Sibutramine (Systemic)


VA CLASSIFICATION
Primary: GA751

Note: Controlled substance classification—

Note: Controlled substance classification


U.S.—Schedule IV
Commonly used brand name(s): Meridia.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Appetite suppressant—

Indications

General considerations
Cardiac valve dysfunction and primary pulmonary hypertension have been associated with the use of centrally acting appetite suppressants. Sibutramine does not promote the release of serotonin (5-hydroxytryptamine, 5-HT) from nerve terminals as do the appetite suppressants that were associated with these adverse events most commonly {01} {09}. A comparison of echocardiograms performed on patients after 0.5 to 16 months (mean 7.6 months) of treatment with 15 mg per day of sibutramine (132 patients) or placebo (77 patients) showed no difference in the incidence of valvular heart disease between the two groups {01}. A second study in 25 patients comparing echocardiograms administered at baseline with those administered after 3 months of treatment with 5 to 30 mg per day of sibutramine detected no cases of valvular heart disease {01}.

In two 12-month studies of sibutramine in obese subjects, maximum weight loss was achieved by 6 months and statistically significant weight loss was maintained over 12 months {01}. Among patients receiving 15 mg per day of sibutramine in clinical weight-loss trials, more than 50% lost ³ 5% of their baseline body weight {15} {16} and about 25% lost ³ 10% of their baseline body weight {15} {16}. However, some weight was regained after discontinuation of sibutramine {14} {16}.

Accepted

Obesity, exogenous (treatment){01}—Sibutramine is indicated for the management of obesity, including weight loss and maintenance of weight loss, in patients on a reduced-calorie diet {01}. Sibutramine should be used only in obese patients with an initial body mass index ³ 30 kg of body weight per square meter of height (kg/m 2) or with an initial body mass index ³ 27 kg/m 2 in the presence of other risk factors, such as hypertension, diabetes, or dyslipidemia {01}. Safety and efficacy of sibutramine use for more than 1 year have not been evaluated in controlled trials {01}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Cyclobutanemethanamine {01}.
Molecular weight—
    Sibutramine hydrochloride monohydrate: 334.33 {04}

Solubility
    In water at pH 5.2: 2.9 mg/mL {01}.

Partition coefficient
    Octanol:water at pH 5: 30.9 {01}.

Mechanism of action/Effect:

Sibutramine is a serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake inhibitor (SNRI) {09} {18}. In vitro testing found sibutramine to be much less potent than its primary and secondary amine metabolites in inhibiting monoamine reuptake {09} {12} {18}. Therefore, the pharmacological actions of sibutramine are thought to be due predominantly to its active metabolites {03} {12}. The metabolites of sibutramine inhibit 5-HT and NE reuptake with potencies comparable to those of fluoxetine and desipramine, respectively {21}. Combined NE and 5-HT reuptake inhibition is thought to promote a sense of satiety, leading to a decrease in energy intake {12} {21}, and, possibly, to increase resting metabolic rate {12}. Randomized, placebo-controlled, double-blind studies in obese and in nonobese subjects have shown significant reductions in self-rated premeal hunger and in energy intake with sibutramine use, even in the absence of an imposed reduced-calorie diet {03} {13}. One study found no difference in the decrease in resting energy expenditure associated with weight loss between subjects receiving sibutramine and subjects receiving placebo, in spite of significantly greater weight loss in the sibutramine group {17}. In another study, basal metabolic rate, as measured by indirect calorimetry, increased more in sibutramine-treated patients than in patients receiving placebo {17}; however, this finding has not been consistent {14}.

The degree of weight loss occurring with sibutramine use is dose-related {10} {15} {16}. Also, the subcutaneous to visceral fat ratio was found to be significantly increased from baseline in sibutramine-treated patients, possibly indicating a preferential reduction in visceral fat {20}.

Studies in rodents indicate that sibutramine administration leads to rapid down-regulation of alpha 2-adrenergic receptors, with a greater effect on postsynaptic than on presynaptic receptors, and down-regulation of beta 1-adrenergic receptors {03}. Sibutramine's metabolites inhibit the reuptake of dopamine in vivo , but much less potently than they inhibit the reuptake of NE and 5-HT {12} {18}. Neither sibutramine nor its active metabolites, at clinically relevant concentrations, cause the release of monoamines {09} {12} {18} or inhibit monoamine oxidase {18} {21}. Also, all active moieties have low affinity for serotonin (5-HT 1, 5-HT 1A, 5-HT 1B, 5-HT 2A, 5-HT 2C) {01}, norepinephrine (beta 1, beta 2, beta 3, alpha 1, alpha 2) {21}, dopamine (D 1, D 2) {01} {21}, benzodiazepine {01} {21}, and glutamate (NMDA) {01} {21} receptors, and they show no evidence of anticholinergic {01} {11} or antihistaminergic {01} {11} actions.


