Metformin and metformin-containing medicines

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Use of metformin to treat diabetes now expanded to patients with moderately reduced kidney function

On 13 October 2016, the European Medicines Agency (EMA) concluded that metformin-containing medicines can now be used in patients with moderately reduced kidney function (GFR [glomerular filtration rate] = 30–59 ml/min) for the treatment of type 2 diabetes. The product information for these medicines will be updated to revise the current contraindication and give information about doses, monitoring and precautions in patients with reduced kidney function.

The recommendations were the result of a review by EMA of metformin-containing medicines following concerns that current scientific evidence does not justify a contraindication in patients with moderate reduction of kidney function. The current product information also varies between countries and products in the EU and is no longer consistent with clinical guidelines.

Metformin may increase the risk of a rare but serious complication called lactic acidosis, which occurs when naturally produced lactic acid builds up in the blood faster than it can be removed. Currently, the product information states that metformin must not be used in patients with reduced kidney function because these patients are considered to be at a higher risk of developing lactic acidosis as their kidneys do not remove metformin efficiently enough.

However, after considering the scientific literature, clinical data, epidemiological studies and clinical guidelines from medical bodies, EMA concluded that the large patient population with moderately reduced kidney function can benefit from use of metformin. Clear dosing recommendations and monitoring before and during treatment aim to minimise any possible increased risk in these patients. The contraindication for patients with severely reduced kidney function will remain (GFR less than 30 ml/min).

Companies marketing metformin-containing medicines will be requested to closely monitor and analyse future lactic acidosis cases and report these during upcoming periodic safety reviews in order to follow up on any changes in the frequency of this side effect. The product information for metformin- containing medicines will be updated to reflect the new recommendations and to ensure that the same advice is given to all patients in the EU.

Information for patients
  • Metformin is used on its own or with other medicines, together with diet and exercise, for the treatment of type 2 diabetes.
  • Up to now, metformin medicines were not recommended for patients with moderate to severe reduction of kidney function. This recommendation has now changed to allow their use in patients with moderately reduced kidney function (GFR=30–59 ml/min). The dose of metformin should be adapted depending on the patient’s kidney function. These medicines should still not be used in patients with severely reduced kidney function (GFR less than 30 ml/min).
  • Patients with reduced kidney function may be at higher risk of lactic acidosis, a rare but serious side effect of metformin medicines caused by build-up of lactic acid in the blood. However, for patients with only moderately reduced kidney function any risk can be minimised by careful checking of dose and monitoring, allowing these patients to get the benefits these medicines can provide.
  • Dehydration (significant loss of body fluids) increases the risk of developing lactic acidosis. If you experience severe vomiting, diarrhoea or fever, are exposed to heat, or drink less fluid than normal, you could become dehydrated. In these cases, stop taking metformin for a short time and speak with your doctor for further instruction.
  • If you have any question or concern about your diabetes treatment or your kidney function level, speak with your doctor, nurse or pharmacist.
Information for healthcare professionals
  • The review of metformin-containing medicines concluded that they can now be used in patients with moderately reduced kidney function (GFR=30–59 ml/min). Use in patients with GFR<30 ml/min is still contraindicated. GFR should be assessed before initiation of treatment and at least annually thereafter.
  • Reduced doses should be considered for patients with moderate reduction of kidney function according to dosage recommendations provided in the updated product information. The product information also details risk factors for lactic acidosis which should be reviewed prior to and during treatment.
  • Several fixed-dose combination products containing metformin are available in Europe (see below). If these products are used in patients with reduced kidney function, restrictions and efficacy regarding the other active substance in the combination, the feasibility of dose adjustment and the alternative of using individual tablets should be considered.
  • Some fixed-dose combination products are still not recommended in patients with moderately reduced kidney function because the other active substance in the combination should not be used in these patients. For example, dapagliflozin/metformin (Ebymect, Xigduo) is not recommended in patients with GFR<60 ml/min; canagliflozin/metformin (Vokanamet) and empagliflozin/metformin (Synjardy) are not recommended in patients with GFR<45 ml/min and should not be started in patients with GFR<60 ml/min.
  • These latest recommendations will result in harmonisation of product information about the use of metformin in patients with reduced kidney function and the precautions for lactic acidosis across the EU. 

References

The review looked at data from a large number of studies including:

Ekström, N. et al., ‘Effectiveness and safety of metformin in 51675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register’, BMJ Open, 2012, 2:e001076.

