Metformin 253720 224611346 2008-07-09T17:27:00Z Fvasconcellos 1051513 +External links (useful ones, that is ; {{drugbox | | IUPAC_name = ''N'',''N''-dimethylimidodicarbonimidic diamide | image = Metformin.svg | image2 = Metformin3d.png | width2 = 250 | CAS_number = 657-24-9 | ATC_prefix = A10 | ATC_suffix = BA02 | PubChem = 4091 | DrugBank = APRD01099 | C = 4 | H = 11 | N = 5 | molecular_weight = 129.164 g/mol<br>165.63 g/mol ([[hydrochloride]]) | synonyms = 1,1-dimethylbiguanide | bioavailability = 50 to 60% under fasting conditions | metabolism = None | elimination_half-life = 6.2 hours | excretion = Active [[Kidney|renal]] tubular excretion by [[SLC22A2|OCT2]] | licence_US = Metformin | pregnancy_AU = C | pregnancy_US = B | legal_UK = POM | legal_US = Rx-only | routes_of_administration = Oral }} '''Metformin''' ([[International Nonproprietary Name|INN]]; trade names '''Glucophage''', '''Riomet''', '''Fortamet''', '''Glumetza''', '''Obimet''', '''Dianben''', '''Diabex''', '''Diaformin''', and others) ({{IPAEng|mɛtˈfɔrmɪn}}) is an oral [[anti-diabetic drug]] from the [[biguanide]] class. It is the [[first-line treatment|first-line]] drug of choice for the treatment of [[diabetes mellitus type 2|type 2 diabetes]], particularly in [[overweight]] and [[obesity|obese]] people and those with normal kidney function,<ref>Clinical Guidelines Task Force, [[International Diabetes Federation]] (2005). {{PDFlink|[http://www.idf.org/webdata/docs/GGT2D%2009%20Oral%20therapy.pdf "Glucose control: oral therapy"]|100&nbsp;[[Kibibyte|KiB]]<!-- application/pdf, 103348 bytes -->}}. In: ''Global Guideline for Type 2 Diabetes''. [[Brussels]]: International Diabetes Federation, 35–8. Retrieved on [[November 6]], [[2007]].</ref><ref>{{NICE|66|Diabetes - type 2 (update)|2008}}</ref><ref>{{cite journal |author=[[American Diabetes Association]] |title=Standards of medical care in diabetes—2007 |journal=Diabetes Care |volume=30 Suppl 1 |issue= |pages=S4–S41 |year=2007 |pmid=17192377 |doi=10.2337/dc07-S004 | url=http://care.diabetesjournals.org/cgi/content/full/30/suppl_1/S4}}</ref> and evidence suggests it may be the best choice for people with [[heart failure]].<ref name=Eurich>{{cite journal |author=Eurich DT, McAlister FA, Blackburn DF, ''et al.'' |title=Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review |journal=BMJ |volume=335 |issue=7618 |pages=497 |year=2007 |pmid=17761999 |doi=10.1136/bmj.39314.620174.80 | url=http://www.bmj.com/cgi/content/full/335/7618/497}}</ref> Metformin is the most popular anti-diabetic drug in the United States and one of the most prescribed drugs in the country overall, with nearly 35 million prescriptions filled in 2006 for generic metformin alone.<ref>{{PDFlink|[http://www.drugtopics.com/drugtopics/data/articlestandard/drugtopics/092007/407652/article.pdf Top 200 Generic Drugs by Units in 2006]|19.4&nbsp;[[Kibibyte|KiB]]<!-- application/pdf, 19902 bytes -->}}. ''Drug Topics'' (March 5, 2007). Retrieved on [[April 8]], [[2007]].</ref> It is also used in the treatment of [[polycystic ovary syndrome]]. When prescribed appropriately, metformin causes few [[adverse drug reaction|adverse effects]]—the most common is gastrointestinal upset—and, unlike many other anti-diabetic drugs, does not cause [[hypoglycemia]]. It also helps reduce [[low-density lipoprotein|LDL cholesterol]] and [[triglyceride]] levels, and may aid weight loss. [[As of 2008]], metformin is one of only two oral anti-diabetics in the [[World Health Organization Model List of Essential Medicines]] (the other being [[glibenclamide]]).