Glibenclamide, Metformin

Pharmacological properties

metformin is a biguanide with an antihyperglycemic effect. reduces plasma glucose 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 due to inhibition of gluconeogenesis and glycogenolysis;
• improves insulin sensitivity in muscles, which leads to improved peripheral uptake and utilization of glucose;
• delays the absorption of glucose in the intestines.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthetase. Increases the transport capacity of all known types of membrane glucose transporters (GLUT).

Regardless of its effect on glycemia, metformin has a positive effect on lipid metabolism. This effect has been proven by the use of therapeutic dosages in controlled medium or long-term clinical trials: metformin reduces the content of total cholesterol, LDL and TG.

In the course of clinical trials to date, this positive effect on lipid metabolism during the combined use of metformin and glibenclamide was not detected.

Glibenclamide - a derivative of a sulfonylurea of ​​the II generation with an average T_½. Stimulates the production of insulin by the pancreas, which causes a sharp decrease in blood glucose. This action depends on the presence of functioning β-cells (islets of Langerhans).

Stimulation of insulin secretion by glibenclamide in response to food intake is important. The use of glibenclamide in patients with diabetes leads to increased insulin secretion, stimulated by food intake. Increased secretion of insulin and C-peptide persists for at least 6 months after treatment.

Metformin and glibenclamide have different mechanisms of influence, but their actions are complementary. Glibenclamide stimulates the secretion of insulin by the pancreas, and metformin reduces the resistance of cells to insulin, that is, increases the sensitivity of peripheral tissues (skeletal muscles) and liver tissue to insulin.

The results of controlled double-blind clinical studies with reference drugs for the treatment of type II 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 complex effect on the regulation of glucose levels.

Children. Throughout the actively controlled double-blind clinical trial, which lasted for 26 weeks, involving 167 patients aged 9 to 16 years with type II diabetes mellitus, who lacked adequate control when dieting and exercise regimen, during treatment with oral hypoglycemic with and without drugs, the use of a fixed combination of metformin hydrochloride at a dose of 250 mg and glibenclamide at a dose of 1.25 mg did not demonstrate a higher efficiency in reducing the level of hl kozilirovannogo hemoglobin (HbA1c) from baseline. Therefore, the drug Glybofor should not be used in children.

Pharmacokinetics

In relation to the combination.The bioavailability of metformin and glibenclamide in 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 combination is independent of food intake. The bioavailability of glibenclamide in combination does not depend on food intake, however, the rate of absorption of glibenclamide increases with food intake.

In relation to metformin. Suction. Following oral administration of a dose of metformin, maximum plasma concentration (C_max) is achieved in 2.5 hours, the time to reach the maximum concentration (t_max) The absolute bioavailability of metformin tablets of 500 or 850 mg is about 50-60% in healthy volunteers. After oral administration, metformin, which is not absorbed, is excreted in the amount of 20-30% with feces.

Following oral administration, the absorption of metformin is saturable and incomplete. The pharmacokinetics of metformin absorption is assumed to be non-linear. When used in recommended doses of metformin and dosing regimens, stable plasma concentrations are reached within 24–48 hours and amount to 1 μg / ml. During controlled clinical trials C_max metformin in blood plasma did not exceed 5 μg / ml even with the use of the drug in maximum doses.

Distribution. Plasma protein binding is negligible. Metformin penetrates red blood cells. C_max in blood is lower than in blood plasma, and is reached after approximately the same time. Red blood cells most likely represent a second distribution chamber. The average volume of distribution (Vd) ranges from 63–276 liters.

Metabolism. Metformin is excreted unchanged in urine. No metabolites have been identified in humans.

The renal clearance of metformin is 400 ml / min. This indicates that metformin is excreted by glomerular filtration and tubular secretion. Following oral administration of T_½ is about 6.5 hours. In case of impaired renal function, renal clearance decreases in proportion to creatinine clearance and therefore T_½ increases, which leads to an increase in the level of metformin in blood plasma.

