Drug Information

 

      

 

Pharmacokinetics

A half-life of semaglutide of approximately 1 week allows for a once-weekly dosing regimen of Ozempic.

Suction

The time to reach Cmax in plasma ranged from 1 to 3 days after a dose of the drug.

The equilibrium concentration of the drug (AUCt / 24) was achieved after 4-5 weeks of a single weekly use of the drug. After s/c 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.

Exposure for doses of semaglutide 0.5 mg and 1 mg increases in proportion to the administered dose.

When semaglutide is injected subcutaneously into the anterior abdominal wall, thigh, or upper arm, a similar exposure is achieved.

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

Distribution

The average Vd of semaglutide in tissues after subcutaneous administration in patients with type 2 diabetes was approximately 12.5 liters. Semaglutide was highly bound to plasma albumin (>99%).

Metabolism

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

breeding

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 intestines.

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

In patients with type 2 diabetes, the clearance of semaglutide was about 0.05 l/h. With an elimination T1 / 2 of approximately 1 week, semaglutide will be present in the general circulation for approximately 5 weeks after the last dose of the drug.

Pharmacokinetics in special groups of patients

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

Age. Based on data obtained during phase 3a clinical studies, which included patients aged 20 to 86 years, it was shown that age did not affect the pharmacokinetics of semaglutide.

Gender. Gender did not affect the pharmacokinetics of semaglutide.

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

Ethnicity. Ethnicity (Hispanic) did not affect the pharmacokinetics of semaglutide.

Body mass. Body weight influenced semaglutide exposure. Higher body weight results in 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.

Renal failure. Renal failure 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 dialysis patients) compared with patients with normal renal function in a single dose study of semaglutide 0.5 mg. This has also been shown in phase 3a clinical trials in patients with type 2 diabetes and renal insufficiency, although experience in patients with end-stage renal disease has been limited.

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

Children and teenagers. Studies of semaglutide in children and adolescents under the age of 18 years have not been conducted.

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Indication
& Dosage

Ozempic pen is indicated for use in adults with type 2 diabetes during diet and exercise to improve glycemic control as:

monotherapy;
combination therapy with other oral hypoglycemic drugs – metformin, metformin and a sulfonylurea derivative, 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 therapy with Ozempic and metformin.
Ozempic for weight loss is indicated to reduce the risk of major CV events* in patients with type 2 diabetes mellitus at high CV risk as an adjunct to standard CV treatment (based on analysis of time to first major CV event – see section “Pharmacological action”, subsection “Assessment of the effect on the cardiovascular system”).

* Major CV events include: CV death, non-fatal myocardial infarction, non-fatal stroke.

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Action

Semaglutide is a GLP-1 (GLP-1R) receptor agonist produced by recombinant DNA biotechnology using a strain of Saccharomyces cerevisiae with subsequent purification.

Semaglutide is a GLP-1 analogue with 94% homology to human GLP-1. Semaglutide acts as a GLP-1R agonist that selectively binds to and activates GLP-1R. GLP-1R serves as a target for native GLP-1.

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

Unlike native GLP-1, the prolonged T1 / 2 of semaglutide (about 1 week) allows you to use it s / c 1 time per week. Binding to albumin is the main mechanism for the 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 against cleavage by the enzyme dipeptidyl peptidase-4.

Semaglutide reduces blood glucose levels 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 for lowering glycemic levels 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 by reducing energy intake. This mechanism involves a general decrease in appetite, including an increase in satiety signals and a decrease in hunger signals, as well as improved control of food intake and a decrease in food cravings. Insulin resistance is also reduced, possibly due to weight loss. In addition, semaglutide reduces the preference for high-fat meals. In animal studies, semaglutide has been shown to be taken up by specific areas of the brain and increase key satiety signals and attenuate key hunger signals. By acting on isolated areas of brain tissue, semaglutide activates neurons associated with satiety and suppresses neurons associated with hunger.

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

In animal studies, semaglutide inhibits the development of atherosclerosis by preventing further development of aortic plaques and reducing inflammation in the plaques.

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Interaction

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

Delayed gastric emptying with semaglutide may interfere with the absorption of concomitant oral medicinal products. Semaglutide should be used with caution in patients receiving oral medicinal products requiring rapid absorption from the gastrointestinal tract.

