Expiration date: 10/2026

Packaging and release form

Solution for subcutaneous administration, 0,25/0,5/1 mg / dose of 3 ml of the drug in colorless glass cartridges. The cartridge is installed in a plastic multidose disposable pen for multiple injections. 1 pre-filled multi-dose disposable pen for multiple injections and 1 cardboard pack containing 4 disposable needles installed in a cardboard needle holder, with instructions for medical use of the drug, instructions for using the pen and a card insert for monitoring the administration of the drug are placed in a pack of cardboard.

Dosage form

A colorless or almost colorless transparent solution.

Composition

1 ml of the solution contains:

active ingredient: semaglutide - 1.34 mg;

excipients: disodium hydrophosphate dihydrate - 1.42 mg, propylene glycol - 14.0 mg, phenol - 5.5 mg, hydrochloric acid diluted with 10% and / or sodium hydroxide solution of 10% - for pH correction up to 7.4, water for injection - up to 1 ml.

Pharmacotherapeutic group

hypoglycemic agent - an analogue of glucagon-like peptide-1

Pharmacodynamics

PHARMACOLOGICAL PROPERTIES

Semaglutide is a chemically synthesized GLP-1 receptor agonist (GLP-1P).

Semaglutide is a synthetic analogue of GLP-1. Semaglutide acts as an agonist of GLP-1P, which selectively binds to and activates GLP-1P. GLP-1P serves as a target for native GLP-1.

GLP-1 is a physiological hormone that has several effects on the regulation of glucose concentration and appetite, as well as on the cardiovascular system (CVS). The effect on glucose concentration and appetite is specifically mediated by GLP-1P located in the pancreas and brain. Pharmacological concentrations of semaglutide reduce blood glucose concentration and body weight through a combination of the effects described below. GLP-1P is also present in specific areas of the heart, blood vessels, immune system, and kidneys, where their activation can have cardiovascular (CC) and microcirculatory effects.

Unlike the native GLP-1, the extended half-life of semaglutide (about 1 week) allows it to be administered subcutaneously (subcutaneously) once a week. Binding to albumin is the main mechanism of long-term action of semaglutide, which leads to a decrease in its excretion by the kidneys and protects against metabolic degradation. In addition, semaglutide is stable with respect to cleavage by the enzyme dipeptidyl peptidase-4.

Semaglutide reduces blood glucose concentration by glucose-dependent stimulation of insulin secretion and suppression of glucagon secretion. Thus, with an increase in blood glucose concentration, insulin secretion is stimulated and glucagon secretion is suppressed. The mechanism of lowering the level of glycemia also includes a slight delay in gastric emptying in the early postprandial phase. During hypoglycemia, semaglutide reduces insulin secretion and does not decrease glucagon secretion.

Semaglutide reduces total body weight and adipose tissue mass, reducing energy consumption. This mechanism affects the overall decrease in appetite, including increased satiety signals and decreased hunger signals, as well as improved food intake control and reduced food cravings. Insulin resistance also decreases, possibly due to a decrease in body weight. In addition, semaglutide reduces the preference for high-fat meals. In animal studies, semaglutide has been shown to be absorbed by specific areas of the brain and enhances key satiety signals and weakens key hunger signals. By acting on isolated areas of brain tissue, semaglutide activates neurons associated with feeling full and suppresses neurons associated with feeling hungry.

In clinical studies, semaglutide had a positive effect on plasma lipids, lowered systolic blood pressure (BP), and reduced inflammation.

In animal studies, semaglutide suppresses the development of atherosclerosis, preventing the further development of aortic plaques and reducing plaque inflammation.

PHARMACODYNAMICS

All pharmacodynamic studies were performed after 12 weeks of therapy (including the period of dose increase) at an equilibrium concentration of semaglutide 1 mg once a week.

Fasting glycemic level and postprandial glycemic level

Semaglutide reduces fasting glucose concentration and postprandial glucose concentration. Compared with placebo, semaglutide 1 mg therapy in patients with type 2 diabetes mellitus (T2DM) resulted in a decrease in glucose concentration in terms of an absolute change from baseline (mmol/L) and a relative decrease compared with placebo (%) in terms of: fasting glucose concentration (1.6 mmol/L; 22%); glucose concentration 2 hours after eating (4.1 mmol/L; 37%); average daily glucose concentration (1.7 mmol/L; 22%) and postprandial peaks of glucose concentration for 3 meals (0.6-1.1 mmol/l). Semaglutide decreased fasting glucose concentration after the first dose.

Pancreatic beta cell function and insulin secretion

Semaglutide improves the function of pancreatic beta cells. After intravenous glucose injection in patients with T2DM, semaglutide improved the first and second phases of the insulin response with a threefold and twofold increase, respectively, and increased the maximum secretory activity of pancreatic beta cells after an arginine stimulation test compared with placebo. In addition, compared with placebo, semaglutide therapy increases fasting insulin concentrations.

Glucagon secretion

Semaglutide reduces fasting glucagon concentration and postprandial glucagon concentration. In patients with DM2, semaglutide leads to a relative decrease in glucagon concentration compared with placebo: fasting glucagon concentration (8-21%), postprandial glucagon response (14-15%) and average daily glucagon concentration (12%).

