Sibutramine

Sibutramine
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]

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Black Box Warning

Title See full prescribing information for complete Boxed Warning. ConditionName: Content

Overview

Sibutramine is a that is FDA approved for the {{{indicationType}}} of . There is a Black Box Warning for this drug as shown here. Common adverse reactions include .

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Condition1

• Dosing Information

• Dosage

Condition2

• Dosing Information

• Dosage

Condition3

• Dosing Information

• Dosage

Condition4

• Dosing Information

• Dosage

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition1

• Developed by:

• Class of Recommendation:

• Strength of Evidence:

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Sibutramine in adult patients.

Non–Guideline-Supported Use

Condition1

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Sibutramine in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Condition1

• Dosing Information

• Dosage

Condition2

There is limited information regarding FDA-Labeled Use of Sibutramine in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition1

• Developed by:

• Class of Recommendation:

• Strength of Evidence:

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Sibutramine in pediatric patients.

Non–Guideline-Supported Use

Condition1

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Sibutramine in pediatric patients.

Contraindications

• Condition1

Warnings

Title See full prescribing information for complete Boxed Warning. ConditionName: Content

• Description

Precautions

• Description

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Clinical Trial Experience of Sibutramine in the drug label.

Body as a Whole

Cardiovascular

Digestive

Endocrine

Hematologic and Lymphatic

Metabolic and Nutritional

Musculoskeletal

Neurologic

Respiratory

Skin and Hypersensitivy Reactions

Special Senses

Urogenital

Miscellaneous

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Sibutramine in the drug label.

Body as a Whole

Cardiovascular

Digestive

Endocrine

Hematologic and Lymphatic

Metabolic and Nutritional

Musculoskeletal

Neurologic

Respiratory

Skin and Hypersensitivy Reactions

Special Senses

Urogenital

Miscellaneous

Drug Interactions

• Drug

• Description

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sibutramine in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Sibutramine during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Sibutramine with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Sibutramine with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Sibutramine with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Sibutramine with respect to specific gender populations.

Race

There is no FDA guidance on the use of Sibutramine with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Sibutramine in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Sibutramine in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Sibutramine in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Sibutramine in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

• Intravenous

Monitoring

There is limited information regarding Monitoring of Sibutramine in the drug label.

• Description

IV Compatibility

There is limited information regarding IV Compatibility of Sibutramine in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• Description

Management

• Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Sibutramine in the drug label.

Pharmacology

There is limited information regarding Sibutramine Pharmacology in the drug label.

Mechanism of Action

• Sibutramine produces its therapeutic effects by norepinephrine, serotonin and dopamine reuptake inhibition. Sibutramine and its major pharmacologically active metabolites (M1 and M2) do not act via release of monoamines.

Structure

• MERIDIA® (sibutramine hydrochloride monohydrate) is an orally administered agent for the treatment of obesity. Chemically, the active ingredient is a racemic mixture of the (+) and (-) enantiomers of cyclobutanemethanamine, 1-(4-chlorophenyl)-N,N-dimethyl-α-(2-methylpropyl)-, hydrochloride, monohydrate, and has an empirical formula of C17H29Cl2NO. Its molecular weight is 334.33.

The structural formula is shown below:

This image is provided by the National Library of Medicine.

• Sibutramine hydrochloride monohydrate is a white to cream crystalline powder with a solubility of 2.9 mg/mL in pH 5.2 water. Its octanol: water partition coefficient is 30.9 at pH 5.0.

• Each MERIDIA capsule contains 5 mg, 10 mg, and 15 mg of sibutramine hydrochloride monohydrate. It also contains as inactive ingredients: lactose monohydrate, NF; microcrystalline cellulose, NF; colloidal silicon dioxide, NF; and magnesium stearate, NF in a hard-gelatin capsule [which contains titanium dioxide, USP; gelatin; FD&C Blue No. 2 (5- and 10-mg capsules only); D&C Yellow No. 10 (5- and 15-mg capsules only), and other inactive ingredients].

Pharmacodynamics

• Sibutramine exerts its pharmacological actions predominantly via its secondary (M1) and primary (M2) amine metabolites. The parent compound, sibutramine, is a potent inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake in vivo, but not in vitro. However, metabolites M1 and M2 inhibit the reuptake of these neurotransmitters both in vitro and in vivo.

• In human brain tissue, M1 and M2 also inhibit dopamine reuptake in vitro, but with ~3-fold lower potency than for the reuptake inhibition of serotonin or norepinephrine.

T1

• A study using plasma samples taken from sibutramine-treated volunteers showed monoamine reuptake inhibition of norepinephrine > serotonin > dopamine; maximum inhibitions were norepinephrine = 73%, serotonin = 54% and dopamine = 16%.

