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Lorcaserin Hydrochloride

Class: Selective Serotonin Receptor Agonists
Chemical Name: (1R)-8-Chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine hydrochloride
Molecular Formula: C11H14ClN•HCl
CAS Number: 846589-98-8
Brands: Belviq

Introduction

Selective serotonin type 2C (5-hydroxytryptamine [5-HT2C]) receptor agonist; anorexigenic agent.1 4 5 8 9

Uses for Lorcaserin Hydrochloride

Obesity

Adjunct to caloric restriction and increased physical activity in the chronic management of obesity.1 2 3 4

Used in patients who are obese (pretreatment body mass index [BMI] ≥30 kg/m2); also used in overweight patients with pretreatment BMI ≥27 kg/m2 in the presence of a weight-related risk factor or disease (e.g., hypertension, type 2 diabetes mellitus, dyslipidemia).1

Indicated only for monotherapy; safety and efficacy in combination with other weight loss products (prescription drugs [e.g., phentermine], OTC drugs, herbal preparations) not established.1

Long-term effects on cardiovascular morbidity and mortality associated with obesity not established; safety and efficacy beyond 2 years of use not established.1 8

Lorcaserin Hydrochloride Dosage and Administration

Administration

Oral Administration

Administer orally twice daily without regard to meals.1

Dosage

Available as lorcaserin hydrochloride hemihydrate; dosage expressed in terms of the anhydrous salt.1

Adults

Obesity
Oral

10 mg twice daily.1

If weight loss during first 12 weeks of therapy is <5% of the patient’s baseline body weight, discontinue lorcaserin; continued therapy is unlikely to be effective.1

Prescribing Limits

Adults

Oral

Maximum 10 mg twice daily.1 Higher dosages associated with greater incidence of adverse reactions.1

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment: Dosage adjustment not necessary.1

Severe hepatic impairment: Use caution; not studied to date.1

Renal Impairment

Mild renal impairment: Dosage adjustment not necessary.1

Moderate renal impairment: Use caution.1

Severe renal impairment, including end-stage renal disease: Use not recommended.1 (See Pharmacokinetics.)

Geriatric Patients

Dosage adjustment based solely on age not necessary.1 (See Geriatric Use under Cautions.)

Cautions for Lorcaserin Hydrochloride

Contraindications

  • Pregnancy.1 (See Pregnancy under Cautions.)

Warnings/Precautions

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

Potentially life-threatening serotonin syndrome or NMS-like reactions reported with serotonergic drugs, including SSRIs, SNRIs, tricyclic antidepressants, bupropion, 5-HT1 receptor agonists (triptans), dietary supplements (St. John's wort [Hypericum perforatum], tryptophan), drugs that impair serotonin metabolism (e.g., MAO inhibitors), dextromethorphan, lithium, tramadol, or antipsychotics or other dopamine antagonists, particularly when used in combination.1

Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1

Severe serotonin syndrome may resemble NMS, which is characterized by hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation in vital signs, and mental status changes.1

Because lorcaserin has serotonergic activity, monitor for possible emergence of manifestations of serotonin syndrome or NMS-like reactions.1

If concurrent therapy with an agent that affects serotonergic neurotransmission is clinically warranted, use extreme caution and carefully observe the patient, particularly during initiation of therapy and dosage increases.1

If serotonin syndrome or NMS signs and symptoms occur, immediately discontinue lorcaserin and any concurrently administered serotonergic or antidopaminergic agents, and initiate supportive and symptomatic treatment.1

Safety of concurrent use of lorcaserin with other serotonergic or antidopaminergic agents (e.g., antipsychotic agents) or drugs that impair serotonin metabolism (e.g., MAO inhibitors) not established.1

Valvular Heart Disease

Regurgitant cardiac valvular disease (primarily affecting mitral and/or aortic valves) reported with drugs with serotonin type 2B (5-HT2B) receptor agonist activity (e.g., fenfluramine, dexfenfluramine [both no longer commercially available in US]).1 2 11 Pooled clinical trial data showed echocardiographic evidence of new valvulopathy at 1 year in 2.4% of patients receiving lorcaserin and 2% of those receiving placebo; none of the patients had symptomatic valvular regurgitation.1 (See Actions.)

