Glimepiride, Metformin

Pharmacological properties

glimepiride is a substance with hypoglycemic activity when administered orally, a sulfonylurea derivative. used for non-insulin-dependent diabetes mellitus.

The effect of glimepiride is realized by stimulating the release of insulin from β-cells of the pancreas. Like other sulfonylurea derivatives, it increases the sensitivity of pancreatic β-cells to physiological stimulation of glucose. In addition, glimepiride, like other sulfonylurea derivatives, is likely to have a pronounced extra-pancreatic effect.

Insulin release. Sulfonylurea regulates the secretion of insulin by closing the ATP-sensitive potassium channels on the β-cell membrane, this leads to depolarization of the cell membrane, as a result of which calcium channels open and a large amount of calcium enters the cells, which in turn stimulates the release of insulin by exocytosis.

Glimepiride, with a high degree of affinity, attaches to a protein on the β-cell membrane bound to the ATP-sensitive potassium channel, but not in the place to which sulfonylurea usually attaches.

Extra-pancreatic activity. The extrapancreatic effect is to increase the sensitivity of peripheral tissues to insulin and to decrease the uptake of insulin by the liver. The transport of glucose from the blood to peripheral muscle and adipose tissues occurs through special transport proteins localized on the cell membrane. It is glucose transport to these tissues that is the stage that limits the rate of glucose uptake. Glimepiride rapidly increases the number of active glucose transporters on the plasma membrane of muscle and fat cells, thereby stimulating glucose uptake.

Glimepiride increases the activity of phospholipase C specific for glycosyl phosphatidylinositol, and this is associated with an increase in the lipogenesis and glycogenesis that are observed in isolated fat and muscle cells under the influence of this substance.

Glimepiride inhibits the formation of glucose in the liver, increasing the intracellular concentration of fructose-2,6-diphosphate, which, in turn, inhibits gluconeogenesis.

Metformin. Metformin is a biguanide with a hypoglycemic effect, which manifests itself in a decrease in both the basal level of glucose in blood plasma and its level in blood plasma after eating. Metformin does not stimulate insulin secretion and does not lead to the development of hypoglycemia.

Metformin has 3 mechanisms of action:

• reduces liver glucose production by inhibiting gluconeogenesis and glycogenolysis;
• in muscle tissue increases insulin sensitivity, improves peripheral uptake and utilization of glucose;
• inhibits the absorption of glucose in the intestine.

Metformin stimulates intracellular glycogen synthesis, affecting glycogen synthase.

Metformin increases the transport capacity of specific glucose membrane transporters (GLUT-1 and GLUT-4).

Regardless of blood glucose, metformin affects lipid metabolism. This was established with the use of the drug in therapeutic doses during controlled medium- or long-term clinical trials: metformin reduces the overall level of cholesterol, LDL and TG.

Pharmacokinetics

Absorption. Glimepiride has full oral bioavailability. Eating does not significantly affect the absorption, only its speed decreases slightly. The maximum concentration in blood plasma is reached approximately 2.5 hours after oral administration (on average 0.3 μg / ml with repeated administration in a daily dose of 4 mg). There is a linear relationship between the dose of the drug, the maximum concentration in plasma and AUC.

Distribution. Glimepiride has a very small volume of distribution (about 8.8 L), approximately equal to the volume of distribution of albumin.Glimepiride has a high degree of binding to plasma proteins (99%) and low clearance (about 48 ml / min).

In animals, glimepiride is excreted in milk, can penetrate the placenta. Penetration through the BBB is negligible.

Biotransformation and elimination. Average T_½, which depends on the concentration in the blood plasma under the condition of repeated administration of the drug, is 5-8 hours. After taking the drug in high doses, an elongation T was noted_½.

After a single dose of radiolabeled glimepiride, 58% of the drug is excreted in the urine and 35% with feces. Unchanged, the substance in the urine is not determined. With urine and feces, 2 metabolites are formed, which are formed due to metabolism in the liver with the participation of the CYP 2C9 enzyme: hydroxy and carboxy derivatives. After oral administration of glimepiride, terminal T_½ of these metabolites were 3–6 and 5–6 hours, respectively.

The comparison showed the absence of significant differences in the pharmacokinetics after taking single and multiple doses, the variability of the results for one individual was very low. No significant accumulation was detected.

