Glucovance

Glucovance

glibenclamide + metformin

Manufacturer:

Merck

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Metformin HCl, glibenclamide.
Description
Each 500/2.5 mg- and 500/5 mg-film-coated tablet contains metformin hydrochloride 500 mg equivalent to metformin 390 mg, and glibenclamide 2.5 mg and 5 mg, respectively.
It also contains the following excipients: Tablet Core: Microcrystalline cellulose, croscarmellose sodium, povidone K30, magnesium stearate.
Film-Coating: Lactose monohydrate, hypromellose, titanium dioxide (E171), macrogol, yellow iron oxide (E172), red iron oxide (E172), Opadry OY-L-24808 (orange) and black iron oxide (E172) for 500 mg/2.5 mg, and Opadry 31-F-22700 (yellow) and Quinoline Yellow Lake (E104) for 500 mg/5mg.
Action
Pharmacotherapeutic Group: Biguanides and sulphonamide(s) in combination. ATC Code: A10BD02.
Pharmacology: Pharmacodynamics: Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore, does not produce hypoglycaemia.
Metformin may act via 3 mechanisms: Reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; increasing insulin sensitivity and improving peripheral glucose uptake and utilization in muscle; and by delaying intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport capacity of all types of membrane glucose transporters (GLUT).
In humans, independently of its action on glycaemia, metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: Metformin reduces total cholesterol, low-density lipoprotein (LDL)-cholesterol and triglyceride levels. In clinical trials conducted so far with combination therapy with metformin and glibenclamide, these favourable effects on lipid metabolism have not been shown.
Glibenclamide is a 2nd generation sulphonylurea with a medium half-life. It causes acute lowering of blood glucose by stimulating the release of insulin by the pancreas, this effect being dependent on the presence of functioning β-cells in the islets of Langerhans.
The stimulation of insulin secretion by glibenclamide in response to a meal is of major importance.
The administration of glibenclamide to diabetics induces an increase in the postprandial insulin-stimulating response. The increased postprandial responses in insulin and C-peptide secretion persist after at least 6 months of treatment.
Metformin and glibenclamide have different mechanisms and sites of action, but their action is complementary. Glibenclamide stimulates the pancreas to secrete insulin, while metformin reduces cell resistance to insulin by acting on peripheral (skeletal muscle) and hepatic sensitivity to insulin.
Results from controlled, double-blind clinical trials versus reference products in the treatment of type 2 diabetes inadequately controlled by monotherapy with metformin or glibenclamide combined with diet and exercise, have demonstrated that the combination had an additive effect on glucose regulation.
Paediatric Patients: In a 26-week, active controlled, double-blind, clinical study performed in 167 paediatric patients 9 to 16 years with type 2 diabetes not adequately controlled with diet and exercise, with or without an oral antidiabetic treatment, a fixed combination of metformin hydrochloride 250 mg and glibenclamide 1.25 mg was not shown more effective to either metformin hydrochloride or glibenclamide in reducing HbA1c from baseline. Therefore, Glucovance should not be used in pediatric patients.
Pharmacokinetics: Related to the Combination: The bioavailability of metformin and glibenclamide in the combination is similar to that noted when metformin 1 tab and glibenclamide 1 tab are taken simultaneously. The bioavailability of metformin in the combination is unaffected by the ingestion of food. The bioavailability of glibenclamide in the combination is unaffected by the ingestion of food, but the absorption speed of glibenclamide is increased by eating.
Related to Metformin: Absorption: After an oral dose of metformin, time to maximum plasma concentration (Tmax) is reached in 2.5 hours. Absolute bioavailability of metformin tablet 500- or 850-mg is approximately 50 to 60% in healthy subjects. After an oral dose, the nonabsorbed fraction recovered in faeces was 20-30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is nonlinear. At the usual metformin doses and dosing schedules, steady-state plasma concentrations are reached within 24 to 48 hrs and are generally <1 mcg/mL. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 4 mcg/mL, even at maximum doses.
Distribution: Plasma protein-binding is negligible. Metformin partitions into erythrocytes.
The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution (Vd) ranged from 63 to 276 L.
Metabolism: Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination: Renal clearance of metformin is >400 mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus, the elimination half-life is prolonged, leading to increased levels of metformin in plasma.
Related to Glibenclamide: Absorption: Glibenclamide is very readily absorbed (>95%) following oral administration. The peak plasma concentration is reached in about 4 hours.
Distribution: Glibenclamide is extensively bound to plasma albumin (99%), which may account for certain drug interactions.
