• Second line treatment of diabetes mellitus type II in adults whose glycaemic management is inadequate after heathy eating and physical activity alone and where combined therapy with metformin and glibenclamide is appropriate.
  
  For the latest PBS indications for glucovance please see

https://www.pbs.gov.au/medicine/item/8810Q-8811R-8838E

Life threatening lactic acidosis can occur due to accumulation of metformin. The main risk factor is renal impairment, other risk factors include old age associated with reduced renal function and high doses of metformin above 2g per day.

• Glucovance may be used instead of a previously prescribed oral medicine. This transfer can generally be made without any transition period, starting for preference with a low dosage and adjusting it thereafter as a function of the metabolic response of each person (person centred care). However, if the individual was previously taking a sulfonylurea with a long half-life, a treatment-free washout period of a few days may be necessary, to minimise the risk of hypoglycaemia due to an additive effect of the two medicines. It is recommended that, when switching an individual to a fixed-dose combination product containing metformin, any previously prescribed individual-component products should be discontinued, to minimise the risk of accidental overdosing or dose related adverse effects. Only one strength of the fixed￾dose combination product should be prescribed and used at any one time.
• Initiation of Treatment

  - Monotherapy failure: In the event of monotherapy failure with metformin or a sulfonylurea, the usual initial dosage is 1 tablet of Glucovance 500 mg/2.5 mg daily.

  - Combination therapy substitution: In individuals already on combination therapy with metformin and sulfonylurea, the initial dosage should be 1 to 2 tablets of Glucovance 500 mg/2.5 mg daily. It is recommended to start with a lower dose of the currently used agents in the fixed combination to reduce the risk of hypoglycaemia.

• Dose titration:

  The dosage should be adjusted every 2 weeks or longer, by increments of 1 tablet, depending on glycaemia results. A gradual increase in the dosage may aid gastrointestinal tolerance and prevent the onset of hypoglycaemia. Note: Diabetes MedsCheck with counselling on managing hypoglycaemia and referral for blood glucose monitoring.

• Maximum daily recommended dose:

  The maximum recommended daily dose is 3 tablets of Glucovance 500 mg/5 mg. In exceptional cases, an increase up to 4 tablets of Glucovance 500 mg/5 mg per day may be recommended.

• Dosing frequency:

  The tablets should be taken at the beginning of meals. The dosage regimen depends on the daily dosage in an individual, such as:

  - Once a day, in the morning at breakfast, for a dosage of 1 tablet/day

  - Twice a day, morning, and evening, for a dosage of 2 or 4 tablets/day

  - Three times a day, morning, noon, and evening, for a dosage of 3 tablets/day.

  The dosing frequency should be adjusted according to the eating habits of each person. However, any intake must be followed by a meal with a sufficiently high carbohydrate content to prevent the onset of hypoglycaemic episodes.

Note: Diabetes MedsCheck with counsellng on managing hypoglycaemia and referral for blood glucose monitoring.

• In the elderly, decreased renal function is frequent and asymptomatic. Therefore, it is recommended that creatinine and/or serum creatinine levels be determined before initiating treatment and regularly thereafter at least two to four times a year in elderly subjects. The dosage of glucovance should be adjusted depending on renal function parameters.
• Ages 65 years and older has been identified as a risk factor for hypoglycaemia in individuals treated with sulfonylureas. Hypoglycaemia can be difficult to recognize in the elderly. Starting and maintenance doses of glibenclamide must be carefully adjusted to reduce the risk of hypoglycaemia.

Note: Diabetes MedsCheck with counselling on managing hypoglycaemia and referral for blood glucose monitoring

• Hypersensitivity to metformin hydrochloride, glibenclamide or other sulfonylureas or sulfonamides or to any of the excipients.
• Any type of metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis)
• Diabetic pre-coma
• Renal failure or renal dysfunction (creatinine clearance < 60 mL/min)
• Acute conditions with the potential to alter renal function such as: dehydration, severe infection shock, intravascular administration of iodinated contrast materials. Glucovance must be discontinued either 48 hours before the test when renal function is known to be impaired, or from the time of the test when renal function is known to be normal (related to metformin).
• Acute or chronic disease which may cause tissue hypoxia such as cardiac or respiratory failure, recent myocardial infarction, shock, acute significant blood loss, sepsis, gangrene.
• Major surgery
• Hepatic insufficiency, acute alcohol intoxication, alcoholism
• Porphyria
• Congenital galactosemia, glucose and galactose malabsorption syndrome or lactase deficiency
• Lactation
• In association with miconazole and glibenclamide (systemic route, oromucosal gel) increased in hypoglycaemic effect with possible chance of hypoglycaemic manifestations, or even coma.

