Expiration date: 07/2027
Short description
The hypoglycemic agent is an analog of glucagon-like peptide-1 (GLP-1).
Indications
The drug Quincent 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 (PGGP) – 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.
Quincent's drug is indicated to reduce the risk of serious 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 onset of the first serious cardiovascular event - see the section "Pharmacological properties", subsection "Assessment of the effect on the CCC").
*Serious cardiovascular events include: death due to cardiovascular pathology, non-fatal myocardial infarction, non-fatal stroke.
Contraindications
Hypersensitivity to semaglutide or any of the excipients of the drug
Medullary thyroid cancer in the anamnesis, including in the family
Multiple endocrine neoplasia (MEN) type 2
Type 1 diabetes mellitus (DM1)
Diabetic ketoacidosis
The use of the drug Quincent 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;
- age under 18;
- severe liver failure;
- end-stage renal insufficiency (creatinine clearance < 15 ml/min);
- chronic heart failure (CHF) of functional class IV (according to the NYHA (New York Cardiological Association) classification).
With caution
Semaglutide 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 breastfeeding
Pregnancy
Animal studies have demonstrated the reproductive toxicity of the drug (see the section "Special instructions", subsection "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 the section "Pharmacokinetics").
Breastfeeding period
In animal studies in lactating rats, semaglutide penetrated into milk. The risk to a breastfed baby cannot be excluded. The use of semaglutide during breastfeeding is contraindicated.
Storage conditions
T=+(02-08)C
Special instructions
The use of the drug Quincent is contraindicated in patients with DM1 or for the treatment of diabetic ketoacidosis.
The Quincent drug 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 at the beginning of treatment with a GLP-1P agonist (see section "Method of administration and doses").
Adverse reactions from the gastrointestinal tract
The use of GPP-1P agonists may be associated with HP from the gastrointestinal tract. This should be taken into account in the treatment of patients with renal insufficiency, as nausea, vomiting and diarrhea can lead to dehydration and deterioration of kidney function.
Acute pancreatitis
When using GPP-1P agonists, cases of acute pancreatitis have been observed. Patients should be informed about the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, therapy with the drug Quincent should be discontinued; in case of confirmation of acute pancreatitis, therapy with the drug Quincent 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, an increase in the activity of pancreatic enzymes is not a prognostic factor for the development of acute pancreatitis.
Hypoglycemia
Patients receiving the drug Quincent in combination with a sulfonylurea derivative or insulin may have an increased risk of hypoglycemia. At the beginning of treatment with Quincent's drug, 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 developing complications of diabetic retinopathy in patients with diabetic retinopathy receiving insulin and semaglutide therapy (see the section "Side effect"). 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 has been associated with a temporary deterioration in 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 in accordance with the NYHA classification. The use of the drug in such patients is contraindicated.
Thyroid disease
In the post-registration period of the use of another analogue of GPP-1, liraglutide, cases of medullary thyroid cancer (MRCC) were noted. The available data are insufficient to establish or exclude a cause-and-effect relationship between the occurrence of MRSH with the use of GPP-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 MCL (in patients with MCL, 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 carried out. 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.
Auxiliary substances
The drug of Quincent contains less than 1 mmol (23 mg) of sodium per dose
of 0.25 / 0.5 mg and 1 mg, that is, in fact, it does not contain sodium.
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 in clinically significant concentrations, semaglutide caused the development of thyroid C-cell tumors without fatal outcome. Tumors of thyroid C cells without fatal outcome observed in rats are characteristic of the group of GPP-1 analogues. It is believed that this risk is low for humans, but cannot be completely excluded.
Fertility
The effect of semaglutide on fertility in humans is unknown. Semaglutide did not affect the fertility of male rats. 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 female body weight.
Influence on the ability to drive vehicles and work with mechanisms
Semaglutide has no or negligible effect on the ability to drive vehicles or work with mechanisms. Patients should be warned that they should take precautions to avoid the development of hypoglycemia while driving and working with mechanisms, especially when using the drug Quincent in combination with a sulfonylurea derivative or insulin.
