Pharmacological properties
Pharmacodynamics. Metformin is a biguanide with antihyperglycemic effect. It reduces the level of glucose in the blood plasma both on an empty stomach and after a meal. It does not stimulate insulin secretion and does not cause a hypoglycemic effect mediated by this mechanism.
Metformin works in three ways:
causes a decrease in glucose production in the liver by inhibiting gluconeogenesis and glycogenolysis; improves insulin sensitivity in muscles, which leads to improved peripheral glucose uptake and utilization; delays glucose absorption in the intestine.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthetase. It increases the transport capacity of all known types of membrane glucose transporters (GLUT).
Independently of its action on glycemia, metformin has a positive effect on lipid metabolism. This effect has been demonstrated at therapeutic doses in controlled medium- or long-term clinical trials: metformin reduces total cholesterol, low-density lipoproteins and triglycerides.
In the course of clinical studies conducted to date, this positive effect on lipid metabolism during the simultaneous use of metformin and glibenclamide has not been detected.
Glibenclamide is a second-generation sulfonylurea with an average half-life of ½. It stimulates insulin production by the pancreas, which causes a sharp decrease in blood glucose levels. This action depends on the presence of functioning β-cells (islets of Langerhans).
The stimulation of insulin secretion by glibenclamide in response to food intake is important. The use of glibenclamide in patients with diabetes mellitus leads to an increase in insulin secretion stimulated by food intake. The increased secretion of insulin and C-peptide persists for at least 6 months after treatment.
Metformin and glibenclamide have different mechanisms of action, but their actions are complementary. Glibenclamide stimulates insulin secretion by the pancreas, while metformin reduces cell resistance to insulin, i.e. increases the sensitivity of peripheral tissues (skeletal muscles) and liver tissues to insulin.
The results of controlled, double-blind clinical trials with reference drugs for the treatment of type 2 diabetes mellitus, which is not adequately controlled by monotherapy with metformin or glibenclamide in combination with diet and exercise, showed that the use of combination therapy had a comprehensive effect on glucose control.
Children. In an active-controlled, double-blind clinical study lasting 26 weeks in 167 patients aged 9 to 16 years with type 2 diabetes mellitus who were inadequately controlled on diet and exercise with or without oral hypoglycemic agents, the fixed combination of metformin hydrochloride 250 mg and glibenclamide 1.25 mg did not demonstrate superior efficacy in reducing glycosylated hemoglobin (HbA1c) from baseline. Therefore, Glibofor should not be used in children.
Pharmacokinetics
In relation to the combination. The bioavailability of metformin and glibenclamide in the combination is the same if 1 tablet of metformin and 1 tablet of glibenclamide are taken at the same time. The bioavailability of metformin in the combination is independent of food intake. The bioavailability of glibenclamide in the combination is independent of food intake, however, the rate of absorption of glibenclamide increases with food intake.
In relation to metformin. Absorption. After oral administration of a dose of metformin, maximum plasma concentration (C max) is reached in 2.5 hours, time to maximum concentration (t max). The absolute bioavailability of metformin tablets 500 or 850 mg is about 50-60% in healthy volunteers. After oral administration, metformin, which is not absorbed, is excreted in the feces in an amount of 20-30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption are nonlinear. When used in recommended doses of metformin and dosing regimens, steady-state plasma concentrations are achieved within 24-48 hours and are 1 μg/ml. During controlled clinical studies, C max of metformin in plasma did not exceed 5 μg/ml even when using the drug in maximum doses.
Distribution. Binding to plasma proteins is negligible. Metformin penetrates into erythrocytes. C max in the blood is lower than in plasma and is reached after approximately the same time. Erythrocytes most likely represent the second distribution chamber. The mean volume of distribution (Vd) ranges from 63 to 276 liters.
Metabolism: Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination. Renal clearance of metformin is 400 ml/min. This indicates that metformin is eliminated by glomerular filtration and tubular secretion. After oral administration, T½ is approximately 6.5 hours. In renal impairment, renal clearance decreases in proportion to creatinine clearance and therefore T½ increases, leading to increased metformin plasma levels.
In relation to glibenclamide
Distribution: Glibenclamide is highly bound to plasma proteins (99%), which may affect interactions with some drugs.
Metabolism: Glibenclamide is completely metabolized in the liver to form two metabolites. Hepatic insufficiency reduces the metabolism of glibenclamide and significantly slows its elimination.
