Generic Name: Sibutramine Hydrochloride
Class: Anorexigenic Agents and Stimulants, Miscellaneous
VA Class: GA751
Chemical Name: 1-(4-chlorophenyl)-N,N-dimethyl-α-(2-methylpropyl)-cyclobutanemethanamine hydrochloride monohydrate
Molecular Formula: C17H26ClN • HCl • H2O
CAS Number: 84485-00-7

Warning(s)

Special Alerts:

On October 8, 2010, the manufacturer announced a voluntary withdrawal of sibutramine from the US market.19 20 The withdrawal was requested by FDA following review of new data on cardiovascular risk.19 20 (See Cardiovascular Effects under Cautions.)

REMS:

FDA approved a REMS for sibutramine to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of sibutramine and consists of the following: medication guide. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Anorexigenic agent.1 4 7 9

Uses for Meridia

Obesity

Adjunct to caloric restriction, increased physical activity, and behavioral modification in the management of exogenous obesity; used for weight loss and maintenance of weight loss.1 4 7 9 (See Special Alerts.)

Slideshow: Newly Approved Weight Loss Drugs - Can They Help You?

Used in patients with initial body mass index (BMI) of ≥30 kg/m2; also used in those with BMI of ≥27 kg/m2 in the presence of risk factor or disease (e.g., adequately controlled hypertension, diabetes mellitus, dyslipidemia).1 4 7

Effect of sibutramine on the morbidity and mortality associated with obesity not established.1 2

Meridia Dosage and Administration

General

  • Allow at least 2 weeks to elapse between discontinuance of an MAO inhibitor and initiation of sibutramine and vice versa.1 7

Administration

Oral Administration

Administer orally without regard to meals.1

Administered once daily in the morning in clinical studies.1

Dosage

Available as sibutramine hydrochloride monohydrate; dosage expressed in terms of the monohydrate.1 10

Adults

Obesity
Oral

Initially, 10 mg once daily.1

If weight loss is inadequate (e.g., <1.8 kg of weight loss) after 4 weeks of treatment, consider increasing dosage to 15 mg daily or discontinuance; take BP and heart rate into account.1 7

If weight loss during the first 3–6 months of therapy is <5% of the patient’s baseline body weight, FDA recommends discontinuance, since continued sibutramine therapy is unlikely to be effective and would expose the patient to unnecessary risks.17

Reserve 5-mg daily dose for patients who do not tolerate 10 mg daily.1

Safety and efficacy >2 years not established in clinical studies.1

Prescribing Limits

Adults

Obesity
Oral

Maximum 15 mg daily.1

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment: Dosage adjustment not needed.1 (See Special Populations under Pharmacokinetics.) Not recommended in severe hepatic impairment.1

Renal Impairment

Not recommended in severe renal impairment.1

Geriatric Patients

Contraindicated in patients >65 years of age.1

Cautions for Meridia

Contraindications

  • History of CAD (e.g., angina, history of MI), CHF, tachycardia, peripheral arterial occlusive disease, cardiac arrhythmia, or cerebrovascular disease (stroke or TIA).1 (See Cardiovascular Effects under Cautions.)

  • Inadequately controlled hypertension (systolic/diastolic BP >145/90 mm Hg).1 (See Cardiovascular Effects under Cautions.)

  • Geriatric patients >65 years of age.1

  • Concurrent or recent (i.e., within 2 weeks) therapy with an MAO inhibitor.1 (See Drug Interactions under Cautions.)

  • Major eating disorder (e.g., anorexia nervosa, bulimia nervosa).1

  • Concurrent therapy with another centrally acting anorexigenic drug.1 (See Specific Drugs under Interactions.)

  • Known hypersensitivity to sibutramine or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Cardiovascular Effects

Substantially increases BP and increases pulse in some patients, particularly when initiated at higher dosages.1 9 Monitoring of BP and pulse required prior to and at regular intervals during therapy.1 7 Consideration of decreased dosage or discontinuance recommended in patients with sustained increases in BP or pulse rate.1 7

Caution in patients with a history of hypertension.1 Should not be used in those with uncontrolled or poorly controlled hypertension.1

Contraindicated in patients with history of CAD (e.g., angina, history of MI), CHF, tachycardia, peripheral arterial occlusive disease, cardiac arrhythmia, or cerebrovascular disease (stroke or TIA).1