In relation to glibenclamide

Suction. After oral administration, glibenclamide is very rapidly absorbed (95%). t_max - 4 hours

Distribution. Glibenclamide actively binds to blood plasma proteins (99%), which may affect the interaction with certain drugs.

Metabolism. Glibenclamide is completely metabolized in the liver to form two metabolites. Hepatic insufficiency reduces the metabolism of glibenclamide and significantly slows down its excretion.

Glibenclamide is excreted in the form of metabolites with bile (60%) and urine (40%). Completely excreted after 45–72 hours. Final T_½ 4–11 hours

Excretion of metabolites with bile increases in patients with renal failure, depending on the degree of impaired renal function, if creatinine clearance is 30 ml / min. Therefore, if creatinine clearance is 30 ml / min, renal failure does not affect the excretion of glibenclamide.

Children.The pharmacokinetics of glibenclamide and metformin in children did not differ from that in healthy adult volunteers with the same body weight and gender.

Indications

Treatment for type II diabetes mellitus in adults, to replace the previous therapy with two drugs (metformin and glibenclamide) in patients with a stable and well-controlled level of glycemia.

Application

Inside. for use in adult patients only.

As with other hypoglycemic agents, the dose of Glybofor is set individually depending on the individual metabolic reaction (glycemia and HbA1c levels).

It is recommended to use Glybofor 500 mg / 5 mg in patients who do not achieve adequate glycemic control when using the drug in lower doses.

When replacing combination therapy with metformin and glibenclamide, treatment with Glibofer should be started in doses according to the preliminary dosage. The dose must be gradually increased, depending on the results of measuring the level of glycemia.

Every ≥2 weeks after the start of therapy, it is necessary to correct the dosage of the drug (increase the dose by 1 tablet) depending on the level of glycemia.

A gradual increase in dose helps to reduce side effects from the digestive tract and prevents the development of hypoglycemia.

The maximum recommended dose is 3 tablets of Glybofor 500 mg / 5 mg / day.

In individual cases, the dose can be increased to 4 tablets Glybofor 500 mg / 5 mg / day.

There are no data on the combined therapy with Glybofor and insulin.

The dosage regimen depends on the individual indications:

• 1 time per day: 1 tablet per day during breakfast;
• 2 times a day: 2 or 4 tablets per day - in the morning and in the evening;
• 3 times a day: 3 tablets per day - in the morning, afternoon and evening.

Tablets should be taken with meals.

You can correct the dosing regimen in accordance with the individual diet. Nevertheless, in order to prevent the occurrence of episodes of hypoglycemia, it is necessary to eat foods rich in carbohydrates after each administration of the drug.

In case of concomitant use with cadeloveloam, it is recommended to take Glybofor at least 4 hours before taking cadeloveloam to minimize the risk of reduced absorption (see INTERACTIONS).

In elderly patients, the dosage of the drug is corrected depending on the parameters of renal function (initial dose - 1 tablet Glybofor 500 mg / 2.5 mg). It is necessary to regularly evaluate renal function (see SPECIAL INSTRUCTIONS).

Contraindications

• Hypersensitivity to metformin, glibenclamide, other components of the drug or to other sulfonylurea preparations, to sulfonamides; in case of diabetes mellitus, when insulin treatment is required: type I diabetes mellitus (insulin-dependent diabetes mellitus), complete secondary inefficiency of glibenclamide therapy for 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; During pregnancy and breastfeeding; combined use with bosentan; combination therapy with miconazole (see interactions).

Side effects

The most common adverse reactions at the beginning of treatment are nausea, vomiting, diarrhea, abdominal pain, lack of appetite. these symptoms in most cases go away on their own. to prevent the occurrence of these side effects, a slow increase in dosage and the use of a daily dose of the drug in 2-3 doses are recommended. short-term visual impairment may develop at the beginning of treatment due to a decrease in glycemia.

