Jardines, 30 pcs., 10 mg, film-coated tablets

Jardines PPO tablets 10mg No. 30

Compound

Active substance: empagliflozin - 10 mg. Excipients: lactose monohydrate - 162.5 mg, microcrystalline cellulose - 62.5 mg, hyprolose (hydroxypropylcellulose) - 7.5 mg, croscarmellose sodium - 5 mg, colloidal silicon dioxide - 1.25 mg, magnesium stearate - 1.25 mg.

Pharmacokinetics

The pharmacokinetics of empagliflozin have been extensively studied in healthy volunteers and patients with type 2 diabetes.

Suction

After oral administration, empagliflozin was rapidly absorbed, the Cmax of empagliflozin in the blood plasma was reached after 1.5 hours. Then the plasma concentration of empagliflozin decreased in two phases: with a rapid distribution phase and a relatively slow terminal phase.

After taking empaglifozine at a dose of 25 mg 1 time/day, the average AUC value during the period of equilibrium plasma concentration was 4740 nmol x h/l, and the Cmax value was 687 nmol/l.

The pharmacokinetics of empagliflozin in healthy volunteers and patients with type 2 diabetes were generally similar.

Food intake does not have a clinically significant effect on the pharmacokinetics of empagliflozin.

Distribution

The apparent Vd during the period of equilibrium plasma concentration was approximately 73.8 L. After oral administration of labeled empagliflozin [14C] to healthy volunteers, plasma protein binding was 86%.

Metabolism

The main pathway of metabolism of empagliflozin in humans is glucuronidation with the participation of uridine-5′-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8 and UGT1A9. The most commonly identified metabolites of empagliflozin are three glucuronic conjugates (2-O, 3-O and 6-O glucuronide). The systemic effect of each metabolite is small (less than 10% of the total effect of empagliflozin).

Removal

T1/2 was approximately 12.4 hours. When using empagliflozin 1 time/day, Css in blood plasma was achieved after the fifth dose. Following oral administration of labeled empagliflozin [14C] in healthy volunteers, approximately 96% of the dose was excreted (41% intestinal, 54% renal). Through the intestines, most of the labeled drug was excreted unchanged. Only half of the labeled drug was excreted unchanged by the kidneys.

Pharmacokinetics in special groups of patients

Renal dysfunction. In patients with mild (60≤GFR<90 ml/min/1.73 m2), moderate (30≤GFR<60 ml/min/1.73 m2) and severe renal failure (GFR<30 ml/min/1.73 m2) and in patients with end-stage renal disease, empagliflozin AUC values ​​increased by approximately 18%, 20%, 66%, and 48%, respectively, compared with patients with normal renal function. In patients with moderate renal impairment and in patients with end-stage renal disease, the plasma Cmax of empagliflozin was similar to that in patients with normal renal function. In patients with mild to severe renal impairment, empagliflozin plasma Cmax was approximately 20% higher than in patients with normal renal function. Data from a population pharmacokinetic analysis showed that the total clearance of empagliflozin decreased as GFR decreased, resulting in increased drug exposure.

Liver dysfunction. In patients with mild, moderate, and severe hepatic impairment (Child-Pugh classification), empagliflozin AUC values ​​increased by approximately 23%, 47%, and 75%, respectively, and Cmax values ​​increased by approximately 4%, 23%, and 48%, respectively. (compared to patients with normal liver function).

BMI, gender, race, and age did not have a clinically significant effect on the pharmacokinetics of empagliflozin.

Children. The pharmacokinetics of empagliflozin have not been studied in children.

Indications for use

For the treatment of type 2 diabetes mellitus in adult patients with inadequate glycemic control, in addition to diet and exercise:

• as monotherapy;
• as part of combination therapy with other hypoglycemic drugs, including insulin.

The drug is indicated for patients with type 2 diabetes mellitus and high cardiovascular risk* in combination with standard therapy for cardiovascular diseases to reduce:

• overall mortality by reducing cardiovascular mortality;
• cardiovascular mortality or hospitalization for heart failure.