Not studied in patients with CHF or hemodynamically important valvular heart disease.1 5-HT2B receptors may be overexpressed in patients with CHF; use with caution in patients with CHF.1

Do not use with serotonergic and dopaminergic drugs that are potent 5-HT2B receptor agonists known to increase risk for cardiac valvulopathy (e.g., cabergoline).1

Consider discontinuance of lorcaserin and evaluate patients if signs or symptoms of valvular heart disease (e.g., dyspnea, dependent edema, CHF, new cardiac murmur) develop.1

Cognitive Impairment

Impaired attention and memory, confusion, somnolence, and fatigue reported.1

Psychiatric Effects

Euphoria, hallucinations, and dissociation reported in patients receiving supratherapeutic doses; do not exceed dosage of 10 mg twice daily.1

Depression and suicidal ideation associated with some CNS agents.1 Monitor patients receiving lorcaserin for emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.1 Discontinue in patients who experience suicidal thoughts or behaviors.1

Hypoglycemia

Weight loss may increase risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin and/or insulin secretagogues (e.g., sulfonylureas).1 Hypoglycemia observed in clinical trials.1

Monitor blood glucose concentrations prior to and during therapy in patients with type 2 diabetes mellitus.1 Consider decrease in dosage of concomitant non-glucose-dependent antidiabetic agents.1 Make appropriate changes to antidiabetic regimen if hypoglycemia develops.1

Not studied in combination with insulin.1

Priapism

Risk of priapism.1 Discontinue immediately if a prolonged (lasting >4 hours) erection occurs.1

Use with caution in patients with conditions that may predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, leukemia) and in patients with anatomic deformation of the penis (e.g., angulation, cavernosal fibrosis, Peyronie's disease).1

Exercise caution if used concomitantly with drugs indicated for treatment of erectile dysfunction (e.g., phosphodiesterase type 5 [PDE5] inhibitors).1

Bradycardia

Bradycardia reported.1 Use with caution in patients with bradycardia or a history of heart block greater than first degree.1

Hematologic Effects

Decreases in WBC (e.g., leukopenia, lymphopenia, neutropenia) and RBC (e.g., anemia, decreased hemoglobin and hematocrit) counts reported.1 Consider periodic monitoring of CBC during treatment.1

Hyperprolactinemia

Moderate elevation of prolactin concentrations reported.1 Measure prolactin concentration if signs and symptoms of prolactin excess (e.g., galactorrhea, gynecomastia) suspected.1

Prolactinoma reported, but causal relationship not established.1

Pulmonary Hypertension

Pulmonary hypertension associated with certain centrally acting, serotonergic, anorexigenic agents (e.g., fenfluramine, dexfenfluramine); clinical trial experience inadequate to determine if lorcaserin increases risk for pulmonary hypertension.1 11

Dependence and Abuse Potential

Hallucinations, sedation, and positive subjective assessments (“high,” “good drug effects”) reported in abuse studies at doses of 40 or 60 mg; these findings suggest potential for psychic dependence.1

Potential for physical dependence, manifested as withdrawal syndrome, not elucidated.1

Specific Populations

Pregnancy

Category X.1 (See Contraindications under Cautions.)

Weight loss offers no potential benefit to pregnant women and may result in fetal harm.1 Maternal exposure in late pregnancy in rats resulted in lower body weight in offspring, which persisted to adulthood.1

If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard of maternal weight loss.1

Lactation

Not known whether distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in patients <18 years of age.1 Use not recommended.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 Consider increased incidence of renal impairment in geriatric patients; base use on renal function.1

Hepatic Impairment

Not studied in severe hepatic impairment; use with caution.1

Renal Impairment

Depending on degree of renal impairment, exposure to major metabolites may be increased.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Use with caution in patients with moderate renal impairment.1

Do not use in patients with severe renal impairment, including end-stage renal disease.1

Common Adverse Effects

Nondiabetic patients: Headache,1 2 3 dizziness,1 2 3 fatigue,1 2 3 nausea,1 2 3 dry mouth,1 2 3 constipation.1 2 3

Diabetic patients: Hypoglycemia,1 4 headache,1 4 back pain,1 4 cough,1 4 fatigue.1 4

Interactions for Lorcaserin Hydrochloride

Metabolized by multiple CYP isoenzymes, including 1A1, 1A2, 2A6, 2B6, 2C19, 2D6, 2E1, and 3A4;6 glucuronidation of lorcaserin is catalyzed by multiple uridine diphosphate-glucuronosyltransferase (UGT) enzymes.7

Inhibits CYP2D6.1

Drugs Affecting Hepatic Microsomal Enzymes

Interactions unlikely since metabolism does not appear to depend on any single pathway.6

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP2D6 substrates: Possible increased exposure to the CYP2D6 substrate drug; use concomitantly with caution.1

Drugs Affecting Uridine Diphosphate-glucuronosyltransferase (UGT)

Inhibition of any single UGT enzyme is unlikely to substantially inhibit glucuronidation of lorcaserin.7

Serotonergic Drugs

Potential pharmacologic interaction (potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions).1 If concurrent use is clinically warranted, exercise extreme caution.1 (See Serotonin Syndrome or Neuroleptic Malignant Syndrome [NMS]-like Reactions under Cautions.)