• Metformin - Lactic acidosis: Lactic acidosis is a rare, but serious metabolic complication that can occur due to metformin accumulation during treatment with metformin. When it occurs, it is fatal in approximately 50% of cases. Lactic acidosis is a medical emergency and must be treated in hospital immediately. The risk of lactic acidosis increases with the degree of renal dysfunction. Reported cases of lactic acidosis in individuals on metformin have occurred primarily in those with diabetes with significant renal insufficiency, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Special caution should be taken in the elderly due to the decrease of renal function with age.
• Glibenclamide
  - Hypoglycaemia: As it contains a sulfonylurea, glucovance exposes a person to a risk of onset of hypoglycaemic episodes. Severe hypoglycaemia, which may be prolonged and is potentially lethal, can be induced by all sulfonylureas. This treatment should only be prescribed if an individual 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, after alcohol intake or during the administration of a combination of hypoglycaemic agents. The use of glibenclamide in the elderly may be associated with a higher risk of hypoglycaemia than in younger adults. Hypoglycaemia may be more severe and more prolonged in the elderly.
• Other Precautions
  - Type I diabetes should be treated with insulin.
  - The usual clinical and laboratory tests for diabetes monitoring, including blood glucose determination, should be performed regularly.
  - Periodic assessment of renal, hepatic, and cardiovascular function and B12 levels sampling are also recommended during prolonged periods of treatment with glucovance.
  - Blood glucose imbalance. In cases of surgery or unusual stress (e.g., febrile infections) or any other cause of diabetic decompensation, temporary insulin therapy should be envisaged instead of this treatment.
  - 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.

• Metformin - Gastrointestinal disorders: Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain, and loss of appetite are very common (>10%): these occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent these gastrointestinal symptoms, it is recommended that this medicinal product be taken in 2 or 3 daily doses. A slow increase of the dose
  may also improve gastrointestinal tolerability.
  - Metabolism and nutrition disorders: Lactic acidosis is a very rare (<0.01%) but serious metabolic complication that can occur due to metformin accumulation during treatment with metformin. The onset of lactic acidosis is often subtle and accompanied only by non-specific symptoms such as malaise, myalgia, respiratory distress, increasing somnolence and non-specific abdominal distress. There may be associated hypothermia, hypotension and resistant bradyarrhythmias with more marked acidosis.
  Note: Diabetes MedsCheck with referral to healthcare team if suspected.
  - Hepatobiliary disorders: Very rare: liver function test abnormalities or hepatitis requiring treatment discontinuation.
  - Skin and subcutaneous tissue disorders: Skin reactions such as erythema, pruritus and urticaria have been reported but the incidence is very rare (<0.01%).
  - Nervous system disorders.
  - Taste disturbance (3 %) is common.
  - Vitamin B12 Levels
  - In controlled, 29-week clinical trials of immediate release metformin, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of individuals. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex is, however, very rarely associated with anaemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B12 supplementation. Measurement of haematologic parameters on an annual basis is advised in those on metformin (glucovance) and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B12 levels). See interventions for further information.
• Glibenclamide
  - Gastrointestinal disorders: Gastrointestinal disorders such as nausea, vomiting, diarrhoea, epigastric fullness or sensation of pressure, anorexia, heartburn, dyspepsia and diarrhoea are the most common adverse reactions for glibenclamide alone, occurring in about 1 to 2% of individuals. . Glibenclamide induced adverse gastrointestinal effects appear to be dose related and may subside following a reduction in dosage.
  - Metabolism and nutrition disorders: Hypoglycaemia which may be not only severe, but also prolonged and fatal
  Note: Diabetes MedsCheck with counselling on managing hypoglycaemia info, referral to CDE BGM)
  - Hepatobiliary disorders: Hepatic porphyria, increased liver enzymes (AST, ALT), abnormal liver function, cholestasis, cholestatic hepatitis, granulomatous hepatitis and bilirubinemia have been reported with sulfonylureas.
  - Skin and subcutaneous tissue disorders: Reactions of skin and mucous membranes: pruritus, erythema, urticaria erythematous, maculopapular rash and bullous skin eruptions or psoriasiform drug eruption occur in 1.5% of glibenclamide treated individuals; if skin reactions persist, the medicine should be discontinued.
  - Porphyria cutanea tarda, pellagra-like changes have been reported with sulfonylureas. A few cases of photosensitization have been reported. In very rare cases, cutaneous or visceral allergic angiitis, exfoliative dermatitis and urticaria evolving to shock have been reported. A cross reactivity to sulphonamide(s) and their derivatives may occur.
• Glucovance - Eye disorders: Transient visual disturbances may occur at the start of treatment due to a decrease in glycaemia levels.
  - Gastrointestinal side effects: Across all glucovance trials, gastrointestinal symptoms (diarrhoea, nausea/vomiting and abdominal pain) were the most common adverse events with glucovance and were more frequent at higher dose levels.
  - Hypoglycaemia: The frequency of hypoglycaemic symptoms in individuals treated with glucovance 250 mg/1.25 mg was highest in those with a baseline HbA1c<7%, lower in those with a baseline HbA1c of between 7 and 8% and was comparable to placebo and metformin in those with a baseline HbA1c >8%.