*High cardiovascular risk is defined as the presence of at least one of the following diseases and/or conditions: IHD (history of myocardial infarction, coronary artery bypass grafting, IHD with damage to one coronary vessel, IHD with damage to several coronary vessels); history of ischemic or hemorrhagic stroke; peripheral arterial disease (with or without symptoms).

Contraindications

• hypersensitivity to empagliflozin and/or any excipient in the drug;
• type 1 diabetes mellitus;
• diabetic ketoacidosis;
• lactose intolerance, lactase deficiency, galactose malabsorption syndrome (the drug contains lactose monohydrate);
• renal failure with GFR <30 ml/min/1.73 m2;
• pregnancy;
• breastfeeding period;
• age over 85 years;
• age under 18 years (due to insufficient data on effectiveness and safety).

Carefully:

• patients at risk of developing hypovolemia (use of antihypertensive drugs with a history of arterial hypotension);
• for gastrointestinal diseases leading to fluid loss;
• age over 75 years;
• use in combination with sulfonylurea derivatives or insulin;
• genitourinary system infections;
• low carbohydrate diet;
• history of diabetic ketoacidosis;
• low secretory activity of pancreatic β-cells.

Directions for use and doses

Monotherapy or combination therapy

The recommended starting dose is 10 mg (1 tablet with a dosage of 10 mg) 1 time / day. The drug should be taken orally with water.

If a daily dose of 10 mg does not provide adequate glycemic control, the dose can be increased to 25 mg (1 tablet with a dosage of 25 mg) 1 time / day.

The maximum daily dose is 25 mg.

Jardines® can be taken with or without food at any time of the day.

When using Jardins® together with sulfonylureas or insulin, a reduction in the dose of sulfonylurea/insulin may be required due to the risk of hypoglycemia.

What to do if you miss one or more doses of the drug

If a dose is missed, the patient should take the drug as soon as he remembers. You should not take a double dose in one day.

Use of the drug in special groups of patients

The use of the drug in patients with renal failure with GFR <30 ml/min/1.73 m2 is contraindicated. Patients with GFR ≥30 ml/min/1.73 m2 do not require dose adjustment. Empagliflozin should not be used in patients with end-stage renal disease or those on hemodialysis.

Patients with impaired liver function do not require dose adjustment.

Storage conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C.

Best before date

3 years. The drug should not be used after the expiration date.

special instructions

The use of Jardins® is contraindicated in patients with type 1 diabetes mellitus.

Diabetic ketoacidosis

Cases of diabetic ketoacidosis, a serious and life-threatening condition requiring urgent hospitalization, have been reported with the use of empagliflozin, including. with fatal outcome. In some of these cases, the manifestations were atypical and were expressed in a moderate increase in blood glucose concentration (not more than 14 mmol/L (250 mg/dL)).

The risk of developing diabetic ketoacidosis should be considered in the event of the appearance of nonspecific symptoms such as nausea, vomiting, lack of appetite, abdominal pain, severe thirst, difficulty breathing, disorientation, unmotivated fatigue or drowsiness.

If such symptoms develop, patients should be promptly evaluated for ketoacidosis, regardless of blood glucose concentration. If ketoacidosis is suspected, the use of Jardins® should be discontinued, the patient examined and treated immediately.

Patients who may be at higher risk of developing diabetic ketoacidosis while taking Jardines include those on a very low carbohydrate diet (in which case this combination may further increase ketone production in the body), and patients with acute medical conditions. , patients with pancreatic diseases suggesting insulin deficiency (for example, type 1 diabetes mellitus, a history of pancreatitis or pancreatic surgery), with reduced insulin dosage (including ineffective insulin pump), patients who abuse alcohol, patients with severe dehydration and patients with a history of ketoacidosis. In such patients, Jardins® should be used with caution. Caution should be exercised when reducing the insulin dose. In patients receiving Jardins®, consider monitoring for ketoacidosis and temporarily discontinuing Jardins® in clinical situations predisposing to the development of ketoacidosis (eg, prolonged fasting due to acute illness or surgery). In such situations, ketone monitoring should be considered even if Jardins® has been discontinued.