Specific Drugs

Drug

Interaction

Comments

Bupropion

Potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions1

Use with extreme caution; carefully observe patients during therapy initiation and dosage increases1

Antidepressants (i.e., SSRIs, SNRIs, tricyclic antidepressants)

Potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions1

Use with extreme caution; carefully observe patients during therapy initiation and dosage increases1

Antipsychotic agents

Potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions1

Use with extreme caution; carefully observe patients during therapy initiation and dosage increases1

Dextromethorphan

Increased dextromethorphan peak concentrations and AUC1

Potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions1

Use with extreme caution; carefully observe patients during therapy initiation and dosage increases1

Dopamine antagonists

Potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions1

Use with extreme caution; carefully observe patients during therapy initiation and dosage increases1

5-HT1 receptor agonists (triptans)

Potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions1

Use with extreme caution; carefully observe patients during therapy initiation and dosage increases1

Linezolid

Potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions1

Use with extreme caution; carefully observe patients during therapy initiation and dosage increases1

Lithium

Potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions1

Use with extreme caution; carefully observe patients during therapy initiation and dosage increases1

MAO inhibitors

Potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions1

Use with extreme caution; carefully observe patients during therapy initiation and dosage increases1

St. John's wort (Hypericum perforatum)

Potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions1

Use with extreme caution; carefully observe patients during therapy initiation and dosage increases1

Tramadol

Potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions1

Use with extreme caution; carefully observe patients during therapy initiation and dosage increases1

Tryptophan and other serotonin precursors

Potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions1

Use with extreme caution; carefully observe patients during therapy initiation and dosage increases1

Lorcaserin Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability not determined.1 Peak plasma concentrations attained approximately 1.5–2 hours following oral administration.1

Food

High-fat meal increased peak plasma concentrations by approximately 9% and AUC by approximately 5%, and delayed time to peak plasma concentration by approximately 1 hour.1

Special Populations

Mild hepatic impairment (Child-Pugh score 5–6): Lorcaserin peak plasma concentration decreased by 7.8%; AUC increased by 22%.1

Moderate hepatic impairment (Child-Pugh score 7–9): Lorcaserin peak plasma concentration decreased by 14.3%; AUC increased by 30%.1

Severe hepatic impairment: Pharmacokinetics not evaluated.1

Mild renal impairment (Clcr 50–80 mL/minute): Lorcaserin sulfamate (metabolite M1) exposure increased by 1.7-fold; N-carbamoyl-glucuronide lorcaserin (metabolite M5) exposure increased by 1.5-fold.1

Moderate renal impairment (Clcr 30–50 mL/minute): M1 exposure increased by 2.3-fold; M5 exposure increased by 2.5-fold.1

Severe renal impairment (Clcr <30 mL/minute): M1 exposure increased by 10.5-fold; M5 exposure increased by 5.1-fold.1 M1 and M5 accumulate.1

In patients with renal impairment, lorcaserin peak concentrations are decreased but AUC is unchanged.1

Distribution

Extent

Distributes into CSF and CNS.1

Plasma Protein Binding

Approximately 70%.1

Elimination

Metabolism

Extensively metabolized in the liver by multiple enzymatic pathways;1 6 7 major metabolites are inactive.1 M1 is the major circulating metabolite and M5 is the major metabolite in urine.1

Elimination Route

Excreted principally in urine (about 92%) as inactive metabolites.1 6

Half-life

Approximately 11 hours.1

Special Populations

Moderate hepatic impairment: Half-life of lorcaserin prolonged by 59%.1

Mild renal impairment: Half-life of M1 prolonged by 26%; half-life of M5 unchanged.1

Moderate renal impairment: Half-lives of M1 and M5 prolonged by 96 and 26%, respectively.1

Severe renal impairment: Half-lives of M1 and M5 prolonged by 508 and 22%, respectively.1

Hemodialysis: Standard 4-hour hemodialysis procedure removes approximately 18% of M5; does not remove lorcaserin or M1.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Exact mechanism of anorexigenic effect unknown; appears to decrease food consumption and promote satiety by selectively activating 5-HT2C receptors on pro-opiomelanocortin neurons in the hypothalamus.1 8 Activation of 5-HT2C receptors stimulates a precursor for α-melanocortin stimulating hormone, which acts on melanocortin-4 receptors to decrease food intake.8