Pharmacological action
Pharmacological properties
The drug of Quincent contains as an active substance semaglutide, which is a chemically synthesized peptide and is an agonist of the GPP-1 receptors (GPP-1P). Semaglutide is an analog of human GLP-1, having 94% homology with the amino acid sequence of endogenous GLP-1.
Semaglutide acts as an agonist of GLP-1P, which selectively binds and activates GLP-1P. GLP-1P serves as a target for native GLP-1.
GPP-1 is a physiological hormone that has several simultaneous effects, including regulation of glucose concentration and appetite, as well as effects on the cardiovascular system (CVS). The effect on glucose concentration and appetite is specifically mediated by GPP-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. GPP-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 long half-life of semaglutide (about 1 week) allows it to be applied subcutaneously (subcutaneously) 1 time per 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 decay. In addition, semaglutide is stable with respect to cleavage by the enzyme dipeptidyl peptidase-4 (DPP-4).
Semaglutide reduces blood glucose concentration through 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 reducing 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 reduce 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 attenuation of hunger signals, as well as improved control of food intake and reduced cravings for food. Insulin resistance is also reduced. In addition, semaglutide reduces the preference for choosing foods with a high fat content. 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, reduced systolic blood pressure (BP) and reduced inflammation.
In animal studies, semaglutide suppressed the development of atherosclerosis, preventing further development of aortic plaques and reducing inflammation in the plaques.
Pharmacodynamics
Pharmacodynamic parameters were evaluated after 12 weeks of therapy (including the period of dose increase) at an equilibrium concentration of semaglutide 1 mg 1 time per week. Fasting glycemic level and postprandial glycemic level
Semaglutide reduces fasting glucose concentration and postprandial glucose (PPG) concentration. Compared with placebo, semaglutide therapy at a dose of 1 mg in patients with type 2 diabetes mellitus (DM2) led to a decrease in glucose concentration in terms of an absolute change from the initial value (mmol/l) and a relative decrease compared with placebo (%) in relation to: fasting glucose concentration (1.6 mmol/l; 22 %); glucose concentration 2 hours after meals (4.1 mmol/l; 37 %); average daily glucose concentration (1.7 mmol/L; 22%) and postprandial peaks in glucose concentration over 3 meals (0.6–1.1 mmol/l). Semaglutide reduced fasting glucose concentration after the first dose was administered.
Pancreatic beta cell function and insulin secretion
Semaglutide improves the function of pancreatic beta cells. After intravenous glucose injection in patients with DM2, semaglutide, compared with placebo, 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. In addition, compared with placebo, semaglutide therapy increases the concentration of insulin on an empty stomach.
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 DM2 was comparable to that of healthy volunteers.
During induced hypoglycemia, semaglutide, compared with placebo, did not alter the counterregulatory response of an increase in glucagon concentration, nor did it exacerbate the decrease in C-peptide concentration in patients with DM2.
Emptying the stomach
Semaglutide caused a slight delay in early postprandial gastric emptying, thereby reducing the rate of ingestion of PG 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 the 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 libitum by suppressing appetite (both on an empty stomach and after meals), improving food intake control, reducing cravings for food, especially with a high fat content.
Fasting lipids and postprandial lipids
Compared with placebo, semaglutide reduced concentrations of triglycerides and very low density lipoprotein cholesterol (VLDL) on an empty stomach 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 repolarization process in the heart was tested in the EFs study. The use of semaglutide in doses exceeding therapeutic ones (at equilibrium concentrations up to 1.5 mg) did not lead to an elongation of the adjusted QT interval.
Clinical efficacy and safety
Both the improvement of glycemic control and the reduction of CC diseases and mortality are an integral part of the treatment of DM2.
The efficacy and safety of semaglutide at doses of 0.5 mg and 1 mg were evaluated in six randomized controlled phase 3a CI. Of these, five CI evaluated the effectiveness of glycemic control as the main goal, while one CI evaluated the outcomes as the main goal. In addition, two phase 3 CY semaglutides were performed with the participation of Japanese patients.
In addition, a phase 3b 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. Phase 3b CI was also conducted to study the efficacy and safety of semaglutide as an adjunct to treatment with a type 2 sodium-dependent glucose transporter inhibitor (SGLT2).