Clinical studies have shown that treatment with empagliflozin does not increase cardiovascular risk. The use of empagliflozin at a dose of 25 mg does not lead to prolongation of the QT interval.

Necrotizing perineal fasciitis (Fournier's gangrene)

Cases of necrotizing perineal fasciitis (also known as Fournier's gangrene), a rare but serious and life-threatening necrotizing infection, have been reported with the use of SGLT2 inhibitors, including empagliflozin, in both female and male patients. Serious outcomes included hospitalization, multiple surgical procedures, and death.

If a patient taking Jardins® develops symptoms such as pain or tenderness, redness, swelling in the genital or perineal area, fever, or malaise, they should be evaluated for the presence of necrotizing fasciitis. If necrotizing fasciitis is suspected, the use of Jardins® should be discontinued and immediate treatment with broad-spectrum antibiotics and, if necessary, excision of necrotic tissue should be prescribed.

Monitoring kidney function

The effectiveness of Jardins® depends on renal function, so it is recommended to monitor renal function before prescribing it and periodically during treatment (at least once a year), as well as before prescribing concomitant therapy that may adversely affect renal function. For patients with renal failure (GFR less than 30 ml/min/1.73 m2), the drug is contraindicated.

Elderly patients

Patients aged 75 years and older have an increased risk of dehydration, so Jardins® should be administered with caution in this age group of patients. These patients treated with empagliflozin were more likely to experience adverse events caused by hypovolemia (compared to patients treated with placebo).

Experience with empagliflozin in patients over 85 years of age is limited, and therefore it is not recommended to prescribe Jardins® to patients over 85 years of age.

Use in patients at risk of developing hypovolemia

According to the mechanism of action, the use of the drug Jardins® can lead to a moderate decrease in blood pressure. Therefore, the drug should be used with caution in cases where a decrease in blood pressure is undesirable, for example, in patients with cardiovascular diseases; patients taking antihypertensive drugs (with a history of arterial hypotension), as well as in patients over 75 years of age.

If a patient taking Jardins® develops conditions that may lead to fluid loss (for example, gastrointestinal diseases), the patient's condition, blood pressure, and hematocrit and electrolyte balance should be carefully monitored. It may be necessary to temporarily stop taking the drug until water balance is restored.

Urinary tract infections

The incidence of adverse events such as urinary tract infections was comparable with empagliflozin 25 mg and placebo, and higher with empagliflozin 10 mg. Complicated urinary tract infections, incl. pyelonephritis and urosepsis were observed in patients taking empagliflozin in post-marketing studies. If complicated urinary tract infections develop, temporary discontinuation of empagliflozin therapy is necessary.

Laboratory urine analysis

According to the mechanism of action, glucose is detected in the urine in patients taking Jardins®.

Increased incidence of lower limb amputations

In long-term clinical studies of another SGLT2 inhibitor, an increased incidence of lower extremity (primarily toe) amputations was observed. It is unknown whether therapy with other SGLT2 inhibitors causes this complication. Patients with diabetes mellitus, incl. Those receiving Jardins® should be advised to take ongoing preventive foot care.

Chronic heart failure

Experience with the drug in patients with NYHA class I-II chronic heart failure is limited, and empagliflozin has never been used in clinical trials in patients with NYHA class III-IV chronic heart failure. It was reported that in the EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) study, 10.1% of patients at the time of the study began to suffer from heart failure. Moreover, the reduction in mortality from acute cardiovascular diseases achieved among them was comparable to that in the general group of study participants.

Liver damage

During clinical studies, cases of liver damage were reported in patients receiving empagliflozin. A cause-and-effect relationship between the use of empagliflozin and liver damage has not been established.

Increased hematocrit level

Cases of increased hematocrit levels have been observed during therapy with empagliflozin.