Paracetamol

When evaluating the pharmacokinetics of paracetamol during a standardized food intake test, semaglutide was found to delay gastric emptying. With the 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 the simultaneous administration of semaglutide and paracetamol, dose adjustment of the latter is not required.

Oral hormonal contraceptives

Semaglutide is not expected to reduce the effectiveness of oral hormonal contraceptives. With the 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; a 20% increase in exposure to levonorgestrel at steady state was observed. Cmax has not changed for any of the components.

Atorvastatin

Semaglutide did not alter the systemic exposure of atorvastatin following a single dose of atorvastatin (40 mg). 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 a single dose of digoxin (0.5 mg).

Metformin

Semaglutide did not change the systemic exposure or Cmax of metformin after the use of metformin at a dose of 500 mg 2 times / day for 3.5 days.

Warfarin

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

Incompatibility

Substances added to Ozempic may cause degradation of semaglutide. Ozempic must not be mixed

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Adverse Effect &
Precautions

The most commonly reported adverse reactions (HP) during clinical trials were gastrointestinal disturbances, including nausea, diarrhea, and vomiting. In general, these reactions were mild or moderate in severity and short-lived.

HP are distributed by system organ classes in accordance with MedDRA, indicating the frequency of their occurrence according to WHO recommendations: very often (≥1 / 10); often (≥1/100 to <1/10); infrequently (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000) and very rare (<1/10000). In each group, the incidence of HP is presented in order of decreasing severity.

Table 1. HP identified during phase 3a clinical trials

Very often Often Infrequently Rarely
From the side of the immune system
Hypersensitivityc Anaphylactic reactions
Angioedema
From the side of metabolism and nutrition
Hypoglycemiaa when co-administered with insulin or a sulfonylurea Hypoglycemiaa when co-administered with other oral hypoglycemic agents
Decreased appetite
From the side of the nervous system
Dizziness Dysgeusia
From the organ of vision
Complications of diabetic retinopathyb
From the side of the heart
Increase in heart rate
From the gastrointestinal tract
Nausea
Diarrhea Vomiting
Abdominal pain
Bloating
Constipation
Dyspepsia
Gastritis
Gastroesophageal reflux disease
Belching
Flatulence Acute pancreatitis
From the side of the liver and biliary tract
Cholelithiasis
General disorders and disorders at the injection site
Fatigue Reactions at the injection site
Laboratory and instrumental data
Increased lipase activity
Increased amylase activity
Weight loss
a Hypoglycemia defined as severe (requiring help from another person) or symptomatic in association with plasma glucose <3.1 mmol/L.

b Complications of diabetic retinopathy are a combination of: the need for retinal photocoagulation, the need for intravitreal administration of drugs, vitreous hemorrhage, the development of blindness associated with diabetes.

The frequency is based on a study of cardiovascular outcomes.

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

d HP from post-marketing sources

Two-Year Study of Cardiovascular Outcomes and Safety

In a population of patients with a high risk of developing cardiovascular diseases, the HP profile was similar to that in other phase 3a clinical studies (described in the subsection “Clinical efficacy and safety”).

Description of individual HP

hypoglycemia

During monotherapy with Ozempic, no episodes of severe hypoglycemia were observed. Severe hypoglycemia has mainly been observed with the use of Ozempic in combination with a sulfonylurea derivative or insulin. Several episodes of severe hypoglycemia have been observed with the use of Ozempic in combination with other, with the exception of a sulfonylurea derivative, oral hypoglycemic drugs.

American Diabetes Association hypoglycemia was observed in 11.3% (0.3 cases/patient-year) of patients when semaglutide 1.0 mg was added 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 therapy with Ozempic at doses of 0.5 mg and 1 mg, patients experienced nausea, diarrhea and vomiting. Most reactions were mild to moderate and short-term. HP caused premature withdrawal from clinical trials in 3.9% and 5.9% of patients, respectively. Most often, HP was reported in the first months of therapy.

Low body weight patients treated with semaglutide may experience more gastrointestinal adverse events.

In clinical studies with the simultaneous use of an SGLT2 inhibitor and semaglutide, constipation and gastroesophageal reflux disease were observed in 6.7% and 4% of patients receiving semaglutide 1.0 mg, respectively, compared with no events in patients receiving placebo. The prevalence of these events has not decreased over time.

