Sibutramine

Sibutramine (usually in the form of the hydrochloride monohydrate salt) is an oral anorexiant. Until 2010 it was marketed and prescribed as an adjunct in the treatment of exogenous obesity along with diet and exercise. It has been associated with increased cardiovascular events and strokes and has been withdrawn from the market in countries and regions including Australia, Canada, China, the European Union (EU), Hong Kong, India, Mexico, Thailand, the UK, and the United States.

Sibutramine is a centrally-acting serotonin-norepinephrine reuptake inhibitor structurally related to amphetamines, although its mechanism of action is distinct.

Sibutramine was originally developed and marketed by Knoll Pharmaceuticals and was most recently manufactured and marketed by Abbott Laboratories before its withdrawal from the market. It was sold under a variety of brand names including Reductil, Meridia and Sibutrex. 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 into two pharmacologically-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 three to four 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 having a mechanism of action similar to tricyclic antidepressants, sibutramine has 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 patients with:


 * 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 or any of the inactive ingredients
 * Patients below 18 and above 65 years of age
 * Concomitant treatment with a MAO inhibitor, antidepressant or other centrally active drugs, particularly other anoretics
 * History of peripheral arterial disease
 * Hypertension that is not sufficiently controlled (e.g., > 145/90 mmHg), caution in controlled hypertension
 * Existing pulmonary hypertension
 * Existing damage on heart valves, coronary heart disease, congestive heart failure, serious arrhythmias, previous myocardial infarction
 * A history of coronary artery disease (e.g., angina, history of myocardial infarction), congestive heart failure, tachycardia, peripheral arterial occlusive disease, arrhythmia or cerebrovascular disease (stroke or transient ischemic attack (TIA))
 * 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
A higher number of cardiovascular events has been observed in people taking sibutramine versus control (11.4% vs. 10.0%). In 2010 the FDA noted the concerns that sibutramine increases the risk of heart attacks and strokes in patients with a history of cardiovascular disease.

Frequently encountered side effects are: dry mouth, paradoxically increased appetite, nausea, strange taste in the mouth, 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 regular monitoring needs to be performed.

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 within two weeks of stopping or starting 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 does not affect 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 administered within a weight management program 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."

In a dissenting article, "Sibutramine: gone, but not forgotten" Professor David Haslam (ex-president of the Royal College of General Practitioners and currently chairman of the National Obesity Forum) says that the SCOUT study is flawed as it only covered high risk patients and did not consider obese patients who do not have cardiovascular complications or similar contra-indications.

The FDA is reviewing preliminary data from a recent study suggesting that patients using sibutramine have a higher number of cardiovascular events (heart attack, stroke, resuscitated cardiac arrest, or death) than patients using a placebo. The preliminary data shows that cardiovascular events were reported in 11.4% of patients using sibutramine compared to 10% of patients using a placebo. This difference is higher than expected, suggesting that sibutramine is associated with an increased cardiovascular risk in the study population. The analysis of these data is ongoing and FDA is making no conclusions about the preliminary findings at this time. These findings highlight the importance of avoiding the use of sibutramine in patients with a history of coronary artery disease (heart disease), congestive heart failure (CHF), arrhythmias, or stroke, as recommended in the current sibutramine labeling. On January 21, 2010, the European Medicines Agency recommended suspension of marketing authorizations for Sibutramine following a six-year study which showed an increased risk of non-fatal but serious cardiovascular events in patients with a known or high risk for cardiovascular disease.

In August 2010 the FDA added a new contraindication for patients over 65 years of age due to the fact that clinical studies of sibutramine did not include sufficient numbers of such patients.

Abbot laboratories announced on October 8, 2010 that it is withdrawing sibutramine from the US market under pressure from the FDA, citing concerns over minimal efficacy coupled with increased risk of adverse cardiovascular events.

Counterfeit weight-loss products
On December 22, 2008, the United States Food and Drug Administration issued an alert to consumers naming 27 different products marketed as “dietary supplements” for weight loss, that illegally contain undisclosed amounts of sibutramine. In March 2009, Dieter Müller et al. published a study of sibutramine poisoning cases from similar Chinese "herbal supplements" sold in Europe, containing as much as twice the dosage of the legally licensed drug.

An additional 34 products were recalled by the FDA on April 22, 2009, further underscoring the risks associated with unregulated "herbal supplements" to unsuspecting persons. This concern is especially relevant to those with underlying medical conditions incompatible with undeclared pharmaceutical adulterants. In January 2010, a similar alert was issued for counterfeit versions of the over-the-counter weight loss drug Alli sold over the Internet. Instead of the active ingredient orlistat, the counterfeit drugs contain sibutramine, and at concentrations at least twice the amount recommended for weight loss.

In March 2010 Health Canada advised the public that illegal "Herbal Diet Natural" had been found on the market, containing sibutramine, which is a prescription drug in Canada, without listing sibutramine as an ingredient. In October 2010 FDA notified consumers that "Slimming Beauty Bitter Orange Slimming Capsules contain the active pharmaceutical ingredient sibutramine, a prescription-only drug which is a stimulant. Sibutramine is not listed on the product label."

In October 2010 the MHRA in the UK issued a warning regarding "Payouji tea" and "Pai You Guo Slim Capsules" which were found to contain undeclared quantities of Sibutramine.

On December 30, 2010 the FDA released a warning regarding "Fruta Planta" dietary products, which were found to contain undeclared amounts of Sibutramine. The recall stated that "there is NO SAFE formula on the US market and that all versions of Fruta Planta contain Sibutramine. All versions of the formula are UNSAFE and should not be purchased from any source."

Some illegal weight loss products imported into Ireland have been found to contain sibutramine.

Detection in body fluids
Sibutramine and its two active N-demethylated metabolites may be measured in biofluids by liquid chromatography-mass spectrometry. Plasma levels of these three species are usually in the 1-10 μg/L range in persons undergoing therapy with the drug. The parent compound and norsibutramine are often not detectable in urine, but dinorsibutramine is generally present at concentrations of >200 μg/L.

Synthesis
The four-membered ring is prepared by removal of the benzylic protons of 4-chlorobenzyl cyanide with sodium hydride, followed by reaction with 1,3-dibromopropane. Reaction with isobutylmagnesium bromide, followed by reductive amination via the Leuckart reaction gives an amine. Methylation with formaldehyde in the Eschweiler-Clarke reaction gives the dimethylamino product, sibutramine.


 * Sibutramine Synthesis.png