Metabolism: Glibenclamide is completely metabolised in the liver to 2 metabolites. Hepatocellular failure decreases glibenclamide metabolism and appreciably slows down its excretion.
Excretion: Glibenclamide is excreted in the form of metabolites via biliary route (60%) and urine (40%), elimination being complete within 45-72 hrs. Its terminal elimination half-life is 4-11 hours.
Biliary excretion of the metabolites increases in cases of renal insufficiency, according to the severity of renal impairment until a creatinine clearance (CrCl) at 30 mL/min. Thus, glibenclamide elimination is unaffected by renal insufficiency as long as the CrCl remains >30 mL/min.
Paediatric Patients: There were no differences in pharmacokinetics of glibenclamide and metformin between paediatric patients, and weight- and gender-matched healthy adults.
Toxicology: Preclinical Safety Data: No preclinical studies have been performed on the combination product. Preclinical evaluation of the constituents metformin and glibenclamide revealed no special hazard for humans based on conventional studies of repeated-dose toxicity, genotoxicity and carcinogenic potential.
Animal studies on metformin and glibenclamide do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development parturition or postnatal development. (see Use in lactation under Contraindications, Use in pregnancy under Precautions and Use in Pregnancy & Lactation).
Indications/Uses
As second-line therapy when diet, exercise and initial treatment with a sulfonylurea or metformin do not result in adequate glycaemic control in patients with type 2 diabetes.
Dosage/Direction for Use
General Consideration: Dosage of Glucovance must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended daily dose of metformin 2000 mg/glibencamide 20 mg. Glucovance should be given with meals with a sufficiently high carbohydrate content to prevent the onsent of hypoglycaemic episode. Glucovance should be initiated at a low dose, with gradual dose escalation described as follows, in order to avoid hypoglycemia (largely due to glibenclamide), to reduce gastrointestinal side effects (largely due to metformin) and to permit determination of the minimum effective dose for adequate control of blood glucose for the individual patient.
With initial treatment and during dose titration, appropriate blood glucose monitoring should be used to determine the therapeutic response to Glucovance and to identify the minimum effective dose for the patient. Thereafter, glycosylated haemoglobin (HbA1c) should be measured at intervals of approximately 3 months to assess the effectiveness of therapy. The therapeutic goal in all patients with type 2 diabetes is to decrease fasting-plasma glucose (FPG), postprandial-plasma glucose (PPG) and HbA1c to normal or as near normal as possible. Ideally, the response to therapy should be evaluated using HbA1c, which is a better indicator of long-term glycemic control than FPG alone.
No studies have been performed specifically examining the safety and efficacy of switching to Glucovance therapy in patients taking concomitant glibenclamide (or other sulfonylurea) plus metformin. Changes in glycemic control may occur in such patients, with either hyperglycemia or hypoglycemia possible. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring.
Glucovance Use in Previously Treated Patients (Second-Line Therapy): Recommended Starting Dose: 500/2.5 mg or 500/5 mg twice daily with meals.
For patients not adequately controlled on either glibenclamide (or another sulfonylurea) or metformin alone, the recommended starting dose of Glucovance is 500/2.5 mg or 500/5 mg twice daily with the morning and evening meals. In order to avoid hypoglycemia, the starting dose of Glucovance should not exceed the daily doses of glibenclamide or metformin already being taken. The daily dose should be titrated in increments of no more than 500/5 mg up to the minimum effective dose to achieve adequate control of blood glucose or to a maximum dose of 2000 mg/20 mg daily.
For patients previously treated with combination therapy of glibenclamide (or another sulfonylurea) plus metformin, if switched to Glucovance, the starting dose should not exceed the daily dose of glibenclamide (or equivalent dose of another sulfonylurea) and metformin already being taken. Patients should be monitored closely for signs and symptoms of hypoglycemia following such a switch and the dose of Glucovance should be titrated as described previously to achieve adequate control of blood glucose.
Specific Patient Populations: Glucovance is not recommended for use during pregnancy or for use in pediatric patients.
The initial and maintenance dosing of Glucovance should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment requires a careful assessment of renal function. Generally, elderly, debilitated and malnourished patients should not be titrated to the maximum dose of Glucovance to avoid the risk of hypoglycemia. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in the elderly (see Precautions).
Overdosage
Overdosage may precipitate hypoglycaemia due to the presence of the sulphonylurea (see Precautions).
High overdosage or the existence of concomitant risk factors may lead to lactic acidosis due to the presence of metformin (see Precautions). Lactic acidosis is a medical emergency and must be treated in hospital. The most effective treatment is to remove lactate and metformin by haemodialysis.
