Forbetes Plus 500/5

Orange caplet and vanilla odor with sign breakline-SANBE which contain Metformin Hydrochloride and micronized Glibenclamide.
Each film-coated caplet contains: Metformin Hydrochloride 500 mg, Glibenclamide 5 mg.
Excipients/Inactive Ingredients: Microcrystalline Cellulose, Croscarmellose Sodium, Povidone K25, Silicon Dioxide Colloidal, Magnesium Stearate, Hydroxypropyl Methylcellulose, Polyethylene Glycol 6000, Talc, Titanium Dioxide, Pigment Yellow No. 5 FDC, Pigment Yellow No. 6 FDC, Vanilla Dry Flavor, Ethyl Alcohol, and Purified Water.

Pharmacology: Pharmacodynamics: Metformin is a biguanide with anti-hyperglycaemic 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: By reducing hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis.
In muscle, by increasing Insulin sensitivity, improving peripheral glucose uptake and utilisation.
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 and report: Metformin reduces total cholesterol, LDL-cholesterol and triglyceride levels. In report conducted so far with combination therapy with Metformin and Glibenclamide, these favourable effects on lipid metabolism have not been shown.
Glibenclamide is a second generation Sulfonylurea 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 beta 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.
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.
Pediatric Patients: Pediatric patients aged 9 to 16 years with type 2 diabetes not adequately controlled with diet and exercise, with or without an oral anti-diabetic 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, this product 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 one caplet of Metformin and one caplet of Glibenclamide 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.

FORBETES PLUS is indicated as second-line therapy when diet, exercise, and initial treatment with a Sulfonylurea or Metformin do not result in adequate glycemic control in patients with type 2 diabetes with HbA1c above 8%.

General Considerations: Dosage of FORBETES PLUS must be individualized on the basic of both effectiveness and tolerance while not exceeding the maximum recommended daily dose of 2,000 mg Metformin/20 mg Glibenclamide. FORBETES PLUS should be given with meals and should be initiated at a low dose, with gradual dose escalation as described as follows, in order to avoid hypoglycemia (largely due to Glibenclamide), to reduce GI 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 this product and to identify the minimum effective dose for the patient. Thereafter, 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 FPG, PPG, and HbA1c to normal or as near normal as possible. Ideally, the response to therapy should be evaluated using HbA1c (glycosylated hemoglobin), 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 this product therapy in patients taking concomitant Glibenclamide (or other Sulfonylurea) plus Metformin. Changes in glycemic control may occur in such patients, with either hyperglycemia or possible. Any change in therapy of type 2 diabetes should undertaken with care and appropriate monitoring.
FORBETES PLUS Used In Previously Treated Patients (Second Line Therapy): Recommended starting dose: 500 mg/2.5 mg or 500 mg/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 FORBETES PLUS 500 mg/2.5 mg or 500 mg/5 mg twice daily with the morning and evening meals. In order to avoid hypoglycemia, the starting dose of FORBETES PLUS 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 mg/5 mg up to the minimum effective dose to achieve adequate control of blood glucose or to a maximum dose of 2,000 mg/20 mg per day. For patients previously treated with combination therapy with Glibenclamide (or another Sulfonylurea) plus Metformin, if switched to FORBETES PLUS, the starting dose should not exceed the daily dose of Glibenclamide (or equivalent dose of another of 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 FORBETES PLUS should be titrated as described previously to achieve adequate control of blood glucose. When FORBETES PLUS is co-administered with a bile acid sequestrant, it is recommended that FORBETES PLUS should be administered at least 4 hours prior to the bile acid sequestrant in order to minimize the risk of reduced absorption (see Interactions).
Pediatric use: Safety and effectiveness of FORBETES PLUS in pediatric patients have not been established.
Geriatric use: No overall differences in effectiveness or safety were observed between elderly patients and younger patients, and other reported has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Metformin Hydrochloride is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is the greater in patients with impaired renal function, FORBETES PLUS should only be used in patients with normal renal function. Because aging is associated with reduced renal function, FORBETES PLUS should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of FORBETES PLUS.