Semaglutide therapy demonstrated sustained, statistically superior and clinically significant improvement in HbA1c and weight loss for up to 2 years compared with placebo and treatment with active control (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 insufficiency did not affect the effectiveness of semaglutide.
Monotherapy
Monotherapy with semaglutide in doses of 0.5 mg and 1 mg 1 time per week for
30 weeks compared with placebo resulted in a statistically more significant decrease in HbA1c (-1.5%, -1.6% vs. 0%, respectively), fasting plasma glucose (GPA) (-2.5 mmol/l, -2.3 mmol/l vs. -0.6 mmol/L, respectively) and body weight (-3.7 kg, -4.5 kg against -1.0 kg, respectively).
Semaglutide compared to sitagliptin, both in combination with
1-2 oral hypoglycemic drugs (PGGP) (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 vs. -1.9 kg, respectively). Therapy with semaglutide 0.5 mg and 1 mg compared with sitagliptin significantly reduced systolic blood pressure from the initial 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 (-l,5% vs. -1.1%), GPN (- 2.2 mmol/l vs. -1.9 mmol/l) and body weight (-4.6 kg against -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 (-1.8% vs. -1.4%), GPN (- 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%), GPN
(-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 PGGP (monotherapy with metformin 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 led to 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 GPN 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 GPN 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 when using 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 led to a statistically more significant decrease in HbA1c (-1.4%, -1.8% vs. -0.1%, respectively), GPN (-1.6 mmol/l,
-2.4 mmol/l vs. -0.5 mmol/L, respectively) and body weight (-3.7 kg, -6.4 kg vs. -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 therapy with an SGLT2 inhibitor (as monotherapy or in combination with a sulfonylurea derivative or metformin).
Semaglutide therapy at a dose of 1 mg 1 time per week as an adjunct to therapy with an SGLT2 inhibitor (as monotherapy or in combination with a sulfonylurea derivative or metformin) compared with placebo 1 time per week for 30 weeks led to a statistically significant decrease in HbA1c (-1.5% versus -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 a sulfonylurea derivative
At the 30th week of CI (see subsection "Assessment of the effect on CCC"), a subgroup of 123 patients undergoing monotherapy with sulfonylurea derivatives was evaluated. At week 30, HbA1c 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 PGGP
At the 30th week of CI (see subsection "Assessment of the effect on CCC"), a subgroup of 867 patients on premixed insulin therapy (in combination or without 2 PGPs) was evaluated. At week 30, HbA1c 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 the treatment goal of reducing HbA1c < 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 HbA1c 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 led to 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 stable for up to 2 years.
After one year of therapy, a greater number of patients achieved body weight loss of ≥ 5% and ≥ 10% with the use of semaglutide 0.5 mg (46% and 13%) and 1 mg (up to 62% and 24%) compared with patients who were on therapy with active comparison drugs sitagliptin and exenatide SV (up to 18% and up to 4%).
In 40-week CI, a greater number of patients achieved body weight loss of ≥ 5% and ≥ 10% with semaglutide 0.5 mg (44% and 14%) 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 CC CI, a greater number of patients achieved body weight loss of ≥ 5% and ≥ 10% with the use of 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 GPN to 2.8 mmol/l and a decrease in 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, there was an improvement in the function of pancreatic beta cells and a decrease in insulin resistance, 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 the treatment of 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 CC risk were randomized to double-blind CI for 104 weeks using semaglutide 0.5 mg or 1 mg 1 time per week or placebo, respectively, in addition to standard therapy for CC diseases over the next two years.
Semaglutide therapy resulted in a 26% reduction in the risk of serious cardiovascular events (CCC), 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 frequency of non-fatal stroke (39%) and a slight decrease in the frequency of non-fatal stroke (26%).
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 (RR) in relation to the time before the onset of nephropathy (new cases of persistent macroalbuminuria, persistent doubling of serum creatinine concentration, the need for constant renal replacement therapy and death due to kidney disease) was 0.64.
In addition to the standard therapy of CC diseases, semaglutide therapy at doses of 0.5 mg and 1 mg compared with placebo, respectively, for 104 weeks led to a significant and steady decrease from the 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 1 mg (5.4–7.3 mmHg) in combination with PGGP or basal insulin. There was no significant difference in diastolic blood pressure between semaglutide and the comparison drugs. Pharmacokinetics
The half-life (T1/2) of semaglutide, equal to approximately 1 week, makes it possible to dose the drug once a week.