Glucose-dependent insulin secretion and glucose-dependent glucagon secretion

Semaglutide reduced high blood glucose concentrations by stimulating insulin secretion and reducing glucagon secretion in a glucose-dependent manner. The rate of insulin secretion after administration of semaglutide to patients with T2DM was comparable to that of healthy volunteers.

During induced hypoglycemia, semaglutide compared with placebo did not alter the counterregulatory response of increased glucagon concentration, nor did it exacerbate the decrease in C-peptide concentration in patients with T2DM.

Emptying the stomach

Semaglutide caused a slight delay in early postprandial gastric emptying, thereby reducing the rate of postprandial glucose entry into the blood.

Body weight and body composition

There was a greater decrease in body weight when using semaglutide compared with the studied comparison drugs (placebo, sitagliptin, delayed-release exenatide (SV), dulaglutide and insulin glargine) (see section "Clinical efficacy and safety"). The loss of body weight when using semaglutide occurred mainly due to the loss of adipose tissue, exceeding the loss of muscle mass by 3 times.

Appetite, calorie intake, and food choices

Compared with placebo, semaglutide reduced calorie intake by 18-35% during three consecutive meals ad libltum. This was facilitated by semaglutide-stimulated appetite suppression both on an empty stomach and after meals, improved food intake control, and decreased cravings for food, especially high-fat ones.

Fasting lipids and postprandial lipids

Compared with placebo, semaglutide reduced fasting concentrations of triglycerides and very low-density lipoprotein cholesterol (VLDL) by 12% and 21%, respectively. The postprandial increase in the concentration of triglycerides and VLDL cholesterol in response to high-fat meals decreased by more than 40%.

Electrophysiology of the Heart (EFS)

The effect of semaglutide on the process of repolarization in the heart was tested in the EFS study. The use of semaglutide in doses exceeding therapeutic ones (at steady-state concentrations up to 1.5 mg) did not lead to an extension of the adjusted QT interval.

Clinical efficacy and safety

Both improving glycemic control and reducing CC morbidity and mortality are an integral part of the treatment of T2DM.

The efficacy and safety of semaglutide at doses of 0.5 mg and 1 mg were evaluated in six randomized controlled trials per phase. Of these, five CI assessed the effectiveness of glycemic control as the main goal, while one CI assessed the outcome as the main goal. In addition, two phase Z semaglutide treatments were performed with the participation of Japanese patients.

In addition, a phase Ib study was conducted to compare the efficacy and safety of semaglutide at doses of 0.5 mg and 1 mg once a week with dulaglutide 0.75 mg and 1.5 mg once a week, respectively. A phase B study was also conducted to study the efficacy and safety of semaglutide as an adjunct to treatment with a sodium-dependent glucose transporter type 2 (SGLT2) inhibitor.

Semaglutide therapy demonstrated sustained, statistically superior, and clinically significant improvements in HbA1c and weight loss for up to 2 years compared with placebo and active-control treatment (sitagliptin, insulin glargine, exenatide SV, and dulaglutide).

Age, gender, race, ethnicity, baseline values of body mass index (BMI) and body weight (kg), duration of diabetes mellitus (DM) and renal failure did not affect the effectiveness of semaglutide.

Monotherapy

Semaglutide monotherapy at doses of 0.5 mg and 1 mg once a week for 30 weeks, compared with placebo, resulted in a statistically more significant decrease in HbA1c (-1.5%, -1.6% versus 0%, respectively), fasting plasma glucose (HDL) (-2.5 mmol/l, -2.3 mmol/L versus -0.6 mmol/L, respectively) and body weight (-3.7 kg, -4.5 kg versus -1.0 kg, respectively).

Semaglutide compared with sitagliptin, both in combination with 1-2 oral hypoglycemic drugs (PGP2) (metformin and/or thiazolidinedione group drugs)

Therapy with semaglutide 0.5 mg and 1 mg once a week for 56 weeks, compared with sitagliptin, led to a steady and statistically more significant decrease in HbA1c (-1.3%, -1.6% vs. -0.5%, respectively), GPN (-2.1 mmol/l, -2.6 mmol/l vs. -1.1 mmol/l, respectively) and body weight (-4.3 kg, -6.1 kg versus -1.9 kg, respectively). Therapy with semaglutide 0.5 mg and 1 mg compared with sitagliptin significantly reduced systolic blood pressure from the baseline value of 132.6 mmHg (-5.1 mmHg, -5.6 mmHg versus -2.3 mmHg, respectively). There were no changes in diastolic blood pressure.

Semaglutide compared to dulaglutide, both in combination with metformin

Therapy with semaglutide 0.5 mg compared with dulaglutide 0.75 mg, both once a week for 40 weeks, led to a steady and statistically superior decrease in HbA1c (-1.5% vs. -1.1%), HPN (-2.2 mmol/l vs. -1.9 mmol/L) and body weight (-4.6 kg vs. -2.3 kg), respectively.