Increased risk of nonfatal MI and stroke reported in overweight or obese patients at increased risk for cardiovascular events (≥55 years of age, history of cardiovascular disease [CAD, peripheral arterial occlusive disease, or stroke] and/or type 2 diabetes mellitus, and ≥1 additional cardiovascular risk factor); effects on body weight relative to placebo were modest.15 16 17 19 21 FDA concluded that the modest increase in weight loss, in the absence of evidence of other associated health benefits, would be outweighed by even a small increase in risk of cardiovascular events.21 22 19 On October 8, 2010, the manufacturer voluntarily complied with FDA's request to voluntarily withdraw sibutramine from the US market.19 20

Health care professionals should stop prescribing and dispensing sibutramine and should contact patients currently taking the drug to inform them of the risks and advise them to stop taking the drug.19 Individuals receiving sibutramine therapy should stop taking the drug and discuss alternatives for weight loss or weight-loss maintenance with their clinician.19

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

Potentially life-threatening serotonin syndrome or NMS-like reactions reported during concurrent therapy with SSRIs or SNRIs and other serotonergic drugs (e.g., 5-HT1 receptor agonists [“triptans”]), drugs that impair serotonin metabolism (e.g., MAO inhibitors), or antipsychotics or other dopamine antagonists.1 (See Contraindications under Cautions and see Specific Drugs under Interactions.)

Symptoms 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 of vital signs, and mental status changes.1

Monitor patients receiving sibutramine for the development of serotonin syndrome or NMS-like signs and symptoms.1 Serotonin syndrome requires immediate medical treatment.1

Drug Interactions

Concomitant use with MAO inhibitor associated with serotonin syndrome.1 7 (See Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions under Cautions and see Specific Drugs under Interactions.)

Glaucoma

May cause mydriasis; caution in patients with angle-closure (narrow-angle) glaucoma.1

Other Warnings

Exclude organic causes (e.g., untreated hypothyroidism) of obesity before initiating sibutramine.1

General Precautions

Pulmonary Hypertension

Pulmonary hypertension associated with anorexigenic drugs that induce serotonin release; risk with sibutramine unknown.1

Seizures

Seizures reported rarely.1 Caution in patients with history of seizures; discontinue if seizures occur.1 6

Bleeding

Bleeding events reported; causal relationship unclear.1 Caution in patients predisposed to bleeding and in those receiving drugs that affect hemostasis or platelet function.1

Cholelithiasis

Weight loss can exacerbate or precipitate gallstone formation.1

CNS Effects

Like other CNS-active drugs, may impair judgment, thinking, or motor skills.1

Specific Populations

Pregnancy

Category C.1 Use during pregnancy not recommended.1

Lactation

Not known whether sibutramine is distributed into milk.1 Use not recommended.1

Pediatric Use

Safety and efficacy in children <16 years of age not established.1

In one clinical study in obese adolescents, 2 patients reported suicidal ideation and one patient attempted suicide.1 Sibutramine inhibits reuptake of serotonin and norepinephrine similarly to the mechanism of some antidepressants; not known whether the drug increases the risk of suicidality in pediatric patients.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; contraindicated in patients >65 years of age.1

Hepatic Impairment

Use not recommended in patients with severe hepatic impairment; not systematically evaluated in these individuals.1

Renal Impairment

Do not use in patients with severe renal impairment, including those with end-stage renal disease receiving dialysis.1 Use with caution in patients with mild or moderate renal impairment.1

Common Adverse Effects

Headache, dry mouth, anorexia, constipation, insomnia, rhinitis, pharyngitis, increased appetite, back pain, flu syndrome, accidental injury, asthenia, nausea, arthralgia, nervousness, dyspepsia, sinusitis.1 7 9

Interactions for Meridia

Metabolized to active metabolites principally by CYP3A4.1 7

Drugs Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interaction likely with drugs that inhibit CYP3A4 with possible alteration in the metabolism of sibutramine.1

Drugs Affecting Hemostasis or Platelet Function.

Possible increased risk of bleeding; caution advised.1

Protein-bound Drugs

Interaction unlikely.1

Specific Drugs

Drug

Interaction

Comments

Alcohol

Pharmacologic interaction unlikely1 7

No clinically important psychomotor interactions reported in limited study1

Excessive alcohol consumption not recommended1 7

Cimetidine

Small increases in AUC and peak plasma concentrations of sibutramine metabolites1 7

CNS drugs

Potential pharmacologic interaction1

Caution advised1 7

Erythromycin

Decreased sibutramine metabolism; altered serum concentrations of sibutramine and its metabolites1 7

Ketoconazole

Decreased sibutramine metabolism; altered serum concentrations of sibutramine and its metabolites1 7