Other actions/effects:

Inhibits 5-HT uptake by platelets as well as by neurons {03}, which may affect platelet functioning {01}.

Absorption:

Rapidly absorbed following oral administration {03}; undergoes extensive first-pass metabolism in the liver to form mono- and di-desmethyl active metabolites (M1, a secondary amine, and M2, a primary amine, respectively) {03}. Absolute bioavailability is unknown, but mass balance studies indicate that at least 77% of a single oral dose is absorbed {01}.

Food increases the time to peak plasma concentration and decreases the peak plasma concentrations of the desmethyl metabolites by about 3 hours and 30%, respectively, but does not affect the area under the plasma concentration–time curves (AUCs) of the desmethyl metabolites {01}.

Distribution:

Rapidly and extensively distributed into tissues {01}.

Protein binding:

Sibutramine—Very high (97%); to human plasma proteins {01}.

M1 and M2—Very high (94%); to human plasma proteins {01}.

Although protein binding is very high, interactions with other highly protein-bound medications are not anticipated because of the low therapeutic concentrations and basic characteristics of sibutramine and its active metabolites {01}.

Biotransformation:

Hepatic {01}. Sibutramine is metabolized principally by the cytochrome P450 3A4 (CYP3A4) isoenzyme to two active desmethyl metabolites, mono-desmethylsibutramine (M1, a secondary amine {03}) and di-desmethylsibutramine (M2, a primary amine {03}), which are hydroxylated and conjugated to inactive metabolites {01}. Mild to moderate hepatic impairment does not significantly alter the pharmacokinetics of sibutramine or its active metabolites {03}.

Half-life:


Elimination:

Sibutramine: 1.1 hours {01}.

M1: 14 hours {01}.

M2: 16 hours {01}.


Time to peak plasma concentration

Sibutramine—1.2 hours {01}.

M1 and M2—3 to 4 hours {01}.

Time to steady-state plasma concentration

Steady-state plasma concentrations of M1 and M2 are reached within 4 days with once-a-day dosing {03}.

Peak plasma concentration

In 18 obese subjects, after each received a single 15-mg dose of sibutramine, the mean peak plasma concentrations of M1 and M2 were 4 nanograms/mL (range 3.2 to 4.8 nanograms/mL) and 6.4 nanograms/mL (range 5.6 to 7.2 nanograms/mL), respectively {01}.

Steady-state plasma concentration

Steady-state plasma concentrations of M1 and M2 are linearly related to sibutramine dosage {03} and are approximately twofold higher than single-dose plasma concentrations {01}.

Elimination:
    Primarily renal, as inactive metabolites {01}. Renal function impairment did not significantly affect maximum plasma concentrations, half-life, or AUC of sibutramine or its active metabolites in 18 nonobese patients {07}.


Precautions to Consider

Carcinogenicity/tumorigenicity

Two-year studies in rats and mice given sibutramine in daily doses that resulted in combined area under the plasma concentration–time curves (AUCs) of the two active metabolites that were 0.5 to 21 times those seen in patients taking the maximum recommended human dose (MRHD) showed an increased incidence of benign tumors of the testicular interstitial cells in male rats. These tumors are commonly seen in rats, and the clinical significance of this finding is unknown. No evidence of carcinogenicity was seen in mice or in female rats. {01}

Mutagenicity

The two active metabolites of sibutramine had equivocal bacterial mutagenic activity in the Ames test {01}. However, neither sibutramine nor its active metabolites showed evidence of mutagenicity in a number of other appropriate tests {01}.

Pregnancy/Reproduction
Fertility—
Studies in rats showed no evidence of impairment of fertility with sibutramine administration {01}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done.