Therapy with semaglutide 1 mg compared with dulaglutide 1.5 mg, both once a week for 40 weeks, led to a steady and statistically superior decrease in HbA1c (-l,8% vs. -1.4%), HDL (-2.8 mmol/l vs. -2.2 mmol/l) and body weight (-6.5 kg vs. -3.0 kg), respectively.

Semaglutide compared to exenatide SV, both in combination with metformin or metformin together with a sulfonylurea derivative

Therapy with semaglutide 1 mg once a week for 56 weeks, compared with exenatide SV 2.0 mg, led to a steady and statistically more significant decrease in HbA1c (-1.5% vs. -0.9%), HPN (-2.8 mmol/l vs. -2.0 mmol/l) and body weight (-5.6 kg vs. -1.9 kg), accordingly.

Semaglutide compared to insulin glargine, both in combination with 1-2 GHP (metformin monotherapy or metformin with a sulfonylurea derivative)

Semaglutide therapy at doses of 0.5 mg and 1 mg once a week compared with insulin glargine for 30 weeks resulted in a statistically more significant decrease in HbA1c (-1.2%, -1.6% vs. -0.8%, respectively) and body weight (-3.5 kg, -5.2 kg vs. +1.2 kg, respectively).

The decrease in HPN was statistically more significant for semaglutide 1 mg compared with insulin glargine (-2.7 mmol/l versus - 2.1 mmol/l). There was no statistically more significant decrease in the HPN index for semaglutide 0.5 mg (-2.0 mmol/l versus -2.1 mmol/l). The proportion of patients who had severe or confirmed (<3.1 mmol/L) episodes of hypoglycemia was lower with semaglutide 0.5 mg (4.4%) and semaglutide 1 mg (5.6%) compared with insulin glargine (10.6%).

More patients achieved HbA1c <7% without severe or confirmed episodes of hypoglycemia and without weight gain when using semaglutide 0.5 mg (47%) and semaglutide 1 mg (64%) compared with insulin glargine (16%).

Semaglutide compared to placebo, both in combination with basal insulin

Semaglutide therapy at doses of 0.5 mg and 1 mg compared with placebo for 30 weeks resulted in a statistically more significant decrease in HbA1c (-1.4%, -1.8% vs. -0.1%, respectively), HDL (-1.6 mmol/l, -2.4 mmol/l vs. -0.5 mmol/l, respectively) and body weight (-3.7 kg, -6.4 kg versus -1.4 kg, respectively). The frequency of severe or confirmed episodes of hypoglycemia did not differ significantly when using semaglutide and placebo. The proportion of patients with HbA1c <8% at screening who reported severe or confirmed (<3.1 mmol/L) episodes of hypoglycemia was higher with semaglutide compared with placebo and comparable in patients with HbA1c >8% at screening.

Semaglutide compared with placebo as an adjunct to SGLT2 inhibitor therapy (as monotherapy or in combination with a sulfonylurea derivative or metformin)

Therapy with semaglutide at a dose of 1 mg once a week as an adjunct to therapy with an SGLT2 inhibitor (as monotherapy or in combination with a sulfonylurea derivative or metformin) compared with placebo once a week for 30 weeks resulted in a statistically significant decrease in HbA1c (-1.5% vs. -0.1%, respectively), GPN (-2.2 mmol/l versus 0 mmol/L, respectively) and body weight (-4.7 kg versus -0.9 kg, respectively).

Combination with monotherapy with sulfonylurea derivatives

At the 30th week of CI (see subsection "Assessment of the effect on cardiovascular system"), a subgroup of 123 patients undergoing monotherapy with sulfonylureas was evaluated. At week 30, the HbA1c index decreased by 1.6% and 1.5% when using semaglutide at doses of 0.5 mg and 1 mg, respectively, and increased by 0.1% when using placebo.

Combination with premixed insulin ± 1-2 PGY

At the 30th week of CI (see subsection "Assessment of the effect on cardiovascular disease"), a subgroup of 867 patients undergoing premixed insulin therapy (in combination or without 2 PGPs) was evaluated. At week 30, the HbA1c index decreased by 1.3% and 1.8% when using semaglutide at doses of 0.5 mg and 1 mg, respectively, and decreased by 0.4% when using placebo.

The ratio of patients who achieved the target reduction in HbA1c

Up to 79% of patients achieved treatment goals for reducing the HbA1c index <7%, and the proportion of such patients was significantly higher with semaglutide compared with patients receiving sitagliptin, exenatide SV, insulin glargine, dulaglutide and placebo.

The proportion of patients who achieved the HbA1c index of less than 7% without severe or confirmed episodes of hypoglycemia and without weight gain was significantly higher when using semaglutide at doses of 0.5 mg and 1 mg (up to 66% and 74%, respectively) compared with patients receiving sitagliptin (27%), exenatide SV (29%), insulin glargine (16%), dulaglutide 0.75 mg (44%) and dulaglutide 1.5 mg (58%).

Body weight

Monotherapy with semaglutide 1 mg or therapy in combination with 1-2 medications resulted in a statistically greater decrease in body weight (loss was up to 6.5 kg) compared with placebo therapy, sitagliptin, exenatide SV, insulin glargine or dulaglutide. The weight loss was sustained for up to 2 years.

