By 2009, it had become the most popular metformin combination.In 2005, the stock of Avandamet was removed from the market, after inspections showed the factory where it was produced was violating good manufacturing practices. The medication pair continued to be prescribed separately, and Avandamet was again available by the end of that year. A generic formulation of metformin/rosiglitazone from Teva received tentative approval from the FDA and reached the market in early 2012.However, following a meta-analysis in 2007 that linked the medications use to an increased risk of heart attack,  concerns were raised over the safety of medicines containing rosiglitazone. In September 2010, the European Medicines Agency  recommended that the medication be suspended from the European market because the benefits of rosiglitazone no longer outweighed the risks.It was withdrawn from the market in the UK and India in 2010, and in New Zealand and South Africa in 2011. From November 2011 until November 2013 the FDA did not allow rosiglitazone or metformin/rosiglitazone to be sold without a prescription; moreover, makers were required to notify patients of the risks associated with its use, and the drug had to be purchased by mail order through specified pharmacies.In November 2013, the FDA lifted its earlier restrictions on rosiglitazone after reviewing the results of the 2009 RECORD clinical trial (a six-year, open-label randomized control trial), which failed to show elevated risk of heart attack or death associated with the medication.
Metformin is distributed to (and appears to accumulate in) red blood cells, with a much longer elimination half-life: 17.6 hours (reported as ranging from 18.5 to 31.5 hours in a single-dose study of nondiabetics).Some evidence indicates that liver concentrations of metformin in humans may be two to three times higher than plasma concentrations, due to portal vein absorption and first-pass uptake by the liver in oral administration. Chemistry
Metformin hydrochloride (1,1-dimethylbiguanide hydrochloride) is freely soluble in water, slightly soluble in ethanol, but almost insoluble in acetone, ether, or chloroform. The pKa of metformin is 12.4. The usual synthesis of metformin, originally described in 1922, involves the one-pot reaction of dimethylamine hydrochloride and 2-cyanoguanidine over heat. According to the procedure described in the 1975 Aron patent, and the Pharmaceutical Manufacturing Encyclopedia, equimolar amounts of dimethylamine and 2-cyanoguanidine are dissolved in toluene with cooling to make a concentrated solution, and an equimolar amount of hydrogen chloride is slowly added. The mixture begins to boil on its own, and after cooling, metformin hydrochloride precipitates with a 96% yield. Derivatives
A new derivative HL156A, also known as IM156, is potential new drug for medical use. History
The biguanide class of antidiabetic medications, which also includes the withdrawn agents phenformin and buformin, originates from the French lilac or goats rue (Galega officinalis), a plant used in folk medicine for several centuries.