Excretion. Glibenclamide is excreted in the form of metabolites with bile (60%) and urine (40%). It is completely excreted after 45-72 hours. The final T ½ is 4-11 hours.
The excretion of metabolites with bile increases in patients with renal insufficiency depending on the degree of renal impairment, if creatinine clearance is 30 ml/min. Therefore, if creatinine clearance is 30 ml/min, renal insufficiency does not affect the excretion of glibenclamide.
Children. The pharmacokinetics of glibenclamide and metformin in children did not differ from those in healthy adult volunteers of similar body weight and gender.
Indication
Treatment of type 2 diabetes mellitus in adults, to replace previous therapy with two drugs (metformin and glibenclamide) in patients with stable and well-controlled glycemia.
Application
Inside. For use in adult patients only.
As with other hypoglycemic agents, the dose of Glibofor is set individually depending on the individual metabolic response (glycemia and HbA1c levels).
It is recommended to use Glibofor 500 mg / 5 mg in patients in whom adequate glycemic control is not achieved when using the drug in lower doses.
When replacing combination therapy with metformin and glibenclamide, treatment with Glibofor should be started at doses according to the previous dosage. The dose should be gradually increased depending on the results of glycemia measurements.
Every ≥2 weeks after the start of therapy, it is necessary to adjust the dosage (additionally increase the dose by 1 tablet) depending on the level of glycemia.
Gradual dose increases help reduce gastrointestinal side effects and prevent the development of hypoglycemia.
The maximum recommended dose is 3 tablets of Glibofor 500 mg / 5 mg/day.
In individual cases, the dose may be increased to 4 tablets of Glibofor 500 mg / 5 mg/day.
There are no data on the combination therapy of Glibofor with insulin.
The dosage regimen depends individually on the indications:
1 time per day: 1 tablet per day during breakfast; 2 times per day: 2 or 4 tablets per day - morning and evening; 3 times per day: 3 tablets per day - morning, afternoon and evening.
The tablets should be taken with meals.
The dosage regimen can be adjusted according to the individual's dietary regimen. However, in order to prevent episodes of hypoglycemia, it is necessary to consume a meal rich in carbohydrates after each dose of the drug.
In case of simultaneous use with colesevelam, it is recommended to take Glibofor at least 4 hours before taking colesevelam to minimize the risk of reduced absorption (see Interactions with other drugs).
In elderly patients, the dosage of the drug is adjusted depending on the parameters of renal function (initial dose - 1 tablet Glibofor 500 mg / 2.5 mg). It is necessary to regularly assess renal function (see Features of use).
Contraindication
Hypersensitivity to metformin, glibenclamide, other components of the drug or to other sulfonylurea drugs, to sulfonamides; in case of diabetes mellitus, when insulin treatment is required: type I diabetes mellitus (insulin-dependent diabetes mellitus), complete secondary ineffectiveness of glibenclamide therapy in type II diabetes mellitus, acidosis, diabetic ketoacidosis, diabetic precoma or coma, condition after pancreatic resection; renal failure or impaired renal function (creatinine clearance 60 ml/min); acute conditions with a risk of developing renal dysfunction: dehydration, severe infectious diseases, shock; acute and chronic diseases that can lead to the development of hypoxia: heart or respiratory failure, recent myocardial infarction, shock; liver failure, acute alcohol intoxication, alcoholism; porphyria; pregnancy and breastfeeding; combined use with bosentan; combined therapy with miconazole (see interactions).
Side effects
The most frequent adverse reactions at the beginning of treatment are nausea, vomiting, diarrhea, abdominal pain, lack of appetite. These symptoms in most cases resolve on their own. To prevent the occurrence of these side effects, it is recommended to slowly increase the dose and use the daily dose of the drug in 2-3 doses. It is possible to develop short-term visual impairment at the beginning of treatment due to a decrease in glycemia.
Blood and lymphatic system disorders: leukopenia, thrombocytopenia, agranulocytosis, hemolytic anemia, bone marrow aplasia, pancytopenia. These are reversible reactions that disappear after discontinuation of treatment.
Metabolism: acute hepatic porphyria, porphyria cutanea, lactic acidosis (see Special warnings and precautions for use).
Hypoglycemia (see Precautions).
Long-term use of metformin may reduce the absorption of vitamin B12, accompanied by a decrease in its level in the blood serum. It is recommended to take this etiology into account if the patient has megaloblastic anemia.