No evidence of teratogenicity was seen in studies in which pregnant rats were given daily doses of sibutramine that produced an AUC of the active metabolites that was approximately 43 times that produced in humans receiving the MRHD. However, maternal toxicity and impaired nest-building behavior, which led to decreased pup survival, were seen. Maternal toxicity and increased incidences of broad short snout, short rounded pinnae, short tail, and short thickened long bones in the limbs of offspring were seen when pregnant Dutch Belted rabbits were given daily doses of sibutramine that produced an AUC of the active metabolites greater than five times that produced in humans receiving the MRHD. Using comparable doses, two studies in New Zealand White rabbits yielded conflicting results. One study found an increased incidence and the other a decreased incidence of cardiovascular anomalies in the offspring of rabbits given sibutramine compared with the offspring of control rabbits. {01}

FDA Pregnancy Category C {01}.

Breast-feeding

It is not known whether sibutramine or its metabolites are distributed into breast milk {01}.

Pediatrics

Appropriate studies on the relationship of age to the effects of sibutramine have not been performed in the pediatric population. Safety and efficacy in children up to 16 years of age have not been established {01}.


Geriatrics


Appropriate studies on the relationship of age to the effects of sibutramine have not been performed in the geriatric population. However, no geriatrics-specific problems have been documented to date and plasma concentrations of sibutramine's active metabolites were similar in subjects 61 to 77 years of age and subjects 19 to 30 years of age after a single 15-mg dose {01}.


Pharmacogenetics

Although pharmacokinetic data indicate that mean maximum plasma concentrations and AUCs are slightly higher in females than in males, this difference is not likely to be clinically significant, and no dosage adjustments based on gender are recommended {01}.


Dental

Use of sibutramine may decrease or inhibit salivary flow {01}, thus contributing to the development of dental caries, periodontal disease, oral candidiasis, and discomfort.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: In a 52-day, single-blind, placebo controlled study of 11 healthy female volunteers, 28 days of treatment with 15 mg per day of sibutramine did not interfere with the efficacy of combined steroid oral contraceptives {03}.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Alcohol    (a single-dose study found no clinically significant psychomotor effects with concomitant use; however, use of excess alcohol with sibutramine is not recommended {01})


» Appetite suppressants, other    (sibutramine has not been studied and should not be used in combination with other centrally acting appetite suppressants {01})


Medications that inhibit cytochrome P450 3A4 (CYP3A4), such as:
Cimetidine or
Erythromycin or
Ketoconazole    (CYP3A4 is involved in sibutramine metabolism and the potential exists for a decrease in sibutramine clearance {03}; in small clinical drug interaction studies, the effects of erythromycin and ketoconazole on sibutramine clearance were small to moderate {01}, and the effects of cimetidine on sibutramine clearance were very small {01})


Medications that may increase blood pressure and/or heart rate, other, such as:
Ephedrine or
Phenylpropanolamine or
Pseudoephedrine or
Cough, cold, and allergy products that contain such agents    (sibutramine may increase blood pressure and/or heart rate; concurrent use has not been evaluated {01})


» Moclobemide    (because of the potentially fatal consequences of combining non-selective, irreversible monoamine oxidase inhibitors with sibutramine, and the increased risk of developing the serotonin syndrome with combined use of sibutramine and the reversible monoamine oxidase–A inhibitor moclobemide, concurrent use is not recommended and a wash-out period of 3 to 7 days is advised between the use of one medication [sibutramine or moclobemide] and the use of the other {22})


» Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline    (there have been reports of serious, sometimes fatal, reactions in patients taking MAO inhibitors in combination with other serotonergic agents; concurrent use is contraindicated and at least 2 weeks should elapse between discontinuing one medication [MAO inhibitor or sibutramine] and beginning the other {01})


» Serotonergics or medications or substances with serotonergic activity (see Appendix II )    (increased risk of development of the serotonin syndrome, a rare but potentially fatal hyperserotonergic state that may occur in patients receiving serotonergic medications, usually in combination; symptoms typically occur shortly [hours to days] after the addition of a serotonergic agent to a regimen that includes serotonin-enhancing drugs or an increase in dosage of a serotonergic agent; symptoms include agitation, diaphoresis, diarrhea, fever, hyperreflexia, incoordination, mental status changes [confusion, hypomania], myoclonus, shivering, or tremor; cardiac arrhythmias, coma, disseminated intravascular coagulation, hypertension or hypotension, renal failure, respiratory failure, seizures, and severe hyperthermia also have been reported; the syndrome usually resolves shortly after discontinuation of serotonergic medications; treatment is essentially symptomatic and supportive {01} {02})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
» Blood pressure and
» Heart rate    (mean increases of 1 to 3 mm Hg in systolic and diastolic blood pressure {01} {11} and four to five beats per minute in heart rate {01} {11} {15} occurred during clinical trials of sibutramine. However, some patients experienced substantial increases in blood pressure, leading to discontinuation of sibutramine in 0.4% of patients {01}. Tachycardia also led to discontinuation of sibutramine in 0.4% of patients {01}. Placebo discontinuation rates for hypertension and tachycardia were 0.4% and 0.1%, respectively {01}. If a sustained increase in blood pressure or heart rate occurs, a reduction in sibutramine dosage or discontinuation of sibutramine therapy should be considered {01} {11})