Acute pancreatitis

The incidence of peer-reviewed acute pancreatitis in phase 3a studies was 0.3% with semaglutide and 0.2% with the comparator. In a two-year study of cardiovascular outcomes, the incidence of acute pancreatitis, confirmed by the results of peer review, was 0.5% with semaglutide and 0.6% with placebo (see section “Special Instructions”).

Complications of diabetic retinopathy

Complications of diabetic retinopathy are a combination of: the need for photocoagulation of the retina, the need for intravitreal administration of drugs, vitreous hemorrhage, the development of blindness associated with diabetes.

The frequency is based on a study of cardiovascular outcomes.

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

d HP from post-marketing sources

Two-Year Study of Cardiovascular Outcomes and Safety

In a population of patients with a high risk of developing cardiovascular diseases, the HP profile was similar to that in other phase 3a clinical studies (described in the subsection “Clinical efficacy and safety”).

Description of individual HP

hypoglycemia

During monotherapy with Ozempic, no episodes of severe hypoglycemia were observed. Severe hypoglycemia has mainly been observed with the use of Ozempic injection in combination with a sulfonylurea derivative or insulin. Several episodes of severe hypoglycemia have been observed with the use of Ozempic in combination with other, with the exception of a sulfonylurea derivative, oral hypoglycemic drugs.

American Diabetes Association hypoglycemia was observed in 11.3% (0.3 cases/patient-year) of patients when semaglutide 1.0 mg was added 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 therapy with Ozempic at doses of 0.5 mg and 1 mg, patients experienced nausea, diarrhea and vomiting. Most reactions were mild to moderate and short-term. HP caused premature withdrawal from clinical trials in 3.9% and 5.9% of patients, respectively. Most often, HP was reported in the first months of therapy.

Low body weight patients treated with semaglutide may experience more gastrointestinal adverse events.

In clinical studies with the simultaneous use of an SGLT2 inhibitor and semaglutide, constipation and gastroesophageal reflux disease were observed in 6.7% and 4% of patients receiving semaglutide 1.0 mg, respectively, compared with no events in patients receiving placebo. The prevalence of these events has not decreased over time.

Acute pancreatitis

The incidence of peer-reviewed acute pancreatitis in phase 3a studies was 0.3% with semaglutide and 0.2% with the comparator. In a two-year study of cardiovascular outcomes, the incidence of acute pancreatitis, confirmed by the results of peer review, was 0.5% with semaglutide and 0.6% with placebo (see section “Special Instructions”).

Complications of diabetic retinopathy

In a two-year clinical study in patients with type 2 diabetes and a high cardiovascular risk, long-term course of diabetes and inadequate glycemic control, confirmed cases of complications of diabetic retinopathy developed in a greater number of patients treated with Ozempic (3.0%), compared with patients receiving placebo (1.8%). Patients with a history of diabetic retinopathy at baseline had a higher absolute risk of complications. In patients with no confirmed history of diabetic retinopathy, the number of events was similar between Ozempic and placebo.

In a clinical study lasting up to 1 year, the frequency of HP associated with diabetic retinopathy was similar in the Ozempic and comparator groups.

Termination of treatment due to HP

The treatment discontinuation rate due to HP was 8.7% for patients treated with Ozempic 1 mg. The most common HP leading 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 1 mg, respectively. These reactions were usually mild.

Immunogenicity

Due to the potential immunogenic properties of protein and peptide drugs, patients may develop antibodies to semaglutide after treatment with Ozempic Australia. At the end of the clinical study, the proportion of patients who had antibodies to semaglutide at any time point was low (1-2%) and no patients had neutralizing antibodies to semaglutide or antibodies with a neutralizing endogenous GLP-1 effect.

Contraindications for use
Hypersensitivity to semaglutide or any of the excipients of the drug;
history of medullary thyroid cancer, incl. in the family;
multiple endocrine neoplasia (MEN) type 2;
type 1 diabetes mellitus (DM1);
diabetic ketoacidosis.
The use of Ozempic 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;
breastfeeding period;
age up to 18 years;
severe liver failure;
terminal stage of renal failure (CC <15 ml / min);
chronic heart failure (CHF) IV functional class (according to the NYHA classification).
Carefully

Ozempic pen 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 section “Preclinical safety data”).