From the nervous system: taste disturbance.
On the part of the organ of vision: short-term visual disturbances may occur at the beginning of treatment due to a decrease in glycemia.
Gastrointestinal tract: digestive system disorders, including nausea, vomiting, diarrhea, abdominal pain, lack of appetite. Most often, these side effects occur at the beginning of treatment and, as a rule, disappear spontaneously. To prevent the occurrence of side effects from the digestive system, it is recommended to slowly increase the dose and use the drug 2-3 times a day.
Skin and subcutaneous tissue disorders: cross-reactivity to sulfonylureas or their derivatives, skin reactions including pruritus, urticaria, macular rash, cutaneous or visceral allergic vasculitis, erythema multiforme, exfoliative dermatitis, photosensitivity, urticaria leading to shock, erythema.
Hepatic: abnormal liver function tests or hepatitis requiring discontinuation of treatment.
Investigations: moderate increases in serum urea and creatinine, hyponatremia, increases in serum urea and creatinine, hyponatremia.
Special instructions
Lactic acidosis. Lactic acidosis is a very rare but serious metabolic complication (high mortality rate in the absence of urgent treatment) that can occur as a result of metformin accumulation. Cases of lactic acidosis have been reported in diabetic patients with renal failure or acute deterioration of renal function who were taking metformin. Caution should be exercised in cases where renal function may be impaired, for example in case of dehydration (severe diarrhea or vomiting), or at the beginning of treatment with antihypertensive agents, diuretics and at the beginning of therapy with nonsteroidal anti-inflammatory drugs. If these exacerbations occur, metformin should be temporarily discontinued.
Other risk factors should be considered to avoid the development of lactic acidosis: poorly controlled diabetes mellitus, ketosis, prolonged fasting, excessive alcohol consumption, liver failure or any condition associated with hypoxia (decompensated heart failure, acute myocardial infarction).
Diagnosis. The risk of lactic acidosis should be considered in the presence of non-specific symptoms such as muscle cramps, indigestion, abdominal pain and severe asthenia. Patients should immediately inform their doctor about the occurrence of such reactions, especially if previously the patients tolerated metformin treatment well. In such cases, metformin should be temporarily discontinued until the situation is clarified. Metformin therapy should be resumed after assessing the benefit/risk ratio in individual cases and assessing renal function.
Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, hypothermia, and may progress to coma. Laboratory diagnostic signs of this complication include: decreased pH, plasma lactate level of 5 mmol/L, increased anion gap, and increased lactate/pyruvate ratio. If lactic acidosis is suspected, the drug should be discontinued and the patient should be hospitalized immediately (see Conditions and Shelf Life). The physician should warn patients about the risk and symptoms of lactic acidosis.
Hypoglycemia. The drug Glibofor contains a sulfonylurea, so patients using this drug are at risk of developing hypoglycemia. After starting therapy, titration of the drug dose can prevent the development of hypoglycemia. The drug should be prescribed to patients who adhere to a regular meal schedule (including breakfast). Regular carbohydrate intake is an important factor, since the risk of hypoglycemia increases in case of untimely meal intake, insufficient or unbalanced carbohydrate intake. Hypoglycemia most often occurs in patients on a low-calorie diet, after intense or prolonged exercise, when drinking alcohol or during combination therapy with hypoglycemic agents.
Diagnosis. Symptoms of hypoglycemia: headache, hunger, nausea, vomiting, increased fatigue, sleep disturbances, anxiety, attacks of aggression, impaired concentration and reactions, depression, confusion, speech defects, visual impairment, tremor, paralysis, paresthesias, dizziness, delirium, convulsions, drowsiness, fainting, shallow breathing, bradycardia. In connection with the counterregulation caused by hypoglycemia, sweating, fear, tachycardia, arterial hypertension, palpitations, angina pectoris and arrhythmia may occur. These symptoms may be absent in the case of slow development of hypoglycemia, autonomic neuropathy or when using β-adrenoceptor blockers, clonidine, reserpine, guanethidine or sympathomimetics.
Patient selection, dose adjustment, and appropriate patient education are important in reducing the risk of hypoglycemia. If patients experience repeated episodes of severe hypoglycemia or episodes associated with hypoglycemia unawareness, other hypoglycemic treatment options should be considered.