Pharmacokinetics was similar in men and women, as well as in individuals of young and old (over 65 years) age. For patients with low creatinine clearance, there is a tendency to increase clearance and lower average plasma concentrations of glimepiride, the reason for which is its faster elimination due to poor binding to blood plasma proteins. Excretion of two metabolites by the kidneys decreased. There is no additional risk of drug cumulation in such patients.

In 5 patients without diabetes, but after surgery on the bile duct, the pharmacokinetics were similar to those in healthy individuals.

Metformin

Absorption. After oral administration of metformin, the time to reach maximum plasma concentration (t_max) is 2.5 hours. The absolute bioavailability of metformin when administered at a dose of 500 mg orally for healthy volunteers is about 50-60%. After oral administration, the unabsorbed fraction in the feces was 20–30%.

Metformin absorption after oral administration is saturable and incomplete. There are suggestions that the pharmacokinetics of metformin absorption is linear. At usual doses and the metformin administration regimen, equilibrium plasma concentration is reached after 24–48 hours and is no more than 1 μg / ml. In controlled clinical trials, C_max metformin in blood plasma did not exceed 4 μg / ml, even when used in higher doses.

Eating reduces the degree and slightly lengthens the absorption time of metformin. After taking a dose of 850 mg with food, a decrease in C_max in blood plasma by 40%, decrease in AUC by 25% and lengthening t_max for 35 minutes The clinical significance of such changes is unknown.

Distribution. Plasma protein binding is negligible. Metformin is distributed in red blood cells. C_max blood less than C_max in plasma and is achieved in about one time. Red blood cells are probably a secondary distribution depot. The average value of the distribution volume ranges from 63–276 liters.

Biotransformation and elimination. Metformin is excreted unchanged in urine. Renal clearance of metformin is 400 ml / min, which indicates that metformin is excreted by glomerular filtration and tubular secretion. After ingestion, terminal T_½ is about 6.5 hours. If renal function is impaired, renal clearance decreases in proportion to creatinine clearance, resulting in T_½ lengthens, which leads to an increase in the level of metformin in blood plasma.

Indications

In the form of an addition to the diet and exercise for patients with non-insulin-dependent diabetes mellitus (type II):

• in the case when monotherapy with glimepiride or metformin does not provide an appropriate level of glycemic control;
• replacement of combination therapy with glimepiride and metformin.

Application

The dose of the antidiabetic drug is set individually depending on the level of glucose in the blood of the patient. as a rule, it is recommended to start treatment with the minimum effective dose and increase the dose of the drug depending on the level of glucose in the patient’s blood. For this, regular monitoring of blood glucose levels is necessary.

The drug is used exclusively in adults. The drug is taken 1 or 2 times a day before or during meals.

In the case of a transition from combination therapy with glimepiride and metformin in the form of separate tablets, Amaril^® M is prescribed taking into account the doses the patient is already taking.

Contraindications

Type I diabetes mellitus (e.g. diabetes mellitus with a history of ketonemia), diabetic ketonemia, diabetic precoma and coma, acute or chronic metabolic acidosis.

Hypersensitivity to any of the excipients that make up the drug, sulfonylurea, sulfonamides or biguanides.

Patients with severely impaired liver function or patients who are on hemodialysis (there is currently no experience with the drug). In case of severe impairment of liver and kidney function, it is necessary to transfer to insulin to achieve proper control of the patient’s blood glucose level.

Pregnancy and lactation, women of reproductive age.

Patients prone to developing lactic acidosis, a history of lactic acidosis, kidney disease or impaired renal function (as evidenced by an increase in plasma creatinine levels of ≥1.5 mg / dL in men and ≥1.4 mg / dL in women or decreased creatinine clearance), which can also be caused by conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia.

X-ray studies with intravascular administration of contrast agents containing iodine (e.g. IV urography, IV cholangiography, angiography and computed tomography (CT)): iodine-containing contrast agents intended for administration during examinations can cause acute renal impairment and lactic acidosis in patients taking amaryl^® M 2 mg / 500 mg. Therefore, patients for whom such studies are planned should temporarily stop using Amaril^® M 2 mg / 500 mg 48 hours before the procedure. In this case, treatment should not be restored until a re-evaluation of renal function is carried out and it is established that it is normal. In addition, the drug is contraindicated in patients with acute symptoms that may cause impaired renal function (dehydration, severe infection, shock).