    (in an 8-week, parallel-group, double-blind study of 20 obese hypertensive patients [10 sibutramine, 10 placebo recipients], during which diet was monitored to minimize weight loss, 24-hour ambulatory blood pressure and heart rate monitoring showed statistically significant increases over baseline values in the sibutramine group compared with the placebo group {05}. Overall, diastolic blood pressure changed from baseline by a decrease of 8 mm Hg in the placebo group and by an increase of 2.2 mm Hg in the sibutramine group during week 4 of the study, and by a decrease of 7.7 mm Hg in the placebo group and by an increase of 3.7 mm Hg in the sibutramine group during week 8 of the study {05}. The magnitude of the diastolic blood pressure increases in the sibutramine group was greatest during the nocturnal hours {05}. Overall, mean arterial pressure was increased from baseline in the sibutramine group and was decreased from baseline in the placebo group {05}; however, the difference between the two groups in mean arterial pressure was not statistically significant {05}. Heart rate increased in both groups, with overall increases of 3.5 and 15.1 beats per minute in the placebo and sibutramine groups, respectively {05})

    (in a 12-week, parallel-group, double-blind study of 113 obese hypertensive patients [54 sibutramine, 59 placebo recipients], during which patients were to follow dietary advice directed toward weight loss, diastolic and systolic blood pressures decreased in both groups {06}. Although the weight loss in the sibutramine group was significantly greater than that in the placebo group, the decrease in blood pressure was greater, though not significantly so, in the placebo group {06}. Heart rate changes from baseline were significantly different between placebo [decreases of 4.3 and 5.8 beats per minute supine and standing, respectively] and sibutramine [increase of 2.4 and decrease of 0.6 beats per minute supine and standing, respectively] groups {06})


Lipids, serum and
Uric acid, serum    (weight loss induced by sibutramine has been accompanied by increases in serum high-density lipoprotein cholesterol concentrations and by decreases in serum triglyceride, total cholesterol, low-density lipoprotein cholesterol, and uric acid concentrations {01} {03} {19})


Liver function tests    (increases in serum concentrations of aspartate aminotransferase [AST (SGOT)], alanine aminotransferase [ALT (SGPT)], gamma-glutamyltransferase [GGT], lactate dehydrogenase [LDH], alkaline phosphate, and bilirubin were reported in 1.6% of sibutramine-treated obese patients and 0.8% of placebo-control patients in clinical trials; clinically significant elevations were rare; abnormal values were sporadic, did not show a clear dose-response relationship, and often diminished with continued treatment {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Anorexia nervosa{01} or
» Hypertension, uncontrolled or poorly controlled{01}    (may be exacerbated)


Risk-benefit should be considered when the following medical problems exist
» Cardiac arrhythmia, or history of or
» Congestive heart failure, or history of or
» Coronary artery disease, or history of or
» Stroke, or history of    (sibutramine is not recommended for use in these patients, because of its association with increases in blood pressure and heart rate {01})


Drug abuse or dependence, history of    (although the abuse potential of sibutramine was found to be very low in rat {18} and human {08} {18} studies, clinical use data are limited and patients should be observed carefully for signs of misuse of sibutramine, such as increasing dosage and drug-seeking behavior {01})


Gallstones, or history of    (weight loss may precipitate or exacerbate gallstone formation {01})


Glaucoma, narrow angle    (sibutramine can cause mydriasis and should be used with caution in patients with narrow angle glaucoma {01})


» Hepatic function impairment, severe or
» Renal function impairment, severe    (pharmacokinetic studies indicate that no dosage adjustment is needed in patients with mild to moderate hepatic function impairment {01}, and a study in 18 nonobese patients with renal function impairment found insignificant changes in the pharmacokinetics of sibutramine's active moieties {07}; however, sibutramine has not been studied in patients with severe hepatic or renal function impairment and use is not recommended in these patients {01})


