Sibutramine: Wikis

  
  

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Sibutramine
Systematic (IUPAC) name
(±)-dimethyl-1-[1-(4- chlorophenyl) cyclobutyl]-N,N,3-trimethylbutan- 1-amine
Identifiers
CAS number 106650-56-0
ATC code A08AA10
PubChem 5210
DrugBank APRD00456
ChemSpider 5021
Chemical data
Formula C17H26ClN 
Mol. mass 279.85 g/mol
Pharmacokinetic data
Bioavailability Absorption 77%, considerable first-pass metabolism
Metabolism Hepatic (CYP3A4-mediated)
Half life sibutramine approx. 1 hour
Metabolite 1: 14 hours
Metabolite 2: 16 hours
Excretion Biliary (sibutramine and active metabolites), renal (inactive metabolites)
Therapeutic considerations
Pregnancy cat. C(AU) C(US) No human data exists; inconclusive evidence of teratogenic potential in animal studies
Legal status Schedule IV (US)
Routes Oral
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Sibutramine, usually available as sibutramine hydrochloride monohydrate, is an orally administered agent for the treatment of obesity, as an appetite suppressant. Serious concerns are being expressed about its safety and has been suspended from use in the UK[1] and EU[2].

It is also under review by the FDA and the European Medicines Agency. It is a centrally-acting serotonin-norepinephrine reuptake inhibitor structurally related to amphetamines,[3] although its mechanism of action is distinct.[4]

Sibutramine is manufactured by Abbott Laboratories, under brand names such as Reductil, Meridia and Sibutrex. It is classified as a Schedule IV controlled substance in the United States, despite having virtually no potential for abuse (due to its lack of appreciable dopaminergic effects). It is likely that the compound's use as an anorectic is the sole reason is it classified as a controlled drug, as "overprescription" of anorectics (as a class) in the mid-20th century resulted in a number of cases of abuse or addiction.

Contents

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.[4]

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[5] for the treatment of obesity.

Contraindications

Sibutramine is contraindicated in patients with:

Side effects

A higher number of cardiovascular events has been observed in people taking sibutramine verses control (11.4% vs. 10.0%).[6] 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.[7]

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.[8] 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.[8]

The concomitant use of sibutramine and drugs which inhibit CYP3A4, such as ketoconazole and erythromycin, may increase plasma levels of sibutramine.[9] Sibutramine does not affect the efficacy of hormonal contraception.[8]

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,[10] the FDA made no attempts to withdraw the drug, but was part of a Senate hearing in 2005.[11] 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.[12]

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."[13]

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.[14]

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.[15]

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.[16][17] 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.[18]

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.[19] 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.[20]

References

  1. ^ "Top obesity drug sibutramine being suspended". http://news.bbc.co.uk/1/hi/health/8473555.stm. Retrieved 2010-01-22. 
  2. ^ (German) Sibutramin-Vertrieb in der Europäischen Union ausgesetzt [1]. Abbott Laboratories in Germany. Press Release 2010-01-21. Retrieved 2010-01-27
  3. ^ "New Drugs". Australian Prescriber 25 (1): 22. 2002.  PDF
  4. ^ a b Heal, DJ; Aspley; Prow; Jackson; Martin; Cheetham (1998). "Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine". International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity 22 Suppl 1: S18–28; discussion S29. PMID 9758240.  edit
  5. ^ U.S. Food and Drug Administration (November 24, 1997). "FDA APPROVES SIBUTRAMINE TO TREAT OBESITY". Press release. http://www.fda.gov/bbs/topics/ANSWERS/ANS00835.html. Retrieved 2007-04-29. 
  6. ^ "Early Communication about an Ongoing Safety Review of Meridia (sibutramine hydrochloride)". http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm191650.htm. 
  7. ^ "Meridia (sibutramine hydrochloride): Follow-Up to an Early Communication about an Ongoing Safety Review". http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm198221.htm. 
  8. ^ a b c "Meridia Side Effects, and Drug Interactions". RxList.com. 2007. http://www.rxlist.com/cgi/generic/sibutramine_ad.htm. Retrieved 2007-04-29. 
  9. ^ (Portuguese) Cloridrato de sibutramina monoidratado. Bula. [Sibutramine hydrochloride monohydrate—label information]. Medley (2007).
  10. ^ Wolfe, Sidney M.; Larry D. Sasich, Elizabeth Barbehenn (March 19, 2002). "Petition to FDA to ban the diet drug sibutramine (MERIDIA) (HRG Publication #1613)". Public Citizen. http://www.citizen.org/publications/print_release.cfm?ID=7160. Retrieved 2007-04-29. 
  11. ^ Bruce Japsen (13 March 2005). "FDA weighs decision on Meridia ; Health advisory likely for Abbott obesity drug". Chicago Tribune. Chicago, Illinois. pp. 1. 
  12. ^ Hearing of 17 November 2004. Related CBS news item 19 November 2004.
  13. ^ Torp-Pedersen, C.; Caterson, I.; Coutinho, W.; Finer, N.; Van Gaal, L.; Maggioni, A.; Sharma, A.; Brisco, W. et al. (2007). "Cardiovascular responses to weight management and sibutramine in high-risk subjects: an analysis from the SCOUT trial". European heart journal 28 (23): 2915–2923. doi:10.1093/eurheartj/ehm217. PMID 17595194.  edit
  14. ^ Early Communication about an Ongoing Safety Review of Meridia (sibutramine hydrochloride), [[U.S. Food and Drug Administration], November 20, 2009
  15. ^ Press Release, European Medicines Agency, January 21, 2010
  16. ^ U.S. Food and Drug Administration (22 December 2008). "FDA warns consumers about tainted weight loss pills". Press release. http://www.fda.gov/bbs/topics/NEWS/2008/NEW01933.html. 
  17. ^ "Consumer directed questions and answers about FDA’s initiative against contaminated weight loss products". U.S. Food and Drug Administration Center for Drug Evaluation and Research. 22 December 2008. http://www.fda.gov/cder/consumerinfo/weight_loss_products.htm. 
  18. ^ Müller, D.; Weinmann, W.; Hermanns-Clausen, M. (2009). "Chinese slimming capsules containing sibutramine sold over the Internet: a case series". Deutsches Arzteblatt international 106 (13): 218–222. doi:10.3238/arztebl.2009.0218. PMID 19471631.  edit
  19. ^ WebMD April 22nd 2009 publication of FDA recall information. [2] 22 April 2009.
  20. ^ "Fake Alli diet pills can pose health risks". CNN.com. http://www.cnn.com/2010/HEALTH/01/23/fake.diet.drug/index.html. Retrieved 2010-24-01. 

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