Source: Web Search Revision Year: 2020 Publisher: Alphapharm Pty Ltd, Level 1, 30 The Bond, 30-34 Hickson Road, Millers Point NSW 2000 www.mylan.com.au
This medicinal product must never be used in case of:
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 patients on metformin have occurred primarily in diabetic patients 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.
The reported incidence of lactic acidosis in patients receiving metformin is very low (approximately 0.03 cases per 1,000 patient years, with approximately 0.015 fatal cases per 1,000 patient years). The onset is often subtle and accompanied by non-specific symptoms such as malaise, myalgia, respiratory distress, hypothermia, increasing somnolence and non-specific abdominal distress. The incidence of lactic acidosis can and should be reduced by also assessing other associated risk factors, such as poorly-controlled diabetes, ketosis, prolonged fasting, alcoholism, hepatic insufficiency and any condition associated with hypoxia.
Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 ยตg/mL and an increased anion gap and lactate/pyruvate ratio.
When metformin is implicated as the cause of lactic acidosis, metformin plasma levels greater than 5 ยตg/mL are generally found (see Section 5.2 PHARMACOKINETIC PROPERTIES). Underlying renal disease, or deterioration in renal function, result in reduced clearance of metformin and drug accumulation and are therefore major risk factors in lactic acidosis. The risk of lactic acidosis may therefore be significantly decreased by regular monitoring of renal function in patients taking Glucovance and those patients on concomitant diuretics. The minimum effective dose of Glucovance is recommended. In addition, Glucovance therapy should be temporarily stopped in the presence of any condition associated with hypoxaemia or dehydration, in patients suffering from serious infections or trauma (particularly if gastrointestinal disturbances are noted or acidosis is suspected) and in those undergoing surgery.
As metformin is excreted by the kidney, it is recommended that creatinine clearance and/or serum creatinine levels be determined before initiating treatment and regularly thereafter:
The intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure. This may induce metformin accumulation and may expose to lactic acidosis. 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. Glucovance may not be reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.
Because Glucovance contains metformin hydrochloride, 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.
Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients should therefore be warned against excessive alcohol intake, acute or chronic, while taking Glucovance, due to the increase of risk of lactic acidosis particularly in case of fasting or malnutrition or hepatic insufficiency.
Glucovance must be discontinued when pancreatitis is combined with sepsis or hypoxia.
As it contains a sulfonylurea, Glucovance exposes the patient 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 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, 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.
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.
Risk factors for hypoglycaemia should be carefully monitored:
Correction of dosage must also be considered whenever the patient’s weight changes, the patient’s lifestyle changes or other factors arise that cause an increased susceptibility to hypoglycaemia or hyperglycaemia.
Age 65 years and older has been identified as a risk factor for hypoglycaemia in patients 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
The pharmacokinetics and/or pharmacodynamics of Glucovance may be modified in patients with hepatic failure or severe renal failure. Renal or hepatic insufficiency may cause increased serum concentrations of glibenclamide and hepatic insufficiency may also diminish glyconeogenic capacity. If hypoglycaemia occurs in such patients, it may be prolonged, and appropriate treatment must be initiated.
In the presence of a genetic defect in metabolism, the elimination half-life of glibenclamide may be prolonged.
It should be borne in mind that there is a possibility of cross sensitivity to sulfonamides and their derivatives.
It is recommended that, when switching the patient to a metformin/glibenclamide fixed-dose combination product, 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 metformin/glibenclamide fixed-dose combination product should be prescribed and used at any one time.
The risks of hypoglycaemia and hyperglycaemia, its symptoms and its treatment, as well as its predisposing conditions, must be explained to the patient and his or her family. Symptoms of hyperglycaemia include severe thirst, dry mouth, frequent micturition, dry skin; while symptoms of hypoglycaemia include intense hunger, sweating, tremor, restlessness, irritability, depression, headaches, disturbed sleep or transient neurological disorders. 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. In particular, the patient should be informed of the importance of adhering to a diet with a regular distribution of carbohydrate intake during the day, following a programme of regular physical exercise and making regular checks on glycaemia. Overweight patients should continue their energy-restricted diet.
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.
Age 65 years and older has been identified as a risk factor for hypoglycaemia in patients 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.
Glucovance should not be administered to children.
No information regarding the effect of metformin or glibenclamide on laboratory tests is available.
Miconazole (systemic route, oromucosal gel): Increase in the hypoglycaemic effect with possible onset of hypoglycaemic manifestations, or even coma (see Section 4.3 CONTRAINDICATIONS).