Glibenclamide: Overdosage of Sulfonylureas, including Glibenclamide tablets, can produce hypoglycemia. Mild hypoglycemic symptoms, without loss of consciousness or neurological findings, should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnoses or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) Glucose solution. This should be followed by a continuous infusion of a more dilute (10%) Glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may recur after apparent clinical recovery.
Metformin Hydrochloride: Hypoglycemia has not seen even with ingestion of up to 85 grams of Metformin Hydrochloride, although lactic acidosis has occurred in such circumstances. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom Metformin overdosage is suspected.

Combinations Metformin Hydrochloride and Glibenclamide are contraindicated in patients with: Hypersensitivity to Metformin Hydrochloride or Glibenclamide or other Sulfonylurea(s) and Sulfonamide(s) or to any of the excipients.
Diabetic pre-coma.
Any type of metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis).
Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels 1.5 mg/dL [males], 1.4 mg/dL [females], or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia.
Disease which may cause tissue hypoxia (especially acute disease, or worsening of chronic disease) such as decompensated heart failure, respiratory failure, recent myocardial infarction, shock.
Hepatic insufficiency, acute alcohol intoxication, alcoholism.
Porphyria.
Lactation.
In association with Miconazole.

Lactic acidosis: Lactic acidosis is a very rare, but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis.
In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), Metformin should be temporarily discontinued and contact with a healthcare professional is recommended.
Medical product that can acutely impair renal function (such as antihypertensive diuretics and NSAIDs) should be initiated with caution in Metformin treated patients. Other risk factor for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis, (see Contraindications and Interactions).
Patients and/or care-givers should be informed of the risk of lactic acidosis. Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptom, the patient should stop taking Metformin and seek immediate attention. Diagnostic laboratory findings are decreased blood pH (<7.35), increased plasma lactate levels (>5 mmol/L) and an increased anion gap and lactate/pyruvate ratio.
The reported incidence of lactic acidosis in patients receiving Metformin hydrochloride is very low (approximately 0.03 cases/1,000 patients-years, with approximately 0.015 fatal cases/1,000 patients-years). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypofunction often in the setting of multiple concomitant medical surgical problems and multiple concomitant meditation. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypofunction and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patient taking Metformin and by use of the minimum effective dose of Metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. this product treatment should not be initiated in patients 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, this product should be promptly with held in the function may significantly limit the ability to clear lactate, this product should generally by avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking this product since alcohol potentiates the effects of Metformin hydrochloride on lactate metabolism. In addition, this product should be temporary discontinued prior to any intravascular radiocontrast study and for any surgical procedure.
The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such is malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient should be instructed to notify the physician immediately if they occur. This product should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood Metformin levels may be useful. Once a patient is stabilized on any dose level of this product, gastrointestinal symptoms, which are common during initiation or therapy with Metformin, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due lactic acidosis or other serious disease.
Level of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking this product do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. 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 a hospital setting. In a patient with lactic acidosis who is taking this product, the drug should be discontinued immediately and general supportive measures promptly instituted. Because Metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and removed the accumulated Metformin. Such management often result in prompt reversal of symptoms and recovery.
Impaired hepatic function: Since impaired hepatic function has been associated with some cases of lactic acidosis, this product should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
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, this product must be stopped immediately and other appropriate corrective measures initiated.
Hypoglycemia: This product 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 level 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.
Renal Function: Metformin is known to be substantially excreted by the kidney, and the risk of Metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive this product. In patients with advanced age, this product should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those >80 years of age, renal function should be monitored regularly and generally, this product should not be titrated to the maximum dose. Before initiation of this product therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and this product discontinued if evidence of renal impairment is present.
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, should be used with caution.
Radiologic studies involving the use if intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scan with intravascular contrast materials).
Intravascular contrast studies with iodinated materials can lead to acute alternation of renal function and have been associated with lactic acidosis in patients receiving Metformin. Therefore, in patients in whom any such study is planned, this product should be temporarily discontinued at the time of or prior to the procedure, and with-held for 48 hours subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal.
Hypoxic states: Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction, and other condition characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on this product therapy, the drug should be promptly discontinued.
Surgery: This product therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.
Alcohol intake: Alcohol is known to potentiate the effect if Metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute chronic, while receiving this product. 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 this product should be avoided in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B12 levels: A decrease to subnormal levels of previously normal serum vitamin B12 without clinical manifestations. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of Metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on Metformin 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. In these patients, routine serum vitamin B12 measurements at two-to three years intervals may be useful.
Other precautions: Treatment of patients with G6PD-deficiency with Sulfonylurea agents can lead to haemolytic anaemia. Since Glibenclamide belongs to the chemical class of Sulfonylurea drugs, caution is recommended when using this product is patients with G6PD-deficiency and a non Sulfonylurea alternative may be considered.
This product contains Lactose. Therefore its use is not recommended in patients with rare hereditary problems of Galactose-intolerance, the Lapp lactase deficiency or Glucose-Galactose malabsorption.
Use in the Elderly: Age of 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 hypoglycemia (see Dosage & Administration).