The plasma clearance of glibenclamide may be prolonged in patients suffering from liver disease. Since glibenclamide is extensively bound to proteins, it is not eliminated by dialysis.
Contraindications
Hypersensitivity to metformin hydrochloride, glibenclamide or other sulphonylurea(s) and sulphonamide(s), or to any of the excipients of Glucovance. Type 1 diabetes (insulin-dependent diabetes), ketoacidosis, diabetic precoma; renal failure or renal dysfunction (CrCl <60 mL/min); acute conditions with the potential to alter renal function eg, dehydration, severe infection, shock, intravascular administration of iodinated contrast materials (see Precautions); acute or chronic disease which may cause tissue hypoxia eg, cardiac or respiratory failure, recent myocardial infarction, shock; hepatic insufficiency, acute alcohol intoxication, alcoholism; porphyria; in association with miconazole (see Precautions).
Special Precautions
Lactic Acidosis: Lactic acidosis is a rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by assessing also other associated risk factors eg, poorly controlled diabetes, ketosis, prolonged fasting, alcoholism, hepatic insufficiency and any condition associated with hypoxia.
Diagnosis: The risk of lactic acidosis must be considered in the event of nonspecific signs eg, muscle cramps with digestive disorders as abdominal pain and severe asthenia.
Lactic acidosis is characterized by acidotic dyspnea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels >5 mmol/L, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, Glucovance should be discontinued and the patient should be hospitalised immediately (see Overdosage).
Hypoglycaemia: As it contains a sulphonylurea, Glucovance exposes the patient to a risk of onset of hypoglycaemic episodes. After treatment initiation, a progressive dose titration may prevent the onset of hypoglycaemia. 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, when alcohol intake or during the administration of a combination of hypoglycaemic agents.
Diagnosis: The symptoms of hypoglycaemia 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 counterregulation caused by the hypoglycaemia, sweating, fear, tachycardia, hypertension, palpitations, angina and arrhythmia can occur. These latter symptoms can be absent when the hypoglycaemia is developed slowly, in case of autonomic neuropathy or when the patients take β-blocking agents, clonidine, reserpine, guanethidine or sympathomimetics.
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 IV 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.
Factors Favouring Hypoglycaemia: 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; overdosage of Glucovance; certain endocrine disturbances eg, thyroid insufficiency, pituitary and adrenal gland insufficiency; concomitant administration of certain other drugs (see Interactions).
Renal and Hepatic Failure: The pharmacokinetics and/or pharmacodynamics of Glucovance may be modified in patients with hepatic failure or severe renal failure. If hypoglycaemia occurs in such patients, it may be prolonged, and appropriate treatment must be initiated.
Patient Information: The risks of hypoglycaemia, its symptoms and its treatment, as well as its predisposing conditions, must be explained to the patient and to his or her family. Similarly, the risk of lactic acidosis must be considered in the event of nonspecific signs eg, muscle cramps accompanied by digestive disorders, abdominal pain and severe asthenia, dyspnoea attributed to acidosis, hypothermia and coma.
In particular, the patient should be informed of the importance of adhering to a diet, following a programme of regular physical exercise and making regular checks on glycaemia.
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 urination, raging thirst and dry skin.
Kidney Function: As metformin is excreted by the kidney, it is recommended that CrCl and/or serum creatinine levels be determined before initiating treatment and regularly thereafter: At least annually in patients with normal renal function; at least 2-4 times a year in patients with serum creatinine levels at the upper limit of normal (ULN) and in elderly subjects.
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 therapy or diuretic therapy, and when starting therapy with a nonsteroidal anti-inflammatory drug (NSAID).
Administration of Iodinated Contrast Materials: The intravascular administration of iodinated contrast materials in radiological studies can lead to renal failure. Depending on the renal function, Glucovance must be discontinued 48 hrs before the test or at the time of the test and may not be reinstituted until 48 hrs afterwards, and only after renal function has been reevaluated and found to be normal (see Interactions).
Concomitant Use of Glibenclamide with Other Medicinal Products: The concomitant use of glibenclamide with alcohol, phenylbutazone or danazol is not recommended (see Interactions).
Surgery: Because Glucovance contains metformin hydrochloride, Glucovance must be discontinued 48 hrs before elective surgery under general, spinal or peridural anesthesia and may not be reinstituted earlier than 48 hrs afterwards or resumption of oral nutrition, and only after renal function has been reevaluated and found to be normal.
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 and regular physical exercise is as necessary as taking Glucovance.
The usual laboratory tests for diabetes monitoring (glycaemia, HbA1c) should be performed regularly.
Treatment of patients with G6PD-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 nonsulphonylurea alternative may be considered.