Description

An oral hypoglycemic drug is an inhibitor of sodium-dependent glucose transporter type 2.

Dosage form

Light yellow, round, biconvex, film-coated tablets with beveled edges, engraved with the company symbol on one side and “S10” on the other side.

Use in children

The use of the drug is contraindicated in people under 18 years of age (due to insufficient data on effectiveness and safety).

Pharmacodynamics

Empagliflozin is a reversible, highly active, selective and competitive inhibitor of sodium glucose transporter type 2 (SGLT2) with a concentration required to inhibit 50% of enzyme activity (IC50) of 1.3 nmol. The selectivity of empagliflozin for SGLT2 is 5000 times greater than the selectivity for sodium-dependent glucose transporter type 1 (SGLT1), responsible for the absorption of glucose in the intestine.

In addition, empagliflozin was found to be highly selective for other glucose transporters responsible for glucose homeostasis in various tissues.

SGLT2 is the major transport protein responsible for the reabsorption of glucose from the glomeruli back into the bloodstream.

Empagliflozin improves glycemic control in patients with type 2 diabetes mellitus (T2DM) by reducing renal glucose reabsorption. The amount of glucose excreted by the kidneys through this mechanism depends on the blood glucose concentration and GFR. Inhibition of SGLT2 in patients with type 2 diabetes and hyperglycemia leads to the excretion of excess glucose by the kidneys.

A 4-week clinical study found that in patients with type 2 diabetes, renal glucose excretion increased immediately after the first dose of empagliflozin; this effect lasted for 24 hours. The increase in glucose excretion by the kidneys persisted until the end of treatment, amounting to an average of about 78 g/day when using empagliflozin at a dose of 25 mg 1 time/day. In patients with type 2 diabetes, an increase in renal glucose excretion led to an immediate decrease in plasma glucose concentrations.

Empagliflozin (at a dose of 10 mg and 25 mg) reduces the concentration of glucose in the blood plasma both when taken on an empty stomach and after a meal.

The mechanism of action of empagliflozin does not depend on the functional state of pancreatic β-cells and insulin metabolism, which contributes to a low risk of the possible development of hypoglycemia. Positive effects of empagliflozin on surrogate markers of β-cell function, including the HOMA-β (Homeostasis Model Assessment-β) index and proinsulin-to-insulin ratio, were observed. In addition, additional excretion of glucose by the kidneys causes a loss of calories, which is accompanied by a decrease in the volume of adipose tissue and a decrease in body weight.

Glucosuria observed during the use of empagliflozin is accompanied by a slight increase in diuresis, which may contribute to a moderate decrease in blood pressure.

In clinical studies using empagliflozin as monotherapy; combination therapy with metformin; combination therapy with metformin in patients with newly diagnosed type 2 diabetes; combination therapy with metformin and sulfonylurea derivatives; combination therapy with pioglitazone ± metformin; combination therapy with linagliptin in patients with newly diagnosed type 2 diabetes; combination therapy with linagliptin added to metformin therapy; combination therapy with linagliptin compared with placebo in patients with inadequate glycemic control while taking linagliptin and metformin; combination therapy with metformin compared with glimepiride (data from a 2-year study); combination therapy with insulin (regimen of multiple insulin injections) ± metformin; combination therapy with basal insulin; Combination therapy with a dipeptidyl peptidase-4 (DPP-4) inhibitor, metformin ± another hypoglycemic oral drug showed a statistically significant decrease in glycosylated hemoglobin (HbA1c), a decrease in fasting plasma glucose concentrations, as well as a decrease in blood pressure and body weight.

