As a result of an earlier EMA review conducted in 2001 the prescribing information for metformin-containing products available in the EU was revised to include a contraindication in all patients with moderate to severe renal impairment, a move which was intended to provide a safety margin to minimise the risk of metformin-associated lactic acidosis.
Data analysed in the 2016 review show that there is no clear relationship between metformin concentration and the occurrence of lactic acidosis. The review authors conclude that metformin has been used regularly in patients with moderate renal impairment at maximum daily doses that were not causing significant metformin or lactate plasma elevations. In addition, recent literature and clinical guidelines in the treatment of type II diabetes recommend the use of metformin in moderate renal impairment.
The data reviewed show a clear relationship between renal function and metformin exposure, leading the authors to recommend a daily dose of 2g/day and 1g/day in patients with moderate renal impairment stages 3a (GFR 45-59ml/min) and 3b (GFR 30-45ml/min), respectively.
The review authors also concluded that the possible elevated risk of lactic acidosis associated with metformin could be sufficiently minimised in patients with a GFR >30ml/min if the following were implemented: a clear dosing recommendation; additional monitoring of GFR levels before and during treatment; and updated warnings in the product literature.
Severe renal impairment
Metformin remains contraindicated in patients with severe renal impairment (GFR <30ml/min) and renal function should be monitored before and at least annually during treatment in all patients. Initiation of drugs that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be undertaken with caution.
Vokanamet (canagliflozin/metformin) and Xigduo (dapagliflozin/metformin) are still not recommended for use in moderate to severe renal impairment (defined as GFR <45ml/min and <60ml/min, respectively).
MIMS entries for metformin-containing products, including Competact (pioglitazone/metformin), Eucreas (vildagliptin/metformin), Glucophage (metformin), Janumet (sitagliptin/metformin), Jentadueto (linagliptin/metformin), Komboglyze (saxagliptin/metformin), Synjardy (empagliflozin/metformin) and Vipdomet (alogliptin/metformin) have been updated to reflect the EMA advice.