Sibutramine

Sibutramine

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Clinical data
Pregnancy category	AU: C US: C (Risk not ruled out) – no human data existing, inconclusive evidence of teratogenic potential in animal studies
Routes of administration	Oral
ATC code	A08AA10 (WHO)
Legal status
Legal status	US: Schedule IV
Pharmacokinetic data
Bioavailability	Resorption 77%, considerable first-pass metabolism
Metabolism	Hepatic (CYP3A4-mediated)
Elimination half-life	sibutramine approx. 1 hour Metabolite 1: 14 hours Metabolite 2: 16 hours
Excretion	Biliary (sibutramine and active metabolites), renal (inactive metabolites)
Identifiers
IUPAC name 1-(4-chlorophenyl)-N,N-dimethyl-a-(2-methylpropyl)- cyclobutanemethanamine
CAS Number	106650-56-0
PubChem CID	5210
DrugBank	APRD00456
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C17H26ClN
Molar mass	279.85 g/mol

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Overview

Sibutramine (trade name Meridia in the USA, Reductil in Europe and other countries), usually as sibutramide hydrochloride monohydrate, is an orally administered agent for the treatment of obesity. It is a centrally-acting serotonin-norepinephrine reuptake inhibitor structurally related to amphetamines, although its mechanism of action is distinct.

Sibutramine is manufactured by Abbott Laboratories. It is classified as a Schedule IV controlled substance in the United States.

Pharmacokinetics

Sibutramine is well absorbed from the GI tract (77%), but undergoes considerable first-pass metabolism reducing its bioavailability. The drug itself reaches its peak plasma level after 1 hour and has also a half-life of 1 hour. Sibutramine is metabolized by cytochrome P450 isozyme CYP3A4 resulting in 2 active primary and secondary amines (called active metabolites 1 and 2) with half-lives of 14 and 16 hours, respectively. Peak plasma concentrations of active metabolites 1 and 2 are reached after 3 to 4 hours. The following metabolic pathway mainly results in two inactive conjugated and hydroxylated metabolites (called metabolites 5 and 6). Metabolites 5 and 6 are mainly excreted in the urine.

Pharmacodynamics

Sibutramine is a neurotransmitter reuptake inhibitor that reduces the reuptake of serotonin (by 53%), norepinephrine (by 54%), and dopamine (by 16%), thereby increasing the levels of these substances in synaptic clefts and helping enhance satiety; the serotonergic action, in particular, is thought to influence appetite. Older anorectic agents such as amphetamine and fenfluramine force the release of these neurotransmitters rather than affecting their reuptake.

Despite its actions upon the aforementioned neurotransmitters, sibutramine failed to demonstrate antidepressant properties in animal studies. It was approved by the U.S. Food and Drug Administration (FDA) in November 1997 for the treatment of obesity.

Contraindications

Sibutramine is contraindicated in:

• Psychiatric conditions as bulimia nervosa, anorexia nervosa, serious depression or preexisting mania
• Patients with a history of or a predisposition to drug or alcohol abuse
• Hypersensitivity to the drug
• Patients below 18 years of age
• Concomitant treatment with a MAO inhibitor, antidepressant or other centrally active drugs, particularly other anoretics
• Hypertension that is not sufficiently controlled (caution in controlled hypertension)
• Existing pulmonary hypertension
• Existing damage on heart valves, coronary heart disease, congestive heart failure, serious arrhythmias, previous myocardial infarction
• Stroke or transient ischemic attack (TIA)
• Hyperthyroidism (overactive thyroid gland)
• Closed angle glaucoma
• Seizure disorders
• Enlargement of the prostate gland with urinary retention (relative C.I.)
• Pheochromocytoma
• Pregnant and lactating women (relative C.I.)

Side effects

Frequently encountered side effects are: dry mouth, paradoxically increased appetite, nausea, strange taste in the mouth, anorgasmia and delayed ejaculation, upset stomach, constipation, trouble sleeping, dizziness, drowsiness, menstrual cramps/pain, headache, flushing, or joint/muscle pain.

Sibutramine can substantially increase blood pressure and pulse in some patients. Therefore all patients treated with sibutramine should have regular monitoring of blood pressure and pulse.

The following side effects are infrequent but serious and require immediate medical attention: cardiac arrhythmias, paresthesia, mental/mood changes (e.g., excitement, restlessness, confusion, depression, rare thoughts of suicide).

Symptoms that require urgent medical attention are seizures, problems urinating, abnormal bruising or bleeding, melena, hematemesis, jaundice, fever and rigors, chest pain, hemiplegia, abnormal vision, dyspnea and edema.

Currently, no case of pulmonary hypertension has been noted, although related compounds (such as Fen-Phen) have shown this rare but clinically significant problem.

Interactions

Sibutramine has a number of clinically significant interactions. The concomitant use of sibutramine and monoamine oxidase inhibitors (MAOIs, such as selegiline) is not indicated, as it may increase the risk of serotonin syndrome, a somewhat rare but serious adverse drug reaction. Sibutramine should not be taken less than two weeks after stopping or before starting use of an MAOI. Taking both sibutramine and certain medications used in the treatment of migraines—such as ergolines and triptans—, as well as opioids, may also increase the risk for serotonin syndrome, as may the use of more than one serotonin reuptake inhibitor at the same time.

The concomitant use of sibutramine and drugs which inhibit CYP3A4, such as ketoconazole and erythromycin, may increase plasma levels of sibutramine. Sibutramine has no effect on the efficacy of hormonal contraception.

Dosage

10 mg once daily (usually in the morning), if this proves insufficient the dose may be increased to 15 mg daily after 4 weeks.

Safety concerns

Studies are ongoing into reports of sudden death, heart failure, renal failure and gastrointestinal problems. Despite a petition by Ralph Nader-founded NGO Public Citizen, the FDA made no attempts to withdraw the drug, but was part of a Senate hearing in 2005. Similarly, Dr. David Graham, FDA "whistleblower", testified before a Senate Finance Committee hearing that sibutramine may be more dangerous than the conditions it is used for.

A large randomized-controlled study with 10,742 patients (SCOUT) examined whether or not sibutramine reduces the risk for cardiovascular complications in people at high risk for heart disease and concluded that "Six-week treatment with sibutramine appears to be efficacious, tolerable and safe in this high-risk population for whom sibutramine is usually contraindicated."

External links

• Meridia (Manufacturer's website)
• RxList