Factors contributing to the occurrence of hypoglycemia:
simultaneous intake of alcohol, especially in combination with fasting; refusal (especially in the elderly) or inability of patients to follow the doctor's recommendations; irregular eating, malnutrition, missed meals, fasting or changing the diet; improper ratio between physical exercise and carbohydrate intake; renal failure; severe liver failure; overdose with Glibofor; some endocrine disorders: thyroid insufficiency, pituitary and adrenal insufficiency; simultaneous intake of certain drugs (see Interaction with other drugs).
Renal and hepatic insufficiency in patients may alter the pharmacokinetics and/or pharmacodynamics of Glibofor. If hypoglycemia occurs in this category of patients, it may become chronic and require appropriate treatment.
Patients and their families should be informed about the risk of hypoglycemia, its symptoms and treatment, as well as its precipitating factors. The risk of lactic acidosis should also be considered in the presence of nonspecific symptoms such as muscle cramps, indigestion, abdominal pain, severe asthenia, acidotic dyspnea, hypothermia, coma.
In particular, patients should be informed about the importance of diet, regular exercise, and glycemic control.
Imbalance of blood glucose levels. In case of surgical interventions or other causes of decompensation of diabetes mellitus, temporary insulin therapy should be considered. Symptoms of hyperglycemia: increased urination, intense thirst, dry skin.
Renal function: Since metformin is excreted by the kidneys, creatinine clearance (estimated by plasma creatinine using the Cockcroft-Gault formula) or glomerular filtration rate should be checked before starting and regularly during metformin treatment:
patients with normal kidney function - at least once a year; patients with creatinine clearance at the lower limit of normal and elderly people - at least 2-4 times a year.
Decreased renal function in the elderly occurs frequently and is asymptomatic. Caution should be exercised in cases where renal function may be impaired, for example, during dehydration or at the beginning of treatment with antihypertensive agents, diuretics and at the beginning of therapy with non-steroidal anti-inflammatory drugs. In such cases, it is also recommended to monitor renal function before starting treatment with metformin.
Cardiac function. Patients with heart failure are at increased risk of hypoxia and renal failure. Metformin may be used in patients with stable chronic heart failure with regular monitoring of cardiac and renal function. Metformin is contraindicated in patients with acute and unstable heart failure (see Adverse Reactions).
Iodinated radiocontrast agents. Intravenous administration of iodinated radiocontrast agents for radiological examinations may lead to renal failure and, as a result, lead to metformin accumulation and an increased risk of lactic acidosis. Depending on the state of renal function, the use of Glibofor should be discontinued 48 hours before or during radiological examinations and not resumed earlier than 48 hours after radiological examinations using radiocontrast agents, only after re-evaluation of renal function and confirmation of the absence of further deterioration of renal condition (see Interactions with other medicinal products).
Concomitant use of glibenclamide with other drugs. Concomitant use of glibenclamide with alcohol, phenylbutazone or danazol is not recommended (see Interactions with other drugs).
Surgical interventions. Since Glibofor contains metformin hydrochloride, it is necessary to stop using the drug 48 hours before elective surgery, which is performed under general, spinal or epidural anesthesia, and not resume earlier than 48 hours after surgery or resumption of oral nutrition and only if normal renal function is determined.
Preventive measures. Patients need to follow a diet, properly distribute carbohydrate intake throughout the day. Overweight individuals need to follow a low-calorie diet.
During therapy with the drug, regular physical exercise should be performed. Laboratory parameters (glycemia and glycosylated hemoglobin - HbA1c) should be regularly monitored.
The perception of alarming signs of low blood glucose levels may be weakened if the patient has autonomic neuropathy. The drug should be used with particular caution in people with impaired renal or hepatic function, or with reduced thyroid, pituitary or adrenal function. Elderly patients are at risk of developing prolonged hypoglycemia, so it is necessary to prescribe glibenclamide to this category of patients with particular caution and carefully monitor their health at the beginning of treatment. In this age group, under certain conditions, it is more expedient to initially use sulfonylureas with a shorter period of action. Patients with diabetes with signs of cerebral sclerosis are at higher risk of developing hypoglycemia. Long intervals between meals, insufficient carbohydrate intake, unusual physical activity, diarrhea or vomiting may increase the risk of developing hypoglycemia. With repeated use of alcohol in large quantities and with its constant use, an unpredictable increase or decrease in the effect of the drug is possible. Constant abuse of laxatives can lead to metabolic disorders. If the treatment plan is not followed, the hypoglycemic effect of the drug is insufficient, or if stressful situations occur, the blood glucose level may increase. Symptoms of hyperglycemia may include dry mouth, itching, fungal or infectious skin diseases, and decreased performance. In unusual stressful situations (trauma, surgery, infectious disease accompanied by an increase in body temperature), metabolic disorders may occur, which can lead to severe hyperglycemia, which may require the patient to temporarily switch to insulin. Patients should be informed of the need to immediately consult a doctor in case of the development of other diseases during treatment with the drug. It is necessary to monitor the intake of tablets by patients who require special care.