<ref>(March 2007) {{PDFlink|[http://www.who.int/medicines/publications/EML15.pdf ''WHO Model List of Essential Medicines'']|612&nbsp;[[Kibibyte|KiB]]<!-- application/pdf, 626969 bytes -->}}, 15<sup>th</sup> edition, [[World Health Organization]], p. 21. Retrieved on [[2007-11-19]].</ref> == History == The [[biguanide]] class of anti-diabetic drugs, which also includes the withdrawn agents [[phenformin]] and [[buformin]], originates from the [[Galega officinalis|French lilac]] (''Galega officinalis''), a plant known for several centuries to reduce the symptoms of [[diabetes mellitus]].<ref name = Witters>{{cite journal | author = Witters L | title = The blooming of the French lilac | journal = J Clin Invest | volume = 108 | issue = 8 | pages = 1105–7 | year = 2001 | pmid = 11602616 | doi = 10.1172/JCI14178}} {{PMC|209536}}</ref> Metformin was first described in the scientific literature in 1957.<ref name = Ungar>{{cite journal | author = Ungar G, Freedman L, Shapiro S | title = Pharmacological studies of a new oral hypoglycemic drug | journal = Proc Soc Exp Biol Med | volume = 95 | issue = 1 | pages = 190–2 | year = 1957 | pmid = 13432032}}</ref> It was first marketed in France in 1979, but did not receive approval by the U.S. [[Food and Drug Administration]] (FDA) for Type 2 diabetes until 1994.<ref name = FDAapproval>{{cite press release | author = Susan M. Cruzan | title = FDA Approves New Diabetes Drug | date = December 30, 1994 | publisher = U.S. [[Food and Drug Administration]] | accessdate = 2007-01-06 | url = http://www.fda.gov/bbs/topics/ANSWERS/ANS00627.html}}</ref> [[Bristol-Myers Squibb]]'s Glucophage was the first branded formulation of metformin to be marketed in the United States, beginning on [[March 3]], [[1995]].<ref>GLUCOPHAGE Label and Approval History. U.S. [[Food and Drug Administration]]. Retrieved on [[2007-01-08]]. Data available for download on [http://www.fda.gov/cder/drugsatfda/datafiles/default.htm FDA website].</ref> [[generic drug|Generic]] formulations are now available. ==Indications== The main use for metformin is in the treatment of [[diabetes mellitus type 2]], especially when this accompanies [[obesity]] and [[insulin resistance]]. Metformin is the only anti-diabetic drug that has been proven to reduce the cardiovascular complications of diabetes, as shown in a large study of overweight patients with diabetes.<ref name = UKPDS>{{cite journal | author = | title = Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group | journal = Lancet | volume = 352 | issue = 9131 | pages = 854–65 | year = 1998 | pmid=9742977| doi = 10.1016/S0140-6736(98)07037-8}}</ref> Unlike the other most-commonly prescribed class of oral diabetes drugs, the [[sulfonylurea]]s, metformin (taken alone) does not induce [[hypoglycemia]].<ref>{{cite journal | author = Kilo C, Mezitis N, Jain R, Mersey J, McGill J, Raskin P | title = Starting patients with type 2 diabetes on insulin therapy using once-daily injections of biphasic insulin aspart 70/30, biphasic human insulin 70/30, or NPH insulin in combination with metformin | journal = J Diabetes Complications | volume = 17 | issue = 6 | pages = 307–13 | year = 2003| pmid=14583174 | doi = 10.1016/S1056-8727(03)00076-X}}</ref> Hypoglycemia during intense exercise has been documented, but is extremely rare.<ref name="isbn0071416137 ">{{cite book |author= DiPiro, Joseph T.; Talbert, Robert L.; Yee, Gary C.; Matzke, Gary R.; Wells, Barbara G.; Posey, L. Michael|title=Pharmacotherapy: a pathophysiologic approach |publisher=McGraw-Hill |location=New York |year=2005 |pages= |isbn=0071416137 |oclc= |doi=}}</ref> It also does not cause weight gain, and may indeed produce minor weight loss.