• Sibutramine and its metabolites (M1 and M2) are not serotonin, norepinephrine or dopamine releasing agents. Following chronic administration of sibutramine to rats, no depletion of brain monoamines has been observed.

• Sibutramine, M1 and M2 exhibit no evidence of anticholinergic or antihistaminergic actions. In addition, receptor binding profiles show that sibutramine, M1 and M2 have low affinity for serotonin (5-HT1, 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C), norepinephrine (β, β1, β3, α1 and α2), dopamine (D1 and D2), benzodiazepine, and glutamate (NMDA) receptors. These compounds also lack monoamine oxidase inhibitory activity in vitro and in vivo.

Pharmacokinetics

• Absorption

• Sibutramine is rapidly absorbed from the GI tract (Tmax of 1.2 hours) following oral administration and undergoes extensive first-pass metabolism in the liver (oral clearance of 1750 L/h and half-life of 1.1 h) to form the pharmacologically active mono- and di-desmethyl metabolites M1 and M2. Peak plasma concentrations of M1 and M2 are reached within 3 to 4 hours. On the basis of mass balance studies, on average, at least 77% of a single oral dose of sibutramine is absorbed. The absolute bioavailability of sibutramine has not been determined.

• Distribution

• Radiolabeled studies in animals indicated rapid and extensive distribution into tissues: highest concentrations of radiolabeled material were found in the eliminating organs, liver and kidney. In vitro, sibutramine, M1 and M2 are extensively bound (97%, 94% and 94%, respectively) to human plasma proteins at plasma concentrations seen following therapeutic doses.

• Metabolism

• Sibutramine is metabolized in the liver principally by the cytochrome P450 (3A4) isoenzyme, to desmethyl metabolites, M1 and M2. These active metabolites are further metabolized by hydroxylation and conjugation to pharmacologically inactive metabolites, M5 and M6. Following oral administration of radiolabeled sibutramine, essentially all of the peak radiolabeled material in plasma was accounted for by unchanged sibutramine (3%), M1 (6%), M2 (12%), M5 (52%), and M6 (27%).
• M1 and M2 plasma concentrations reached steady-state within four days of dosing and were approximately two-fold higher than following a single dose. The elimination half-lives of M1 and M2, 14 and 16 hours, respectively, were unchanged following repeated dosing.

• Excretion

• Approximately 85% (range 68-95%) of a single orally administered radiolabeled dose was excreted in urine and feces over a 15-day collection period with the majority of the dose (77%) excreted in the urine. Major metabolites in urine were M5 and M6; unchanged sibutramine, M1, and M2 were not detected. The primary route of excretion for M1 and M2 is hepatic metabolism and for M5 and M6 is renal excretion.

T2

• Effect of Food

• Administration of a single 20 mg dose of sibutramine with a standard breakfast resulted in reduced peak M1 and M2 concentrations (by 27% and 32%, respectively) and delayed the time to peak by approximately three hours. However, the AUCs of M1 and M2 were not significantly altered.

• Special Populations

• Geriatric

• Plasma concentrations of M1 and M2 were similar between elderly (ages 61 to 77 yr) and young (ages 19 to 30 yr) subjects following a single 15-mg oral sibutramine dose. Plasma concentrations of the inactive metabolites M5 and M6 were higher in the elderly; these differences are not likely to be of clinical significance. Sibutramine is contraindicated in patients over 65 years of age (see CONTRAINDICATIONS).

• Pediatric

• The safety and effectiveness of sibutramine in pediatric patients under 16 years old have not been established.

• Gender

• Pooled pharmacokinetic parameters from 54 young, healthy volunteers (37 males and 17 females) receiving a 15-mg oral dose of sibutramine showed the mean Cmax and AUC of M1 and M2 to be slightly (≤ 19% and ≤ 36%, respectively) higher in females than males. Somewhat higher steady-state trough plasma levels were observed in female obese patients from a large clinical efficacy trial. However, these differences are not likely to be of clinical significance. Dosage adjustment based upon the gender of a patient is not necessary (see DOSAGE AND ADMINISTRATION).

• Race

• The relationship between race and steady-state trough M1 and M2 plasma concentrations was examined in a clinical trial in obese patients. A trend towards higher concentrations in Black patients over Caucasian patients was noted for M1 and M2. However, these differences are not considered to be of clinical significance.

