(British Approved Name Modified, US Adopted Name, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish):

Hidrocloruro de metformina; LA-6023 (metformin or metformin hydrochloride); Metformiinihydrokloridi; Metformin Hidroklorur; Metformin hydrochlorid; Metformine, chlorhydrate de; Metformin-hidroklorid; Metforminhydroklorid; Metformini hydrochloridum; Metformino hidrochloridas.

C₄H₁₁N₅,HCI = 165,6.

CAS — 657-24-9 (metformin); 1115-70-4 (metformin hydrochloride).

ATC — A10BA02.

Pharmacopoeias. In China, Europe, Japan, and US.

European Pharmacopoeia, 6th ed. (Metformin Hydrochlonde). White or almost white crystals. Freely soluble in water slightly soluble in alcohol practically insoluble in acetone and in dichloromethane.

The United States Pharmacopeia 31, 2008 (Metformin Hydrochloride). A white crystalline powder. Freely soluble in water slightly soluble in alcohol practically insoluble in acetone and in dichloromethane.

Adverse Effects, Treatment, and Precautions

As for biguanides in general.

Breast feeding. Based on animal studies the UK and US licensed product information warns that metformin may be distributed into breast milk, and that the possible effects on the infant should be considered if women wish to breast feed while receiving the drug. However, a study in 7 breast-feeding women receiving metformin at a median dose of 1.5 g daily found the concentrations in milk to be about a third of those in maternal plasma, resulting in a mean calculated dose to the infants of 40 micrograms/kg daily. Blood samples were taken from 4 of the infants: metformin concentrations were undetectable in 2, and were very low (10 to 15% of maternal values) in the others. Given these results the authors considered that women receiving metformin need not be discouraged from breast feeding. Similar results from 3 other studies’ that included 13 women have provided further evidence that metformin is distributed into breast milk, that concentrations in milk are less than those in maternal plasma, and that breast-fed infants would be exposed to a very small percentage of the maternal dose. Six infants were breastfed with no adverse effects that could be attributed to metformin. A prospective study of weight, height, and motor-social development over 6 months, in infants of women taking metformin (1.5 to 2.55 g daily) for poly cystic ovary syndrome, found no difference between 61 infants who were breast-fed and 50 who were formula-fed.

Fasting. For the view that metformin could be used with little risk of hypoglycaemia in fasting Muslim patients during Ramadan, and suggestions for modifying the timing of doses, see under Precautions of Insulin.

Pregnancy. Insulin is generally preferred for treatment of diabetes during pregnancy. However, there are limited data to suggest that metformin does not increase the risk of congenital abnormalities and does not adversely affect pregnancy outcome in diabetic women. A controlled study comparing insulin with metformin in gestational diabetes is underway.The use of metformin to improve ovulation in polycystic ovary syndrome (PCOS) is increasing. There is growing evidence to suggest that metformin used before and during pregnancy in these women does not increase the risk of congenital abnormalities, and may reduce first trimester spontaneous abortion,’which is common in women with PCOS.

Interactions

As for biguanides in general.

Pharmacokinetics

Metformin hydrochloride is slowly and incompletely absorbed from the gastrointestinal tract the absolute bioavailability of a single 500-mg dose is reported to be about 50 to 60%, although this is reduced somewhat if taken with food. Once absorbed, protein binding in plasma is negligible the drug is excreted unchanged in the urine. The plasma elimination half-life is reported to range from about 2 to 6 hours after oral doses. Metformin crosses the placenta and is distributed into breast milk in small amounts.

Uses and Administration

Metformin hydrochloride is a biguanide antidiabetic. It is given orally in the treatment of type 2 diabetes mellitus, and is the drug of first choice in overweight patients. Initial dosage is 500 mg two or three times daily or 850 mg once or twice daily with or after meals, gradually increased if necessary, at intervals of at least 1 week, to 2 to 3 g daily doses of 3 g daily are associated with an increased incidence of gastrointestinal adverse effects. Gastrointestinal effects are also common on beginning therapy, and the BNF recommends starting therapy more gradually with 500 mg at breakfast for at least 1 week, then increasing to 500 mg twice daily for at least 1 week, with further increases as required, up to a usual maximum of 2 g daily in 3 divided doses with meals. A modified-re-lease preparation is also available, which is given in an initial dose of 500 mg once daily and may be increased in increments of 500 mg, at intervals of at least 1 week, to a maximum of 2 g once daily with the evening meal. If glycaemic control is not adequate the dose may be divided to give 1 g twice daily with meals. If doses above 2 g daily are required, they should be given as the standard preparation. For doses used in children and adolescents, see below.

Metformin is also used as the chlorophenoxyacetate and as the embonate.