Because 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 or Operate Machinery: Patients should be alerted to the symptoms of hypoglycemia, and should be advised to exercise caution when driving or using machines.
Use in pregnancy: No preclinical and clinical data on exposed pregnancies are available for Glucovance.
Risk Related to Diabetes: When uncontrolled, diabetes (gestational or permanent) gives rise to an increase in congenital abnormalities and perinatal mortality. Diabetes must be controlled as far as possible during the period of conception in order to reduce the risk of congenital abnormalities.
Risk Related to Metformin (see Pharmacology: Toxicology under Actions): Studies in animals have shown no evidence of teratogenic activity. In the absence of a teratogenic effect in animals, foetal malformation in humans is not to be expected since to date, substances known to cause malformation in humans have proved to be teratogenic in well-conducted animal studies in 2 species.
Clinical studies involving a few small series have not shown evidence of foetal malformation directly related to metformin.
Risk Related to Glibenclamide (see Pharmacology: Toxicology under Actions): Studies in animals have shown no evidence of teratogenic activity. In the absence of a teratogenic effect in animals, foetal malformation in humans is not to be expected since to date, substances known to cause malformation in humans have proved to be teratogenic in well-conducted animal studies in 2 species.
In clinical practice, there are currently no relevant data on which to base an evaluation of potential malformation or fetotoxicity due to glibenclamide when administered during pregnancy.
Management: Adequate blood glucose control allows pregnancy to proceed normally in this category of patients. Glucovance must not be used for the treatment of diabetes during pregnancy.
It is imperative that insulin be used to achieve adequate blood glucose control. It is recommended that the patient be transferred from oral antidiabetic therapy to insulin as soon as pregnancy is planned or if pregnancy is exposed to Glucovance. Neonatal blood glucose monitoring is recommended.
Use In Pregnancy & Lactation
Use in pregnancy: No preclinical and clinical data on exposed pregnancies are available for Glucovance.
Risk Related to Diabetes: When uncontrolled, diabetes (gestational or permanent) gives rise to an increase in congenital abnormalities and perinatal mortality. Diabetes must be controlled as far as possible during the period of conception in order to reduce the risk of congenital abnormalities.
Risk Related to Metformin (see Pharmacology: Toxicology: Preclinical safety Data under Actions): Studies in animals have shown no evidence of teratogenic activity. In the absence of a teratogenic effect in animals, foetal malformation in humans is not to be expected since to date, substances known to cause malformation in humans have proved to be teratogenic in well-conducted animal studies in 2 species.
Clinical studies involving a few small series have not shown evidence of foetal malformation directly related to metformin.
Risk Related to Glibenclamide (see Pharmacology: Toxicology: Preclinical Safety Data under Actions): Studies in animals have shown no evidence of teratogenic activity. In the absence of a teratogenic effect in animals, foetal malformation in humans is not to be expected since to date, substances known to cause malformation in humans have proved to be teratogenic in well-conducted animal studies in 2 species.
In clinical practice, there are currently no relevant data on which to base an evaluation of potential malformation or fetotoxicity due to glibenclamide when administered during pregnancy.
Management: Adequate blood glucose control allows pregnancy to proceed normally in this category of patients. Glucovance must not be used for the treatment of diabetes during pregnancy.
It is imperative that insulin be used to achieve adequate blood glucose control. It is recommended that the patient be transferred from oral antidiabetic therapy to insulin as soon as pregnancy is planned or if pregnancy is exposed to Glucovance. Neonatal blood glucose monitoring is recommended.
Use in lactation: Metformin is excreted in milk in lactating rats. In humans, in the absence of data concerning passage of metformin and glibenclamide into breast milk, and in view of the risk of neonatal hypoglycaemia, Glucovance is contraindicated in the event of breastfeeding.
Adverse Reactions
The following adverse reactions may occur under treatment with Glucovance. Frequencies are defined as follows: Very common (>1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Within each frequently grouping, undesirable effects are presented in order of decreasing seriousness.
Investigations: Uncommon: Average to moderate elevations in serum urea and creatinine concentrations. Very Rare: Hyponatremia.
Blood and Lymphatic System Disorders: These are reversible upon treatment discontinuation. Rare: Leukopenia, thrombocytopenia. Very Rare: Agranulocytosis, haemolytic anaemia, bone marrow aplasia and pancytopenia.
Nervous System Disorders: Common: Taste disturbance.
Eye Disorders: Transient visual disturbances may occur at the start of treatment due to decreased glycaemia levels.