On the part of the blood and lymphatic system: leukopenia, thrombocytopenia, agranulocytosis, hemolytic anemia, bone marrow aplasia, pancytopenia. These are reversible reactions that disappear after discontinuation of treatment.

Metabolism: acute hepatic porphyria, porphyria of the skin, lactic acidosis (see SPECIAL INSTRUCTIONS).

Hypoglycemia (see SPECIAL INSTRUCTIONS).

With prolonged use of metformin, absorption of vitamin B may decrease₁₂accompanied by a decrease in its level in blood serum. It is recommended to consider such an etiology in the presence of megaloblastic anemia in the patient.

Disulfiram-like reaction with alcohol.

From the nervous system: taste disturbance.

From the side of the organ of vision: short-term visual impairment may occur at the beginning of treatment due to a decrease in the level of glycemia.

From the digestive tract: disorders of the digestive system, 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, a slow increase in dosage and the use of the drug 2-3 times a day are recommended.

On the part of the skin and subcutaneous tissue: cross-reactivity to sulfonylurea or its derivatives, skin reactions, including pruritus, urticaria, maculopapular rash, skin or visceral allergic vasculitis, erythema multiforme, exfoliative dermatitis, photosensitivity, urticaria, leading to development of shock.

On the part of the liver: impaired liver function indicators or hepatitis, requiring treatment stop.

Research: a moderate increase in the level of urea and creatinine in the blood serum, hyponatremia, an increase in the level of urea and creatinine in the blood serum, hyponatremia.

special instructions

Lactic acidosis.lactic acidosis is a very rare but serious metabolic complication (high mortality rate in the absence of emergency treatment), which can occur as a result of cumulation of metformin. cases of lactic acidosis have been reported in patients with diabetes mellitus with renal failure or a sharp deterioration in renal function, taking metformin. caution must 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 drugs, diuretics, and at the beginning of NSAID therapy. when these exacerbations occur, it is necessary to temporarily stop the use of metformin.

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).

Diagnostics. The risk of developing lactic acidosis should be considered in the presence of nonspecific symptoms such as muscle cramps, indigestion, abdominal pain and severe asthenia. Patients should immediately inform the doctor about the occurrence of such reactions, especially if previously the patients tolerated treatment with metformin well. In such cases, it is necessary to temporarily stop the use of metformin until the situation is clarified. Metformin therapy should be resumed after evaluating the benefit / risk ratio in individual cases and evaluating renal function.

Lactic acidosis is characterized by acidic shortness of breath, abdominal pain, hypothermia, further development of coma is possible. Laboratory diagnostic signs of this complication include: a decrease in pH, a plasma lactate level of 5 mmol / L, an increase in the anion interval, and an increase in the ratio of lactate / pyruvate content. If lactic acidosis is suspected, it is necessary to discontinue use of the drug and immediately hospitalize the patient (see OVERDOSAGE). The doctor should warn patients about the risk of development and symptoms of lactic acidosis.

Hypoglycemia. The drug Glybofor contains sulfonylurea, so patients using this drug have a risk of developing hypoglycemia. After starting therapy, titration of a dose of the drug can prevent the development of hypoglycemia. The drug is prescribed to patients who adhere to a regular meal schedule (including breakfast). Regular consumption of carbohydrates is an important factor, since the risk of hypoglycemia increases in case of untimely food intake, insufficient or unbalanced intake of carbohydrates. Hypoglycemia most often occurs in patients on a low-calorie diet, after intense or prolonged exercise, with alcohol, or with combination therapy with hypoglycemic agents.

Diagnostics.Symptoms of hypoglycemia: headache, hunger, nausea, vomiting, fatigue, sleep disturbances, anxiety, attacks of aggression, impaired concentration and reactions, depression, confusion, speech defects, blurred vision, trembling, paralysis, paresthesia, dizziness, delirium, cramps, drowsiness, fainting, shallow breathing, bradycardia. In connection with the counter-regulation caused by hypoglycemia, sweating, fear, tachycardia, 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 β-adrenergic receptor blockers, clonidine, reserpine, guanethidine, or sympathomimetics are used.