Action. A review of the action of metformin considered that although a number of possible mechanisms have been suggested, the major action of metformin lay in increasing glucose transport across the cell membrane in skeletal muscle. There is also some evidence in vitro that it can inhibit the formation of advanced glycosylation end-products.

Administration in children. In children aged 10 years and older with type 2 diabetes mellitus, oral metformin hydrochloride may be used in a starting dose of 500 mg or 850 mg once daily, or 500 mg twice daily, given with or after a meal. It may be gradually increased if needed, at intervals of at least 1 week, to a maximum of 2 g daily given in 2 or 3 divided doses. Modified-release preparations are generally not licensed for use in children.

Although rare, the incidence of type 2 diabetes is increasing in children and adolescents, related in part to the increase in obesity occurring particularly in westernised countries. A small placebo-controlled study of patients aged 10 to 17 years with type 2 diabetes found that metformin improved glycaemic control and that adverse effects were similar to those in adults. In obese children and adolescents with hyperinsulinaemia, who are at risk of developing type 2 diabetes, small studies of metformin use have reported improvements in body composition and fasting insulin concentrations. There has also been some interest in the use of metformin as an adjunct to insulin in adolescents with type 1 diabetes improvements in glycaemic control and reductions in insulin doses have been reported.

Diabetes mellitus. Results of the United Kingdom Prospective Diabetes Study (UKPDS) showed that intensive blood glucose control with metformin reduces the risk of diabetic complications and death in overweight patients with type 2 diabetes.The study also generated some concern regarding intensive therapy with metformin plus a sulfonylurea (see under Interactions) but this was not borne out on further analysis and such combinations are widely used. Metformin is also used with the thiazolidinediones, or with insulin in patients requiring combined or more intensive therapy. Metformin has also been investigated for the prevention of type 2 diabetes in patients at high risk. Although metformin treatment for an average 2.8 years reduced the incidence of type 2 diabetes by 31% in a study of patients with impaired glucose tolerance, intensive lifestyle modification was actually more effective (58% reduction). Lifestyle modification was also more effective than metformin in reducing cardiovascular risk factors and the development of the metabolic syndrome. The durability of these effects is unknown but follow-up of this study is ongoing.

There is some interest in using oral hypoglycaemics as adjuncts to insulin therapy in patients with type 1 diabetes. Short-term results from small studies have suggested that metformin may be beneficial, in this context, in adolescents with pubertal insulin resistance (see also Administration in Children, above) and perhaps in adults who are overweight or otherwise at risk of reduced insulin sensitivity.

Polycystic ovary syndrome. It has been suggested that hyper -insulinism may play a pathogenetic role in stimulating the abnormal androgen production from the ovary seen in women with polycystic ovary syndrome (PCOS). Most early studies ofmetformin in PCOS were small, observational, and of short duration, with mixed results. Although there were reports of reduced insulin levels, increased insulin sensitivity, and improved androgen concentrations, other studies failed to confirm these effects. Later randomised studies were also small, but some were of longer duration. These reported weight reductions of obese patients, reductions in insulin levels and increased sensitivity, improved androgen and other hormonal measures, improved menstrual patterns, and reduced hirsutism, but again, not consistently. Metformin has also been reported to increase the rate of spontaneous ovulation, and may improve the outcome of IVF procedures. Combination ofmetformin with clo-mifene appeared to improve ovulatory response, compared with clomifene alone, in studies of women with PCOS, though there is also a report of no apparent benefit. Furthermore, 2 large, placebo-controlled studies have found that metformin, either alone or with clomifene, did not improve the rate of ovulation, pregnancy, or live births in women with polycystic ovary syndrome.

Some consider that current evidence supports a trial ofmetformin in patients with anovulation, androgen excess, and vascular risk factors, but because of the lack of data on long-term safety such use should be supervised by an endocrinologist or a physician with suitable expertise.

Preparations

British Pharmacopoeia 2008: Metformin Tablets

The United States Pharmacopeia 31, 2008: Glipizide and Metformin Hydrochloride Tablets; Glyburide and Metformin Hydrochloride Tablets; Metformin Hydrochloride Extended-Release Tablets; Metformin Hydrochloride Tablets.