  • Decreases energy intake; does not alter energy expenditure or respiratory quotient.5

  • Exhibits receptor selectivity at recommended daily dosage: Approximately 14- and 60-fold higher potency at 5-HT2C receptors compared with 5-HT2A and 5-HT2B receptors, respectively.1 9 Approximately 7- and 11-fold greater affinity for 5-HT2C receptors than for 5-HT2A and 5-HT2B receptors, respectively.1

  • Does not affect serotonin, norepinephrine, or dopamine release or uptake.10

Advice to Patients

  • Importance of using lorcaserin in conjunction with a reduced-calorie diet and increased physical activity.1 If weight loss during the first 12 weeks of therapy is <5% of initial body weight, importance of discontinuing therapy since continued treatment is unlikely to be effective.1 Importance of not increasing dosage beyond the recommended dosage.1

  • Potential risk of serotonin syndrome and NMS-like reactions with concurrent use of SSRIs, SNRIs, MAO inhibitors, triptans, tramadol, tryptophan, St. John’s wort, antipsychotic agents, or other serotonergic agents or dopamine antagonists.1 Importance of immediately contacting clinician if signs and symptoms of these syndromes (e.g., high fever, stiff muscles, sweating, fast or irregular heart beat, change in BP, confusion, coordination problems, restlessness, nausea, vomiting, diarrhea) develop.1

  • Importance of seeking medical attention if signs or symptoms of valvular heart disease (e.g., dyspnea, dependent edema) develop.1

  • Potential for lorcaserin to impair judgment, thinking, or motor skills; avoid driving or operating hazardous machinery until the drug’s effects on the individual are known.1

  • Risk of suicidality; importance of being alert to and seeking medical attention in the event of suicidality, emergence or worsening of depression, or unusual changes in mood or behavior.1

  • Importance of men discontinuing the drug and seeking immediate medical attention if an erection persists >4 hours.1

  • Importance of blood glucose monitoring in patients with type 2 diabetes mellitus treated with insulin and/or insulin secretagogues (e.g., sulfonylureas).1

  • Importance of advising women of childbearing potential to avoid pregnancy and breast-feeding; importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. 1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illness (e.g., cardiac disease, diabetes mellitus, conditions that may predispose to priapism).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.1

Lorcaserin Hydrochloride Hemihydrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

10 mg (of lorcaserin hydrochloride)

Belviq (C-IV)

Eisai

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: January 27, 2014
Last reviewed: January 27, 2014
Date modified: February 08, 2016

References

1. Eisai Inc. Belviq (lorcaserin hydrochloride) tablets prescribing information. Woodcliff Lake, NJ; 2012 Aug.

2. Smith SR, Weissman NJ, Anderson CM et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010; 363:245-56. [PubMed 20647200]

3. Fidler MC, Sanchez M, Raether B et al. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab. 2011; 96:3067-77. [PubMed 21795446]

4. O'Neil PM, Smith SR, Weissman NJ et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study. Obesity (Silver Spring). 2012; 20:1426-36. [PubMed 22421927]

5. Martin CK, Redman LM, Zhang J et al. Lorcaserin, a 5-HT(2C) receptor agonist, reduces body weight by decreasing energy intake without influencing energy expenditure. J Clin Endocrinol Metab. 2011; 96:837-45. [PubMed 21190985]

6. Usmani KA, Chen WG, Sadeque AJ. Identification of human cytochrome P450 and flavin-containing monooxygenase enzymes involved in the metabolism of lorcaserin, a novel selective human 5-hydroxytryptamine 2C agonist. Drug Metab Dispos. 2012; 40:761-71. [PubMed 22266842]

7. Sadeque AJ, Usmani KA, Palamar S et al. Identification of human UDP-glucuronosyltransferases involved in N-carbamoyl glucuronidation of lorcaserin. Drug Metab Dispos. 2012; 40:772-8. [PubMed 22259019]

8. Hurren KM, Berlie HD. Lorcaserin: an investigational serotonin 2C agonist for weight loss. Am J Health Syst Pharm. 2011; 68:2029-37. [PubMed 22011982]

9. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 022529: Pharmacology review. 2012 Jun 27. From FDA website.

10. Thomsen WJ, Grottick AJ, Menzaghi F et al. Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization. J Pharmacol Exp Ther. 2008; 325:577-87. [PubMed 18252809]

11. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 022529: Medical review(s). From FDA website.

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