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Lactic acidosis: 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.
Diagnosis: 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.
Hypoglycaemia: As it contains a sulphonylurea, Glucovance exposes the patient to a risk of onset of hypoglycaemic episodes. After treatment initiation, a progressive dose titration may prevent the onset of hypoglycaemia. This treatment should only be prescribed if the patient adheres to a regular meal schedule (including breakfast). It is important that carbohydrate intake is regular since the risk of hypoglycaemia is increased by a late meal, insufficient or unbalanced carbohydrate intakes. Hypoglycaemia is more likely to occur in case of energy-restricted diet, after intensive or prolonged exercise, when alcohol intake or during the administration of a combination of hypoglycaemic agents.
Diagnosis: The symptoms of hypoglycaemia are: headache, hunger, nausea, vomiting, extreme tiredness, sleep disorder, restlessness, aggression, impaired concentration and reactions, depression, confusion, speech impediment, visual disturbances, trembling, paralysis and paraesthesia, dizziness, delirium, convulsions, somnolence, unconsciousness, superficial breathing and bradycardia. Due to a counterregulation caused by the hypoglycaemia, sweating, fear, tachycardia, hypertension, palpitations, angina and arrhythmia can occur. These latter symptoms can be absent when the hypoglycaemia is developed slowly, in case of autonomic neuropathy or when the patients take beta-blocking agents, clonidine, reserpine, guanethidine or sympathomimetics.
Management of hypoglycaemia: Moderate hypoglycaemic symptoms without loss of consciousness or neurological manifestations should be corrected by the immediate intake of sugar. An adjustment to the dosage and/or changes to meal patterns should be ensured. Severe hypoglycaemic reactions with coma, seizures or other neurological signs are also possible and constitute a medical emergency requiring immediate treatment with intravenous glucose once the cause is diagnosed or suspected, prior to prompt hospitalisation of the patient.
The careful selection of patients and dosage and adequate instructions for the patient are important to reduce the risk of hypoglycaemic episodes. If the patient encounters repeated episodes of hypoglycaemia, which are either severe or associated with unawareness of the situation, antidiabetic treatment options other than Glucovance should be taken into consideration.
Factors favouring hypoglycaemia: concomitant administration of alcohol, especially combined with fasting; refusal or (more particularly in elderly patients) inability of the patient to co-operate; malnutrition, irregular meals, missed meals, fasting or changes to diet; poor balance between physical exercise and carbohydrate intake; renal failure; severe liver failure; overdose of Glucovance; certain endocrine disturbances: thyroid insufficiency, pituitary and adrenal gland insufficiency; concomitant administration of certain other drugs (see Interactions).
Patient information: The risks of hypoglycaemia, its symptoms and its treatment, as well as its predisposing conditions, must be explained to the patient and his or her family. Similarly, the risk of lactic acidosis must be considered in the event of non-specific signs such as muscle cramps accompanied by digestive disorders, abdominal pain and severe asthenia, dyspnoea attributed to acidosis, hypothermia and coma.
In particular, the patient should be informed of the importance of adhering to a diet, following a programme of regular physical exercise and making regular checks on glycaemia.
Blood sugar imbalance: In case of surgery or any other cause of diabetic decompensation, temporary insulin therapy should be envisaged instead of this treatment.
The symptoms of hyperglycaemia are: increased urinating, raging thirst and a dry skin.
Cardiac function: Patients with heart failure are more at risk of hypoxia and renal insufficiency. In patients with stable chronic heart failure, Glucovance may be used with a regular monitoring of cardiac and renal function.
For patients with acute and unstable heart failure, Glucovance is contraindicated.
Renal function: GFR should be assessed before treatment initiation and regularly thereafter [See Dosage & Administration]. 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 Contraindications].
Administration of iodinated contrast materials: Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, resulting in metformin accumulation and an increased risk of lactic acidosis. Glucovance 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 Dosage & Administration and Interactions.
Concomitant use of glibenclamide with other medicinal products: The concomitant use of glibenclamide with alcohol, phenylbutazone or danazol is not recommended (see Interactions).
Surgery: Because Glucovance contains metformin hydrochloride, Glucovance must be discontinued 48 hours before elective surgery under general, spinal or peridural anaesthesia and may not be reinstituted earlier than 48 hours following surgery or resumption of oral nutrition 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.
Regular physical exercise is as necessary as taking Glucovance.
The usual laboratory tests for diabetes monitoring (glycaemia, HbA1c) should be performed regularly.
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.
Treatment of patients with G6PD-deficiency with sulphonylurea agents can lead to haemolytic anaemia. Since glibenclamide belongs to the chemical class of sulphonylurea drugs, caution is recommended when using Glucovance in patients with G6PD-deficiency and a non-sulphonylurea alternative may be considered.
Because this medicinal product contains lactose, it is contraindicated in case of congenital galactosemia, glucose and galactose malabsorption syndrome or in case of lactase deficiency.
Effects on ability to drive and use machines: Patients should be alerted to the symptoms of hypoglycaemia and should be advised to exercise caution when driving or using machines.
Renal and hepatic failure: The pharmacokinetics and/or pharmacodynamics of Glucovance may be modified in patients with hepatic failure or severe renal failure. If hypoglycaemia occurs in such patients, it may be prolonged, and appropriate treatment must be initiated.
Use in the Elderly: Age 65 years and older has been identified as a risk factor for hypoglycemia in patients treated with sulfonylureas. Hypoglycemia can be difficult to recognize in the elderly. Starting and maintenance doses of glibenclamide must be carefully adjusted to reduce the risk of hypoglycaemia (see Dosage & Administration).