Proprietary Preparations

Argentina: Baligluc DBI AP Diab Dos Glucaminol Glucogood Glucophage Islotin Mectin Medobis Metforal Metfori † Oxemet Redugluc

Australia: Diabex Diaformin Glucohexal Glucomet Glucophage Novomet

Austria: Clonarol Desugar Diabetex Glucomin Glucophage Meglucon Orabet †

Belgium: Glucophage Metformax

Brazil: Diaformin Dimefor Formetf Formyn Glicefor Glifage Glucoformin Metfordin † Metformed Teutoformin

Canada: Glucophage Glumetza Glycon †

Chile: Diaglitab Fintaxim Glafornil Glicenex Glidanil Glifortex Glucophage Hipoglucin Menarini-Metforal †

Czech Republic: Adimet Diaphage Glucomerck Glucophage Gluformin Glumetsan Langerin Metfirex Metfogamma Siofor Stadamet

Denmark: Glucophage Orabet

Finland: Diformin Glucophage Metforem Oramet

France: Diabamyl † Glucophage Stagid

Germany: Biocos Diabesin Diabetase † Espaformin † Glucobon Glucophage Juformin Mediabet Meglucon Mescorit Met Metfodoc Metfogamma Metfor † Metform † MetSurrir Siofor Thiabet

Greece: Glucofree Glucophage Metforil Sukontrol

Hong Kong: CP-Metform Diabetmin Diaformin Glucomet Glucophage Glumet Guamet Melbin

Hungary: Adimet Gluformin Maformin † Meforal Meglucon Merckformin Metfogamma Metrivin † Stadamet

India: Bigomet † Emfor Emnorm Exermet Formin † Glumet Glyciphage Glyree M Insumet Metlong Walaphage X-Met

Indonesia: Benofomin Diabex Eraphage Forbetes Formell Gliformin Glucofor Glucophage Glucotika Gludepatic Glufor Glumin Gradiab Methormyl Methpica Metphar Regius Tudiab Zumamet

Ireland: Glucophage

Israel: Apophage Glucomin Glucophage Glufor

Italy: Glucophage Metbay Metfonorm Metforal Metiguanide

Japan: Glycoran Melbin

Malaysia: Diabemet † Diabetmin Glucomet Glucophage Glumet Riomet Xmet

Mexico: Aglumet Anglucid Apozemia Dabex Debeone Dimefor Dinamel Ficonax Forlucyl Glucophage Glunovag Harbamind Ifor Meglubet Melbexa Mifelar Pharmafet Pre-Dial

The Netherlands: Diabex Dianorm † Finormet † Glucophage Glumeff Niformina

Norway: Glucophage

New Zealand: Glucomet Glucophage † Metomin

Philippines: Diafat Diazen Euform Fornidd Glucare Glucoform Glucomed Glucophage Glumet Glyformin Horsulin Humamet L-Max Insunex Neoform Nidcor Sucranorm Vimetrol Xmet

Poland: Glucophage † Gluformin Metfogamma Metformax Metifor Siofor

Portugal: Diabex Glucophage Mekoll Risidon Stagid

Russia: Bagomet Formin Gliformin Glucophage Metfogamma Siofor

South Africa: Glucophage Metforal

Singapore: Diabetmin Diamin † Glucophage Glycomet Glycoran † Metforal

Spain: Dianben

Sweden: Glucophage

Switzerland: Gluconormine Glucophage Metfin

Thailand: Ammiformin Deson Diamet Formin Gluco Glucoles-500 Glucolyte Glucomet † Glucono Glucophage Gluformin Glustress † Glutabloc Gluzolyte Macromin † Maformin ME-F † Meformed Metfor Metfron Miformin Pocophage Poli-Formin Prophage Serformin Siamformet

Turkey: Glifor Glucophage Gluformin Glukofen

UAE: Dialon

UK: Glucophage Metsol

USA: Fortamet Glucophage Glumetza Riomet

Venezuela: Diaformina DimeforF Glafornil Glucaminol Glucofage

Multi-ingredient

Argentina: Avandamet DBI Duo Glucovance Gludex Plus Isloglib Medobis G Metformin Duo Rosiglit-Met

Australia: Avandamet Glucovance

Belgium: Avandamet Glucovance

Brazil: Glucovance Starform

Canada: Avandamet

Chile: Avandamet Bi-Euglucon M Diaglitab Plus Glifortex-G Glimet Glucovance Glukaut Hipoglucin DA

Czech Republic: Avandamet Competact Eucreas Glibomet Glubrava Glucovance

Denmark: Avandamet

Finland: Avandamet

France: Avandamet Competact Eucreas Glucovance

Germany: Avandamet

Greece: Avandamet Normell

Hong Kong: Avandamet Glucovance

Hungary: Avandamet

India: Betaglim M † Diaforte Diaglip M Exermet GM Exermet GZ Exermet P Gliclamet Glimiprex MF Glimulin-MF † Glinil M Glizid-M Glycigon-M Glycinorm M Glygard M Metaglez P-Glitz M Piomed M Piosafe MF Roglin-M Rosicon MF

