Glucovance 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 and 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 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 + Glibenclamide (Glucovance) must be immediately discontinued, at least temporarily, until the situation is clarified. Reintroduction of metformin + glibenclamide (Glucovance) should then be discussed taking into account the benefit/risk ratio on an individual basis as well as renal function.
Hypoglycemia: As it contains a sulfonylurea, metformin + glibenclamide (Glucovance) exposes the patient to a risk of onset of hypoglycemia. After treatment initiation, a progressive dose titration may prevent the onset of hypoglycemia. This treatment must 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 hypoglycemia is increased by a late meal, insufficient or unbalanced carbohydrate intakes. Hypoglycemia is more likely to occur in case of energy-restricted diet, after intensive or prolonged exercise, when alcohol is consumed or during the administration of a combination of hypoglycemic agents.
Diagnosis: The symptoms of hypoglycemia 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 counter regulation caused by the hypoglycemia, sweating, fear, tachycardia, hypertension, palpitations, angina and arrhythmia can occur. These latter symptoms can be absent when the hypoglycemia is developed slowly, in case of autonomic neuropathy or when the patient takes beta-blocking agents, clonidine, reserpine, guanethidine or other sympathomimetics.
Management of hypoglycemia: Moderate hypoglycemic symptoms without loss of consciousness or neurological manifestations must be corrected by the immediate intake of sugar. An adjustment to the dosage and/or changes to meal patterns must be ensured. Severe hypoglycemic 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 hospitalization of the patient.
The careful selection of patients and dosage and adequate instructions for the patient are important to reduce the risk of hypoglycemic episodes. If the patient encounters repeated episodes of hypoglycemia, which are either severe or associated with unawareness of the situation, antidiabetic treatment options other than metformin + glibenclamide (Glucovance) must be taken into consideration.
Factors favoring hypoglycemia: Concomitant administration of alcohol, especially combined with fasting; Refusal or (more particularly in elderly patients) inability of the patient to cooperate; 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 metformin + glibenclamide (Glucovance); Certain endocrine disturbances: thyroid insufficiency, pituitary and adrenal gland insufficiency; Concomitant administration of certain other medicines.
Renal and hepatic impairment: The pharmacokinetics and/or pharmacodynamics of metformin + glibenclamide (Glucovance) may be modified in patients with hepatic failure or severe renal failure. If hypoglycemia occurs in such patients, it may be prolonged, and appropriate treatment must be initiated.
Information for the patient: The risks of hypoglycemia, 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, dyspnea attributed to acidose, hypothermia and coma.
In particular, the patient should be informed of the importance of adhering to a diet, following a program of regular physical exercise and making regular checks on glycemia.
Infectious diseases: The doctor should be informed if the patient is suffering from any infectious illnesses such as flu, infection of the air passages or urinary tract infection.
Blood sugar imbalance: The doctor should be informed in case of surgery or any other cause of diabetic decompensation since temporary treatment with insulin should be envisaged. The symptoms of hyperglycemia are increased urination, raging thirst and a dry skin.
Renal function: As metformin 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/1.73 m².
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 to 6 months in patients with CrCl between 30 and 44 mL/min or eGFR between 30 and 44 mL/min/1.73 m². In case creatinine clearance or GFR is below 45 mL/min/1.73 m², it is not recommended to initiate metformin + glibenclamide (Glucovance).
In case CrCl or eGFR is below 30 mL/min or 30 mL/min/1.73 m² respectively, metformin+glibenclamide (Glucovance) 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, due to dehydration (severe or prolonged diarrhea or vomiting), 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 + glibenclamide (Glucovance).
Cardiac function: Patients with heart failure are more at risk of hypoxia and renal insufficiency. In patients with stable chronic heart failure, metformin + glibenclamide (Glucovance) may be used with a regular monitoring of cardiac and renal function.
For patients with acute and unstable heart failure, metformin + glibenclamide (Glucovance) is contraindicated.
Other Precautions: All patients should continue their diet, with a regular distribution of carbohydrate intake during the day and should get some regular exercise. Overweight patients should continue their energy-restricted diet.
The usual laboratory tests for diabetes monitoring 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 glucose-6-phosphate-dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Since glibenclamide belongs to the chemical class of sulfonylurea drugs, caution is recommended when using metformin + glibenclamide (Glucovance) in patients with G6PD deficiency and a non-sulfonylurea alternative may be considered.
Lactose: Because metformin + glibenclamide (Glucovance) contains lactose, it is contraindicated in case of congenital galactosemia, glucose and galactose malabsorption syndrome or in case of lactase deficiency.
Effects on the ability to drive and use machines: Patients must be alerted to the symptoms of hypoglycemia and must be advised to exercise caution when driving or using machines.
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 hypoglycemia (see Dosage & Administration).