» Hypertension, well-controlled or
» Hypertension, history of    (may be exacerbated; sibutramine should be used with caution in these patients and should not be used in patients with uncontrolled or poorly controlled hypertension {01})


Neurological impairment, including developmental delay or
Seizures, history of    (increased risk of seizures occurring; seizures were reported in < 0.1% of patients in premarketing studies of sibutramine {01} {22})


Sensitivity to sibutramine

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood pressure and
» Heart rate    (recommended in all patients before starting therapy with sibutramine and at regular intervals during treatment {01} {19}; tachycardia or hypertension, when seen in patients during clinical trials, usually developed during the first 8 weeks of sibutramine treatment {19}; if sustained elevations occur, a decrease in sibutramine dosage or discontinuation of sibutramine therapy should be considered {01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Dysmenorrhea{01}{19} (painful menstruation)
    
edema{01} (swelling of body or of feet and ankles)
    
hypertension{01}{16} (increased blood pressure)
    
influenza-like symptoms{01} (chills; achiness)
    
mental depression{01}{10}
    
palpitation or tachycardia{01}{15}{19} (fast or irregular heartbeat)

Incidence rare
    
Abnormal bleeding{01} (bruising or red spots or patches on skin; excessive bleeding following injury)
    
acute interstitial nephritis{01} (swelling of body or of feet and ankles; unusual weight gain)
    
emotional lability{01}{16} (rapidly changing moods)
    
migraine{01}{15} (severe headache)
    
seizures{01}
    
skin rash{01}{10}

Note: Abnormal bleeding may be related to inhibition of serotonin uptake into platelets caused by sibutramine and its metabolites {01}.
A single case of biopsy-confirmed acute interstitial nephritis was reported during premarketing studies. The patient fully recovered after discontinuing sibutramine and receiving dialysis and oral corticosteroids. {01}
Seizures were reported in < 0.1% of patients in premarketing studies of sibutramine. Some of these patients had predisposing factors, including prior history of epilepsy or brain tumor. If seizures develop, sibutramine should be discontinued. {01}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Central nervous system (CNS) stimulation{14}
including anxiety{01}
insomnia{10}{14}{15} (trouble in sleeping), irritability or unusual impatience{10}
or nervousness{01}
    
constipation{01}{15}{19}
    
dizziness{10}{14}{19}
    
dryness of mouth{10}{14}{15}
    
headache{01}{10}
    
rhinitis{01}{14} (stuffy or runny nose)

Incidence less frequent
    
Abdominal pain{01}{10}{15}
    
back pain{01}
    
diarrhea{01}
    
drowsiness{01}{11}
    
dyspepsia{01} (indigestion)
    
increased appetite{01}{19}
    
increased sweating{01}{19}
    
increased thirst{01}
    
nausea{10}{14}{15}
    
paresthesia{01}{10}{19} (burning, itching, prickling, or tingling of skin)
    
taste perversion{01} (change in sense of taste)
    
vasodilation{01} (unusual warmth or flushing of skin)





Overdose
For specific information on the agents used in the management of sibutramine overdose, see Beta-adrenergic Blocking Agents (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose

Note: Experience with sibutramine overdose is very limited. In reported cases, few adverse effects and no apparent sequelae occurred. Increased heart rate (120 beats per minute) was reported in a 45-year-old male who ingested 400 mg of sibutramine. {01}


Treatment of overdose
Treatment of sibutramine overdose is symptomatic and supportive {01}.

Specific treatment—Beta-adrenergic blocking agents may be used cautiously to control elevated blood pressure or tachycardia {01}.

Monitoring—Cardiac and vital signs should be monitored {01}.

Supportive care—Establish and maintain patent airway {01}. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation {01}.