After one year of therapy, a greater number of patients receiving semaglutide 0.5 mg (46% and 13%) and 1 mg (up to 62% and 24%) achieved weight loss of ≥5% and ≥10% compared with patients treated with active comparison drugs sitagliptin and exenatide SV (up to 18% and up to 4%).

In CI lasting 40 weeks, a greater number of patients receiving semaglutide 0.5 mg (44% and 14%) achieved weight loss of ≥5% and ≥10% compared with patients receiving dulaglutide 0.75 mg (23% and 3%). A greater number of patients receiving semaglutide 1 mg (up to 63% and 27%) achieved weight loss of ≥5% and ≥10% compared with patients receiving dulaglutide 1.5 mg (30% and 8%).

In terms of body weight loss ≥5% and ≥10%, more patients received semaglutide 0.5 mg (36% and 13%) and 1 mg (47% and 20%), compared with patients receiving placebo 0.5 mg (18% and 6%) and 1 mg (19% and 7%).

GPN and postprandial increase in glucose concentration

During all three daily meals, semaglutide 0.5 mg and 1 mg showed a significant decrease in the concentration of HDL to 2.8 mmol/l and a decrease in the postprandial increase in glucose concentration to 1.2 mmol/l (the difference between the values before and after meals obtained after three meals) (in addition, see the section "Pharmacodynamics").

Pancreatic beta cell function and insulin resistance

During therapy with semaglutide 0.5 mg and 1 mg, pancreatic beta cell function improved and insulin resistance decreased, which is confirmed by an assessment of homeostatic models of pancreatic beta cell function (NOMA-B) and insulin resistance (HOMA-IR) (in addition, see the section "Pharmacodynamics").

Lipids

During treatment with semaglutide, an improvement in the fasting blood lipid profile was observed, mainly in the group receiving a dose of 1 mg (in addition, see the section "Pharmacodynamics").

Assessment of the impact on the CCC

3,297 patients with DM2 and high risk of CC were randomized in a double-blind trial lasting 104 weeks to receive semaglutide 0.5 mg or 1 mg once a week or placebo 0.5 mg or 1 mg in addition to standard CC disease therapy for the next two years.

Semaglutide therapy resulted in a 26% reduction in the risk of a primary combined outcome, including death due to CC pathology, non-fatal myocardial infarction (MI), and non-fatal stroke. This was primarily due to a significant decrease in the incidence of non-fatal stroke (39%) and a slight decrease in the incidence of non-fatal stroke (26%), but no changes in the incidence of death due to CC pathology.

The risk of myocardial or peripheral artery revascularization decreased significantly, while the risk of unstable angina requiring hospitalization and the risk of hospitalization due to heart failure decreased slightly. Microcirculatory outcomes included 158 new or worsened cases of nephropathy. The relative risk in relation to the time before the onset of nephropathy (new cases of persistent macroalbuminuria, persistent doubling of serum creatinine concentration, the need for continuous renal replacement therapy and death due to kidney disease) was 0.64.

In addition to the standard therapy of CC diseases, therapy with semaglutide at doses of 0.5 mg and 1 mg compared with placebo of 0.5 mg and 1 mg for 104 weeks resulted in a significant and sustained decrease from baseline values of HbA1c (-1.1% and -1.4% versus -0.4% and -0.4%, respectively).

Blood pressure

There was a significant decrease in mean systolic blood pressure when using semaglutide 0.5 mg (3.5-5.1 mmHg) and semaglutide 1 mg (5.4-7.3 mmHg) in combination with GHP or basal insulin. There was no significant difference in diastolic blood pressure between semaglutide and the comparison drugs.

Pharmacokinetics

The semaglutide half-life of approximately 1 week makes possible a once-weekly dosing regimen.

Absorption

The time to reach the maximum concentration (Cmax) in plasma ranged from 1 to 3 days after administration of the drug dose.

The steady-state concentration of the drug (AUCt/24) was reached after 4-5 weeks of a single weekly application of the drug. After subcutaneous administration of semaglutide in doses of 0.5 mg and 1 mg, the average steady-state concentrations in patients with DM2 were about 16 nmol/l and 30 nmol/l, respectively.

Exposure for semaglutide 0.5 mg and l mg doses increases in proportion to the dose administered.

Subcutaneous injection of semaglutide into the anterior abdominal wall, hip, or shoulder results in a similar exposure.

The absolute bioavailability of semaglutide after subcutaneous administration was 89%.

Distribution

The average tissue distribution of semaglutide after subcutaneous administration to patients with T2DM was approximately 12.5 liters. Semaglutide was significantly bound to plasma albumin (> 99%).

Biotransformation

Semaglutide is metabolized by proteolytic cleavage of the protein's peptide backbone and subsequent beta-oxidation of the side chain fatty acid.

Elimination

The gastrointestinal tract and kidneys are the main routes of elimination of semaglutide and its metabolites. 2/3 of the administered dose of semaglutide is excreted by the kidneys, 1/3 through the intestine.

Approximately 3% of the administered dose is excreted by the kidneys as unchanged semaglutide.