Pregnancy: Teratogenic Effects: Pregnancy Category B.
Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities.
Most experts recommend that Insulin be used during pregnancy to maintain blood glucose as close to normal as possible. Because animal reproduction studies are not always predictive of human response, this product should not be used during pregnancy unless clearly needed.
There are no adequate and well-controlled studies in pregnant woman with this product or its individual components. No animal studies have been conducted with the combined products this product. The following data are based on findings in studies performed with the individual products.
Glibenclamide: Glibenclamide component in this product based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to Glibenclamide.
Metformin Hydrochloride: Metformin alone was not teratogenic. Determination of fetal concentration demonstrated a partial placental barrier to Metformin.
Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a Sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. It is not recommended that this product be used during pregnancy. However, if it is used this product should be discontinued at least two weeks before the expected delivery date.
Nursing Mothers: Although it is not known whether Glibenclamide is excreted in human milk, some Sulfonylurea drugs are known to be excreted in human milk. Studies in lactating show that Metformin is excreted into milk an reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue this product, taking into account the importance of the drug to the mother. If this product is discontinued, and if diet alone is inadequate for controlling blood glucose, Insulin therapy should be considered.

During treatment initiation, the most common adverse reactions are nausea, vomiting, diarrhoea, abdominal pain and loss of appetite which resolve spontaneously in most cases. To prevent them, it is recommended to take this product in 2 or 3 daily doses and to increase slowly the doses. Transient visual disturbances may occur at the start of treatment due to a decrease in glycaemia levels.
The following adverse reactions may occur under treatment with this product. Frequencies are defined as follows: very common: >1/10; common ≥1/100, <1/10; uncommon: ≥1/1,000; rare ≥1/10,000, <1/1,000; very rare <1/10,000.
Blood and Lymphatic System Disorders: These are reversible upon treatment discontinuation.
Rare: Leukopenia, thrombocytopenia. Very rare: Agranulocytosis, haemolytic anaemia, bone marrow aplasia and pancytopenia.
Metabolism and Nutrition Disorders: Hypoglycaemia (see Precautions).
Uncommon: Crises of hepatic porphyria and porphyria cutanea. Very rare: Lactic acidosis (see Precautions). Decrease of vitamin B12 absorption with decrease of 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.
Nervous System Disorders: Common: Taste disturbance.
Eye Disorders: Transient visual disturbances may occur at the start of treatment due to a decrease in glycaemia levels.
Gastrointestinal disorders: Very common: Gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite. These undesirable effects occur more frequently during treatment initiation and resolve spontaneously in most cases. To prevent them, it is recommended that this product be taken in 2 or 3 daily doses. A slow increase of the dose may also improve gastrointestinal tolerability.
Skin and Subcutaneous Tissue Disorders: A cross reactivity to sulphonamide(s) and their derivatives may occur. Rare: Skin reactions such as pruritus, urticaria, maculopapular rash. Very rare: cutaneous or visceral allergic angiitis, erythema multiforme, exfoliative dermatitis, photosensitization, urticaria evolving to shock.
Hepatobiliary Disorders: Very rare: Liver function test abnormalities or hepatitis requiring treatment discontinuation.
Investigations: Uncommon: Average to moderate elevations in serum urea and creatinine concentrations.
Very rare: Hyponatremia.