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 (see Section 4.3 CONTRAINDICATIONS).
Bosentan: There is an increased risk of hepatotoxicity if bosentan is given with glibenclamide. Such use should be avoided. The hypoglycaemic effect of glibenclamide may also be reduced.
Phenylbutazone (systemic route): Increase in the hypoglycaemic effect of sulfonylureas (displacement of sulfonylureas from proteinbinding sites and/or decrease in their elimination). Preferably use another anti-inflammatory agent exhibiting fewer interactions, or else warn the patient and step up self-monitoring; if necessary, adjust the dosage during treatment with the anti-inflammatory agent and after its withdrawal.
Cimetidine:
Reduced clearance of metformin has been reported during cimetidine pharmacokinetic interaction study.
Anticoagulants:
Metformin increases the elimination rate of vitamin K antagonists during pharmacokinetics interaction study.
Nifedipine:
A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of metformin and nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount of metformin excreted in the urine. Tmax and half-life of metformin were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on the pharmacokinetics of nifedipine.
Organic cation transporters (OCT):
Metformin is a substrate of both transporters OCT1 and OCT2.
Co-administration of metformin with:
Carbonic anhydrase inhibitors:
Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with Metformin hydrochloride tablet may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.
NSAID:
May increase the risk of lactic acidosis and adversely affect renal function.
Therefore, caution is advised when these drugs are co-administered with metformin and a dose adjustment may be considered, particularly in patients with renal impairment.
Fluconazole:
Increase in the half-life of sulfonylurea with possible onset of hypoglycaemic manifestations. Warn the patient and step up blood glucose self-monitoring, and possibly adjust the dosage of the antidiabetic during treatment with fluconazole and after its withdrawal.
Alcohol:
Increased risk of lactic acidosis during acute alcoholic intoxication, particularly in cases of fasting or malnutrition and hepatic insufficiency. Avoid drinking alcoholic beverages and taking drugs that contain alcohol.
Alcohol:
In very rare cases, intolerance to alcohol may occur. Disulfiram-like reactions have occurred very rarely following the concomitant use of alcohol and glibenclamide. This disulfiram effect has been reported with other sulfonylureas, notably for chlorpropamide, glibenclamide, glipizide, tolbutamide. Excessive alcohol ingestion may dangerously increase the hypoglycaemic action (via inhibition of compensation reactions or delaying its metabolic inactivation), which may facilitate the onset of a hypoglycaemic coma. Avoid consumption of alcohol and alcohol-containing medications.
Danazol:
If the combination cannot be avoided, warn the patient and step up self-monitoring of blood glucose. Possibly adjust the dosage of the antidiabetic during treatment with danazol and after its withdrawal.
Diuretics:
Lactic acidosis due to metformin triggered by any functional renal insufficiency, related to diuretics and more particularly to loop diuretics. Thiazide diuretic therapy may impair glucose tolerance. Dosage adjustment of metformin may be required.
Other calcium channel blockers may affect glucose control in diabetic patients.
Beta-blockers:
Co-administration of metformin and beta-blockers may result in a potentiation of the antihyperglycaemic action. Monitoring of blood glucose should be undertaken during dosage adjustment of either agent.
Other drugs given at the same time as sulfonylureas may cause undesirable depression or elevation of the blood sugar level.
Beta-blockers, clonidine, reserpine, guanethidine and sympathomimetics:
All beta-blockers, clonidine, reserpine, guanethidine and sympathomimetics mask some of the symptoms of hypoglycaemia: palpitations and tachycardia. Most non-cardioselective beta-blockers increase the incidence and severity of hypoglycaemia. Warn the patient and step up blood glucose self-monitoring, especially at the start of treatment.
Other drugs that may potentiate the hypoglycaemic action of glibenclamide:
Anabolic steroids, bezafibrate, chloramphenicol, clofibrate, co-trimoxazole, coumarin derivatives, disopyramide, fenfluramine, fluoxetine, gemfibrozil, guanethidine, heparin, MAO-inhibitors, nonsteroidal anti-inflammatory agents, pentoxifylline (oxpentifylline) (parenteral, in high doses), phenylbutazone, phosphamides, probenecid, quinolone antibiotics, salicylates, sulphinpyrazone, tetracycline compounds and certain long-acting sulfonamides.
Other drugs that may cause an attenuation of the hypoglycaemic action of glibenclamide:
Acetazolamide, calcium channel blockers, cimetidine, diazoxide, glucagon, isoniazid, nicotinic acid (high dosage), oestrogens, progestogens, phenothiazine derivatives, phenytoin, ranitidine, rifampicin, saluretics, sympathomimetic agents, thyroid hormones and large doses of laxatives.