Treatment for hypoglycemia. With moderate symptoms of hypoglycemia without loss of consciousness or neurological manifestations, you must immediately take sugar. It is necessary to ensure the correction of the dose of the drug and / or to correct the diet. Severe hypoglycemic reactions with coma, convulsions and other neurological signs that can cause emergency conditions are possible. This requires emergency treatment with iv glucose when diagnosed or suspected of hypoglycemia before hospitalization.

The selection of patients, dose adjustment, and the provision of appropriate instructions to patients are important to reduce the risk of hypoglycemia. If patients experience repeated episodes of severe hypoglycemia or episodes associated with ignorance of the manifestations of hypoglycemia, other options for hypoglycemic treatment 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 the inability of patients to follow the doctors recommendations;
• irregular eating, malnutrition, skipped meals, fasting or changing a diet;
• inadequate balance between exercise and carbohydrate intake;
• renal failure;
• severe liver failure;
• an overdose of the drug Glybofor;
• some endocrine disorders: thyroid gland insufficiency, pituitary and adrenal gland insufficiency;
• concomitant use of certain drugs (see INTERACTIONS).

Renal and hepatic insufficiency in patients can change the pharmacokinetics and / or pharmacodynamics of the drug Glybofor. If hypoglycemia occurs in this category of patients, it can become chronic and requires proper treatment.

It is necessary to inform patients and their family about the risk of developing hypoglycemia, its symptoms and treatment, as well as its causing factors. You should also consider the risk of lactic acidosis in the presence of nonspecific symptoms, such as muscle cramps, digestive disorders, abdominal pain, severe asthenia, acidic shortness of breath, hypothermia, coma.

In particular, patients should be informed about the importance of dieting, regular exercise and glycemic control.

Imbalance in blood glucose. In the case of surgical interventions or other causes of decompensation of diabetes mellitus, it is necessary to provide temporary insulin therapy. Symptoms of hyperglycemia: increased urination, extreme thirst, dry skin.

Kidney function. Since metformin is excreted by the kidneys, it is necessary to check the creatinine clearance (can be estimated by the level of plasma creatinine using the Cockcroft-Gault formula) or glomerular filtration rate before starting and regularly during metformin treatment:

• patients with normal renal function - at least 1 time per year;
• for patients with creatinine clearance at the lower limit of normal and for elderly people - at least 2–4 times a year.

Reduced renal function in the elderly occurs often 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 drugs, diuretics, and at the beginning of NSAID therapy. In such cases, it is also recommended to monitor renal function before starting treatment with metformin.

Cardiac function. Patients with heart failure have a higher risk of developing hypoxia and renal failure. In patients with stable chronic heart failure, metformin can be used with regular monitoring of cardiac and renal function. Metformin is contraindicated in individuals with acute and unstable heart failure (see CONTRAINDICATIONS).

Iodine-containing radiopaque agents. In / in the introduction of iodine-containing radiopaque agents for radiological studies can lead to renal failure and, as a result, lead to cumulation of metformin and an increased risk of lactic acidosis. Depending on the state of renal function, the use of the drug Glybofor should be discontinued 48 hours before or during radiological studies and should not be resumed earlier than 48 hours after an X-ray examination using radiopaque substances, only after a repeated assessment of renal function and confirmation of the absence of further renal impairment (see INTERACTIONS).

The combined use of glibenclamide with other drugs. The simultaneous use of glibenclamide with alcohol, phenylbutazone or danazole is not recommended (see INTERACTIONS).

