Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Focus Pharmaceuticals Ltd, Capital House, 85 King William Street, London EC4N 7BL, United Kingdom
Lactic acidosis, a very rare, but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis.
Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with impaired renal failure or acute worsening of renal function. Special caution should be paid to situations where renal function may become impaired, for example in case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), or when initiating antihypertensive therapy or diuretic therapy and when starting therapy with a non-steroidal anti-inflammatory drug (NSAID). In the acute conditions listed, metformin should be temporarily discontinued and contact with a health care professional is recommended.
Other associated risk factors should be considered to avoid lactic acidosis such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia (such as decompensated heart failure, acute myocardial infarction) (see section 4.3).
The risk of lactic acidosis must be considered in the event of non-specific signs such as muscle cramps, digestive disorders as abdominal pain and severe asthenia. Patients should be instructed to notify these signs immediately to their physicians if they occur, notably if patients had a good tolerance to metformin before. Metformin should be discontinued, at least temporarily, until the situation is clarified. Reintroduction of metformin should then be discussed taking into account the benefit/risk ratio in an individual basis as well as renal function.
Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in metformin treated patients. Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see sections 4.3 and 4.5).
Patients and/or care-givers should be informed on the risk of lactic acidosis.
Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH (<7.35), increased plasma lactate levels (>5 mmol/l) and an increased anion gap and lactate/pyruvate ratio. In case of lactic acidosis, the patient should be hospitalised immediately (see section 4.9).
Physicians should alert the patients on the risk and on the symptoms of lactic acidosis.
As metformin is excreted by the kidney, creatinine clearance (this can be estimated from serum creatinine levels by using the Cockcroft-Gault formula) or eGFR should be determined before initiating treatment and regularly thereafter:
Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy, diuretic therapy or when starting therapy with a non-steroidal anti-inflammatory drug (NSAID).
In these cases, it is also recommended to check renal function before initiating treatment with metformin.
Metformin is contraindicated in patients with GFR<30 ml/min and should be temporarily discontinued in the presence of conditions that alter renal function, see section 4.3.
Patients with heart failure are more at risk of hypoxia and renal insufficiency. In patients with stable chronic heart failure, metformin may be used with a regular monitoring of cardiac and renal function.
For patients with acute and unstable heart failure, metformin is contraindicated (see section 4.3).
Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, resulting in metformin accumulation and an increased risk of lactic acidosis. In patients with eGFR >60 ml/min/1.73m² metformin must be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and has not deteriorated further, see section 4.2 and 4.5.
In patients with moderate renal impairment (eGFR between 45 and 60 ml/min/1.73m²), metformin must be discontinued 48 hours before administration of iodinated contrast media and not be reinstituted until at least 48 hours afterwards and only after renal function has been re-evaluated and has not deteriorated further (see section 4.5).
Metformin must be discontinued at the time of surgery under general, spinal or epidural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that renal function has been re-evaluated and found to be stable.
The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with metformin is initiated.
No effect of metformin on growth and puberty has been detected during controlled clinical studies of one year duration, but no long term data on these specific points are available. Therefore, a careful follow-up of the effect of metformin hydrochloride on these parameters, in metformin hydrochloride treated children, especially pre-pubescent children, is recommended.
Only 15 subjects aged between 10 and 12 years were included in the controlled clinical studies conducted in children and adolescents. Although efficacy and safety of metformin in these children did not differ from efficacy and safety in older children and adolescents, particular caution is recommended when prescribing to children aged between 10 and 12 years.
All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.
The usual laboratory tests for diabetes monitoring should be performed regularly.
Metformin hydrochloride alone does not cause hypoglycaemia, but caution is advised when it is used in combination with insulin or other oral antidiabetics (e.g. sulphonylureas or meglitinides).
This product contains:
Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition or hepatic impairment.
Consumption of alcohol or alcohol-containing medicinal products should be avoided.
Intravascular administration of iodinated contrast media may lead to renal failure, resulting in metformin hydrochloride accumulation and a risk of lactic acidosis.
In patients with eGFR >60 ml/min/1.73m², metformin must be discontinued prior to, or at the time of the imaging procedure, and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable, see section 4.2 and 4.4.
In patients with moderate renal impairment (eGFR between 45 and 60 ml/min/1.73m²), metformin must be discontinued 48 hours before administration of iodinated contrast media and not be reinstituted until at least 48 hours afterwards and only after renal function has been re-evaluated and has not deteriorated further.
Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclooxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such products in combination with metformin, close monitoring of renal function is necessary.
Medicinal products with intrinsic hyperglycaemic activity such as glucocorticoids (systemic and local routes) and sympathomimetics:
More frequent blood glucose monitoring may be required, especially at the beginning of treatment. If necessary, adjust the metformin dosage during therapy, with the respective medicinal product, and upon its discontinuation.
Organic cation transporters (OCT)
Metformin is a substrate of both transporters OCT1 and OCT2.
Co-administration of metformin with:
Caution is therefore advised, especially in patients with renal impairment, when these drugs are co-administered with metformin, as metformin plasma concentration may increase. If needed, dose adjustment of metformin may be considered as OCT inhibitors/inducers may alter the efficacy of metformin.
Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with increased risk of congenital abnormalities and perinatal mortality.
A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital abnormalities. Animal studies do not indicate harmful effects with respect to pregnancy, embryonic or foetal development, parturition or post-natal development (see section 5.3).
When the patient plans to become pregnant and during pregnancy, it is recommended that diabetes is not treated with metformin but insulin be used to maintain blood glucose levels as close to normal as possible, to reduce the risk of malformations of the foetus.
Metformin hydrochloride is excreted into human breast milk. No adverse effects were observed in breast-fed new-borns/infants. However, as only limited data are available, breast-feeding is not recommended during metformin treatment. A decision on whether to discontinue breast-feeding should be made, taking into account the benefit of breast-feeding and the potential risk to adverse effects on the child.
Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.
Metformin has no influence on the ability to drive and use machines.
Metformin monotherapy does not cause hypoglycaemia and therefore has no effect on the ability to drive or to use machines.
However, patients should be alerted to the risk of hypoglycaemia when metformin is used in combination with other antidiabetic agents (e.g. sulphonylureas, insulin, meglitinides).
During treatment initiation, the most common adverse reactions are nausea, vomiting, diarrhoea, abdominal pain and loss of appetite which resolve spontaneously in most cases. To prevent them, it is recommended to take metformin in 2 or 3 daily doses and to increase the doses slowly.
Adverse events are which have been associated with Metformin are given below, listed by system organ class and frequency. Undesirable effects are especially likely to occur at treatment onset or at dose increase.
The following adverse reactions may occur under treatment with metformin. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to<1/100), rare (≥1/10000 to<1/1000), very rare (<1/10000), not known (cannot be estimated from the available data).
Very rare: Lactic acidosis (serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis)
Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of metformini.
Common: Taste disturbance
Very common: nausea, vomiting, diarrhoea, abdominal pain and loss of appetiteii
Very rare: liver function test abnormalities or hepatitisiii
Very rare: Skin reactions such as erythema, pruritus, urticaria
i Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia
ii These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that metformin be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.
iii Isolated reports of liver function test abnormalities or hepatitis resolving upon metformin discontinuation
In published and post marketing data and in controlled clinical studies in a limited paediatric population aged 10-16 years treated during 1 year, adverse event reporting was similar in nature and severity to that reported in adults.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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