Use during pregnancy or breastfeeding
Pregnancy: There are no preclinical or clinical data on the use of Glibofor during pregnancy.
Risks associated with diabetes. Uncontrolled diabetes during pregnancy (gestational or permanent) increases the risk of congenital anomalies and perinatal mortality. Diabetes should be controlled at the time of conception to reduce the risk of congenital anomalies.
Risk associated with metformin. Preclinical studies have not revealed any adverse effects on pregnancy, embryonal/fetal development, parturition or postnatal development. There are limited data from the use of metformin in pregnant women that do not indicate an increased risk of congenital anomalies.
Risk associated with glibenclamide. Glibenclamide is contraindicated for use during pregnancy. Preclinical studies have not revealed any teratogenic effects. In the absence of teratogenic effects in animals, fetal malformations in humans are not expected, since substances that cause malformations in humans have a teratogenic effect on two animal species during research. In clinical practice, there are no relevant data on the basis of which an assessment of potential malformations or fetotoxicity is formed when using glibenclamide during pregnancy.
Treatment. Adequate control of blood glucose levels contributes to the normal course of pregnancy in this category of patients. Glibofor should not be used for the treatment of diabetes during pregnancy.
When planning pregnancy, as well as in the event of pregnancy, it is recommended to switch from oral hypoglycemic therapy to insulin therapy to maintain blood glucose levels as close to normal as possible. It is recommended to monitor the blood glucose level in the newborn.
Breastfeeding. Metformin is excreted in human milk, but no adverse effects have been observed in breastfed infants/newborns who received metformin monotherapy. However, since there is no information on the excretion of glibenclamide in human milk and because of the risk of hypoglycemia in the newborn, the use of glibenclamide during breastfeeding is contraindicated.
Fertility: Metformin did not affect animal fertility at doses of 600 mg/kg/day, which is almost 3 times the maximum recommended daily human dose based on body surface area. Glibenclamide did not affect animal fertility at oral doses of 100 and 300 mg/kg/day.
Children. The drug is not recommended for use in pediatric practice.
The ability to influence the reaction speed when driving vehicles or other mechanisms.
Patients should be particularly careful when driving or operating machinery due to the risk of developing symptoms of hypoglycemia.
Interactions
contraindicated interactions
Both glibenclamide and bosentan inhibit the function of the pump that removes bile salts from the cell. This leads to intracellular accumulation of bile salts, which have a cytotoxic effect, so this combination should not be used together.
Not recommended interactions
In relation to sulfonylurea drugs
Alcohol - Antabuse effect (alcohol intolerance), especially for chlorpropamide, glibenclamide, glipizide, tolbutamide. Increased risk of hypoglycemic reactions (due to suppression of compensatory reactions) may lead to hypoglycemic coma (see Precautions). Alcohol and alcohol-containing medications should be avoided.
Phenylbutazone (for systemic use): enhances the hypoglycemic effect of sulfonylurea derivatives (replaces their binding to plasma proteins and / or reduces their excretion). It is recommended to use another anti-inflammatory drug with fewer interactions or to warn the patient and increase self-monitoring. If necessary, the dose of the drug should be adjusted when used after stopping anti-inflammatory drugs.
In relation to all hypoglycemic drugs
Danazol: If this combination is necessary, the patient should be warned about increased self-monitoring of blood glucose levels. If necessary, the dose of the drug should be adjusted during and after the use of danazol.
In relation to metformin
Alcohol: Increased risk of lactic acidosis during acute alcohol intoxication, especially in the case of fasting (see Precautions), malnutrition or hepatic insufficiency. Alcohol and alcohol-containing medications should be avoided.
