Regulatory approval, 1997–2010
Sibutramine was originally developed in 1988 by Boots in Nottingham, UK,[2] and marketed by Knoll Pharmaceuticals after BASF/Knoll AG purchased the Boots Research Division in 1995.
In 1997, the Food and Drug Administration (FDA) approved sibutramine for weight loss and maintenance of weight loss in people with a BMI greater than or equal to 30 kg/m2 or for people with a BMI greater than or equal to 27 kg/m2 who have other cardiovascular risk factors in the United States, where it was additionally classified as a Schedule IV controlled substance.[33] It was manufactured and marketed by Abbott Laboratories,[34] and was sold under a variety of brand names including Reductil, Meridia, Siredia, and Sibutrex.
In 2002, studies looked into reports of sudden death, heart failure, renal failure and gastrointestinal problems. Despite a 2002 petition by Ralph Nader-founded NGO Public Citizen,[35] the FDA made no attempts to withdraw the drug, but was part of a Senate hearing in 2005.[36] Similarly, in 2004, David Graham, FDA "whistleblower", testified before a Senate Finance Committee hearing that sibutramine may be more dangerous than the conditions it is used for.[37]
Between January 2003 and November 2005, a large randomized-controlled "Sibutramine Cardiovascular OUTcomes" (SCOUT) study with 10,742 patients 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 use of silbutramine had a RR 1.16 for the primary outcome (composit of nonfatal MI, nonfatal CVA, cardiac arrest, and CV death).[38]
In April 2010 David Haslam, chairman of the National Obesity Forum), argued that the SCOUT study was flawed as it only covered high-risk patients and did not consider obese patients who did not have cardiovascular complications or similar contraindications.[39]
On January 21, 2010, the European Medicines Agency recommended suspension of marketing authorizations for sibutramine based on the SCOUT study results.[40]
In August 2010 the FDA added a new contraindication for patients over 65 years of age because clinical studies of sibutramine did not include sufficient numbers of such patients.[17]
On October 8, 2010, the FDA recommended against continued prescribing because of unnecessary cardiovascular risks to patients, asking Abbott Laboratories to voluntarily withdraw.[34] Abbott announced the same day that it was withdrawing sibutramine from the US market, citing concerns over minimal efficacy coupled with increased risk of adverse cardiovascular events.[41] As a result of this withdrawal, Japanese pharmaceutical company Eisai discontinued development of a version of the drug along with rescinding its filed Marketing Authorisation Application.[42]
Counterfeit weight-loss products, 2008–present
On December 22, 2008, the FDA issued an alert to consumers naming 27 different products marketed as "dietary supplements" for weight loss, that illegally contain undisclosed amounts of sibutramine.[43][44] 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.[45]
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.[46] 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.[47]