Lorazepam

No significant changes in pharmacokinetics of active sibutramine metabolites or lorazepam1

MAO inhibitors (e.g., phenelzine, selegiline)

Potentially fatal serotonin syndrome1 7

Concomitant use contraindicated1

Allow at least 2 weeks to elapse between discontinuance of the MAO inhibitor and initiation of sibutramine and vice versa1 7

Olanzapine

Increased peak plasma concentration and AUC of sibutramine and increased peak plasma concentration of its active secondary metabolite; no significant effect on olanzapine pharmacokinetics1

Omeprazole

Increased peak plasma concentration and AUC of sibutramine and its active secondary metabolite; no significant effect on omeprazole pharmacokinetics1

Oral contraceptives

Suppression of ovulation not inhibited1

Alternative contraceptive precautions not needed1 7

Serotonergic drugs (dihydroergotamine, lithium, opiate agonists [e.g., dextromethorphan, fentanyl, meperidine, pentazocine], sumatriptan, tryptophan, serotonin-reuptake inhibitors)

Potential for serotonin syndrome; potentially serious or fatal1 7

Sibutramine should not be used with other serotonergic agents; if such use is clinically indicated, monitor carefully1 7

Simvastatin

Decreased peak plasma concentrations and AUC of sibutramine and its active secondary metabolite; increased simvastatin acid AUC1

Sympathomimetic agents (ephedrine, pseudoephedrine)

Potential pharmacologic interaction with drugs that may increase BP and pulse1 7

Caution1 7

Meridia Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed from the GI tract; undergoes extensive first-pass hepatic metabolism to active mono- and di-desmethyl metabolites (M1, M2).1

77% of a single oral dose is absorbed; absolute bioavailability undetermined.1

Food

Food reduces peak plasma concentrations of M1 and M2 by 27 and 32%, respectively, and delays time to peak plasma concentrations by about 3 hours but does not affect AUCs of M1 or M2.1

Special Populations

Geriatric patients: Plasma concentrations of M1 and M2 metabolites are similar to those in younger adults.1

Moderate hepatic impairment: Combined AUCs of M1 and M2 metabolites increased by 24% compared with values in healthy individuals.1

Moderate or severe renal impairment: AUC of M1 metabolite increased by 24–46% compared with values in healthy individuals.1 End-stage renal disease: AUC of M2 metabolite decreased by 50% in patients receiving dialysis compared with values in healthy individuals.1 AUCs of inactive M5 and M6 metabolites increased twofold to threefold or eightfold to 11-fold in patients with moderate or severe renal impairment, respectively, and increased 22- to 33-fold in those with end-stage renal disease receiving dialysis compared with values in healthy individuals.1

Distribution

Extent

Extensively distributed, highest concentration in liver and kidney.1

Plasma Protein Binding

Sibutramine: 97%.1

M1 and M2: 94% each.1

Elimination

Metabolism

Principally metabolized in the liver by CYP3A4 to active mono-desmethyl (M1) and di-desmethyl (M2) metabolites; then hydroxylated and conjugated to inactive metabolites (M5 and M6).1

Elimination Route

Excreted principally in urine (77%) as inactive metabolites and in feces.1

Half-life

Sibutramine: 1.1 hours.1

M1: 14 hours.1

M2: 16 hours.1

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).1 Protect from heat and moisture.1

Actions

  • Anorectic effects principally due to active metabolites (M1 and M2) that inhibit reuptake (but not release) of serotonin, norepinephrine, and, to a lesser extent, dopamine at the neuronal synapse, thus promoting a sense of satiety.1 2 3 7 9

  • Increase energy expenditure through thermogenic effects in animals: not confirmed in humans.3 7 10

Advice to Patients

  • Importance of reading the manufacturer’s patient information (medication guide) prior to beginning therapy and rereading it each time the prescription is renewed.1

  • Importance of informing clinician of the presence of, or any history of, cardiovascular disease, including CAD (e.g., angina, MI), CHF, tachycardia, peripheral arterial occlusive disease, cardiac arrhythmia, or cerebrovascular disease (stroke, TIA).6 Importance of informing clinician of any other concomitant disease (e.g., glaucoma, seizures, high BP, major eating disorder).6

  • Importance of immediately informing clinician if any signs or symptoms suggestive of cardiovascular disease (e.g., chest pain, palpitation, abnormal heart rate or rhythm) occur.19

  • Importance of notifying clinician if rash, urticaria, or other manifestations of allergic reaction occur.1

  • Importance of monitoring BP and pulse at regular intervals.1

  • Importance of not taking an extra dose if one is missed.6

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription or OTC drugs, especially other drugs for promoting weight loss, decongestants, antidepressants, cough suppressants, lithium, dihydroergotamine, sumatriptan, or tryptophan because of potential for interactions.1

  • Potential for sibutramine to impair judgment, thinking, or motor skills; avoid driving or operating machinery until effects on the individual are known.1 6

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.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.