<ref>{{cite journal |author=Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE |title=Metabolic effects of metformin in non-insulin-dependent diabetes mellitus |journal=N Engl J Med |volume=333 |issue=9 |pages=550–4 |year=1995 |pmid=7623903|doi=10.1056/NEJM199508313330903 | url=http://content.nejm.org/cgi/content/abstract/333/9/550}}</ref> Metformin also modestly reduces [[low density lipoprotein|LDL]] and [[triglyceride]] levels.<ref name=Bolen/> It is also being used increasingly in [[polycystic ovary syndrome]] (PCOS),<ref name=Lord>{{cite journal | author = Lord JM, Flight IHK, Norman RJ | title = Metformin in polycystic ovary syndrome: systematic review and meta-analysis | journal = BMJ | year = 2003 | volume = 327 | issue = 7421 | pages = 951–3 | pmid=14576245 |url=http://www.bmj.com/cgi/content/full/327/7421/951 | doi = 10.1136/bmj.327.7421.951}}</ref> [[non-alcoholic fatty liver disease]] (NAFLD)<ref name=Marchesini>{{cite journal | author = Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N | title = Metformin in non-alcoholic steatohepatitis | journal = [[The Lancet|Lancet]] | year = 2001 | volume = 358 | issue = 9285 | pages = 893–4 | pmid=11567710 | doi = 10.1016/S0140-6736(01)06042-1}}</ref> and premature puberty,<ref>{{cite journal |author=Ibáñez L, Ong K, Valls C, Marcos MV, Dunger DB, de Zegher F |title=Metformin treatment to prevent early puberty in girls with precocious pubarche |journal=J. Clin. Endocrinol. Metab. |volume=91 |issue=8 |pages=2888–91 |year=2006 |pmid=16684823 |doi=10.1210/jc.2006-0336}}</ref> three other diseases that feature [[insulin resistance]]; these indications are [[as of 2007|still]] considered experimental. Although metformin is [[Off-label use|not licensed]] for use in PCOS, the United Kingdom's [[National Institute for Health and Clinical Excellence]] recommends that women with PCOS and a [[body mass index]] above 25 be given metformin when other therapy has failed to produce results.<ref name="NICE2004">{{NICE | 11 | Fertility: assessment and treatment for people with fertility problems | 2004}}</ref> The benefit of metformin in NAFLD has not been extensively studied and may be only temporary.<ref name=Nair>{{cite journal | author = Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP | title = Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial | journal = Aliment Pharmacol Ther | year =2004 | volume = 20 | issue = 1 | pages = 23–28 | pmid = 15225167 | doi = 10.1111/j.1365-2036.2004.02025.x}}</ref> It may reduce weight gain in patients taking [[atypical antipsychotic]]s.<ref name="pmid18182600">{{cite journal |author=Wu RR, Zhao JP, Jin H, ''et al'' |title=Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial |journal=JAMA |volume=299 |issue=2 |pages=185–93 |year=2008 |pmid=18182600 |doi=10.1001/jama.2007.56-b}}</ref> == Mechanism of action == The exact [[mechanism of action]] of metformin is uncertain, despite its known therapeutic benefits. It appears to act mainly by reducing hepatic [[gluconeogenesis]], but it also decreases absorption of glucose from the [[gastrointestinal tract]] and increases insulin sensitivity by increasing peripheral utilization of glucose.<ref>{{cite book| author=[[Royal Pharmaceutical Society of Great Britain]] and the [[British Medical Association]] |title=[[British National Formulary]] |chapter=Chapter 6:Endocrine system -- 6.1.2.2 Biguanides |chapterurl=http://bnf.org/bnf/bnf/54/4185.htm |edition=54}}</ref> Evidence suggests that increased peripheral utilization of glucose may be due to improved insulin binding to insulin receptors since metformin is not effective in patients who no longer have any residual insulin production.