A clinical trial examined the effect of Jardins® on the incidence of cardiovascular events in patients with type 2 diabetes and high cardiovascular risk (defined as the presence of at least one of the following diseases and/or conditions: coronary artery disease (history of myocardial infarction, coronary artery bypass grafting). arteries, ischemic heart disease with damage to one coronary vessel, ischemic heart disease with damage to several coronary vessels), a history of ischemic or hemorrhagic stroke, peripheral arterial disease with or without symptoms), receiving standard therapy, which included hypoglycemic drugs and drugs for the treatment of cardiovascular diseases. The primary endpoint was cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. Additional prespecified endpoints included cardiovascular death, all-cause mortality, development of nephropathy or progressive worsening of nephropathy, and hospitalization for heart failure.

Empagliflozin improved overall survival by reducing cardiovascular death and reducing the risk of hospitalization for heart failure. Jardins® was also shown in a clinical trial to reduce the risk of nephropathy or progressive worsening of nephropathy.

In patients with baseline macroalbuminuria, it was found that JARDINS® resulted in sustained normo- or microalbuminuria significantly more often than placebo (risk ratio 1.82 [95% CI 1.40; 2.37]).

Side effects

The overall incidence of adverse reactions was similar in patients receiving empagliflozin or placebo in clinical studies. The most common adverse reaction was hypoglycemia, observed when empagliflozin was used in combination with sulfonylureas or insulin (see description of individual adverse reactions).

Adverse reactions (ADRs) observed in patients receiving empagliflozin in placebo-controlled studies are presented below in Table 1. ADRs are divided into system-organ classes and their frequency of occurrence according to WHO recommendations: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000) or very rare (<1/10,000) ); NRs are also identified, the frequency of which is unknown (cannot be estimated based on the available data).

Table 1.

ADRs registered in clinical trials and post-registration observation period

1 Additional information is provided in the subsections below. 2 Based on post-marketing data.

Description of selected adverse reactions

• Hypoglycemia

The incidence of hypoglycemia depended on the concomitant hypoglycemic therapy used and was similar in patients taking empagliflozin or placebo alone, as well as in the case of adding empagliflozin to metformin, in the case of adding empagliflozin to pioglitazone (± metformin) and in the case of adding empagliflozin to linagliptin + metformin . When empagliflozin was used in combination with metformin and a sulfonylurea, and when empagliflozin was used in combination with insulin (± metformin and ± sulfonylurea), the incidence of hypoglycemia was higher than when using placebo in the same combination.

• Severe hypoglycemia (a condition requiring medical attention)

The incidence of severe hypoglycemia was low (<1%) and similar in patients receiving empagliflozin and placebo as monotherapy, and when empagliflozin was added to metformin (± sulfonylureas), when empagliflozin was added to pioglitazone (± metformin), and in case of adding empagliflozin to linagliptin + metformin. When empagliflozin was used in combination with basal insulin (± metformin and ± sulfonylurea), the incidence of hypoglycemia was higher than when using placebo in the same combination.

• Increased urination

An increase in urinary output (measured by symptoms such as pollakiuria, polyuria, nocturia) was observed with empagliflozin (10 mg dose: 3.5%, 25 mg dose: 3.3%), compared with placebo (1.4%). The incidence of nocturia was comparable in the group of patients taking empagliflozin and in the group of patients taking placebo (less than 1%). The increase in urinary output was mostly mild or moderate in intensity.

• Urinary tract infections

The incidence of urinary tract infections was similar with empagliflozin 25 mg and placebo (7.0% and 7.2%, respectively), but higher with empagliflozin 10 mg (8.8%). As with placebo, urinary tract infections with empagliflozin were more common in patients with a history of chronic or recurrent urinary tract infections. The incidence of urinary tract infections was similar in patients taking empagliflozin and placebo. Urinary tract infections were more common in women.

• Genital infections

The incidence of adverse events such as vaginal candidiasis, vulvovaginitis, balanitis and other genital infections was higher with empagliflozin (10 mg dose: 4.0%, 25 mg dose: 3.9%) than with placebo (1.0%). Genital infections were more common in women. The intensity of genital infections was mild or moderate.