Note: Forced diuresis and hemodialysis are of unknown benefit in the treatment of sibutramine overdose {01}.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Sibutramine (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
  Conditions affecting use, especially:





Dental—Decreased salivary flow may contribute to caries, periodontal disease, oral candidiasis, and discomfort
Contraindicated medications—Monoamine oxidase (MAO) inhibitors

Other medications, especially other appetite suppressants, serotonergics, or medications or substances with serotonergic activity
Other medical problems, especially anorexia nervosa; cardiac arrhythmia, or history of; congestive heart failure, or history of; coronary artery disease, or history of; hepatic or renal function impairment, severe; hypertension, or history of; or stroke, or history of

Proper use of this medication
» Taking as directed; not increasing dose, not taking more frequently, and not taking for a longer time than directed by physician, because of potential cardiovascular adverse effects

Following reduced-calorie diet, as directed by physician

Taking with or without food, on a full or empty stomach, as directed by physician

» Proper dosing
Missed dose: Taking as soon as possible if remembered within 2 to 3 hours; not taking if remembered later; returning to regular dosing schedule; not doubling doses

» Proper storage

Precautions while using this medication
» Importance of regular visits to physician to check progress of therapy and monitor blood pressure and heart rate

» Not increasing dosage if effect diminishes; checking with physician

» Not taking an MAO inhibitor within 2 weeks of taking sibutramine; not taking sibutramine within 2 weeks of taking an MAO inhibitor

Limiting alcohol consumption

» Notifying physician as soon as possible if skin rash, hives, or other allergic reaction occurs

» Possible dizziness, drowsiness, or impaired judgment; caution in driving or doing other things that require alertness and sound judgment until effects are known

Possible dryness of mouth; using sugarless candy or gum, ice, or saliva substitute for relief; checking with physician or dentist if dry mouth continues for more than 2 weeks


Side/adverse effects
Signs of potential side effects, especially dysmenorrhea, edema, hypertension, influenza-like symptoms, mental depression, palpitation or tachycardia, abnormal bleeding, acute interstitial nephritis, emotional lability, migraine, seizures, and skin rash


General Dosing Information
Sibutramine should not be prescribed until organic causes for obesity, such as untreated hypothyroidism, have been ruled out {01}.

In sibutramine obesity trials of 6 months or longer, the patients who lost at least 1.8 kg (4 pounds) of body weight during the first 4 weeks of treatment were much more likely than the patients who lost less than this to subsequently lose at least 5% of their initial body weight at a given dose {01}. If a patient does not lose at least 1.8 kg (4 pounds) in the first 4 weeks of sibutramine treatment, therapy should be re-evaluated and sibutramine dosage should be increased, or sibutramine use should be discontinued {01}.

The abuse potential of sibutramine was found to be very low in rat {18} and human {08} {18} studies designed to assess potential for abuse as a psychostimulant and in rat {18} studies designed to assess potential for abuse as an hallucinogen.

Diet/Nutrition
Sibutramine may be taken with or without food {01}.

A reduced-calorie diet must be followed during sibutramine therapy in order to achieve significant weight loss {01} {19}.


Oral Dosage Form

SIBUTRAMINE HYDROCHLORIDE MONOHYDRATE CAPSULES

Usual adult dose
Obesity, exogenous
Oral, initially 10 mg once a day, usually in the morning. If weight loss is inadequate (< 1.8 kg [4 pounds]) after four weeks of therapy, dosage may be increased to 15 mg once a day, taking into consideration effects on heart rate and blood pressure. {01}


Note: Patients who do not tolerate the 10-mg dose may benefit from a 5-mg dose {01}.


Usual adult prescribing limits
15 mg per day {01}.

Usual pediatric dose
Safety and efficacy in children up to 16 years of age have not been established {01}.

Usual geriatric dose
See Usual adult dose .

Note: Dosing in elderly patients should be approached cautiously because of the high incidence of concomitant disease states and medication use in this population {01}.


Strength(s) usually available
U.S.—


5 mg (Rx) [Meridia (colloidal silicon dioxide) (D&C Yellow No. 10) (FD&C Blue No. 2) (gelatin) (lactose monohydrate) (microcrystalline cellulose) (magnesium stearate) (titanium dioxide){01}]


10 mg (Rx) [Meridia (colloidal silicon dioxide) (FD&C Blue No. 2) (gelatin) (lactose monohydrate) (microcrystalline cellulose) (magnesium stearate) (titanium dioxide){01}]


15 mg (Rx) [Meridia (colloidal silicon dioxide) (D&C Yellow No. 10) (gelatin) (lactose monohydrate) (microcrystalline cellulose) (magnesium stearate) (titanium dioxide){01}]

Canada—
Not commercially available.