<ref>{{cite journal | author = Bailey CJ, Turner RC | title = Metformin | journal = N Engl J Med | volume = 334 | issue = 9 | pages = 574–9 | year = 1996 | pmid = 8569826 | doi = 10.1056/NEJM199602293340906}}</ref> The 'average' person with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one third.<ref name = Hundal>{{cite journal | author = Hundal R, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi S, Schumann W, Petersen K, Landau B, Shulman G | title = Mechanism by which metformin reduces glucose production in type 2 diabetes | journal = Diabetes | volume = 49 | issue = 12 | pages = 2063–9 | year = 2000 | pmid = 11118008 | doi = 10.2337/diabetes.49.12.2063 | url=http://diabetes.diabetesjournals.org/cgi/reprint/49/12/2063 | format=PDF}}</ref> A 2001 study showed that metformin stimulates the hepatic enzyme [[AMP-activated protein kinase]] (AMPK), which plays an important role in the metabolism of [[lipid|fat]]s and glucose.<ref name = Zhou>{{cite journal | author = Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman M, Goodyear L, Moller D | title = Role of AMP-activated protein kinase in mechanism of metformin action | journal = J Clin Invest | volume = 108 | issue = 8 | pages = 1167–74 | year = 2001 | pmid = 11602624 |url=http://www.jci.org/cgi/content/full/108/8/1167#SEC4 | doi = 10.1172/JCI13505}}</ref> The molecular targets with which metformin directly interacts remain elusive. Metformin is not metabolized, rather it is primarily excreted in the urine with an elimination half-life of 6.2 hours.<ref name = Heller>{{cite journal | author = Heller, Jacqueline B. | title = Metformin overdose in dogs and cats | journal = Veterinary Medicine | issue = April | year = 2007 | pages = 231–233 | url=http://www.aspca.org/site/DocServer/vetm0407_231-234.pdf?docID=11061 }}</ref> == Adverse effects == ===Lactic acidosis=== The most serious potential [[adverse drug reaction|side effect]] of metformin is [[lactic acidosis]]; this complication is very rare, and seems limited to those with impaired liver or kidney function. [[Phenformin]], another biguanide, was withdrawn because of an increased risk of [[lactic acidosis]] (up to 60 cases per [[million]] patient-years). However, metformin is safer than phenformin, and the risk of developing lactic acidosis is not increased by the medication so long as it is not prescribed to known high-risk groups.<ref name = Salpeter>{{cite journal | author = Salpeter S, Greyber E, Pasternak G, Salpeter E | title = Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-analysis | journal = [[Archives of Internal Medicine|Arch Intern Med]] | volume = 163 | issue = 21 | pages = 2594–602 | year = 2003 | pmid = 14638559 | doi = 10.1001/archinte.163.21.2594}}</ref> ===Gastrointestinal=== The most common adverse effect of metformin is gastrointestinal upset, including [[diarrhea]], cramps, nausea and vomiting; metformin is more commonly associated with gastrointestinal side effects than most other anti-diabetic drugs.<ref name=Bolen>{{cite journal |author=Bolen S, Feldman L, Vassy J, ''et al'' |title=Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus |journal=Ann Intern Med |volume=147 |issue=6 |pages=386–99 |year=2007 |pmid=17638715 |doi=}}</ref> In a clinical trial of 286 subjects, 53.2% of the 141 who were given immediate-release metformin (as opposed to [[placebo]]) reported diarrhea, versus 11.7% for placebo, and 25.5% reported nausea/vomiting, versus 8.3% for those on placebo.