Severe infections, conditions before and after surgical interventions, serious injury. During any surgical intervention, it is necessary to temporarily postpone treatment with this drug (with the exception of small procedures that do not require restrictions on food and fluid intake). Therapy cannot be resumed until the patient begins to take food on his own, and indicators of renal function are not within normal limits.

Malnutrition, starvation or exhaustion of the patient.

Hypofunction of the pituitary or adrenal gland.

Impaired liver function (since there have been cases of lactic acidosis with impaired liver function, this drug should generally not be prescribed to patients with clinical or laboratory signs of liver disease), pulmonary infarction, severe impaired pulmonary function and other conditions that may be accompanied by hypoxemia (cardiac or pulmonary failure, recent myocardial infarction, shock), excessive alcohol consumption, dehydration, gastrointestinal disturbances, including diarrhea and vomiting.

Congestive heart failure requiring medical treatment and recent myocardial infarction, severe cardiovascular failure or respiratory failure.

Since the drug Amaryl^® M 2 mg / 500 mg contains lactose; it should not be prescribed to patients with genetic diseases such as galactose intolerance, Lapp lactose deficiency or glucose / galactose malabsorption syndrome.

Side effects

Lactic acidosis: see special instructions and overdose.

Hypoglycemia: see SPECIAL INSTRUCTIONS and OVERDOSAGE.

From the gastrointestinal tract: gastrointestinal symptoms (diarrhea, nausea, vomiting, bloating, lack of appetite, dyspepsia, constipation, abdominal pain) are the most common reactions to taking metformin and metformin monotherapy was observed almost 30% more often than patients taking a placebo, especially at the beginning of treatment. These symptoms are usually transient and disappear on their own with continued treatment. In some cases, a temporary dose reduction may be helpful. During clinical trials, metformin had to be canceled due to reactions from the gastrointestinal tract in about 4% of patients.

Since the symptoms of the gastrointestinal tract at the beginning of treatment are dose-dependent, the severity of their manifestations can be reduced by gradually increasing the dose and taking the drug with food. Since significant diarrhea and / or vomiting can lead to dehydration and prerenal azotemia, in this situation, the drug should be temporarily stopped.

The occurrence of nonspecific gastrointestinal symptoms in patients taking stable doses of Amaryl^® M 2 mg / 500 mg, may be associated with concomitant diseases or lactic acidosis, and not with the use of the drug.

Treatment with glimepiride can sometimes cause nausea, vomiting, a feeling of bloating or tension in the epigastric region, abdominal pain and diarrhea.

From the sensory organs: at the beginning of treatment with metformin, about 3% of patients may complain of an unpleasant or metallic taste in the mouth, which usually disappears on its own. At the beginning of treatment, transient visual impairment due to a change in blood glucose levels may be noted.

On the part of the skin and sensitivity: allergic or pseudo-allergic reactions (e.g. erythema, pruritus, urticaria or rash) can sometimes be detected. Most of these reactions are mild, but can progress to serious and are accompanied by shortness of breath and a decrease in blood pressure, sometimes before the development of shock. If hives occur, consult a doctor immediately. Cross-allergic reactions with sulfonylurea or sulfonamide, or their derivatives, are possible.

On the part of blood indicators: thrombocytopenia is rarely possible, in some cases - leukopenia or hemolytic anemia, erythrocytopenia, granulocytopenia, agranulocytosis, pancytopenia. Careful monitoring of the patients condition is necessary, since during treatment Amaril^® M 2 mg / 500 mg, together with other sulfonylurea preparations, cases of aplastic anemia have been reported. If these phenomena occur, the drug should be discontinued and appropriate treatment started. Post-registration experience with Amaril^® M 2 mg / 500 mg indicates cases of severe thrombocytopenia with a platelet count of 10,000 / μl and thrombocytopenic purpura (frequency unknown).

In patients who took metformin for a long time, a decrease in vitamin B levels was noted₁₂ in blood plasma. The level of folic acid in blood plasma did not significantly decrease. While taking Amaril^® M 2 mg / 500 mg was recorded only megaloblastic anemia without increasing the frequency of symptoms of neuropathy. In this regard, it is necessary to carefully monitor the level of vitamin B₁₂ in a blood plasma or periodically additionally parenteral vitamin B₁₂.

