Generic Name: sibutramine

Brand Names: Meridia

Uses

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.

Use in patients with initial body mass index (BMI) of ≥30 kg/m²; also use in those with BMI of ≥27 kg/m² in the presence of risk factor or disease (e.g., hypertension, diabetes mellitus, dyslipidemia).

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

Dosage and Administration

General

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

Administration

Oral Administration

Administer orally without regard to meals.

Administered once daily in the morning in clinical studies.

Dosage

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

Adults

Obesity

Oral

Initially, 10 mg once daily.

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.

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

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

Prescribing Limits

Adults

Obesity

Oral

Maximum 15 mg daily.

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment: Dosage adjustment not needed. (See Special Populations under Pharmacokinetics.)

Geriatric Patients

Select dosage with caution.

Cautions

Contraindications

• Concurrent or recent (i.e., within 2 weeks) therapy with an MAO inhibitor. (See Drug Interactions under Cautions.)
• Major eating disorder (e.g., anorexia nervosa, bulimia nervosa).
• Concurrent therapy with another centrally acting anorexigenic drug. (See Specific Drugs under Interactions.)
• Known hypersensitivity to sibutramine or any ingredient in the formulation.

Warnings/Precautions

Warnings

Cardiovascular Effects

Substantially increases BP and increases pulse in some patients, particularly when initiated at higher dosages. Measure BP and pulse before starting therapy; monitor at regular intervals.

Consider decreased dosage or discontinuance in patients with sustained increases in BP or pulse rate.

Caution in patients with a history of hypertension.

Should not be used in those with uncontrolled or poorly controlled hypertension.

Drug Interactions

Concomitant use with MAO inhibitor associated with serotonin syndrome. Serotonin syndrome requires immediate medical attention; symptoms include excitement, hypomania, restlessness, loss of consciousness, confusion, disorientation, anxiety, agitation, motor weakness, myoclonus, tremor, hemiballismus, hyperreflexia, ataxia, dysarthria, incoordination, hyperthermia, shivering, pupillary dilation, diaphoresis, emesis, tachycardia. (See Contraindications under Cautions.)

Glaucoma

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

Cardiovascular Disease

Should not be used in those with a history of CAD, CHF, arrhythmias, stroke, or in those with uncontrolled or poorly controlled hypertension. (See Cardiovascular Effects under Cautions.)

Other Warnings

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

General Precautions

Pulmonary Hypertension

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

Seizures

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

Bleeding

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

Cholelithiasis

Weight loss can exacerbate or precipitate gallstone formation.

CNS Effects

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

Specific Populations

Pregnancy

Category C. Use during pregnancy not recommended.

Lactation

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

Pediatric Use

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

In one clinical study in obese adolescents, 2 patients reported suicidal ideation and one patient attempted suicide. 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.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution due to greater frequency of decreased renal, hepatic, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.

Hepatic Impairment

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

Renal Impairment

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

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.

Interactions

Metabolized to active metabolites principally by CYP3A4.

Drugs Affecting Hepatic Microsomal Enzymes

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

Drugs Affecting Hemostasis or Platelet Function.

Possible increased risk of bleeding; caution advised.

Protein-bound Drugs

Interaction unlikely.

Specific Drugs

Pharmacokinetics

Absorption

Bioavailability

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

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

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.

Special Populations

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

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

Moderate or severe renal impairment: AUC of M₁ metabolite increased by 24–46% compared with values in healthy individuals. End-stage renal disease: AUC of M₂ metabolite decreased by 50% in patients receiving dialysis compared with values in healthy individuals. 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.

Distribution

Extent

Extensively distributed, highest concentration in liver and kidney.

Plasma Protein Binding

Sibutramine: 97%.

M₁ and M₂: 94% each.

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).

Elimination Route

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

Half-life

Sibutramine: 1.1 hours.

M₁: 14 hours.

M₂: 16 hours.

Stability

Storage

Oral

Capsules

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

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

Advice to Patients

• Importance of reading the manufacturer’s patient information prior to beginning therapy and rereading it each time the prescription is renewed.
• Importance of notifying clinician if rash, urticaria, or other manifestations of allergic reaction occur.
• Importance of monitoring BP and pulse at regular intervals.
• Importance of not taking an extra dose if one is missed.
• 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.
• Importance of informing clinician of any concomitant disease (e.g., glaucoma, seizures, high BP, cardiac disease, major eating disorder).
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

AHFS Drug Information. © Copyright, 1959-2009, Selected Revisions June 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.