Absorption
The time to reach the maximum concentration (Cmax) in plasma was from 1 to 3 days after administration of the drug dose.
The equilibrium concentration of the drug (AUCt/24) was reached after 4-5 weeks of single weekly use of the drug. After subcutaneous administration of semaglutide at doses of 0.5 mg and 1 mg, the average values of its equilibrium concentration in patients with DM2 were about 16 nmol / l and 30 nmol / l, respectively.
The exposure for semaglutide doses of 0.5 mg and 1 mg increases proportionally to the administered dose.
With the injection of semaglutide into the anterior abdominal wall, hip or shoulder, a similar exposure is achieved.
The absolute bioavailability of semaglutide after subcutaneous administration was 89%. Distribution
The average volume of semaglutide distribution in tissues after subcutaneous administration to patients with DM2 was approximately 12.5 liters. Semaglutide was significantly bound to plasma albumin (> 99%).
Metabolism
Semaglutide is metabolized by proteolytic cleavage of the protein peptide backbone and subsequent beta-oxidation of the side chain fatty acid.
Withdrawal
The gastrointestinal tract (GI 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, semaglutide clearance 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 is administered.
Special patient groups
There is no need to adjust the dose of semaglutide depending on age, gender, race and ethnicity, body weight, presence of renal or hepatic insufficiency.
Elderly patients
Based on data obtained during phase 3a CI, 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 (Caucasian, Negroid 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. Higher body weight leads to lower exposure. Semaglutide doses of 0.5 mg and 1 mg provide sufficient exposure of the drug in the body weight range from 40 to 198 kg.
Patients with renal insufficiency
Renal insufficiency did not have a 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 equal to 0.5 mg was studied. This was also shown based on phase 3a CI data for patients with DM2 and renal insufficiency, although the experience of use in patients with end-stage kidney disease was limited.
Patients with 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
Studies of semaglutide in children and adolescents under 18 years of age have not been conducted.
Method of application and dosage
Dosage regimen
The initial dose of the drug Quincent 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 the drug Quincent is not therapeutic. Administration of more than 1 mg per week is not recommended.
The drug can be used as monotherapy or in combination with one or more hypoglycemic drugs (see the section "Clinical efficacy and safety").
When adding the drug Quincent 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 the drug Quincent to ongoing therapy with a sulfonylurea derivative or insulin, a dose reduction of a sulfonylurea derivative or insulin should be provided in order to reduce the risk of hypoglycemia (see the section "Special instructions").
The use of the drug Quincent does not require self-monitoring of blood glucose concentration.
Self-monitoring of blood glucose concentration is necessary to correct the dose of sulfonylurea and insulin, especially at the beginning of treatment with the drug Quincent 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, the drug should be administered as soon as possible within 5 days of the scheduled dose administration. If the duration of the skip is more than 5 days, the missed dose does not need to be administered. The next dose of the Quincent drug should be administered on the usual scheduled day. In each case, patients can resume their usual one-time weekly administration schedule.
Special patient groups
Elderly patients (≥ 65 years old)
No dose adjustment is required depending on age. The experience of using semaglutide in patients aged 75 years and older is limited.
Patients with liver failure
Dose adjustment is not 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 the drug Quincent in such patients is contraindicated.
Patients with renal insufficiency
Dose adjustment is not required in patients with renal insufficiency. There is no experience of using the drug in patients with end-stage renal insufficiency; the use of the drug Quincent in such patients is contraindicated.
Children and teenagers
The use of the drug Quincent in children and adolescents under the age of 18 is contraindicated due to the lack of safety and efficacy data.
Method of application
The drug is used once a week at any time, regardless of the meal.
The drug of Quincent is injected subcutaneously into the abdomen, hip or shoulder. The injection site may change without dose adjustment. The Quincent drug 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.
Vacation from the pharmacy
The drug is dispensed strictly by prescription.
Overdose
Overdoses of up to 4 mg in a single dose and up to 4 mg per week were reported during CI. The most common HP reported was nausea. All patients recovered without complications.