• Hypovolemia

The incidence of hypovolemia (expressed as decreased blood pressure, orthostatic hypotension, dehydration, syncope) was similar with empagliflozin (10 mg dose: 0.6%, 25 mg dose: 0.4%) and placebo (0.3%). In patients over the age of 75 years, the incidence of hypovolemia was comparable in patients taking empagliflozin 10 mg (2.3%) and placebo (2.1%), but higher in patients taking empagliflozin 25 mg (4.3%).

• Decrease in GFR and increase in plasma creatinine concentration

The overall incidence of decreased GFR and increased plasma creatinine concentrations was similar between empagliflozin and placebo with metformin (increased plasma creatinine concentration: empagliflozin 10 mg 0.6%, empagliflozin 25 mg 0.1%, placebo 0.5%; decreased GFR: empagliflozin 10 mg 0.1%, empagliflozin 25 mg 0%, placebo 0.3%). There was an initial transient increase in plasma creatinine concentration (mean change from baseline after 12 weeks: empagliflozin 10 mg - 0.02 mg/dL, empagliflozin 25 mg - 0.01 mg/dL) and an initial transient decrease in estimated GFR ( mean change from baseline after 12 weeks: empagliflozin 10 mg - 1.34 ml/min/1.73 m2, empagliflozin 25 mg - 1.37 ml/min/1.73 m2). In long-term studies, these changes were usually reversible with continued treatment or after discontinuation of the drug.

Use during pregnancy and breastfeeding

The use of empagliflozin during pregnancy is contraindicated due to insufficient data on efficacy and safety.

Data obtained from preclinical studies in animals indicate that empagliflozin passes into breast milk. The risk of exposure to newborns and children during breastfeeding cannot be excluded. The use of empagliflozin during breastfeeding is contraindicated. If it is necessary to use empagliflozin during breastfeeding, breastfeeding should be discontinued.

Interaction

Pharmacodynamic interaction

Diuretics. Empagliflozin may enhance the diuretic effect of thiazide and loop diuretics, which, in turn, may increase the risk of dehydration and hypotension.

Insulin and drugs that increase insulin secretion, such as sulfonylureas, may increase the risk of hypoglycemia. Therefore, when using empagliflozin simultaneously with insulin and drugs that enhance its secretion, it may be necessary to reduce their dose to avoid the risk of hypoglycemia.

Pharmacokinetic interaction

In vitro drug interaction assessment. Empagliflozin does not inhibit, inactivate or induce CYP450 isoenzymes. The main pathway of metabolism of empagliflozin in humans is glucuronidation with the participation of uridine-5′-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8 and UGT1A9. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. Drug interactions between empagliflozin and drugs that are substrates of CYP450 and UGT isoenzymes are considered unlikely.

Empagliflozin is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but does not inhibit these proteins at therapeutic doses. Based on in vitro data, empagliflozin is unlikely to interact with drugs that are P-gp substrates. Empagliflozin is a substrate for the organic anion transporters OAT3, OATP1B1 and OATP1B3, but is not a substrate for organic anion transporter 1 (OAT1) and organic cationic transporter 2 (OCT2). However, drug interactions between empagliflozin and drugs that are substrates for the transporter proteins described above are considered unlikely.

In vivo assessment of drug interactions. When empagliflozin was co-administered with other commonly used drugs, no clinically significant pharmacokinetic interactions were observed. The results of pharmacokinetic studies indicate that there is no need to change the dose of Jardins® when used simultaneously with commonly used drugs.

The pharmacokinetics of empagliflozin does not change in healthy volunteers when co-administered with metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin and in patients with type 2 diabetes when co-administered with torasemide and hydrochlorothiazide. When empagliflozin was co-administered with gemfibrozil, rifampicin and probenecid, an increase in the AUC of empagliflozin was observed by 59%, 35% and 53%, respectively, but these changes were not considered clinically significant.

Empagliflozin does not have a clinically significant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, torsemide and oral contraceptives in healthy volunteers.