Eppenga, W.L. et al., ‘Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: A population-based cohort study’, Diabetes Care, 2014, Vol. 37 (8), p. 2218.

Inzucchi, S.E. et al., ‘Metformin in patients with type 2 diabetes and kidney disease: a systematic review’, JAMA, 2014, Vol. 312, p. 2668.

Richy, F.F. et al., ‘Incidence of lactic acidosis in patients with type 2 diabetes with and without renal impairment treated with metformin: a retrospective cohort study’, Diabetes Care, 2014, Vol. 37 (8), p. 2291.

Roussel, R. et al., ‘Metformin use and mortality among patients with diabetes and atherothrombosis’, Arch Intern Med, 2010, Vol. 170, p. 1892.

Salpeter, S.R. et al., ‘Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus’, Cochrane Database Syst Rev, 2010, CD00296.

Solini, A. et al., ‘Age, renal dysfunction, cardiovascular disease, and antihyperglycemic treatment in type 2 diabetes mellitus: findings from the Renal Insufficiency and Cardiovascular Events Italian Multicenter Study’, J Am Geriatr Soc, 2013, Vol. 61, p. 1253.

More about the medicine

Metformin is a medicine used on its own or in combination with other medicines for the treatment of type 2 diabetes. Metformin is used together with diet and exercise to improve control of blood glucose (sugar) levels. Medicines containing metformin alone have been authorised nationally in the EU since the 1960s, marketed as Glucophage and other tradenames. The following medicines containing combinations of metformin with other diabetes medicines in the same tablet have been authorised centrally through EMA: pioglitazone/metformin (Competact, Glubrava), dapagliflozin/metformin (Ebymect, Xigduo), sitagliptin/metformin (Efficib, Janumet, Ristfor, Velmetia), linagliptin/metformin (Jentadueto), saxagliptin/metformin (Komboglyze), alogliptin/metformin (Vipdomet), canagliflozin/metformin (Vokanamet), vildagliptin/metformin (Eucreas, Icandra, Zomarist) and empagliflozin/metformin (Synjardy). In addition, the combination glibenclamide/metformin (Glucovance) has been nationally authorised. See further information about the centrally authorised medicines.

More about the procedure

The review of metformin-containing medicines was initiated on 28 January 2016 at the request of the Netherlands, under Article 31 of Directive 2001/83/EC.

The review was carried out by the Committee for Medicinal Products for Human Use (CHMP), responsible for questions concerning medicines for human use, which adopted the Agency’s opinion.

The CHMP opinion was forwarded to the European Commission, which issued a final legally binding decision applicable in all EU Member States on 12/12/2016.

Key facts

Approved nameMetformin and metformin-containing medicines
International non-proprietary name (INN) or common name

metformin

Associated names
Class
Reference numberEMEA/H/A-31/1432
TypeArticle 31 referrals

This type of referral is triggered when the interest of the Community is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines.