Chlorpromazine:
At high dosages (100 mg per day of chlorpromazine), elevation in blood glucose (reduction in release of insulin). Precaution for use: warn the patient and step up self-monitoring of blood glucose. Possibly adjust the dosage of the antidiabetic during treatment with the neuroleptic and after its withdrawal.
Corticosteroids (glucocorticoids) and tetracosactide (tetracosactrin) (systemic and local routes):
Elevation in blood glucose sometimes accompanied by ketosis (decreased carbohydrate tolerance with corticosteroids). Precaution for use: warn the patient and step up self-monitoring of blood glucose. Possibly adjust the dosage of the antidiabetic during treatment with corticosteroids and after their withdrawal.
ฮฒ2-agonists:
Elevation in blood glucose due to the 2 agonist. Precaution for use: warn the patient, step up blood glucose monitoring and possibly transfer to insulin therapy.
Angiotensin converting enzyme inhibitors (e.g. captopril, enalapril):
ACE inhibitors may decrease the blood glucose levels. If necessary, adjust the dosage of Glucovance during therapy with an ACE inhibitor and upon its discontinuation.
Desmopressin:
Reduction in antidiuretic activity.
The potential effects of the combination of metformin and glibenclamide or glibenclamide alone on fertility have not been investigated in animal studies.
Fertility of male or female rats was unaffected by metformin alone at oral doses up to 600 mg/kg/day, approximately 3 times the maximum recommended daily dose on a body surface area basis
The patient should be transferred from Glucovance to insulin during pregnancy. When uncontrolled, diabetes gives rise to an increase in congenital abnormalities and perinatal mortality. It is important to achieve strict normoglycaemia during pregnancy.
There are no adequate and well-controlled studies with metformin and glibenclamide in pregnant women. No studies in pregnant animals have been conducted with the combination of metformin and glibenclamide. Metformin alone was not teratogenic in rats and rabbits at oral doses up to 600 mg/kg/day and 140 mg/kg/day, respectively, approximately 3 and 1 times the maximum recommended daily dose on a body surface area basis. Sulfonylureas such as glibenclamide may enter the foetal circulation and cause neonatal hypoglycaemia. Embryotoxicity and/or birth defects have been demonstrated in animals dosed with glibenclamide alone.
Studies on lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Although it is not known whether glibenclamide is excreted in milk, some sulfonylurea drugs are known to be excreted in human milk. In view of the potential risk of neonatal hypoglycaemia, Glucovance should not be used in nursing mothers.
Until optimal control is achieved, or when changing from one product to another, or when tablets are not taken regularly, the patient’s alertness and capacity to react may be impaired to such an extent that they may not be fit to drive or to operate machinery.
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.
Lactic acidosis (see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE) 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. The patient and the patient’s physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a medical emergency that must be treated in hospital. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted.
A decrease of vitamin B12 absorption with decrease of serum levels has been observed in patients treated long-term with metformin. Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia. Therefore, serum B12 levels should be appropriately monitored or periodic parenteral B12 supplementation considered.
Very rare: liver function test abnormalities or hepatitis requiring treatment discontinuation.
Skin reactions such as erythema, pruritus and urticaria have been reported but the incidence is very rare (<0.01%).
Taste disturbance (3%) is common.
Clinical experience in the use of glibenclamide has shown that side effects serious enough to compel discontinuation of therapy are uncommon, even during long-term therapy. However, if adverse effects persist, the drug should be discontinued.
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 patients. Glibenclamide induced adverse gastrointestinal effects appear to be dose related and may subside following a reduction in dosage.
Hypoglycaemia which may be not only severe, but also prolonged and fatal (see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE). Disulfiram effect with alcohol intake.
Hepatic porphyria, increased liver enzymes (AST, ALT), abnormal liver function, cholestasis, cholestatic hepatitis, granulomatous hepatitis and bilirubinemia have been reported with sulfonylureas.
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 patients; if skin reactions persist, the drug 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.
Transient visual disturbances may occur at the start of treatment due to a decrease in glycaemia levels.
Haematological disorders, reversible when treatment is stopped: leukopenia, thrombocytopenia, thrombocytopenic purpura; more rarely: agranulocytosis, eosinophilia, haemolytic anaemia, aplastic anaemia, bone marrow aplasia, pancytopenia and coagulation disorders.
Occasional average to moderate elevations in serum urea and creatinine concentrations. Isolated cases of hyponatremia.