Surgical interventions. Since Glybofor contains metformin hydrochloride, it is necessary to discontinue use of the drug 48 hours before the planned surgical intervention, which is carried out under general, spinal or epidural anesthesia, and not resume earlier than 48 hours after the operation or restoration of oral nutrition and only if normal function is determined the kidneys.

Preventative measures.Patients need to follow a diet, properly distribute carbohydrate intake throughout the day. Overweight individuals must follow a low-calorie diet.

During therapy, regular exercise should be performed. It is necessary to regularly monitor laboratory indicators (the level of glycemia and glycosylated hemoglobin - HbA1c).

Treatment of patients with glucose-6-phosphate dehydrogenase deficiency using sulfonylurea can lead to the development of hemolytic anemia. Since glibenclamide is in this class, it is necessary to use Glybofor with special care in patients with glucose-6-phosphate dehydrogenase deficiency and take into account the transition to alternative therapy with drugs that are not derivatives of sulfonylurea.

Perhaps weakening the perception of alarming signs of low blood glucose if the patient has autonomic neuropathy. It should be used with extreme caution in patients with impaired renal or hepatic function, or decreased thyroid, pituitary, or adrenal cortex. In elderly patients, there is a risk of prolonged hypoglycemia, therefore, it is necessary to carefully prescribe glibenclamide in this category of patients and carefully monitor their health at the beginning of treatment. In this age group, under certain conditions, it is advisable to first use sulfonylurea preparations with a shorter period of action. Diabetic patients with signs of cerebral sclerosis have a higher risk of developing hypoglycemia. Significant intervals between meals, inadequate carbohydrate intake, unusual physical activity, diarrhea, or vomiting can increase the risk of hypoglycemia. With repeated use of alcohol in large quantities and with its constant use, an unpredictable strengthening or weakening of the effect of the drug is possible. The 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 in the presence of stressful situations, 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, an infectious disease accompanied by fever), metabolic disorders are possible, which can lead to severe hyperglycemia, which may require the patient to switch to insulin temporarily. Patients should be informed of the need to immediately consult a doctor if other diseases develop during treatment with the drug. It is necessary to control the administration of tablets by patients in need of special care.

Use during pregnancy or lactation

Pregnancy. Preclinical and clinical data on the use of the drug Glybofor during pregnancy are absent.

The risk associated with diabetes. Uncontrolled diabetes during pregnancy (gestational or persistent) increases the risk of developing congenital malformations and perinatal mortality. It is necessary to control diabetes during the period of fertilization to reduce the risk of developing congenital abnormalities.

The risk associated with metformin. Preclinical studies have not revealed a negative effect on pregnancy, development of the embryo or fetus, childbirth and postpartum development. There are limited data on the use of metformin in pregnant women, which do not indicate an increased risk of congenital anomalies.

The risk associated with glibenclamide. Glibenclamide is contraindicated in pregnancy. Preclinical studies have not revealed 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 teratogenic effects in animals of two types during research. In clinical practice, there are no relevant data on the basis of which an assessment of potential defects or fetotoxicity when using glibenclamide during pregnancy is formed.

Treatment. Adequate control of blood glucose levels contributes to the normal course of pregnancy in this category of patients. Glybofor should not be used to treat 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 as possible to normal. It is recommended to monitor the blood glucose level in the newborn.

Lactation. Metformin passes into human breast milk, but in newborns / infants who were breastfed with metformin monotherapy in the mother, side effects were not observed. However, since data on the penetration of glibenclamide into human breast milk are not available, and also due to the risk of hypoglycemia in a newborn, the drug is contraindicated during breast-feeding.

Fertility. Metformin did not affect animal fertility when applied at a dose of 600 mg / kg / day, which was almost 3 times higher than the maximum recommended daily dose for humans based on body surface area. Glibenclamide did not affect animal fertility when administered orally at a dose of 100 and 300 mg / kg / day.

Children. The drug is not recommended for use in pediatric practice.

The ability to influence the reaction rate when driving vehicles or other mechanisms.