On the part of the liver and biliary tract: in some cases, it is possible to increase the activity of liver enzymes and impaired liver function (e.g. cholestasis and jaundice), as well as hepatitis, which can progress to liver failure.

Other reactions: in some cases, allergic vasculitis, hypersensitivity of the skin to light and a decrease in plasma sodium levels may be noted.

In the event of the above adverse reactions or other undesirable reactions or unexpected changes in the condition, the patient should immediately inform the doctor. Certain adverse reactions, including severe hypoglycemia, certain changes in blood counts, severe allergic or pseudo-allergic reactions, and liver failure under certain conditions can pose a threat to the patients life. In the event of such reactions, the patient should immediately inform the doctor about this and stop further administration of Amaril^® M 2 mg / 500 mg before receiving instructions from a doctor.

Unforeseen adverse reactions to this drug, with the exception of the already known reactions to glimepiride and metformin, have not been identified with local clinical trials of phase I and open trials of phase III.

Adverse events in children with the use of metformin as monotherapy. Adverse events that were noted during a clinical study in a small group of children aged 10–16 years who received metformin for 1 year, as well as side effects reported in the literature and during post-marketing surveillance, were similar in their characteristics and degree severity with adverse events recorded in adults.

Adverse events following post-marketing surveillance. The frequency of adverse events, regardless of the causal connection with the use of the studied drug, during the post-marketing surveillance study to re-study the drug for 6 years with 1235 patients with non-insulin-dependent diabetes mellitus (type II) was 2.75% (34 / 1235 patients, 35 cases). These adverse events included the following: hypoglycemia with a frequency of 0.8% (10/1235 patients, 10 cases); abdominal pain - 0.56% (7/1235 patients, 7 cases); bloating - 0.48% (6/1235 patients, 6 cases); vomiting and dyspepsia - 0.16% each phenomenon (2/1235 patients, 2 cases); hypertrophy of the prostate gland, increased heart rate, dizziness, diarrhea, nausea, edema of the lower extremities, cardiac arrest and colorectal cancer - 0.08% each phenomenon (1/1235 patients, 1 case). The frequency of adverse reactions to the drug, for which a causal relationship with the use of the studied drug cannot be excluded, was 2.02% (25/1235 patients, 26 cases), including hypoglycemia with a frequency of 0.8% ( 10/1235 patients, 10 cases); bloating and abdominal pain - 0.48% each reaction (6/1235 patients, 6 cases); increased heart rate, vomiting, dyspepsia and dizziness - 0.08% each reaction (1/1235 patients, 1 case). Serious adverse events included cardiac arrest and rectal cancer with a frequency of 0.08% for each event (1/1235 patients, 1 case), none of them had a causal relationship with the use of the study drug. Unexpected side effects included dyspepsia with a frequency of 0.16% (2/1235 patients, 2 cases); hypertrophy of the prostate gland, swelling of the lower extremities and colorectal cancer - 0.08% for each phenomenon (1/1235 patients, 1 case). Of these, an undesirable drug reaction, for which a causal relationship with the use of this drug cannot be excluded, was dyspepsia.

Adverse events when using glimepiride (for oral administration) as monotherapy according to the results of post-marketing surveillance. The frequency of adverse events, regardless of the causal relationship with the use of the studied drug, during the study in the framework of post-marketing surveillance for 6 years with 12 056 patients was 1.2% (149/12 056 patients, 181 cases).Most often, among the adverse events noted hypoglycemia - with a frequency of 0.75% (90/12 056 patients, 102 cases); further in order of decreasing frequency are vertigo (dizziness) - 0.08% (10/12 056 patients, 10 cases); liver dysfunction - 0.07% (8/12 056 patients, 8 cases) and abdominal pain - 0.06% (7/12 056 patients, 7 cases). Of these, new adverse events that were not previously noted during clinical trials conducted in the pre-registration period were arthralgia, dyspepsia, facial edema (2 cases for each phenomenon), impotence, alopecia, hyperemia and gastritis (1 case for each phenomenon )

special instructions

Warning

When taking Amaril^® M 2 mg / 500 mg:

- The occurrence of severe lactic acidosis or hypoglycemia is possible (see SPECIAL INSTRUCTIONS AND OVERDOSAGE);

- the risk of mortality from cardiovascular complications increases.

