indication

For the treatment of obesity.

pharmacology

Sibutramine is an orally administered agent for the treatment of obesity. 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 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. 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-HT_1A, 5-HT_1B, 5-HT_2A, 5-HT_2C), norepinephrine (b, b1, b3, a1 and a2), dopamine (D1 and D2), benzodiazepine, and glutamate (NMDA) receptors. These compounds also lack monoamine oxidase inhibitory activity in vitro and in vivo.

mechanism of action

Sibutramine produces its therapeutic effects by inhibition of norepinephrine (NE), serotonin (5-hydroxytryptamine, 5-HT), and to a lesser extent, dopamine reuptake at the neuronal synapse. By inhibiting the reuptake of these neurotransmitters, sibutramine promotes a sense of satiety and decrease in appetite, thereby reducing food intake. Data from animal studies also suggest that sibutramine may also increase energy expenditure through thermogenic effects in both the basal and fed states, but this has not been confirmed in humans. Sibutramine and its major pharmacologically active metabolites (M1 and M2) do not act via release of monoamines.

toxicity

Side effects include dry mouth, anorexia, insomnia, constipation and headache.

biotransformation

Hepatic

absorption

Rapid absorption following oral administration. Absolute bioavailability is not known, but at least 77% of a single oral dose of sibutramine is absorbed.

half life

1.1 hours

route of elimination

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. 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. The primary route of excretion for M1 and M2 is hepatic metabolism and for M5 and M6 is renal excretion.

drug interactions

Almotriptan: Increased risk of CNS adverse effects

Amitriptyline: Increased risk of CNS adverse effects

Amoxapine: Increased risk of CNS adverse effects

Citalopram: Risk of serotoninergic syndrome

Clomipramine: Increased risk of CNS adverse effects

Cyclosporine: Sibutramine increases the effect and toxicity of cyclosporine

Desipramine: Increased risk of CNS adverse effects

Desvenlafaxine: Increased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.

Dextromethorphan: Combination associated with possible serotoninergic syndrome

Dihydroergotamine: Possible serotoninergic syndrome with this combination

Doxepin: Increased risk of CNS adverse effects

Ergotamine: Possible serotoninergic syndrome with this combination

Erythromycin: Erythromycin increases the effect and toxicity of sibutramine

Escitalopram: Risk of serotoninergic syndrome

Fluoxetine: Risk of serotoninergic syndrome

Fluvoxamine: Risk of serotoninergic syndrome

Frovatriptan: Increased risk of CNS adverse effects

Imipramine: Increased risk of CNS adverse effects

Isocarboxazid: Possible serotoninergic syndrome with this combination

Ketoconazole: Ketoconazole increases the levels and toxicity of sibutramine

Lithium: Possible serotoninergic syndrome with this combination

Meperidine: Possible serotoninergic syndrome

Methysergide: Possible serotoninergic syndrome

Moclobemide: Possible serotoninergic syndrome with this combination

Naratriptan: Increased risk of CNS adverse effects

Nefazodone: Risk of serotoninergic syndrome

Nortriptyline: Increased risk of CNS adverse effects

Paroxetine: Risk of serotoninergic syndrome

Phenelzine: Possible serotoninergic syndrome with this combination

Rasagiline: Possible serotoninergic syndrome with this combination

Telithromycin: Telithromycin may reduce clearance of Sibutramine. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Sibutramine if Telithromycin is initiated, discontinued or dose changed.

Tramadol: Sibutramine may incrase the serotonergic effect of the Tramadol. Concomitant therapy should be avoided.

Tranylcypromine: Increased risk of serotonin syndrome. Avoid concomitant therapy.

Trazodone: Increased risk of serotonin syndrome. Avoid concomitant therapy.

Trimipramine: Increased risk of serotonin syndrome. Concomitant therapy is contraindicated.

Venlafaxine: Increased risk of serotonin syndrome. Concurrent therapy should be avoided.

Vilazodone: Sibutramine may enhance the serotonergic effect of Serotonin Modulators. This may cause serotonin syndrome. Avoid combination.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of sibutramine by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of sibutramine if voriconazole is initiated, discontinued or dose changed.

Zolmitriptan: Use of sibutramine, which inhibits serotonin reuptake, and zolmitriptan, a serotonin 5-HT1D receptor agonist, may cause serotonin syndrome. Concomitant therapy is contraindicated.