year Weight Management in Patients with Type 2 Diabetes Mellitus
- Weight loss among patients with type 2 diabetes mellitus who were treated with lorcaserin hydrochloride was statistically significantly greater than that among patients treated with placebo (Table 8).
Effect of lorcaserin hydrochloride on Cardiometabolic Parameters and Anthropometry in Patients with Type 2 Diabetes Mellitus
- Patients in Study 3 were taking either metformin and/or a sulfonylurea at study start, and had inadequate glycemic control (HbA1c range 7-10%). Changes in HbA1c and fasting glucose with lorcaserin hydrochloride use are shown in Table 9.
How Supplied
Tablets
- 10-mg tablets are supplied as blue-colored, round, biconvex, film-coated tablets debossed with "A" on one side and "10" on the other side and are available as follows:
- NDC 62856-529-60 Bottle of 60
Storage
- Store at 25°C (77°F): excursions permitted to 15-30°C (59-86°F)
Images
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Patient Counseling Information
- Lorcaserin hydrochloride 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 lorcaserin hydrochloride 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 lorcaserin hydrochloride 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 lorcaserin hydrochloride 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 lorcaserin hydrochloride.
- Men who have an erection lasting greater than 4 hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention.
- Patients should be instructed to avoid pregnancy or breastfeeding while undergoing lorcaserin hydrochloride therapy and to talk to their prescribing physician should they get pregnant or decide to breastfeed.
- 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 lorcaserin hydrochloride.
Precautions with Alcohol
Alcohol-Lorcaserin Hydrochloride Hemihydrate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
- BELVIQ[1]
Look-Alike Drug Names
There is limited information regarding Lorcaserin Hydrochloride Hemihydrate Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.
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