In patients with DM2, the clearance of semaglutide was about 0.05 l/h. With an elimination half-life of approximately 1 week, semaglutide will be present in the general bloodstream for approximately 5 weeks after the last dose of the drug.

Special patient groups

No dose adjustment of semaglutide is required depending on age, gender, race and ethnicity, body weight, presence of renal or hepatic insufficiency.

Age

Based on the data obtained during the phase II study, which included patients aged 20 to 86 years, it was shown that age did not affect the pharmacokinetics of semaglutide.

Paul

Gender did not affect the pharmacokinetics of semaglutide.

Species

The racial group (white, black, or African American, Asian) did not affect the pharmacokinetics of semaglutide.

Ethnicity

Ethnicity (Latin American) did not affect the pharmacokinetics of semaglutide.

Body weight

Body weight affected semaglutide exposure. A higher body weight leads to a lower exposure. Doses of semaglutide equal to 0.5 mg and 1 mg provide sufficient exposure of the drug in the body weight range from 40 to 198 kg.

Kidney failure

Renal failure had no clinically significant effect on the pharmacokinetics of semaglutide. This has been shown in patients with varying degrees of renal insufficiency (mild, moderate, severe or in patients on dialysis) Compared with patients with normal renal function, a single dose of semaglutide of 0.5 mg was used in the study. This was also shown based on phase III data for patients with T2DM and renal insufficiency, although the experience of use in patients with end-stage kidney disease was limited.

Liver failure

Liver failure did not affect semaglutide exposure. The pharmacokinetic properties of semaglutide were evaluated during a study of a single dose of semaglutide equal to 0.5 mg in patients with varying degrees of liver failure (mild, moderate, severe) compared with patients with normal liver function.

Children and teenagers

No studies of semaglutide in children and adolescents under 18 years of age have been conducted.

Indications

Semavic® is indicated for use in adult patients with type 2 diabetes mellitus on the background of diet and exercise to improve glycemic control as:

• monotherapy;
• combination therapy with other oral hypoglycemic drugs (PGPs) - metformin, metformin and sulfonylurea derivatives, metformin and/or thiazolidinedione, in patients who have not achieved adequate glycemic control during previous therapy;
• combination therapy with insulin in patients who have not achieved adequate glycemic control on semaglutide and metformin therapy.

Semavic® is indicated to reduce the risk of major cardiovascular events* in patients with type 2 diabetes mellitus and high cardiovascular risk as an adjunct to standard treatment of cardiovascular diseases (based on an analysis of the time of the first major cardiovascular event - see the section "Pharmacological properties", subsection "Assessment effects on cardiovascular system").

*Major cardiovascular events include: death due to cardiovascular pathology, non-fatal myocardial infarction, and non-fatal stroke.

Contraindications

• Hypersensitivity to semaglutide or any of the excipients;
• history of medullary thyroid cancer, including family history;
• multiple endocrine neoplasia (MEN) type 2;
• Type 1 diabetes mellitus (DM1);
• diabetic ketoacidosis.

The use of Semavic® is contraindicated in the following groups of patients and in

the following conditions / diseases due to the lack of data on efficacy and

safety or limited experience of use:

• pregnancy and breastfeeding;
• under the age of 18;
• severe liver failure;
• end-stage renal failure (creatinine clearance < 15 ml/min);
• chronic heart failure (CHF) of functional class IV (according to the NYHA classification (New York Heart Association))

With caution

Semavic® is recommended to be used with caution in patients with renal

insufficiency and in patients with a history of pancreatitis (see section "Special

instructions").

Use during pregnancy and lactation

Pregnancy

Animal studies have demonstrated the reproductive toxicity of the drug (see the section "Preclinical safety data").

Data on the use of semaglutide in pregnant women are limited. It is contraindicated to use semaglutide during pregnancy. Women with preserved reproductive potential are recommended to use contraception during semaglutide therapy. If the patient is preparing for pregnancy, or pregnancy has already occurred, semaglutide therapy should be discontinued. Due to the long half-life, semaglutide therapy should be discontinued at least 2 months before the planned onset of pregnancy (see section "Pharmacokinetics").

Breastfeeding period

In lactating rats, semaglutide penetrated into the milk. The risk to a breastfed baby cannot be excluded. It is contraindicated to use semaglutide during breastfeeding.

Method of administration and dosage

Dosage regimen

The initial dose of Semavic® is 0.25 mg once a week. After 4 weeks of use, the dose should be increased to 0.5 mg once a week. To further improve glycemic control after at least 4 weeks of using the drug at a dose of 0.5 mg once a week, the dose can be increased to 1 mg once a week.

The 0.25 mg dose of Semavic® is not therapeutic. Administration of more than 1 mg per week is not recommended.

Semavic® can be used as monotherapy or in combination with one or more hypoglycemic drugs (see section "Clinical efficacy and safety").

When Semavic® is added to previous therapy with metformin and/or thiazolidinedione, or an SGLT2 inhibitor, therapy with metformin and/or thiazolidinedione, or an SGLT2 inhibitor can be continued at the same doses.

When adding Semavic® to ongoing therapy with a sulfonylurea derivative or insulin, a dose reduction of the sulfonylurea derivative or insulin should be considered in order to reduce the risk of hypoglycemia (see section "Special instructions").

