Glucovance Special Precautions

General: GLUCOVANCE: Hypoglycemia: GLUCOVANCE is capable of producing hypoglycemia or hypoglycemic symptoms, therefore, proper patient selection, dosing, and instructions are important to avoid potential hypoglycemic episodes. The risk of hypoglycemia is increased when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents or ethanol. Renal or hepatic insufficiency may cause elevated drug levels of both glibenclamide and metformin hydrochloride and the hepatic insufficiency may also diminish gluconeogenic capacity, both of which increase the risk of hypoglycemic reactions. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs. 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.
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.
Glibenclamide: Haemolytic anemia: Treatment of patients with glucose-6-phosphate-dehydrogenase 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.
Metformin hydrochloride: Renal function: As metformin hydrochloride is substantially excreted by the kidney, it is recommended that CrCl or eGFR should be determined before initiating treatment and regularly thereafter: At least annually in patients with CrCl above 60 mL/min or eGFR above 60 mL/min/1.73m².
Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution is needed in situations where renal function may become acutely impaired, due to 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.
In these cases, it is also recommended to check renal function before initiating treatment with GLUCOVANCE.
Use of concomitant medications that may affect renal function or metformin disposition: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion (see Interactions), should be used with caution.
Administration of iodinated contrast agents: 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.
Hypoxic states: Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause pre-renal azotemia. When such events occur in patients on GLUCOVANCE therapy, the drug should be promptly discontinued.
Surgery: Because Glucovance contains metformin, Glucovance must be discontinued 48 hours before elective major surgery, and may not be reinstituted earlier than 48 hours afterwards and only after renal function has been re-evaluated and found to be normal.
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 dry skin.
Alcohol intake: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving GLUCOVANCE. Due to its effect on the gluconeogenic capacity of the liver, alcohol may also increase the risk of hypoglycemia.
Impaired hepatic function: Since impaired hepatic function has been associated with some cases of lactic acidosis, GLUCOVANCE should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B₁₂ levels: In controlled clinical trials with metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B₁₂ without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B₁₂ absorption from the B₁₂-intrinsic factor complex, is, however, very rarely associated with anemia (see ADVERSE REACTIONS) and appears to be rapidly reversible with discontinuation of metformin or Vitamin B₁₂ supplementation.
It is recommended that vitamin B12 serum levels are monitored annually. 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 (see ADVERSE REACTIONS).
Change in clinical status of patients with previously controlled type 2 diabetes: A patient with type 2 diabetes previously well controlled on metformin who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, GLUCOVANCE must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS).
Other precautions: 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.
Information for Patients: GLUCOVANCE: Patients should be informed of the potential risks and benefits of GLUCOVANCE (Metformin HCl and Glibenclamide Tablets) and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters.
The risks of lactic acidosis associated with metformin therapy, its symptoms, and conditions that predispose to its development, as noted in the previously mentioned text, should be explained to patients. Patients should be advised to discontinue GLUCOVANCE immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of GLUCOVANCE, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members.
Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving GLUCOVANCE.
Laboratory Tests: Periodic fasting blood glucose and glycosylated hemoglobin (HbA1c) measurements should be performed to monitor therapeutic response.
Initial and periodic monitoring of hematologic parameters (e.g. hemoglobin/hematocrit and red blood cell indices) and renal function (creatinine clearance, this can be estimated using the Cockcroft-Gault formula, and/or serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, Vitamin B₁₂ deficiency should be excluded.
Effects on ability to drive and use machines: Patients must be alerted to the symptoms of hypoglycaemia and must be advised to exercise caution when driving or using machines.