Lactic Acidosis: Lactic acidosis is a very rare, but serious (high mortality in the absence of prompt treatment), metabolic complication. Risk factors include poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, severe infection, hepatic insufficiency, and any condition associated with hypoxia (such as decompensated cardiac failure, acute myocardial infarction) or the concomitant use of medications which might cause lactic acidosis (such as NRTIs), (see also Contraindications).
Lactic acidosis can occur due to Metformin accumulation. Reported cases of lactic acidosis in patients treated with Metformin have occurred primarily in diabetic patients with acute renal failure or acute worsening of renal function.
Special caution should therefore be paid to situations where renal function may become acutely impaired (see also Contraindications), for example in case of dehydration (severe or prolonged diarrhoea or vomiting) or when initiating drugs which can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs).
In the acute conditions listed, Metformin must be immediately and temporarily discontinued.
The following non-specific symptoms could be signs of lactic acidosis: such as muscle cramps, digestive disorders as abdominal pain and severe asthenia.
Diagnosis: Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain, and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH (below 7.35), plasma lactate levels above 5 mmol/L, and an increased anion gap and lactate/pyruvate ratio. In case of lactic acidosis, the patient should be immediately hospitalised (see also Overdosage).
Physicians must alert the patients on the risk and on the symptoms of lactic acidosis.
Patients should be instructed to immediately seek medical attention and to stop taking Metformin. Metformin must be immediately discontinued, at least temporarily, until the situation is clarified. Reintroduction of Metformin should then be discussed taking into account the benefit/risk ratio on an individual basis as well as renal function.
Renal Function: As Metformin is excreted by the kidney, it is recommended that creatinine clearance or GFR be determined before initiating treatment and regularly thereafter: at least annually in patients with normal renal function,
at least two to four times a year in patients with creatinine clearance or GFR at the lower limit of normal or between 45 and 59 mL/min and in elderly subjects.
at least four times a year in patients with creatinine clearance or GFR between 30 and 44 mL/min. In case creatinine clearance or GFR is <45 mL/min, it is not recommended to initiate Metformin.
In case creatinine clearance or GFR is <30 mL/min, Metformin is contraindicated (see Contraindications). Special caution should be exercised in situations where renal function may become impaired, for example in the elderly, in case of dehydration, or when initiating antihypertensive therapy or diuretic therapy and 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.
Cardiac Function: 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 Contraindications).
Administration of Iodinated Contrast Materials: The intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure. This may induce Metformin accumulation and may expose to lactic acidosis. Therefore, depending on the renal function, Metformin must be discontinued 48 hours before the test or from the time of the test and may not be reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see Interactions).
Surgery: Metformin must be discontinued 48 hours before elective major surgery. Therapy may be restarted no earlier than 48 hours following surgery and only after renal function has been re-evaluated and found to be normal.
Other Precautions: 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 alone does not cause hypoglycaemia, but caution is advised when it is used in combination with Insulin or other oral antidiabetics (e.g. Sulfonylureas or Meglitinides).
The tablet shells may be present in the feces. It is recommended that patients be advised that this is normal.
Effects on 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. Sulfonylureas, Insulin, or Meglitinides).