StatusEuropean Commission final decision
Opinion date13/10/2016

All documents

Name Language First published Last updated
Metformin Article-31 referral - CHMP assessment report (English only) 2016-12-21  
Metformin Article-31 referral - Changes to product information (English only) 2016-10-14  
Metformin Article-31 referral - Use of metformin to treat diabetes now expanded to patients with moderately reduced kidney function (English only) 2016-10-14 2016-12-21
Metformin Article-31 referral - Review started (English only) 2016-01-29  
Metformin Article-31 referral - Notification (English only) 2016-01-29  
Metformin Article-31 referral - CHMP list of questions (English only) 2016-01-29  
Metformin Article-31 referral - Annex I BG = bălgarski 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I ES = español 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I CS = čeština 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I DA = dansk 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I DE = Deutsch 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I ET = eesti keel 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I EL = elliniká 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I EN = English 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I FR = français 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I IT = italiano 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I LV = latviešu valoda 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I LT = lietuvių kalba 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I HU = magyar 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I MT = Malti 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I NL = Nederlands 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I PL = polski 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I PT = português 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I RO = română 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I SK = slovenčina 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I SL = slovenščina 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I FI = suomi 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I SV = svenska 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I HR = Hrvatski 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I IS = Islenska 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex I NO = Norsk 2016-02-03 2016-12-21
Metformin Article-31 referral - Annex II BG = bălgarski 2016-12-21  
Metformin Article-31 referral - Annex II ES = español 2016-12-21  
Metformin Article-31 referral - Annex II CS = čeština 2016-12-21  
Metformin Article-31 referral - Annex II DA = dansk 2016-12-21  
Metformin Article-31 referral - Annex II DE = Deutsch 2016-12-21  
Metformin Article-31 referral - Annex II ET = eesti keel 2016-12-21  
Metformin Article-31 referral - Annex II EL = elliniká 2016-12-21  
Metformin Article-31 referral - Annex II EN = English 2016-12-21  
Metformin Article-31 referral - Annex II FR = français 2016-12-21  
Metformin Article-31 referral - Annex II IT = italiano 2016-12-21  
Metformin Article-31 referral - Annex II LV = latviešu valoda 2016-12-21  
Metformin Article-31 referral - Annex II LT = lietuvių kalba 2016-12-21  
Metformin Article-31 referral - Annex II HU = magyar 2016-12-21  
Metformin Article-31 referral - Annex II MT = Malti 2016-12-21  
Metformin Article-31 referral - Annex II NL = Nederlands 2016-12-21  
Metformin Article-31 referral - Annex II PL = polski 2016-12-21  
Metformin Article-31 referral - Annex II PT = português 2016-12-21  
Metformin Article-31 referral - Annex II RO = română 2016-12-21  
Metformin Article-31 referral - Annex II SK = slovenčina 2016-12-21  
Metformin Article-31 referral - Annex II SL = slovenščina 2016-12-21  
Metformin Article-31 referral - Annex II FI = suomi 2016-12-21  
Metformin Article-31 referral - Annex II SV = svenska 2016-12-21  
Metformin Article-31 referral - Annex II HR = Hrvatski 2016-12-21  
Metformin Article-31 referral - Annex II IS = Islenska 2016-12-21  
Metformin Article-31 referral - Annex II NO = Norsk 2016-12-21  
Metformin Article-31 referral - Annex III BG = bălgarski 2016-12-21  
Metformin Article-31 referral - Annex III ES = español 2016-12-21  
Metformin Article-31 referral - Annex III CS = čeština 2016-12-21  
Metformin Article-31 referral - Annex III DA = dansk 2016-12-21  
Metformin Article-31 referral - Annex III DE = Deutsch 2016-12-21  
Metformin Article-31 referral - Annex III ET = eesti keel 2016-12-21  
Metformin Article-31 referral - Annex III EL = elliniká 2016-12-21  
Metformin Article-31 referral - Annex III EN = English 2016-12-21  
Metformin Article-31 referral - Annex III FR = français 2016-12-21  
Metformin Article-31 referral - Annex III IT = italiano 2016-12-21  
Metformin Article-31 referral - Annex III LV = latviešu valoda 2016-12-21  
Metformin Article-31 referral - Annex III LT = lietuvių kalba 2016-12-21  
Metformin Article-31 referral - Annex III HU = magyar 2016-12-21  
Metformin Article-31 referral - Annex III MT = Malti 2016-12-21  
Metformin Article-31 referral - Annex III NL = Nederlands 2016-12-21  
Metformin Article-31 referral - Annex III PL = polski 2016-12-21  
Metformin Article-31 referral - Annex III PT = português 2016-12-21  
Metformin Article-31 referral - Annex III RO = română 2016-12-21  
Metformin Article-31 referral - Annex III SK = slovenčina 2016-12-21  
Metformin Article-31 referral - Annex III SL = slovenščina 2016-12-21  
Metformin Article-31 referral - Annex III FI = suomi 2016-12-21  
Metformin Article-31 referral - Annex III SV = svenska 2016-12-21  
Metformin Article-31 referral - Annex III HR = Hrvatski 2016-12-21  
Metformin Article-31 referral - Annex III IS = Islenska 2016-12-21  
Metformin Article-31 referral - Annex III NO = Norsk 2016-12-21  
Metformin Article-31 referral - Timetable for the procedure (English only) 2016-01-29 2016-09-16

Document description

  • Questions and answers (Q&A) - easy-to-understand summary of key issues and Committee conclusions
  • Summary of Opinion - contains the CHMP opinion of the referred medicine(s)
  • List of the medicines affected by the referral (Annex I)
  • Scientific conclusions of the Committee (Annex II)

The following two documents are sometimes available:

  • Changes to the summary of product characteristics, labeling or package leaflet (also known as Annex III) - available when changes have been recommended by the Committee
  • Conditions of the marketing authorisation (also known as Annex IV) - available when the Committee recommends measures to be taken for the marketing authorisation(s) such as safety measures or extra studies

Current status:
European Commission final decision

More information on Metformin and metformin-containing medicines