Patients should be especially careful in driving vehicles or working with other mechanisms because of the risk of developing symptoms of hypoglycemia.

Interactions

Contraindicated interactions

In relation to glibenclamide

• Miconazole (for systemic use, oral gel): increased hypoglycemic effect with possible manifestations of hypoglycemia or even coma (see CONTRAINDICATIONS).
• Bozentan: the risk of decreasing the hypoglycemic effect of glibenclamide, since bosentan reduces the concentration of glibenclamide in the blood plasma. With concomitant use, there is a risk of increased levels of liver enzymes.

Both glibenclamide and bosentan inhibit the function of the pump, which removes bile salts from the cell. This leads to intracellular accumulation of bile salts having a cytotoxic effect, therefore, this combination should not be used.

Not recommended interactions

In relation to sulfonylurea preparations

• Alcohol - the effect of antabuse (intolerance to alcohol), especially for chlorpropamide, glibenclamide, glipizide, tolbutamide. An increased risk of developing hypoglycemic reactions (by inhibiting compensatory reactions) can lead to hypoglycemic coma (see SPECIAL INSTRUCTIONS). Avoid drinking alcohol and medicines containing alcohol.
• Phenylbutazone (for systemic use): increased hypoglycemic effect of sulfonylurea derivatives (replaces their connection with blood 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 strengthen self-control. If necessary, the dose should be decontaminated when used after stopping anti-inflammatory drugs.

In relation to all hypoglycemic drugs

• Danazole: if this combination is mandatory, it is necessary to warn the patient about increased self-monitoring of blood glucose levels. If necessary, the dose should be decontaminated during use and after discontinuation of danazol.

In relation to metformin

• Alcohol: increased risk of lactic acidosis during acute alcohol intoxication, especially during fasting (see SPECIAL INSTRUCTIONS), malnutrition, or liver failure. Avoid drinking alcohol and medicines containing alcohol.

Combinations to be used with caution

In relation to all hypoglycemic drugs

• Chlorpromazine: when taken at high doazz (100 mg of chlorpromazine per day), an increase in blood glucose (decrease in insulin production). The patient should be warned and self-monitoring of blood glucose levels should be strengthened. If necessary, the dose of the hypoglycemic drug must be disordered during administration and after stopping the use of antipsychotics.
• Corticosteroids (glucocorticoids) and tetracosactides (systemic and local effects): an increase in blood glucose, sometimes accompanied by ketosis (reduce carbohydrate tolerance). The patient should be warned and self-monitoring of blood glucose levels should be strengthened. If necessary, the dose should be corrected when taking and after stopping the use of corticosteroids.
• β₂agonists: increased blood glucose. The patient should be warned and blood glucose control strengthened, if necessary, transfer the patient to insulin therapy.
• ACE inhibitors (e.g. captopril, enalapril): a decrease in blood glucose.If necessary, you should correct the dose of the drug Glybofor during and after stopping the use of ACE inhibitors.

In relation to metformin

• Diuretics: increased risk of developing lactic acidosis due to the use of metformin with functional renal failure associated with diuretics, especially loop diuretics.
• Iodine-containing radiopaque substances. Intravascular administration of iodine-containing radiopaque agents can lead to renal failure. This can cause accumulation of metformin in the body and lactic acidosis. Depending on the state of renal function, the use of the drug Glybofor should be discontinued 48 hours before or during radiological studies and should not be resumed earlier than 48 hours after an X-ray examination using radiopaque substances and after a repeated assessment of kidney function and confirmation of the absence of further renal impairment.

In relation to glibenclamide

• Β-adrenoreceptor blockers mask some of the symptoms of hypoglycemia: heart palpitations and tachycardia. Most non-cardioselective β-adrenoreceptor blockers increase the incidence and severity of hypoglycemia. The patient needs to control the level of glucose in the blood, especially at the beginning of treatment.
• Fluconazole: T Extension_½ sulfonylureas with prob