The use of Semavic® does not require self-monitoring of blood glucose concentration.

Independent monitoring of blood glucose concentration is necessary to adjust the dose of sulfonylurea and insulin, especially at the beginning of treatment with Semavic® and when reducing the dose of insulin. It is recommended to use a step-by-step approach to reducing the dose of insulin.

Missed dose

If a dose is missed, Semavic® should be administered as soon as possible within 5 days of the scheduled dose. If the duration of the skip is more than 5 days, the missed dose does not need to be administered. The next dose of Semavic® should be administered on the usual scheduled day. In each case, patients can resume their usual one-time weekly administration schedule.

The use of the drug in special clinical groups of patients

Elderly patients (≥65 years old)

No age-related dose adjustment is required. The experience of using semaglutide in patients aged 75 years and older is limited.

Patients with liver failure

No dose adjustment is required in patients with hepatic insufficiency (see section

"Pharmacokinetics"). The experience of using semaglutide in patients with severe hepatic insufficiency is limited; the use of Semavic® in such patients is contraindicated.

Patients with renal insufficiency

No dose adjustment is required in patients with renal insufficiency. There is no experience of using the drug in patients with end-stage renal failure; the use of Semavic® in such patients is contraindicated.

Children and teenagers

The use of Semavic® in children under the age of 18 is contraindicated due to the lack of data on efficacy and safety.

Method of application

Semavic® is used once a week at any time, regardless of food intake. Semavic® is injected subcutaneously into the abdomen, hip or shoulder. The injection site may change without dose adjustment. Semavic® should not be administered intravenously or intramuscularly.

If necessary, the day of weekly administration can be changed, provided that the time interval between two injections is at least 3 days (> 72 hours).

After choosing a new day of administration, the drug should be continued once a week. Further information on the method of application is provided in the section "Instructions for use".

Side effects

The most frequently reported adverse reactions (HP) during CI were gastrointestinal disorders, including nausea, diarrhea, and vomiting. In general, these reactions were mild to moderate in severity and short-term.

The adverse reactions possible with the use of semaglutide are classified into systemic organ classes according to the MedDRA dictionary of regulatory activity, indicating the frequency of their occurrence according to WHO recommendations.:

Very common: (≥1/10), common (≥1/100, but <1/10), infrequent (≥1/1 000, but <1/100), rare (≥1/10 000, but <1/1 000), very rare (<1/10 000) and unknown (impossible to estimate based on available data). In each group, the incidence of HP is presented by decreasing severity.

Table 1. Adverse reactions identified during phase 3a CI

The organ system

MedDRA Very Common Often Infrequent Rarely Unknown

Disorders of the immune

system Hypersensitivity to anaphylactic reactions

Metabolic and nutritional disorders Hypoglycemia when combined with insulin or a sulfonylurea derivative Hypoglycemia when combined with other GHP, Decreased appetite

Nervous system disorders Dizziness Dysgeusia

Visual organ disorders and complications of diabetic retinopathy

Cardiac disorders Increased heart rate

(HR)

Gastrointestinal disorders Nausea

Diarrhea Vomiting

Abdominal pain Bloating Constipation

Dyspepsia

Gastritis Gastroesophageal reflux disease Belching

Flatulence Acute pancreatitis

Disorders of the liver and biliary

tract Cholelithiasis

Skin and subcutaneous tissue disorders Angioedema

General disorders and reactions at the injection site Fatigue Reactions at the injection site

Laboratory and instrumental data Increased lipase activity Increased amylase activity

Weight

loss and hypoglycemia, defined as severe (requiring the help of another person) or symptomatic in combination with a concentration of glucose in blood plasma < 3.1 mmol/L.

b complications of diabetic retinopathy are a combination of: the need for retinal photocoagulation, the need for intravitreal medication, vitreous hemorrhage, and the development of diabetes-related blindness.

The frequency is based on a study of CC outcomes.

c is a group term that also includes adverse reactions associated with hypersensitivity, such as rash and urticaria.

d HP from post-marketing sources.

2-year study of CC outcomes and safety

In the population of patients at high risk of developing CC diseases, the HP profile was similar to that in other clinical trials (described in the section "Clinical efficacy and safety").

Description of individual adverse reactions

Hypoglycemia

No episodes of severe hypoglycemia were observed during semaglutide monotherapy. Severe hypoglycemia was mainly observed when semaglutide was used in combination with a sulfonylurea derivative or insulin.

Several episodes of severe hypoglycemia have been observed when using semaglutide in combination with other GHPs, with the exception of the sulfonylurea derivative.

Hypoglycemia according to the American Diabetes Association classification was observed in 11.3% (0.3 cases/patient-year) of patients with the addition of semaglutide at a dose of 1.0 mg to SGLT2 inhibitor therapy compared with 2.0% (0.04 cases/patient-year) of patients receiving placebo. Severe hypoglycemia was reported in 0.7% (0.01 events/patient-year) and 0% of patients, respectively.

