Glucophage/Glucophage Forte/Glucophage XR Special Precautions

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 diarrhea 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 characterized by acidotic dyspnea, 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 hospitalized (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 CrCl (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: At least annually in patients with normal renal function, at least every 3 to 6 months in patients with CrCl between 45 and 59 mL/min or eGFR between 45 and 59 mL/min/1.73 m² and in elderly subjects, at least every 3 months in patients with CrCl between 30 and 44 mL/min or eGFR between 30 and 44 mL/min/1.73 m². In case CrCl is below 30 mL/min or eGFR is below 30 mL/min/1.73 m² respectively, metformin is contraindicated (see Contraindications).
Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution is needed in situations where renal function may become acutely impaired, for example due to dehydration (severe or prolonged diarrhea 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. 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).
Other precautions: It is recommended that all patients should continue their diet with a regular distribution of carbohydrate intake during the day and that overweight patients continue their energy-restricted diet.
It is recommended that the usual laboratory tests for diabetes monitoring should be performed regularly.
Metformin alone never causes hypoglycemia, although caution is advised when it is used in combination with insulin, sulphonylureas or meglitinides.
Effects on the Ability to Drive and to Use Machines: Metformin monotherapy does not cause hypoglycemia and therefore has no effect on the ability to drive or to use machines. However, it is recommended that patients should be alerted to the risk of hypoglycemia when metformin is used in combination with other antidiabetic agents such as sulphonylureas, insulin or meglitinides.
Glucophage/Glucophage Forte: Metformin may reduce vitamin B12 serum levels. The risk of low vitamin B12 levels increases with increasing metformin dose, treatment duration, and/or in patients with risk factors known to cause vitamin B12 deficiency. In case of suspicion of vitamin B12 deficiency (such as anemia or neuropathy), vitamin B12 serum levels should be monitored. Periodic vitamin B12 monitoring could be necessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should be continued for as long as it is tolerated and not contra-indicated and appropriate corrective treatment for vitamin B12 deficiency provided in line with current clinical guidelines.
Use in Children: Children from 10 years of age and adolescents: The diagnosis of type 2 diabetes mellitus must 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 on these parameters in metformin-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 efficacy and safety in children below 12 did not differ from efficacy and safety in older children, particular caution is recommended when prescribing to children aged between 10 and 12 years.
Glucophage XR: Metformin may reduce vitamin B12 serum levels. The risk of low vitamin B12 levels increases with increasing metformin dose, treatment duration, and/or in patients with risk factors known to cause vitamin B12 deficiency. In case of suspicion of vitamin B12 deficiency (such as anemia or neuropathy), vitamin B12 serum levels should be monitored. Periodic vitamin B12 monitoring could be necessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should be continued for as long as it is tolerated and not contra-indicated and appropriate corrective treatment for vitamin B12 deficiency provided in line with current clinical guidelines. The tablet shells may be present in the feces. It is recommended that patients be advised that this is normal and this is not linked with a decrease in therapeutic activity.