• Renal Insufficiency

• The disposition of sibutramine metabolites (M1, M2, M5 and M6) following a single oral dose of sibutramine was studied in patients with varying degrees of renal function. Sibutramine itself was not measurable.
• In patients with moderate and severe renal impairment, the AUC values of the active metabolite M1 were 24 to 46% higher and the AUC values of M2 were similar as compared to healthy subjects. Cross- study comparison showed that the patients with end - stage renal disease on dialysis had similar AUC values of M1 but approximately half of the AUC values of M2 measured in healthy subjects (CLcr ≥ 80 mL/ min). The AUC values of inactive metabolites M5 and M6 increased 2 - 3 fold (range 1 - to 7 - fold) in patients with moderate impairment (30 mL/ min < CLcr = 60 mL/ min) and 8 - 11 fold (range 5 - to 15 - fold) in patients with severe impairment (CLcr ≤ 30 mL/ min) as compared to healthy subjects. Cross - study comparison showed that the AUC values of M5 and M6 increased 22 - 33 fold in patients with end - stage renal disease on dialysis as compared to healthy subjects. Approximately 1% of the oral dose was recovered in the dialysate as a combination of M5 and M6 during the hemodialysis process, while M1 and M2 were not measurable in the dialysate.
• Sibutramine should not be used in patients with severe renal impairment, including those with end-stage renal disease on dialysis.

• Hepatic Insufficiency

• In 12 patients with moderate hepatic impairment receiving a single 15-mg oral dose of sibutramine, the combined AUCs of M1 and M2 were increased by 24% compared to healthy subjects while M5 and M6 plasma concentrations were unchanged. The observed differences in M1 and M2 concentrations do not warrant dosage adjustment in patients with mild to moderate hepatic impairment. Sibutramine should not be used in patients with severe hepatic dysfunction.

• Drug-Drug Interactions

• In vitro studies indicated that the cytochrome P450 (3A4)-mediated metabolism of sibutramine was inhibited by ketoconazole and to a lesser extent by erythromycin. Phase 1 clinical trials were conducted to assess the interactions of sibutramine with drugs that are substrates and/or inhibitors of various cytochrome P450 isozymes. The potential for studied interactions is described below.

• Ketoconazole

• Concomitant administration of 200 mg doses of ketoconazole twice daily and 20 mg sibutramine once daily for 7 days in 12 uncomplicated obese subjects resulted in moderate increases in AUC and Cmax of 58% and 36% for M1 and of 20% and 19% for M2, respectively.

• Erythromycin

• The steady-state pharmacokinetics of sibutramine and metabolites M1 and M2 were evaluated in 12 uncomplicated obese subjects following concomitant administration of 500 mg of erythromycin three times daily and 20 mg of sibutramine once daily for 7 days. Concomitant erythromycin resulted in small increases in the AUC (less than 14%) for M1 and M2. A small reduction in Cmax for M1 (11%) and a slight increase in Cmax for M2 (10%) were observed.

• Cimetidine

• Concomitant administration of cimetidine 400 mg twice daily and sibutramine 15 mg once daily for 7 days in 12 volunteers resulted in small increases in combined (M1 and M2) plasma Cmax (3.4%) and AUC (7.3%).

• Simvastatin

• Steady-state pharmacokinetics of sibutramine and metabolites M1 and M2 were evaluated in 27 healthy volunteers after the administration of simvastatin 20 mg once daily in the evening and sibutramine 15 mg once daily in the morning for 7 days. Simvastatin had no significant effect on plasma Cmax and AUC of M2 or M1 and M2 combined. The Cmax (16%) and AUC (12%) of M1 were slightly decreased. Simvastatin slightly decreased sibutramine Cmax (14%) and AUC (21%). Sibutramine increased the AUC (7%) of the pharmacologically active moiety, simvastatin acid and reduced the Cmax (25%) and AUC (15%) of inactive simvastatin.

• Omeprazole

• Steady-state pharmacokinetics of sibutramine and metabolites M1 and M2 were evaluated in 26 healthy volunteers after the co-administration of omeprazole 20 mg once daily and sibutramine 15 mg once daily for 7 days. Omeprazole slightly increased plasma Cmax and AUC of M1 and M2 combined (approximately 15%). M2 Cmax and AUC were not significantly affected whereas M1 Cmax (30%) and AUC (40%) were modestly increased. Plasma Cmax (57%) and AUC (67%) of unchanged sibutramine were moderately increased. Sibutramine had no significant effect on omeprazole pharmacokinetics.

• Olanzapine

• Steady-state pharmacokinetics of sibutramine and metabolites M1 and M2 were evaluated in 24 healthy volunteers after the co-administration of sibutramine 15 mg once daily with olanzapine 5 mg twice daily for 3 days and 10 mg once daily thereafter for 7 days. Olanzapine had no significant effect on plasma Cmax and AUC of M2 and M1 and M2 combined, or the AUC of M1. Olanzapine slightly increased M1 Cmax (19%), and moderately increased sibutramine Cmax (47%) and AUC (63%). Sibutramine had no significant effect on olanzapine pharmacokinetics.