Contraindicated Combination: Related to Glibenclamide: Miconazole: Increase in the hypoglycaemic effect with possible onset of hypoglycaemic manifestations (see Contraindications).
Combination Not Recommended: Related to Sulfonylurea(s): Alcohol: Increase of the hypoglycaemic reaction (inhibition of compensation reactions), which may facilitate the onset of a hypoglycaemic coma manifestations (see Contraindications). Avoid consumption of alcohol and alcohol-containing medications.
Related to All Antidiabetic Agents: Danazol: If the combination cannot avoided, warn the patient and step up self-monitoring of blood glucose. Possibly adjust the dosage of the antidiabetic treatment during treatment with Danazol and after its withdrawal.
Related to Metformin: Alcohol: Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition or hepatic impairment.
Iodinated contrast agents: This product must 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 reevaluated and found to be stable, see Precautions.
Combinations Requiring Precautions: Related to All Antidiabetic Agents: 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 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 treatment with the neuroleptic and after its withdrawal.
Beta-agonists: Elevation in blood glucose due to the beta-agonists.
Precaution for use: warn the patient, step up blood glucose monitoring and possibly transfer to Insulin therapy.
Drugs reducing glycemic control: Certain drugs tend to produce hyperglycemia and may lead to loss of blood glucose control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administrated to a patient receiving this product, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving this product, the patient should be observed closely for hypoglycemia.
Drugs that potentiate the hypoglycemic action of this product The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, Chloramphenicol, Probenecid, Coumarins, monoamine oxidase inhibitors, beta-adrenergic blocking agents, and potentially with Ciprofloxacin. When such drugs are administered to a patient receiving this product, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving this product, the patient should be observed closely for loss of blood glucose control.
Related to Metformin: Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclooxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting of using such products in combination with Metformin, close monitoring of renal function is necessary.
Organic cation transporters (OCT): Metformin is a substrate of both transporters OCT1 and OCT2.
Co-administration of Metformin with: Inhibitors of OCT1 (such as Verapamil) may reduce efficacy of Metformin.
Inducers of OCT1 (such as Rifampicin) may increase gastrointestinal absorption and efficacy.
Inhibitors of OCT2 (such as Cimetidine, Dolutegravir, Ranolazine, Trimethoprim, Daclatasvir, Vandetanib, Isavuconazole) may decrease the renal elimination of Metformin and thus lead to an increase Metformin plasma concentration.
Inhibitors of both OCT1 and OCT2 (such as Crizotinib, Olaparib) may alter efficacy and renal elimination of Metformin.
Caution is therefore advised, especially in patients with renal impairment, when these drugs are coadministered with Metformin, as Metformin plasma concentration may increase. If needed, dose adjustment of Metformin may be considered as OCT inhibitors/ inducers may alter the efficacy of Metformin.
Related to Glibenclamide: Beta-blockers: All beta-blockers 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.
Angiotensin converting enzyme inhibitors (e.g., Captopril, Enalapril): ACE inhibitors may decrease the blood glucose levels. If necessary, adjust the dosage of this product during therapy with an ACE inhibitor and upon its discontinuation.
Fluconazole: Increase in the 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 treatment during treatment with Fluconazole and after its withdrawal.
Bosentan: Risk of decreased hypoglycaemic effect of Glibenclamide because Bosentan reduces plasma concentration of Glibenclamide. An increase 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.
Bile acid sequestrants: When co-administered simultaneously the plasma concentration of Glibenclamide is reduced which may lead to a reduced hypoglycaemic effect. This effect was not observed if Glibenclamide is given in a certain period of time before taking the other medicine. It is recommended that this product should be administered at least 4 hours prior a bile acid sequestrant.

Store below 30°C.

Antidiabetic Agents

A10BD02 - metformin and sulfonylureas ; Belongs to the class of combinations of oral blood glucose lowering drugs. Used in the treatment of diabetes.

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