HP from the gastrointestinal tract

During semaglutide therapy at doses of 0.5 mg and 1 mg, patients experienced nausea, diarrhea, and vomiting. Most of the reactions were mild to moderate in severity and short-term. HP caused premature withdrawal from CI in 3.9% and 5.9% of patients, respectively. HP was most often reported in the first months of therapy.

Patients with low body weight may experience more gastrointestinal HP during treatment with semaglutide. In CI, with simultaneous use of the SGLT2 inhibitor and semaglutide, constipation and gastroesophageal reflux disease were observed in 6.7% and 4% of patients treated with semaglutide 1.0 mg, respectively, compared with no events in patients treated with placebo. The prevalence of these events has not decreased over time.

Acute pancreatitis

The incidence of acute pancreatitis, confirmed by expert evaluation, in phase 3a studies was 0.3% with semaglutide and 0.2% with the reference drug. In a 2-year study of cardiovascular outcomes, the incidence of acute pancreatitis, confirmed by expert evaluation, was 0.5% with semaglutide and 0.6% with placebo (see section "Special instructions")

Complications of diabetic reminopamy

In a 2-year CI involving patients with type 2 diabetes and high CC risk, prolonged diabetes, and inadequate glycemic control, confirmed cases of diabetic retinopathy complications developed in a larger number of patients treated with semaglutide (3.0%) compared with patients treated with placebo (1.8%). In patients with a history of diabetic retinopathy at the beginning of CI, the absolute risk of complications increased. In patients with no confirmed history of diabetic retinopathy, the number of events was the same when using semaglutide and placebo.

In CI lasting up to 1 year, the incidence of HP associated with diabetic retinopathy was the same in the group of semaglutide and comparison drugs.

Discontinuation of treatment due to HP

The frequency of treatment discontinuation due to HP was 8.7% for patients receiving semaglutide 1 mg. The most common HP that led to discontinuation of treatment were gastrointestinal disorders.

Reactions at the injection site

Injection site reactions (such as injection site rash, redness) have been reported in 0.6% and 0.5% of patients treated with semaglutide 0.5 mg and l mg, respectively. These reactions were usually mild in nature.

Immunogenicity

Due to the potential immunogenic properties of protein and peptide drugs, patients may develop antibodies to semaglutide after therapy. At the end of the CI, the proportion of patients who had antibodies to semaglutide at any given time was low (1-2%) and none of the patients had neutralizing antibodies to semaglutide or antibodies with an endogenous GLP-1 neutralizing effect.

Overdose

Symptoms

Overdoses of up to 4 mg in a single dose and up to 4 mg per week have been reported during CI. The most common HP reported was nausea. All patients recovered without complications.

Treatment

There is no specific antidote for semaglutide overdose. In case of overdose, appropriate symptomatic therapy is recommended. Given the long elimination period of the drug (approximately 1 week), an extended period of monitoring and treatment of overdose symptoms may be required.

Drug interaction

Pharmacodynamic interaction

In vitro studies of semaglutide have shown a very low probability of inhibition or induction of cytochrome P450 (CYP) system enzymes and inhibition of drug transporters.

Delayed gastric emptying when using semaglutide may affect the absorption of concomitant oral medications. Semaglutide should be used with caution in patients receiving oral medications that require rapid absorption into the gastrointestinal tract.

Paracetamol

When evaluating the pharmacokinetics of paracetamol during a standardized meal test, it was found that semaglutide delays gastric emptying. With simultaneous administration of semaglutide at a dose of 1 mg, AUC0-60 min and Cmax of paracetamol decreased by 27% and 23%, respectively. The total exposure to paracetamol (AUC0-5 h) did not change. When taking semaglutide and paracetamol at the same time, no dose adjustment of the latter is required.

Oral hormonal contraceptives

It is not assumed that semaglutide reduces the effectiveness of oral hormonal contraceptives. When combined oral hormonal contraceptive drug (0.03 mg ethinylestradiol/ 0.15 mg levonorgestrel) and semaglutide were used simultaneously, the latter had no clinically significant effect on the total exposure of ethinylestradiol and levonorgestrel. Exposure to ethinyl estradiol was not affected; there was a 20% increase in levonorgestrel exposure at steady state. The cmax has not changed for any of the components.

Atorvastatin

Semaglutide did not alter the systemic exposure of atorvastatin after administration of a single dose of atorvastatin (40 mg). The cmax of atorvastatin decreased by 38%. This change was considered to be clinically insignificant.

Digoxin

Semaglutide did not alter systemic exposure or Cmax of digoxin after administration of a single dose of digoxin (0.5 mg).

Metformin

Semaglutide did not alter systemic exposure or Cmax of metformin after administration of 500 mg metformin twice daily for 3.5 days.

Warfarin

Semaglutide did not alter the systemic exposure or Cmax of the R- and S-isomers of warfarin after administration of a single dose of warfarin (25 mg). Based on the definition of the international normalized ratio (INR), there were also no clinically significant changes in the pharmacodynamic effects of warfarin.

Incompatibility

Semaglutide should not be mixed with other medicines, including infusion solutions. Substances added to semaglutide can cause its degradation.

Usage Guide

The Semavic® pre-filled pen allows the administration of 0.25 mg, 0.5 mg and 1 mg doses.