• Lorazepam

• Steady-state pharmacokinetics of sibutramine and metabolites M1 and M2 after sibutramine 15 mg once daily for 11 days were compared in 25 healthy volunteers in the presence or absence of lorazepam 2 mg twice daily for 3 days plus one morning dose. Lorazepam had no significant effect on the pharmacokinetics of sibutramine metabolites M1 and M2. Sibutramine had no significant effect on lorazepam pharmacokinetics.

• Drugs Highly Bound to Plasma Proteins

• Although sibutramine and its active metabolites M1 and M2 are extensively bound to plasma proteins (≥94%), the low therapeutic concentrations and basic characteristics of these compounds make them unlikely to result in clinically significant protein binding interactions with other highly protein bound drugs such as warfarin and phenytoin. In vitro protein binding interaction studies have not been conducted.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Sibutramine in the drug label.

Clinical Studies

• Observational epidemiologic studies have established a relationship between obesity and the risks for cardiovascular disease, non-insulin dependent diabetes mellitus (NIDDM), certain forms of cancer, gallstones, certain respiratory disorders, and an increase in overall mortality. These studies suggest that weight loss, if maintained, may produce health benefits for some patients with chronic obesity who may also be at risk for other diseases.

• The long-term effects of sibutramine on the morbidity and mortality associated with obesity have not been established. Weight loss was examined in 11 double-blind, placebo-controlled obesity trials (BMI range across all studies 27-43) with study durations of 12 to 52 weeks and doses ranging from 1 to 30 mg once daily. Weight was significantly reduced in a dose-related manner in sibutramine-treated patients compared to placebo over the dose range of 5 to 20 mg once daily. In two 12-month studies, maximal weight loss was achieved by 6 months and statistically significant weight loss was maintained over 12 months. The amount of placebo-subtracted weight loss achieved on sibutramine was consistent across studies.

• Analysis of the data in three long-term (≥ 6 months) obesity trials indicates that patients who lose at least 4 pounds in the first 4 weeks of therapy with a given dose of sibutramine are most likely to achieve significant long-term weight loss on that dose of sibutramine. Approximately 60% of such patients went on to achieve a placebo-subtracted weight loss of ≥ 5% of their initial body weight by month 6. Conversely, of those patients on a given dose of sibutramine who did not lose at least 4 pounds in the first 4 weeks of therapy, approximately 80% did not go on to achieve a placebo-subtracted weight loss of ≥ 5% of their initial body weight on that dose by month 6.

• Significant dose-related reductions in waist circumference, an indicator of intra-abdominal fat, have also been observed over 6 and 12 months in placebo-controlled clinical trials. In a 12-week placebo-controlled study of non-insulin dependent diabetes mellitus patients randomized to placebo or 15 mg per day of sibutramine, Dual Energy X-Ray Absorptiometry (DEXA) assessment of changes in body composition showed that total body fat mass decreased by 1.8 kg in the sibutramine group versus 0.2 kg in the placebo group (p < 0.001). Similarly, truncal (android) fat mass decreased by 0.6 kg in the sibutramine group versus 0.1 kg in the placebo group (p < 0.01). The changes in lean mass, fasting blood sugar, and HbA1 were not statistically significantly different between the two groups.

• Eleven double-blind, placebo-controlled obesity trials with study durations of 12 to 52 weeks have provided evidence that sibutramine does not adversely affect glycemia, serum lipid profiles, or serum uric acid in obese patients. Treatment with sibutramine (5 to 20 mg once daily) is associated with mean increases in blood pressure of 1 to 3 mm Hg and with mean increases in pulse rate of 4 to 5 beats per minute relative to placebo. These findings are similar in normotensives and in patients with hypertension controlled with medication. Those patients who lose significant (≥ 5% weight loss) amounts of weight on sibutramine tend to have smaller increases in blood pressure and pulse rate (see WARNINGS).

• In Study 1, a 6-month, double-blind, placebo-controlled study in obese patients, Study 2, a 1-year, double-blind, placebo-controlled study in obese patients, and Study 3, a 1-year, double-blind, placebo-controlled study in obese patients who lost at least 6 kg on a 4-week very low calorie diet (VLCD), sibutramine produced significant reductions in weight, as shown below. In the two 1-year studies, maximal weight loss was achieved by 6 months and statistically significant weight loss was maintained over 12 months.

T3

How Supplied

Storage

There is limited information regarding Sibutramine Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Sibutramine in the drug label.

Precautions with Alcohol

• Alcohol-Sibutramine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• ®

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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