Gastrointestinal Disorders: Very Common: Gastrointestinal disorders eg, nausea, vomiting, diarrhoea, abdominal pain and loss of appetite. These adverse reactions occur more frequently during treatment initiation and resolve spontaneously in most cases. To prevent them, it is recommended that Glucovance be taken in 2 or 3 daily doses. A slow increase of the dose may also improve gastrointestinal tolerability.
Skin and Subcutaneous Tissue Disorders: Rare: Skin reactions eg, pruritus, urticaria, maculopapular rash. Very Rare: Cutaneous or visceral allergic angiitis, erythema multiforme, exfoliative dermatitis, photosensitization, urticaria evolving to shock.
A cross-reactivity to sulphonamide(s) and their derivatives may occur.
Metabolism and Nutrition Disorders: Hypoglycaemia (see Precautions). Uncommon: Crises of hepatic porphyria and porphyria cutanea. Very Rare: Lactic acidosis (see Precautions). Decreased vitamin B12 absorption with decreased serum levels during long-term use of metformin. Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia.
Disulfiram-like reaction with alcohol intake.
Hepatobiliary Disorders: Very Rare: Liver function test abnormalities or hepatitis requiring treatment discontinuation.
Drug Interactions
Contraindicated Combination: Related to Glibenclamide: Miconazole (Systemic Route, Oromucosal Gel): Increased hypoglycaemic effect with possible onset of hypoglycaemic manifestations or even coma (see Contraindications).
Inadvisable Combinations: Related to Sulphonylurea(s): Alcohol: Antabuse effect (intolerance to alcohol), notably for chlorpropamide, glibenclamide, glipizide, tolbutamide.
Increased hypoglycaemic reaction (inhibition of compensation reactions), which may facilitate the onset of a hypoglycaemic coma (see Precautions).
Avoid consumption of alcohol and alcohol-containing medications.
Phenylbutazone (Systemic Route): Increased hypoglycaemic effect of sulphonylurea(s) [displacement of sulphonylurea(s) from protein-binding sites and/or decreased 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.
Related to All Antidiabetic Agents: 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.
Related to Metformin: Alcohol: Increased risk of lactic acidosis during acute alcoholic intoxication, particularly in cases of fasting or malnutrition and hepatocellular failure.
Avoid drinking alcoholic beverages and taking drugs that contain alcohol.
Combinations Requiring Precautions: Related to All Antidiabetic Agents: Chlorpromazine: At high dosages (chlorpromazine 100 mg daily), 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 Tetracosactides (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 its withdrawal.
Beta2-Agonists: Elevation in blood glucose due to the β2-agonists.
Precaution for Use: Warn the patient, step-up blood glucose monitoring and possibly transfer to insulin therapy.
Angiotensin-Converting Enzyme (ACE) Inhibitors (eg, 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.
Related to Metformin: Diuretics: Lactic acidosis due to metformin triggered by any functional renal insufficiency, related to diuretics and more particularly to loop diuretics.
Iodinated Contrast Materials: Intravascular administration of iodinated contrast materials may lead to renal failure. This may induce metformin accumulation and may expose to lactic acidosis. Depending on the renal function, Glucovance must be discontinued 48 hrs before the test or at the time of the test, and not reinstituted until 48 hrs afterwards, and only after renal function has been reevaluated and found to be normal.
Related to Glibenclamide: β-Blockers: All β-blockers mask some of the symptoms of hypoglycaemia (palpitations and tachycardia). Most noncardioselective β-blockers increase the incidence and severity of hypoglycaemia.
Warn the patient and step-up blood glucose self-monitoring, especially at the start of treatment.
Fluconazole: Increased half-life of sulphonylurea 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.
Bosentan: Risk of decreased hypoglycaemic effect of glibenclamide because bosentan reduces the plasma concentration of glibenclamide. An increased risk of liver enzyme elevations was reported in patients receiving glibenclamide concomitantly with bosentan.
Warn the patient, set-up monitoring of glycaemia and liver enzymes, and adjust the dosage of the antidiabetic treatment if necessary.
Other Interaction: Combination to be Taken into Account: Related to Glibenclamide: Desmopressin: Reduction in antidiuretic activity.
Incompatibilities: Not applicable.
Storage
Store below 30°C.
Shelf-Life: 3 years.
MIMS Class
ATC Classification
A10BD02 - metformin and sulfonylureas ; Belongs to the class of combinations of oral blood glucose lowering drugs. Used in the treatment of diabetes.
Presentation/Packing
500/2.5 mg FC tab (orange, capsule-shaped, biconvex, with '2.5' engraved on one side) 120's. 500/5 mg FC tab (yellow, capsule-shaped, biconvex, with '5' engraved on one side) 120's.
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