Risk of death due to cardiovascular complications. As you know, the appointment of oral hypoglycemic agents compared with treatment using only the patient’s diet or diet with insulin leads to increased mortality from cardiovascular complications. This warning is based on a study by the University Group Diabetes Program (UGDP), which was conducted to evaluate the effectiveness of drugs that lower blood glucose levels to prevent or delay the development of cardiovascular complications in patients with non-insulin-dependent diabetes mellitus. According to this study, it was found that in patients who were treated for 5–8 years with diet control with a fixed dose of tolbutamide (1.5 g / day) or phenformin (100 mg / day), an increase in the frequency of death from cardiovascular complications 2.5 times compared with patients who were treated only by diet control, which allowed canceling therapy with tobutamide or phenformin. Despite the differences in the interpretation of these results, the UGDP research data provide a significant basis for safety concerns and given the similarity of the mechanism of action and may also apply to other sugar-lowering drugs of these classes.

The patient should be informed about the potential dangers and benefits of using glimepiride and alternative treatment regimens.

Special precautions. During the first week of treatment, careful monitoring of the patients condition is necessary due to the increased risk of hypoglycemia. The risk of hypoglycemia in patients exists with the following conditions:

- unwillingness or inability of the patient to cooperate with a doctor (especially in old age);

- malnutrition, irregular nutrition, skipping meals;

- imbalance between physical activity and carbohydrate intake;

- changes in diet;

- drinking alcohol, especially in combination with skipping meals;

- impaired renal function (patients with impaired renal function may have greater sensitivity to the hypoglycemic effect of this drug);

- an overdose of the drug;

- certain non-metabolic diseases of the endocrine system (for example, dysfunction of the thyroid gland and adenohypophysial or adrenocortical insufficiency), which affect carbohydrate metabolism and counter-regulation of hypoglycemia;

- simultaneous use of other drugs (see INTERACTIONS).

If there are factors that increase the risk of hypoglycemia, the dose of Amaril should be adjusted^® M 2 mg / 500 mg or the entire treatment regimen. This must also be done in case of any disease or lifestyle changes of the patient. Symptoms of hypoglycemia, reflecting adrenergic counter-regulation, may be smoothed out or completely absent in cases when hypoglycemia develops gradually: in the elderly, in patients with autonomic neuropathy, or in those who are simultaneously receiving treatment with sympatholytics.

General precautions

Hypoglycemia. From experience with other sulfonylureas, it is known that, despite the initial success of the measures taken, repeated episodes of hypoglycemia are possible. In this regard, the patient should be closely monitored.Possible symptoms of hypoglycemia include headache, a strong feeling of hunger ("wolf" appetite), nausea, vomiting, apathy, drowsiness, anxiety, sleep disturbances, anxiety, aggressiveness, impaired attention, depression of alertness and reaction, depression, confusion, impaired speech, aphasia, impaired vision, tremor, paresis, impaired sensitivity, dizziness, helplessness, loss of self-control, delirium, seizures of central genesis, drowsiness and loss of consciousness up to coma, shallow breathing and br adicardia. In addition, signs of adrenergic counter-regulation may occur: increased sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina and cardiac arrhythmias.

The clinical presentation of a severe attack of hypoglycemia may resemble a stroke. Patients with severe hypoglycemia require immediate therapy and a doctors examination, in some cases hospitalization. Hypoglycemia control can almost always be quickly established with the immediate intake of carbohydrates (glucose or sugar, for example, a piece of sugar, fruit juice with sugar, tea with sugar, etc.). For such cases, patients should have at least 20 g of sugar. Patients, as well as their family members, should be informed about the risk of hypoglycemia, symptoms, treatment and factors contributing to its occurrence. Others may need help to prevent complications. Artificial sugar substitutes are ineffective for controlling hypoglycemia.

Lactic acidosis. Lactic acidosis is a rare but rather serious metabolic complication that develops as a result of cumulation of metformin during treatment with this drug. If this condition occurs, then in almost 50% of cases it ends lethally. Lactic acidosis can occur in certain pathophysiological conditions, such as diabetes mellitus, as well as in any conditions accompanied by significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by an increase in blood lactate level (≥5 mmol / l), a decrease in blood pH, an electrolyte imbalance, an increase in the anion interval and the lactate / pyruvate ratio. In cases where lactic acidosis is caused by metformin, the level of metformin in blood plasma, as a rule, exceeds 5 μg / ml.

