Source: Υπουργείο Υγείας (CY) Revision Year: 2021 Publisher: Laboratori Guidotti S.p.A, Via Livornese 897, La Vettola 56122, PISA, Italy Local Representative, Menarini Hellas S.A., An. Damvergi 7, Athens, Greece, Τel.: 210-8316111
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.
In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), metformin should be temporarily discontinued and contact with a health care professional is recommended.
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 of the risk of lactic acidosis. Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking metformin and seek immediate medical attention. 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.
The risk of lactic acidosis must be considered if non-specific signs such as muscle cramps occur in combination with gastrointestinal symptoms (such as abdominal pain) and severe asthenia.
Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings show decreased blood pH, plasma lactate levels above 5 mmol/l, and an increased anion gap and lactate/pyruvate ratio.
If metabolic acidosis is suspected, metformin hydrochloride should be discontinued and the patient should be hospitalised immediately (see section 4.9).
Physicians should inform patients about the risks and symptoms of lactic acidosis.
GFR should be assessed before treatment initiation and regularly thereafter, see section 4.2, 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.
Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diuretic therapy and when starting therapy with non-steroidal anti-inflammatory drug (NSAIDs).
Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, resulting in metformin accumulation and an increased risk of lactic acidosis. Metformin should 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 sections 4.2 and 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 must be confirmed before treatment with metformin hydrochloride is initiated.
No effect of metformin hydrochloride 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 metformin hydrochloride efficacy and safety 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.
Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases ofFasting, malnutrition orhepatic impairment.
The consumption of alcohol and alcohol-containing medicinal products.should be avoided.
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 sections 4.2 and 4.4.
In subjects with Type 2 diabetes, the concurrent administration of metformin (1,000 mg twice daily) and ranolazine 500 mg and 1,000 mg twice daily has increased the plasmatic exposure of metformin by 1.4 and 1.8 times respectively. A study conducted on seven healthy volunteers demonstrated how cimetidine, administered at a dose of 400 mg twice daily, increased the systemic exposure of metformin (AUC) by 50% and the Cmax by 81%.
Therefore during concomitant administration of metformin and cationic pharmaceutical products eliminated by renal tubular secretion, the blood glucose level must be strictly monitored, the dosage adjusted to within the recommended posology and changes made to the treatment of diabetes.
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 postnatal development.
When the patient plans to become pregnant and during pregnancy, it is recommended that diabetes is not treated with metformin, but insulin should be used to maintain blood glucose levels as close to normal as possible, to reduce the risk of malformations of the foetus.
Metformin is excreted into human breast milk. No adverse effects have been shown in breastfed newborns/infants of treated mothers. However, as only limited data is available, breastfeeding is not recommended during metformin treatment. A decision on whether to discontinue breast-feeding should be made, taken into account the benefit of breast-feeding and the potential risk to adverse effects on the child.
The fertility of male and female rats was not affected by metformin when administered at doses as high as 600 mg/kg/daily, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.
Metformin hydrochloride monotherapy has no effects on the ability to drive and use machines. However, patients should be alerted of the risks of hypoglycaemia when metformin hydrochloride is administered in combination with other anti-diabetic medicinal products (sulphonylureas, insulin or meglitinides).
The following undesirable effects may occur under treatment with metformin.
The prevalence is defined as follows: very common ≥1/10; common >1/100, <1/10; uncommon >1/1,000, <1/100; rare >1/10,000, <1/1,000; very rare <1/10,000; not known (cannot be estimated on the basis of available data).
Common: taste disturbance.
Very common: nausea, vomiting, diarrhoea, abdominal pain and loss of appetite.
These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that metformin hydrochloride is taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.
Very rare: skin reactions such as erythema, pruritus and urticaria.
Very rare: lactic acidosis (see section 4.4), decrease of vitamin B12 absorption with decrease of serum levels during long-term use of metformin hydrochloride. Consideration of such aetiology is recommended if a patient presents megaloblastic anaemia.
Very rare: isolated cases of anomalies have been reported in tests for hepatic function or hepatitis that were resolved by discontinuing treatment with metformin.
In published and post marketing data and in controlled clinical studies in a limited paediatric population aged 10 to 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 the national reporting system listed in Appendix V.*
Not applicable.
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