Overdose

Symptoms: During controlled clinical trials in healthy volunteers, single doses of empagliflozin reaching 800 mg (32 times the maximum daily dose) and multiple doses reaching 100 mg (4 times the maximum daily dose) in patients with type 2 diabetes. were well tolerated. The observed increase in urine volume was independent of the dose and had no clinical significance.

Treatment: In case of overdose of empagliflozin, supportive treatment should be carried out according to the clinical condition of the patient. Elimination of empagliflozin by hemodialysis has not been studied.

Impact on the ability to drive vehicles and operate machinery

Clinical studies on the effect of empagliflozin on the ability to drive vehicles and operate machinery have not been conducted. Patients should be careful when driving vehicles and machinery, because When using the drug Jardins® (especially in combination with sulfonylurea derivatives and/or insulin), hypoglycemia may develop.

Description of the drug JARDINS® (DZHARDINS)

Cases of diabetic ketoacidosis, a serious and life-threatening condition requiring urgent hospitalization, have been reported with the use of empagliflozin, including. with fatal outcome. In some of these cases, the manifestations were atypical and were expressed in a moderate increase in blood glucose concentration (not more than 14 mmol/L (250 mg/dL)).

The risk of developing diabetic ketoacidosis should be considered in the event of the appearance of nonspecific symptoms such as nausea, vomiting, lack of appetite, abdominal pain, severe thirst, difficulty breathing, disorientation, unmotivated fatigue or drowsiness. If such symptoms develop, patients should be promptly evaluated for ketoacidosis, regardless of blood glucose concentration. If ketoacidosis is suspected, empagliflozin should be discontinued, the patient assessed and treated promptly.

Patients who may be at higher risk of developing diabetic ketoacidosis include those on a very low carbohydrate diet (in which case this combination may further increase the body's production of ketones), patients with acute illness, and patients with pancreatic disease. glands suggestive of insulin deficiency (eg, type 1 diabetes mellitus, history of pancreatitis, or pancreatic surgery), with reduced insulin dosage (including insulin pump failure), patients with alcohol abuse, patients with severe dehydration, and patients with a history of ketoacidosis .Caution should be exercised when reducing the dose of insulin. In patients receiving empagliflozin, consider monitoring for ketoacidosis and temporarily discontinuing empagliflozin in clinical situations predisposing to the development of ketoacidosis (eg, prolonged fasting due to acute illness or surgery).

It is recommended to monitor renal function before starting treatment and periodically during treatment (at least once a year), as well as before prescribing concomitant therapy that may adversely affect renal function. In patients with renal failure (GFR <45 ml/min/1.73 m2), empagliflozin is contraindicated.

Patients aged 75 years and older have an increased risk of dehydration. These patients were more likely to experience adverse reactions caused by hypovolemia.

Use with caution in cases where a decrease in blood pressure is undesirable, for example, in patients with cardiovascular diseases; patients taking antihypertensive drugs (with a history of arterial hypotension), as well as in patients over 75 years of age.

If a patient receiving empagliflozin develops conditions that may lead to fluid loss (for example, gastrointestinal diseases), the patient's condition, blood pressure, and hematocrit and electrolyte balance should be carefully monitored. Temporary discontinuation of empagliflozin may be required until fluid balance is restored.

If complicated urinary tract infections develop, temporary discontinuation of empagliflozin therapy is necessary.

According to the mechanism of action, glucose is detected in the urine in patients receiving empagliflozin.

Impact on the ability to drive vehicles and machinery

During the treatment period, patients should be careful when driving vehicles and machinery, because When using epagliflozin (especially in combination with sulfonylurea derivatives and/or insulin), hypoglycemia may develop.

Jardiance®

Empagliflozin is a reversible, highly active, selective and competitive inhibitor of sodium glucose transporter type 2 with a concentration required to inhibit 50% of enzyme activity (IC50) of 1.3 nmol. The selectivity of empagliflozin is 5000 times greater than the selectivity of sodium-dependent glucose transporter type 1, responsible for the absorption of glucose in the intestine.

In addition, empagliflozin was found to be highly selective for other glucose transporters responsible for glucose homeostasis in various tissues.