One syringe pen contains 3 ml of the solution.

The packaging of Semavic® includes disposable needles.

The patient should be advised to discard the injection needle after each injection according to local requirements.

The Semavic® pen is intended for individual use only. Semavic® should not be used if it looks different from a clear, colorless or almost colorless solution.

Semavic® should not be used if it has been frozen.

Semavic® can be administered using needles up to 8 mm long. The pen is designed for use with disposable injection needles.

Always remove the needle after each injection and store the Semavic® pen with the needle disconnected. This will help prevent clogging of the needles, contamination, infection, leakage of the solution and administration of the wrong dose of the drug.

Special instructions

The use of semaglutide is contraindicated in patients with DM1 or for the treatment of diabetic ketoacidosis.

Semaglutide does not replace insulin.

Diabetic ketoacidosis has been reported in insulin-dependent patients who experienced rapid discontinuation of treatment or a decrease in the dose of insulin when starting treatment with a GLP-1P agonist (see section "Dosage and administration").

Gastrointestinal reactions

The use of GLP-1P agonists may be associated with gastrointestinal HP. This should be taken into account when treating patients with renal insufficiency, as nausea, vomiting and diarrhea can lead to dehydration and deterioration of kidney function.

Acute pancreatitis

Cases of acute pancreatitis have been observed with the use of GLP-1P agonists. Patients should be informed about the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, semaglutide therapy should be discontinued; if acute pancreatitis is confirmed, semaglutide therapy should not be resumed. Caution should be exercised in patients with a history of pancreatitis. In the absence of other signs and symptoms of acute pancreatitis, increased activity of pancreatic enzymes is not a predictor of the development of acute pancreatitis.

Hypoglycemia

Patients receiving semaglutide in combination with sulfonylurea derivatives or insulin may have an increased risk of hypoglycemia. At the beginning of treatment with semaglutide, the risk of hypoglycemia can be reduced by reducing the dose of a sulfonylurea derivative or insulin.

Diabetic retinopathy

There was an increased risk of complications of diabetic retinopathy in patients with diabetic retinopathy receiving insulin and semaglutide therapy (see section "Side effects"). Caution should be exercised when using semaglutide in patients with diabetic retinopathy receiving insulin therapy. Such patients should be under constant supervision and receive treatment in accordance with clinical recommendations. A rapid improvement in glycemic control was associated with a temporary worsening of diabetic retinopathy, but other causes cannot be excluded.

Heart failure

There is no experience of using semaglutide in patients with CHF of functional class IV according to the NYHA classification. The use of the drug in such patients is contraindicated.

Thyroid disease

In the post-marketing period of the use of another GLP-1 analog, liraglutide, cases of medullary thyroid cancer (MRCC) were noted. The available data is insufficient to establish or exclude a causal relationship between the occurrence of breast cancer and the use of GLP-1 analogues. It is necessary to inform the patient about the risk of breast cancer and about the symptoms of a thyroid tumor (the appearance of a lump in the neck, dysphagia, shortness of breath, persistent hoarseness of the voice).

A significant increase in the concentration of calcitonin in blood plasma may indicate breast cancer (in patients with breast cancer, the concentration of calcitonin in blood plasma is usually >50 ng/l). If an increase in the concentration of calcitonin in the blood plasma is detected, further examination of the patient should be performed. Patients with thyroid nodules detected during a medical examination or during an ultrasound of the thyroid gland should also be additionally examined.

The use of semaglutide in patients with a personal or family history of breast cancer or with MENG type 2 syndrome is contraindicated.

Preclinical safety data

Preclinical data based on studies of pharmacological safety, repeated dose toxicity and genotoxicity have not revealed any danger to humans.

In 2-year carcinogenicity studies in rats and mice at clinically significant concentrations, semaglutide caused the development of C-cell tumors of the thyroid gland without fatal outcome. Thyroid C-cell tumors without fatal outcome observed in rats are characteristic of the group of GLP-1 analogues. It is believed that this risk is low for humans, but it cannot be completely eliminated.

Fertility

The effect of semaglutide on human fertility is unknown. Semaglutide had no effect on male rat fertility. Among female rats, an increase in the estrous cycle and a slight decrease in the number of ovulations were observed at doses accompanied by a decrease in the female's body weight.

Effects on the ability to drive vehicles and mechanisms

Semaglutide has no or negligible effect on the ability to drive vehicles or operate machinery. Patients should be warned that they should take precautions to avoid the development of hypoglycemia while driving vehicles and when working with mechanisms, especially when using semaglutide in combination with a sulfonylurea derivative or insulin.

Storage temperature

from 2℃ to 8℃

Special storage conditions

Storage conditions

Store at a temperature of 2 °C to 8 °C (in the refrigerator), but not near the freezer. Protect from light. Do not freeze.

A syringe pen with the drug that is used or carried as a spare should be stored at a temperature of no more than 30 ° C or at a temperature from 2 ° C to 8 ° C (in the refrigerator) for 6 weeks.

Do not freeze.

After use, cover the pen with a cap to protect it from light.

Semavic® should be protected from exposure to excessive heat and light.

Keep out of reach of children