Combinations to be used with caution
In relation to all hypoglycemic drugs
Chlorpromazine: when taken in high doses (100 mg of chlorpromazine per day), an increase in blood glucose levels (reduced insulin production). The patient should be warned and self-monitoring of blood glucose levels should be increased. If necessary, the dose of the hypoglycemic drug should be adjusted during and after discontinuation of neuroleptics. Corticosteroids (glucocorticoids) and tetracosactide (systemic and local action): an increase in blood glucose levels, sometimes accompanied by ketosis (reduce carbohydrate tolerance). The patient should be warned and self-monitoring of blood glucose levels should be increased. If necessary, the dose of the drug should be adjusted during and after discontinuation of corticosteroids. β 2 -agonists: an increase in blood glucose levels. The patient should be warned and self-monitoring of blood glucose levels should be increased, and if necessary, the patient should be transferred to insulin therapy. ACE inhibitors (e.g. captopril, enalapril): decrease in blood glucose levels. If necessary, the dose of Glibofor should be adjusted during and after discontinuation of ACE inhibitors.
In relation to metformin
Diuretics: increased risk of lactic acidosis due to metformin use in the presence of functional renal failure associated with diuretics, especially loop diuretics. Iodine-containing radiopaque agents. Intravascular administration of iodinated radiopaque agents may lead to renal failure. This may cause metformin accumulation in the body and lactic acidosis. Depending on the state of renal function, Glibofor should be discontinued 48 hours before or during radiological examinations and not resumed earlier than 48 hours after radiological examinations using radiopaque agents and after re-evaluation of renal function and confirmation of the absence of further deterioration of renal condition.
In relation to glibenclamide
β-Adrenergic blockers mask some symptoms of hypoglycemia: palpitations and tachycardia. Most non-cardioselective β-blockers increase the frequency and severity of hypoglycemia. The patient needs to monitor blood glucose levels, especially at the beginning of treatment. Fluconazole: prolongation of T ½ of sulfonylureas with possible manifestations of hypoglycemia. The patient should be warned about this and self-monitoring of blood glucose levels should be increased. If necessary, the dose of the drug should be adjusted during and after discontinuation of fluconazole. Bile acid sequestrants: with simultaneous use, the concentration of glibenclamide in the blood plasma decreases, which may lead to a decrease in its hypoglycemic effect. This effect is absent if glibenclamide is taken in advance of the use of another drug. It is recommended to use the drug Glibofor at least 4 hours before taking bile acid sequestrants.
Interactions to consider
The effect of glibenclamide (development of hypoglycemic reactions) may be enhanced with simultaneous use with: other oral hypoglycemic drugs and insulin, anabolic steroids and male sex hormones, antidepressants (fluoxetine, MAO inhibitors), quinolone derivatives, chloramphenicol, clofibrate and its analogues, coumarin derivatives, disopyramide, fenfluramine, PAS, pentoxifylline (administered parenterally in high doses), perhexiline, pyrazolone derivatives, probenecid, salicylates, sulfonamides, tetracycline drugs, tritoqualine, cytostatics such as cyclophosphamide.
Taking β-adrenergic receptor blockers, clonidine, guanethidine and reserpine may reduce recognition of early symptoms of hypoglycemia.
A decrease in the effect of glibenclamide (development of hyperglycemic reactions) is possible with simultaneous use with: acetazolamide, β-adrenoreceptor blockers, barbiturates, diazoxide, diuretics, glucagon, isoniazid, corticosteroids, NICOTINATE, phenothiazine derivatives, phenytoin, rifampicin, thyroid hormones, female sex hormones (gestagens, estrogens), sympathomimetics. H2-receptor blockers, clonidine and reserpine can both weaken and enhance the hypoglycemic effect of the drug. In some cases, pentamidine can lead to severe hypoglycemia or hyperglycemia. The effect of coumarin derivatives can both strengthen and weaken.
Overdose
Overdose may lead to hypoglycemia, since the drug contains a sulfonylurea (see Special instructions). A significant overdose of metformin or the presence of concomitant risk factors may lead to the development of lactic acidosis (see Special instructions). Lactic acidosis is an emergency and should be treated in a hospital. The most effective measure for removing lactate and metformin from the body is hemodialysis.
Plasma clearance of glibenclamide may be prolonged in patients with liver disease.
Due to its strong protein binding, glibenclamide is not removed during hemodialysis.
Storage conditions
In a place protected from light at a temperature not exceeding 25 c.