The frequency of reported cases of lactic acidosis in patients taking metformin hydrochloride is very low (about 0.03 cases / 1000 patient-years, including about 0.015 fatal cases / 1000 patient-years). Reported cases occurred mainly in patients with diabetes with severe renal failure caused by both kidney damage and a decrease in renal hemodynamics, very often with numerous concomitant therapeutic / surgical pathologies and taking a large number of drugs.

The risk of lactic acidosis increases in proportion to the severity of renal dysfunction and the patients age. However, the risk of lactic acidosis in patients taking metformin can be significantly reduced by constantly monitoring kidney function and using minimal effective doses of metformin.

In addition, if any conditions accompanied by hypoxemia or dehydration appear, you should stop taking this drug.

Due to the fact that with impaired liver function, the ability to excrete lactate may decrease, the drug should not be taken in patients with clinical or laboratory signs of liver disease. Patients should be cautioned against excessive alcohol consumption (both single and chronic) during treatment with this drug, since alcohol enhances the effect of metformin hydrochloride on lactate metabolism.In addition, the drug should be temporarily discontinued before any studies with intravascular administration of radiopaque agents and before any surgical intervention.

Quite often, lactic acidosis begins almost imperceptibly and is accompanied only by nonspecific symptoms, such as malaise, myalgia, respiratory distress syndrome, increased drowsiness and nonspecific abdominal syndrome. With more severe acidosis, hypothermia, arterial hypotension, and resistant bradyarrhythmia can occur. Both the patient and the doctor must be aware of how important such symptoms can be. Therefore, the patient should be instructed to immediately inform the doctor of the appearance of such symptoms. It may also be useful to study such indicators as the level of electrolytes and ketone bodies in blood plasma, blood glucose, blood pH, the concentration of lactate and metformin in the blood. If the patient has achieved stabilization when taking any dose of Amaril^® M 2 mg / 500 mg, the occurrence of nonspecific gastrointestinal symptoms, which are usually noted at the beginning of therapy, is most likely not associated with the use of the drug. Gastrointestinal symptoms that occur over time can be caused by lactic acidosis or another serious illness. Fasting plasma lactate in fasting venous blood, exceeding the upper limit of normal, but 5 mmol / L in patients taking this drug, does not necessarily mean the inevitable onset of lactic acidosis. It can be explained by other mechanisms, such as, for example, uncontrolled diabetes mellitus or obesity, intense physical activity, or a technical problem during a blood test.

The occurrence of lactic acidosis should be suspected in any patient with diabetes mellitus who has metabolic acidosis, and there are no signs of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a condition requiring urgent inpatient treatment. In patients with lactic acidosis receiving amaryl^® M 2 mg / 500 mg, you should immediately stop taking it and immediately take the necessary general supportive measures. Due to the fact that metformin hydrochloride is excreted by dialysis (clearance up to 170 ml / min with proper hemodynamics), hemodialysis is recommended immediately to correct acidosis and remove accumulated metformin. Such therapeutic measures often contribute to the rapid disappearance of the symptoms of lactic acidosis.

- The optimal level of glucose in the blood should be maintained by simultaneously following a diet and performing physical exercises, as well as, when necessary, by reducing body weight and by regular use of Amaril^® M 2 mg / 500 mg. Clinical symptoms of an insufficient decrease in blood glucose are an increase in the frequency of urination (oliguria), severe thirst, dry mouth and dry skin.

- Patients should be informed of the benefits and potential risks associated with the use of Amaril^® M 2 mg / 500 mg, as well as the importance of dieting and regular exercise.

- The response to all diabetes treatments should be monitored by periodically measuring fasting glucose and glycosylated hemoglobin in order to reduce these levels to normal. At the beginning of treatment, when setting a dose, fasting glucose can be used to determine the therapeutic response. In the future, the concentration of both glucose and glycosylated hemoglobin should be monitored. Determining glycosylated hemoglobin levels may be particularly useful in assessing long-term control.

- If the patient is being treated by another doctor (for example, during hospitalization, accident, need to seek medical help on the weekend), he must inform him about his diabetes and previous treatment.

- In exceptional stressful situations (for example, trauma, surgery, an infectious disease with a high body temperature), the regulation of blood glucose levels may be impaired, and it may be necessary to temporarily transfer the patient to insulin to ensure proper metabolic control.

- Treatment with Amaril^® M 2 mg / 500 mg should be started