<ref name = DF&C>{{cite book |title= Drug Facts and Comparisons 2005 |year= 2004 |month= October |publisher= [[Lippincott Williams & Wilkins]] |edition= 59th edition |id= ISBN 1-57439-193-3}}</ref> Gastrointestinal upset can cause severe discomfort for patients; it is most common when metformin is first administered, or when the dose is increased. The discomfort can often be avoided by beginning at a low dose (1 to 1.7 grams per day) and increasing the dose gradually. Gastrointestinal upset after prolonged, steady use is less common. Long-term use of metformin has been associated with increased [[homocysteine]] levels<ref name=Wulffele>{{cite journal | journal= J Intern Med | year= 2003|month= Nov | title = Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial | author = Wulffele MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B, Donker AJ, Stehouwer CD. | volume= 254 | issue =5 |pages= 455–63| pmid = 14535967 | doi= 10.1046/j.1365-2796.2003.01213.x}}</ref> and [[malabsorption]] of [[cyanocobalamin|vitamin B<sub>12</sub>]].<ref name = Andres>{{cite journal | author = Andrès E, Noel E, Goichot B | title = Metformin-associated vitamin B12 deficiency | journal = Arch Intern Med | volume = 162 | issue = 19 | pages = 2251–2 | year = 2002 | pmid = 12390080 | doi = 10.1001/archinte.162.19.2251-a}}</ref><ref name = Gilligan>{{cite journal | author = Gilligan M | title = Metformin and vitamin B12 deficiency | journal = Arch Intern Med | volume = 162 | issue = 4 | pages = 484–5 | year = 2002 | pmid = 11863489 | doi = 10.1001/archinte.162.4.484}}</ref> Higher doses and prolonged use are associated with increased incidence of B<sub>12</sub> deficiency, and some researchers recommend screening or prevention strategies.<ref>{{cite journal | author = Ting R, Szeto C, Chan M, Ma K, Chow K | title = Risk factors of vitamin B(12) deficiency in patients receiving metformin | journal = Arch Intern Med | volume = 166 | issue = 18 | pages = 1975–9 | year = 2006 | pmid = 17030830 | doi = 10.1001/archinte.166.18.1975}}</ref> ===Hormonal=== There is an initial report, involving four patients with impaired thyroid function, that metformin can suppress the [[Thyroid-stimulating hormone|TSH]] level with no accompanying symptoms of hyperthyroidism or changes in measured [[Thyroxine|thyroid hormone]] levels. The mechanism is currently unknown.<ref name="pmid16219720">{{cite journal |author=Vigersky RA, Filmore-Nassar A, Glass AR |title=Thyrotropin suppression by metformin |journal=J Clin Endocrinol Metab |volume=91 |issue=1 |pages=225–7 |year=2006 |pmid=16219720 |doi=10.1210/jc.2005-1210}}</ref> ==Interactions== The [[H2 antagonist|H<sub>2</sub>-receptor antagonist]] [[cimetidine]] causes an increase in the plasma concentration of metformin, by reducing [[clearance (medicine)|clearance]] of metformin by the kidneys;<ref>{{cite journal |author=Somogyi A, Stockley C, Keal J, Rolan P, Bochner F |title=Reduction of metformin renal tubular secretion by cimetidine in man |journal=Br J Clin Pharmacol |volume=23 |issue=5 |pages=545–51 |year=1987 |pmid=3593625 |doi=}}</ref> both metformin and cimetidine are cleared from the body by [[Renal physiology#Secretion|tubular secretion]], and both, particularly the [[cation]]ic (positively [[electric charge|charged]]) form of cimetidine, may compete for the same transport mechanism.<ref name=RxList>{{cite web | url = http://www.rxlist.com/cgi/generic/metformi_ad.htm | title = Glucophage Side Effects & Drug Interactions | year = 2007 | accessdate = 2007-11-19 | publisher = RxList.com}}</ref> A small [[blind experiment|double-blind]], [[randomized controlled trial|randomized]] study found the [[antibiotic]] [[cefalexin]] to also increase metformin concentrations by a similar mechanism;<ref>{{cite journal |author=Jayasagar G, Krishna Kumar M, Chandrasekhar K, Madhusudan Rao C, Madhusudan Rao Y |title=Effect of cephalexin on the pharmacokinetics of metformin in healthy human volunteers |journal=Drug Metabol Drug Interact |volume=19 |issue=1 |pages=41–8 |year=2002 |pmid=12222753 |doi=}}</ref> theoretically, other cationic medications may produce the same effect.