Sodium-dependent glucose transporter type 2 is the primary transport protein responsible for the reabsorption of glucose from the glomeruli back into the bloodstream.

Empagliflozin improves glycemic control in patients with type 2 diabetes mellitus (T2DM) by reducing renal glucose reabsorption. The amount of glucose excreted by the kidneys through this mechanism depends on the concentration of glucose in the blood and the glomerular filtration rate (GFR). Inhibition of sodium-dependent glucose transporter type 2 in patients with type 2 diabetes and hyperglycemia leads to the excretion of excess glucose by the kidneys.

In a 4-week clinical study, it was found that in patients with type 2 diabetes, renal glucose excretion increased immediately after the first dose of empagliflozin; this effect lasted for 24 hours. The increase in renal glucose excretion persisted until the end of treatment, averaging about 78 g/day when using empagliflozin at a dose of 25 mg once daily. In patients with type 2 diabetes, an increase in renal glucose excretion led to an immediate decrease in plasma glucose concentrations.

Empagliflozin (at a dose of 10 mg and 25 mg) reduces the concentration of glucose in the blood plasma both when taken on an empty stomach and after a meal.

The mechanism of action of empagliflozin does not depend on the functional state of pancreatic beta cells and insulin metabolism, which contributes to a low risk of possible development of hypoglycemia. Positive effects of empagliflozin on surrogate markers of beta cell function, including the HOMA-β (Homeostasis Model-B) index and proinsulin-to-insulin ratio, were observed. In addition, additional excretion of glucose by the kidneys causes a loss of calories, which is accompanied by a decrease in the volume of adipose tissue and a decrease in body weight.

Glucosuria observed during the use of empagliflozin. is accompanied by a slight increase in diuresis, which may contribute to a moderate decrease in blood pressure.

In clinical studies using empagliflozin as monotherapy; combination therapy with metformin; combination therapy with metformin in patients with newly diagnosed type 2 diabetes; combination therapy with metformin and sulfonylurea derivatives; combination therapy with pioglitazone +/- metformin; combination therapy with linagliptin in patients with newly diagnosed type 2 diabetes; combination therapy with linagliptin added to metformin therapy; combination therapy with linagliptin compared with placebo in patients with inadequate glycemic control while taking linagliptin and metformin; combination therapy with metformin compared with glimepiride (data from a 2-year study); combination therapy with insulin (regimen of multiple insulin injections) +/- metformin; combination therapy with basal insulin: combination therapy with a dipeptidyl peptidase-4 (DPP-4) inhibitor, metformin +/- another hypoglycemic oral drug has been shown to have a statistically significant decrease in glycosylated hemoglobin (HbAlc), a decrease in fasting plasma glucose concentrations, and a decrease in blood pressure and body weight.

A clinical trial examined the effect of JARDINS® on the incidence of cardiovascular events in patients with type 2 diabetes and high cardiovascular risk (defined as the presence of at least one of the following diseases and/or conditions: coronary artery disease (history of myocardial infarction, coronary artery bypass grafting). arteries, ischemic heart disease with damage to one coronary vessel, ischemic heart disease with damage to several coronary vessels), a history of ischemic or hemorrhagic stroke, peripheral arterial disease with or without symptoms), receiving standard therapy, which included hypoglycemic drugs and drugs for the treatment of cardiovascular diseases. The primary endpoint was cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Additional prespecified endpoints included cardiovascular death, all-cause mortality, development of nephropathy or progressive worsening of nephropathy, and hospitalization for heart failure.

Empagliflozin improved overall survival by reducing cardiovascular death. Empagliflozin reduced the risk of hospitalization for heart failure. JARDINS® was also shown in a clinical trial to reduce the risk of nephropathy or progressive worsening of nephropathy.

In patients with baseline macroalbuminuria, it was found that JARDINS® resulted in sustained normo- or microalbuminuria significantly more often than placebo (hazard ratio 1.82, 95% CI 1.40, 2.37).