Indonesia: Avandamet Glucovance

Ireland: Avandamet

Israel: Avandamet

Italy: Avandamet Bi-Euglucon M Glibomet Gliconorm Glicorest Glucomide Pleiamide Suguan M

Malaysia: Avandamet Glucovance

Mexico: Apometglu Avandamet Bi-Dizalon Bi-Euglucon M Bi-Pradia Duo-Anglucid Glimetal Glucotec Glucovance Imalet Insogen Plus Insusym-Forte Maviglin Mellitron Midaphar-ma Mifelar-C Nadib-M Norfaben M Obinese Sibet-C Sil-Norboral Wadil

The Netherlands: Avandamet Glucovance

Norway: Avandamet

Philippines: Avandamet Euglo Plus Glucovance

Poland: Avandamet

Portugal: Avandamet Competact Glucovance

Russia: Glibomet Glucovance

South Africa: Glucovance

Singapore: Avandamet Glucovance

Spain: Avandamet

Sweden: Avandamet

Switzerland: Avandamet Diabiformine Glucovance

Thailand: Avandamet

UK* Avandamet Competact Eucreas

USA: Actoplus Met Avandamet Diofen Glucovance Glybofen Janumet Metaglip

Venezuela: Avandamet Bi-Euglucon Diaformina Plus Glucovance Starform

The symbol † denotes a preparation no longer actively marketed.

Drug trade names: Glucophage XR, Riomet, Fortamet, Glumetza, Obimet, Dianben, Diabex, Diaformin

Metformin is the only biguanide currently approved for the treatment of type 2 diabetes mellitus. It was originally developed in the 1950s in Europe and has been used there for many years. This agent was approved for use in the United States in 1995. While the mechanism of action is not completely clear at the present time, we do know that metformin is not an insulin secretagogue. It is effective in reducing hepatic and renal gluconeogenesis, thereby lowering fasting blood glucose values. Metformin also is effective in reducing postprandial blood glucose by a mechanism that is thought to involve retardation of gastrointestinal absorption. There also are some data that metformin improves peripheral insulin sensitivity by increasing the expression of glucose transporters and by increasing non-oxidative glucose metabolism.

Metformin usually is given initially as one 500-mg tablet once daily with a meal. One week later, the dose should be increased to 500 mg twice daily and can eventually reach a maximum of 2500 mg/day. Most studies show maximum effect with 2000 mg/day, with no additional efficacy at 2500 mg/day. There also are 850-mg tablets, allowing for convenient twice-daily dosing. Most studies analyzing the effects of metformin show that patients will on average lower HgbA₁C by 1.5%-1.9% when it is used as monotherapy.

This agent can be added to a sulfonylurea or insulin therapy (Current Oral Antidiabetic Therapy: A Summary of Oral Therapy), in which case a further decrease in HgbA₁C of 1.5% can be expected. Metformin alone is not associated with hypoglycemia, but this can occur when combined with insulin or sulfonylurea therapy. Metformin has the added benefit of reducing triglycerides and inducing mild weight loss in some overweight patients. The use of metformin to achieve glycemic control was studied in a subset of 342 obese diabetic patients in the United Kingdom Prospective Diabetes Study (UKPDS). Although reduction in myocardial infarction endpoints did not quite reach statistical significance (P<.052) in the insulin- and sulfonylurea-intensively treated groups, the obese diabetic patients treated with metformin had significant reductions in myocardial infarction, nonfatal stroke, and all cause mortality. The increased effect of metformin on prevention of macro vascular disease may be related to its known effects on decreasing low-density lipoprotein and triglyceride levels. More information should be available with the release of the UKPDS results concerning lipid profiles.

The main potential complication of metformin use is the risk of lactic acidosis. Unlike its predecessor phenformin, metformin does not strongly inhibit oxidative metabolism of glucose. Due to the absence of this effect, the risk of lactic acidosis is present, but much lower. The incidence of lactic acidosis is quite rare; however, it is recommended to avoid using metformin in patients who are predisposed to lactic acidosis or cannot metabolize lactate. Therefore, patients with a history of hepatic insufficiency, renal insufficiency, severe cardiac or respiratory disease, chronic metabolic acidosis, or alcohol abuse should not take metformin. It also is recommended that metformin should be stopped at the time of any interventional procedures, particularly surgical procedures or those requiring contrast dye. This will prevent a rise in metformin levels should acute renal failure occur. Metformin also should be used with caution in elderly patients secondary to their diminished renal function.

There are no known drug interactions and the most commonly seen side effect from metformin use is gastrointestinal irritation. Administering the tablet with food and beginning with the 500-mg dose usually prevents or ameliorates this side effect. Less than 5% of individuals will actually require cessation of metformin due to gastrointestinal side effects.