<ref name=RxList/> ==Contraindications== Metformin is [[contraindication|contraindicated]] in people with any condition that could increase the risk of [[lactic acidosis]], including [[kidney]] disorders ([[creatinine]] levels over 150 μmol/l,<ref name="Jones2003">{{cite journal | author = Jones G, Macklin J, Alexander W | title = Contraindications to the use of metformin | journal = BMJ | volume = 326 | issue = 7379 | pages = 4–5 | year = 2003 | pmid = 12511434 | doi = 10.1136/bmj.326.7379.4 | url=http://www.bmj.com/cgi/content/full/326/7379/4}}</ref> although this is an arbitrary limit), [[lung disease]] and [[liver disease]]. [[Heart failure]] has long been considered a contraindication for metformin use, although a 2007 [[systematic review]] showed metformin to be the only anti-diabetic drug ''not'' associated with harm in people with heart failure.<ref name=Eurich/> It is recommended that metformin be temporarily discontinued before any [[medical imaging|radiographic study]] involving [[iodine|iodinated]] [[radiocontrast|contrast]] (such as a contrast-enhanced [[computed tomography|CT scan]] or [[angiogram]]), as contrast dye may temporarily impair kidney function, indirectly leading to lactic acidosis by causing retention of metformin in the body.<!--really the main mechanism?--><ref name="RCR">Weir J ([[March 19]], [[1999]]). [http://web.archive.org/web/20040104141219/http://www.rcr.ac.uk/pubtop.asp?PublicationID=70 Guidelines with Regard to Metformin-Induced Lactic Acidosis and X-ray Contrast Medium Agents]. [[Royal College of Radiologists]]. Retrieved on [[2007-10-26]] through the [[Internet Archive]].</ref><ref name="ESUR">{{cite journal |author=Thomsen HS, Morcos SK |title=Contrast media and the kidney: European Society of Urogenital Radiology (ESUR) guidelines |journal=Br J Radiol |volume=76 |issue=908 |pages=513–8 |year=2003 |pmid=12893691 |url= http://bjr.birjournals.org/cgi/content/full/76/908/513 |doi=10.1259/bjr/26964464}}</ref> It is recommended that metformin be resumed after two days, assuming kidney function is normal.<ref name="RCR"/><ref name="ESUR"/> == Overdosage == A review of intentional and accidental metformin overdoses reported to [[Poison control center]]s over a 5-year period found that serious adverse events were rare, though elderly patients appeared to be at greater risk.<ref>{{cite journal |author=Spiller HA, Quadrani DA |title=Toxic effects from metformin exposure |journal=The Annals of pharmacotherapy |volume=38 |issue=5 |pages=776–80 |year=2004 |pmid=15031415 |doi=10.1345/aph.1D468}}</ref> Intentional overdoses with up to 63 g of metformin have been reported in the medical literature.<ref name="63g">{{cite journal |author=Gjedde S, Christiansen A, Pedersen SB, Rungby J |title=Survival following a metformin overdose of 63 g: a case report |journal=Pharmacol. Toxicol. |volume=93 |issue=2 |pages=98–9 |year=2003 |pmid=12899672|doi=10.1034/j.1600-0773.2003.930207.x}}</ref> The major potentially life-threatening complication of metformin overdose is [[lactic acidosis]]. Treatment of metformin overdose is generally supportive, but may include [[sodium bicarbonate]] to address acidosis and [[hemodialysis|standard hemodialysis]] or [[hemofiltration|continuous veno-venous hemofiltration]] to rapidly remove metformin and correct acidosis.