Although a causal relationship has not been established, the following adverse effects have been reported in patients receiving:
Glibenclamide: paraesthesia, blindness, deafness, diplopia, visual disturbances, tremor, convulsions (other than withdrawal), encephalopathy, confusion, acute psychosis, abnormal renal function, acute renal failure, ocular disturbances (accommodation changes, crystalline lens changes), lactic acidosis, alopecia/hypotrichosis, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), arthralgia, arthritis, cerebrovascular disorders, headache, facial oedema, angioedema and increased sweating.
Glucovance: dystonia, muscle contractions involuntary, disorientation, grand mal seizure, unconsciousness, unresponsiveness, myocardial infarction, tachycardia, chest pain, pulmonary hypertension, pancreatitis, cholelithiasis, acute gallstone pancreatitis, gastrointestinal haemorrhage, disseminated intravascular coagulation, haemorrhage, acute renal failure, dermatitis, overdose, dehydration, metabolic acidosis, hypoglycaemic coma and elevated blood glucose level.
In double-blind U.S clinical trials involving Glucovance as initial therapy or as second-line therapy, a total of 642 patients received Glucovance, 312 received metformin therapy, 324 received glibenclamide therapy, and 161 received placebo. The percent of patients reporting events and types of adverse events reported in clinical trials of Glucovance (all strengths) as initial therapy and secondline therapy are listed in Table 1.
Table 1. Most Common Clinical Adverse Events (>5%) in Double-Blind US Clinical Studies of Glucovance Used as Initial or Second-Line Therapy:
. \4<>.Number (%) of Patients|
| Adverse Event | Placebo N=161 | Glibenclamide N=324 | Metformin N=312 | Glucovance N=642 |
|---|---|---|---|---|
| Upper respiratory infection | 22 (13.7) | 57 (17.6) | 51 (16.3) | 111 (17.3) |
| Diarrhoea | 9 (5.6) | 20 (6.2) | 64 (20.5) | 109 (17.0) |
| Headache | 17 (10.6) | 37 (11.4) | 29 (9.3) | 57 (8.9) |
| Nausea/vomiting | 10 (6.2) | 17 (5.2) | 38 (12.2) | 49 (7.6) |
| Abdominal pain | 6 (3.7) | 10 (3.1) | 25 (8.0) | 44 (6.9) |
| Dizziness | 7 (4.3) | 18 (5.6) | 12 (3.8) | 35 (5.5) |
In controlled clinical trials of Glucovance there were no hypoglycaemic episodes classified as Serious Adverse Event. The incidence of reported symptoms of hypoglycaemia (such as dizziness, shakiness, sweating, and hunger), in the initial therapy trial of Glucovance are summarised in Table 2. The frequency of hypoglycaemic symptoms in patients treated with Glucovance 250 mg/1.25 mg was highest in patients 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%. For patients with a baseline HbA1c of between 8% and 11% treated with Glucovance 500 mg/2.5 mg as initial therapy, the frequency of hypoglycaemic symptoms was 30-35%. As second-line therapy in patients inadequately controlled on sulfonylurea or metformin alone, approximately 6.8% and 12.3% respectively of all patients treated with Glucovance experienced hypoglycaemic symptoms.
The incidence of gastrointestinal side effects (diarrhoea, nausea/vomiting and abdominal pain) in the initial therapy trial are summarised in Table 2. Across all Glucovance trials, gastrointestinal symptoms were the most common adverse events with Glucovance and were more frequent at higher dose levels. In controlled trials, <2% of patients discontinued Glucovance therapy due to gastrointestinal adverse events.
Table 2. Treatment Emergent Symptoms of Hypoglycaemia or Gastrointestinal Adverse Events in a Placebo –and Active- Controlled Trial of Glucovance as Initial Therapy:
| Variable | Placebo N=161 | Glibenclamide tablets N=160 | Metformin tablets N=159 | Glucovance 250 mg/1.25 mg tablets N=158 | Glucovance 500 mg/2.5 mg tablets N=162 |
|---|---|---|---|---|---|
| Mean Final Dose | 0 mg | 5.3 mg | 1317 mg | 2.78 mg/557 mg | 4.1 mg/824 mg |
| Number (%) of patients with symptoms of hypoglycaemia | 5 (3.1) | 34 (21.3) | 5 (3.1) | 18 (11.4) | 61 (37.7) |
| Number (%) of patients with gastrointestinal adverse events | 39 (24.2) | 38 (23.8) | 69 (43.3) | 50 (31.6) | 62 (38.3) |
Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reportingproblems.
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
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