On October 8, 2010, the manufacturer announced a voluntary withdrawal of sibutramine from the US market.20 (See Cardiovascular Effects under Cautions.)

Sibutramine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

5 mg

Meridia ( C-IV)

Abbott

10 mg

Meridia ( C-IV)

Abbott

15 mg

Meridia ( C-IV)

Abbott

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2013, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Abbott. Meridia (sibutramine hydrochloride monohydrate) capsules prescribing information. North Chicago, IL; 2010 Aug.

2. Anon. Sibutramine for obesity. Med Lett Drugs Ther. 1998; 40:32. [PubMed 9529518]

3. Stock MJ. Sibutramine: a review of the pharmacology of a novel anti-obesity agent. Int J Obes Relat Metab Disord. 1997; 21(Suppl 1):S25-29. [PubMed 9130038]

4. National Institutes of Health, National Heart, Lung, and Blood Institute. Clinical Guidelines on the identification, evaluation and treatment of overweight and obesity in adults. The evidence report. Bethesda, MD; June 1998. From NHLBI web site.

5. Anon. American Heart Association urges caution on new diet drug. American Heart Association media advisory. Dallas, TX; 1997.

6. Abbott. Meridia (sibutramine hydrochloride monohydrate) capsules patient information. North Chicago, IL; 2010 Jan.

7. Luque CA, Rey JA. Sibutramine: a serotonin-norepinephrine reuptake-inhibitor for the treatment of obesity. Ann Pharmacother. 1999; 33:968-78. [IDIS 436183] [PubMed 10492502]

8. Smith IG, Goulder MA. Randomized placebo-controlled trial of long-term treatment with sibutramine in mild to moderate obesity. J Fam Pract. 2001; 50:505-12. [PubMed 11407998]

9. Lean ME. Sibutramine—a review of clinical efficacy. Int J Obesity. 1997; 21:S30-6.

10. Abbott, Abbott Park, IL: Personal communication.

11. Baumgarten AH (US Food and Drug Administration Chicago District Office, Chicago, IL): Personal communication to White M (Abbott Laboratories, Abbott Park, IL); 2002 Jul 19.

12. Wolfe SH, Sasich LD, Barbehenn E (Public Citizen Health Research Group, Washington, DC): Personal communication to Thompson T (US Department of Health and Human Services, Washington DC); 2002 Mar 19.

13. Sun E (Abbott Laboratories, Abbott Park, IL): Personal communication to Thompson T (US Department of Health and Human Services, Washington DC); 2002 Jun 4.

15. James WPT. The SCOUT study: risk-benefit profile of sibutramine in overweight high-risk cardiovascular patients. Eur Heart J. 2005; 7(suppl L):L44-8.

16. Torp-Pedersen C, Caterson I, Coutinho W et al. Cardiovascular responses to weight management and sibutramine in high-risk subjects: an analysis from the SCOUT trial. Eur Heart J. 2007; 28:2915-23. [PubMed 17595194]

17. Food and Drug Administration. Follow-up to the November 2009 early communication about an ongoing safety review of sibutramine, marketed as Meridia. Rockville, MD; 2010 Jan 21. From FDA website.

18. Food and Drug Administration. Early communication about an ongoing safety review of Meridia (sibutramine hydrochloride), Rockville, MD; 2009 Nov 20. From FDA website.

19. Food and Drug Administration. Drug safety communication: FDA recommends against the continued use of Meridia (sibutramine). Rockville, MD; 2010 Oct 8. From FDA website.

20. Abbott. Abbott to voluntarily withdraw Meridia (sibutramine) in the U.S. Abbott Park, IL; 2010 Oct 8. Press release from Abbott website.

21. Egan AG, Avigan M. Memorandum to the file, NDA 20-632, Meridia (sibutramine hydrochloride monohydrate). Rockville, MD: Food and Drug Administration; 2010 Oct 4. From FDA website.

22. Food and Drug Administration. Questions and answers: FDA recommends against the continued use of Meridia (sibutramine). Available from website. Accessed 2010 Oct 8.

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