<ref name="cvvh">{{cite journal |author=Harvey B, Hickman C, Hinson G, Ralph T, Mayer A |title=Severe lactic acidosis complicating metformin overdose successfully treated with high-volume venovenous hemofiltration and aggressive alkalinization |journal=Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies |volume=6 |issue=5 |pages=598–601 |year=2005 |pmid=16148825 |doi=}}</ref><ref name="hd">{{cite journal |author=Guo PY, Storsley LJ, Finkle SN |title=Severe lactic acidosis treated with prolonged hemodialysis: recovery after massive overdoses of metformin |journal=Seminars in dialysis |volume=19 |issue=1 |pages=80–3 |year=2006 |pmid=16423187 |doi=10.1111/j.1525-139X.2006.00123.x}}</ref> ==Formulations== [[Image:Metformin 500mg Tablets.jpg|200px|thumb|Metformin 500&nbsp;mg tablets]] Metformin IR (immediate release) is available in 500 mg, 850 mg, and 1000 mg tablets, all now generic in the US. Metformin SR (slow release) or XR (extended release) was introduced in 2004, in 500&nbsp;mg and 750&nbsp;mg strengths, mainly to counteract the most common gastrointestinal side effects, as well as to increase patient compliance by reducing [[pill burden]]. No difference in effectiveness exists between the two preparations. ===Combinations=== Metformin is often prescribed to [[Diabetes mellitus type 2|type 2]] diabetes patients in combination with [[rosiglitazone]]. This drug actively reduces insulin resistance, complementing the action of the metformin. In 2002, the two drugs were combined into a single product, '''Avandamet''', marketed by [[GlaxoSmithKline]].<ref>{{cite press release | title = FDA Approves GlaxoSmithKline's Avandamet (rosiglitazone maleate and metformin HCl), The Latest Advancement in the Treatment of Type 2 Diabetes | publisher = [[GlaxoSmithKline]] | date = October 12, 2002 | accessdate = 2006-12-27 | url = http://www.docguide.com/news/content.nsf/news/8525697700573E1885256C4F0075B2B3}}</ref> In 2005, all current stock of Avandamet was seized by the FDA and removed from the market, after inspections showed the factory where it was produced was violating [[Good Manufacturing Practice]]s.<ref>{{cite press release | title = Questions and Answers about the Seizure of Paxil CR and Avandamet | publisher = U.S. [[Food and Drug Administration]] | date = March 4, 2005 | accessdate = 2006-12-27 | url = http://www.fda.gov/oc/qanda/PaxilandAvandamet.html}}</ref> The drug pair continued to be prescribed separately in the absence of Avandamet, which was available again by the end of that year. In the United States, metformin is also available in combination with [[pioglitazone]] (trade name '''Actoplus Met'''), the [[sulfonylurea]]s [[glipizide]] (trade name '''Metaglip''') and [[glibenclamide]] (trade name '''Glucovance'''), the [[dipeptidyl peptidase-4 inhibitors|dipeptidyl peptidase-4 inhibitor]] [[sitagliptin]] (trade name '''Janumet'''), and the [[meglitinide]] [[repaglinide]] ('''PrandiMet'''). Generic formulations of metformin/glipizide, metformin/glibenclamide, and metformin/rosiglitazone are available. ==References== {{Reflist|2}} ==External links== *{{dmoz|Health/Pharmacy/Drugs_and_Medications/M|Metformin}} *[http://www.merck.com/mmpe/lexicomp/metformin.html Metformin drug information] from Lexi-Comp. Includes dosage information and a comprehensive list of international brand names {{-}} {{Oral hypoglycemics}} [[Category:Anti-diabetic drugs]] [[Category:Guanidines]] [[Category:World Health Organization essential medicines]] [[de:Metformin]] [[fr:Metformine]] [[it:Metformina]] [[hu:Metformin]] [[nl:Metformine]] [[pl:Metformina]] [[pt:Metformina]] [[sq:Metformin]]