Packaging and storage:
Store at 25 ºC (77 ºF), with excursions between 15 and 30 ºC (59 and 86 ºF) permitted, in a tight, light-resistant container, unless otherwise specified by manufacturer. Protect from heat and moisture. {01}

Auxiliary labeling:
   • May cause dizziness or drowsiness

Note: Sibutramine is a controlled substance in the U.S.




Developed: 04/26/1999



References
  1. Meridia package insert (Knoll—US), Rev 11/97, Rec 2/98.
  1. Reviewers' responses to Psychiatric Disease Advisory Panel Memos #7 of 4/30/97 and #9 of 6/10/97; Reviewers' responses to Neurology Advisory Panel Memos #8 of 4/30/97 and #9 of 6/10/97.
  1. McNeely W, Goa KL. Sibutramine: a review of its contribution to the management of obesity. Drugs 1998 Dec; 56(6): 1093-124.
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 666.
  1. Study number BPI 855. Part 2–medical review, sibutramine new drug approval package. Food and Drug Administration; 1997. URL: http://www.fda.gov/cder/foi/nda/index97.htm [accessed 1998 Dec].
  1. Study number SB 2057. Part 2–medical review, sibutramine new drug approval package. Food and Drug Administration; 1997. URL: http://www.fda.gov/cder/foi/nda/index97.htm [accessed 1998 Dec].
  1. Johnson F, Velagapudi R, Hind I, et al. Effects of renal dysfunction on the pharmacokinetics of sibutramine and its metabolites [abstract]. J Clin Pharmacol 1997; 37(9): 865.
  1. Cole JO, Levin A, Beake B, et al. Sibutramine: a new weight loss agent without evidence of the abuse potential associated with amphetamines. J Clin Psychopharmacol 1998; 18(3): 231-6.
  1. Gundlah C, Martin KF, Heal DJ, et al. In vivo criteria to differentiate monoamine reuptake inhibitors from releasing agents: sibutramine is a reuptake inhibitor. J Pharmacol Exp Ther 1997; 283(2): 581-91.
  1. Weintraub M, Rubio A, Golik A, et al. Sibutramine in weight control: a dose-ranging, efficacy study. Clin Pharmacol Ther 1991; 50: 330-7.
  1. King DJ, Devaney N. Clinical pharmacology of sibutramine hydrochloride (BTS 54524), a new antidepressant, in healthy volunteers. Br J Clin Pharmacol 1988; 26: 607-11.
  1. Heal DJ, Cheetham SC, Prow MR, et al. A comparison of the effects on central 5-HT function of sibutramine hydrochloride and other weight-modifying agents. Br J Pharmacol 1998; 125: 301-8.
  1. Rolls BJ, Shide DJ, Thorwart ML, et al. Sibutramine reduces food intake in non-dieting women with obesity. Obes Res 1998 Jan; 6(1): 1-11.
  1. Seagle HM, Bessesen DH, Hill JO. Effects of sibutramine on resting metabolic rate and weight loss in overweight women. Obes Res 1998 Mar; 6(2): 115-21.
  1. Hanotin C, Thomas F, Jones SP, et al. Efficacy and tolerability of sibutramine in obese patients: a dose-ranging study. Int J Obes Relat Metab Disord 1998 Jan; 22(1): 32-8.
  1. Bray GA, Ryan DH, Gordon D, et al. A double-blind randomized placebo-controlled trial of sibutramine. Obes Res 1996 May; 4(3): 263-70.
  1. Astrup A, Hansen DL, Lundsgaard C, et al. Sibutramine and energy balance. Int J Obes Relat Metab Disord 1998 Aug; 22 Suppl 1: S30-S35.
  1. Heal DJ, Aspley S, Prow MR, et al. Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine. Int J Obes Relat Metab Disord 1998 Aug; 22 Suppl 1: S18-S29.
  1. Lean MEJ. Sibutramine: a review of clinical efficacy. Int J Obes Relat Metab Disord 1997 Mar; 21 Suppl 1: S30-S36.
  1. Van Gaal LF, Wauters MA, Peiffer FW, et al. Sibutramine and fat distribution: is there a role for pharmacotherapy in abdominal/visceral fat reduction? Int J Obes Relat Metab Disord 1998; 22 Suppl 1: S38-S40.
  1. Stock MJ. Sibutramine: a review of the pharmacology of a novel anti-obesity agent. Int J Obes Relat Metab Disord 1997 Mar; 21 Suppl 1: S25-S29.
  1. Reviewers' responses to monograph development, 2/99.
Hide
(web1)