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Glimepiride: In exceptional stress situations (e.g. trauma, surgery, febrile infections) blood glucose regulation may deteriorate, and a temporary change to insulin may be necessary to maintain good metabolic control.
In the initial weeks of treatment, the risk of hypoglycaemia may be increased and necessitates especially careful monitoring.
Factors favouring hypoglycaemia include: unwillingness or (more commonly in older patients) incapacity of the patient to cooperate; undernourishment, irregular mealtimes or skipped meals; imbalance between physical exertion and carbohydrate intake; alterations of diet; consumption of alcohol, especially in combination with skipped meals; impaired renal function; severe impairment of liver function; overdosage with glimepiride; certain uncompensated disorders of the endocrine system affecting carbohydrate metabolism or counter-regulation of hypoglycaemia (as for example in certain certain disorders of thyroid function and in anterior pituitary or corticoadrenal insufficiency); concurrent administration of certain other medicines (see Interactions); treatment with glimepiride in the absence of any indication.
If such risk factors for hypoglycaemia are present, it may be necessary to adjust the dosage of glimepiride or the entire therapy. This also applies whenever illness occurs during therapy or the patient's lifestyle changes.
Those symptoms of hypoglycaemia which reflect the body's adrenergic counter-regulation (see Adverse Reactions) may be milder or absent where hypoglycaemia develops gradually, in the elderly, and where there is autonomic neuropathy or where the patient is receiving concurrent treatment with beta-blockers, clonidine, reserpine, guanethidine or other sympatholytic drugs.
Hypoglycaemia can almost always be promptly controlled by immediate intake of carbohydrates (glucose or sugar).
It is known from other sulfonylureas that, despite initially successful countermeasures, hypoglycaemia may recur. Patients must, therefore, remain under close observation.
Severe hypoglycaemia further requires immediate treatment and follow-up by a physician and, in some circumstances, in-patient hospital care.
Treatment of patients with G6PD deficiency with sulfonylurea agents can lead to haemolytic anaemia. Since glimepiride belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered.
Metformin: Lactic acidosis: 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 associated to 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 Contraindications and Interactions).
Diagnosis: Patients and/or care-givers should be informed of the risk of lactic acidosis. 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.
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.
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 or diuretic therapy and when starting therapy with an NSAID.
Administration of iodinated contrast agent: Intravascular administration of iodinated contrast agents may lead to contrast induces 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 48 hours after provided that renal function has been re-evaluated and found to be stable (see Dosage & Administration and Interactions).
Surgery: Metformin must be discontinued at the time of surgery under general, spinal or epidural anesthesia. 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.
Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients with hypothyroidism (see Adverse Reactions).
Long-term treatment with metformin has been associated with a decrease in vitamin B12 serum levels which may cause peripheral neuropathy. Monitoring of the vitamin B12 level is recommended (see Adverse Reactions).
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 never causes hypoglycaemia, although caution is advised when it is used in combination with insulin or sulfonylureas.
Effects on ability to drive and use machines: Glimepiride: Alertness and reactions may be impaired due to hypo- or hyperglycaemia, especially when beginning or after altering treatment or when glimepiride is not taken regularly. This may, for example, affect the ability to drive or operate machinery.
Metformin: 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 (sulfonylureas, insulin, repaglinide).