There is no specific antidote for overdose with the drug Quincent. In case of overdose, appropriate symptomatic therapy is recommended. Given the long withdrawal period of the drug (approximately 1 week), an extended period of monitoring and treatment of overdose symptoms may be required.
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 or moderate in severity and short-term.
HP are distributed by systemic organ classes in accordance with MedDRA, indicating the frequency of their occurrence according to WHO recommendations: very often (≥ 1/10); often (≥ 1/100, but < 1/10); infrequently (≥ 1/1000, but < 1/100);
rare (≥ 1/10000, but < 1/1000); very rare (< 1/10000) and unknown (impossible to estimate based on available data). In each group, HP development rates are presented according to severity reduction.
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 others, with the exception of the sulfonylurea derivative, PGGP.
Hypoglycemia according to the classification of the American Diabetes Association 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 therapy with an SGLT2 inhibitor 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.
Adverse reactions from the gastrointestinal tract
During semaglutide therapy at doses of 0.5 mg and 1 mg, nausea, diarrhea and vomiting were observed in patients. Most of the reactions were mild to moderate and short-term. HP caused premature retirement from CI in 3.9% and 5.9% of patients, respectively. Adverse reactions were most often reported in the first months of therapy.
Patients with low body weight may experience more gastrointestinal HP when treated 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 the absence of 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 the results of an expert assessment, in phase 3a studies was 0.3% when using semaglutide and 0.2% when using a comparison 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.
Complications of diabetic retinopathy
In a 2-year CI involving patients with DM2 and high CC risk, long-term diabetes and inadequate glycemic control, confirmed cases of complications of diabetic retinopathy developed in more 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 increase in the absolute risk of complications was higher. 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 semaglutide group and comparison drugs.
Discontinuation of treatment due to adverse reactions
The frequency of discontinuation of treatment due to HP was 8.7 % for patients receiving semaglutide 1 mg. The most frequent HP that led to discontinuation of treatment were gastrointestinal disorders.
Reactions at the injection site
Injection site reactions (such as rash at the injection site, redness) have been reported in 0.6% and 0.5% of patients treated with semaglutide 0.5 mg and 1 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 a neutralizing endogenous GLP-1 effect.
Composition
1 ml of the drug contains:
Active ingredient: semaglutide 1.34 mg;
Excipients: sodium hydrophosphate dihydrate, phenol, propylene glycol, sodium hydroxide or hydrochloric acid, water for injection.
For the syringe pen of the Quincent 0.25/0.5 mg/dose:
One pre-filled syringe pen contains 2 mg of semaglutide / 1.5 ml of the drug solution.
For the syringe pen of the Quincent 1 mg/dose:
One pre-filled syringe pen contains 4 mg of semaglutide /3 ml of the drug solution.
Interaction with other drugs
In vitro studies of semaglutide have shown a very low probability of inhibition or induction of cytochrome P450 (SUR) 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 use of semaglutide at a dose of 1 mg AUC0-60 min and Cmax of paracetamol decreased by 27% and 23%, respectively. The total exposure of paracetamol (AUC0-5 h) did not change. With simultaneous administration of semaglutide and paracetamol, dose adjustment of the latter is not required.
Oral hormonal contraceptives
It is not assumed that semaglutide reduces the effectiveness of oral hormonal contraceptives. With simultaneous use of a combined oral hormonal contraceptive drug (0.03 mg ethinylestradiol / 0.15 mg levonorgestrel) and semaglutide, the latter did not have a clinically significant effect on the total exposure of ethinylestradiol and levonorgestrel. Ethinyl estradiol exposure 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 regarded as clinically insignificant.
Digoxin
Semaglutide did not change the systemic exposure or Cmax of digoxin after administration of a single dose of digoxin (0.5 mg).
Metformin
Semaglutide did not change the systemic exposure or Cmax of metformin after administration of metformin at a dose of 500 mg 2 times a day 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), no clinically significant changes in the pharmacodynamic effects of warfarin were also observed.
Incompatibility
Substances added to the Quincent preparation can cause degradation of semaglutide. The drug of Quincent should not be mixed with other medicines, including infusion solutions.