Data on the use of semaglutide in pregnant women are limited. Semaglutide is contraindicated during pregnancy. Women of reproductive potential are advised to use contraception during therapy with semaglutide. If the patient is preparing for pregnancy, or pregnancy has already occurred, semaglutide therapy should be discontinued. Due to the long T1 / 2, semaglutide therapy must be stopped at least 2 months before the planned onset of pregnancy (see the Pharmacokinetics section).

breastfeeding period

In lactating rats, semaglutide was excreted into milk. A risk to a breastfed child cannot be excluded. Semaglutide is contraindicated during breastfeeding.

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 the body weight of the female.

Application for violations of liver function
Dose adjustment is not required in patients with hepatic impairment.

The use of the drug in severe liver failure is contraindicated.

Application for violations of kidney function
The drug is recommended to be used with caution in patients with renal insufficiency.

The use of the drug in patients with end-stage renal failure (CC <15 ml / min) is contraindicated.

Use in children
The use of the drug under the age of 18 is contraindicated.

Use in elderly patients
Dose adjustment is not required in elderly patients (≥65 years).

Experience with the use of semaglutide in patients aged 75 years and older is limited.

special instructions
The use of Ozempic is contraindicated in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Ozempic is not a substitute for insulin. Diabetic ketoacidosis has been reported in insulin-dependent patients who experienced a rapid discontinuation of treatment or a decrease in insulin dose when starting treatment with a GLP-1R agonist (see section “Dosage regimen”).

Reactions from the gastrointestinal tract

The use of GLP-1R agonists may be associated with HP from the gastrointestinal tract. This should be taken into account when treating patients with renal insufficiency, because. nausea, vomiting, and diarrhea can lead to dehydration and poor kidney function.

Acute pancreatitis

With the use of GLP-1R agonists, cases of acute pancreatitis have been observed. Patients should be informed about the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, Ozempic therapy should be discontinued; If acute pancreatitis is confirmed, Ozempic should not be restarted. 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 predictor of the development of acute pancreatitis.

hypoglycemia

Patients receiving Ozempic in combination with a sulfonylurea or insulin may be at an increased risk of hypoglycemia. At the start of treatment with Ozempic, the risk of hypoglycaemia can be reduced by reducing the dose of the sulfonylurea 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 section “Side Effects”). Caution should be exercised when using semaglutide in patients with diabetic retinopathy receiving insulin therapy. Such patients should be monitored closely and treated according to clinical guidelines. A rapid improvement in glycemic control has been associated with a temporary worsening of diabetic retinopathy, but other causes cannot be ruled out.

Heart failure

There is no experience with the use of Ozempic vs Wegovy in patients with NYHA functional class IV chronic heart failure. The use of the drug in such patients is contraindicated.

Thyroid diseases

In the post-registration period of use of another GLP-1 analogue, liraglutide, cases of medullary thyroid cancer (MTC) have been noted. The available data are insufficient to establish or rule out a causal relationship in the occurrence of MTC with the use of GLP-1 analogues. It is necessary to inform the patient about the risk of MTC and about the symptoms of a thyroid tumor (appearance of induration in the neck, dysphagia, shortness of breath, persistent hoarseness). A significant increase in plasma calcitonin concentration may indicate MTC (in patients with MTC, plasma calcitonin concentrations are 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 physical 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 MTC or MEN type 2 is contraindicated.

Preclinical safety data

Preclinical data based on pharmacological safety studies, repeated dose toxicity and genotoxicity did not reveal any hazard to humans.

In two-year carcinogenicity studies in rats and mice at clinically relevant concentrations, semaglutide caused non-fatal thyroid C-cell tumors. Non-fatal thyroid C-cell tumors observed in rats are characteristic of the group of GLP-1 analogues. In humans, this risk is considered to be low, but cannot be completely ruled out.

Influence on the ability to drive vehicles and mechanisms

The drug Ozempic does not affect or slightly affects the ability to drive vehicles or work with mechanisms. Patients should be advised to take precautions to avoid hypoglycaemia while driving or operating machinery, especially when using Ozempic in combination with a sulfonylurea or insulin.

Overdose
Symptoms: In clinical studies, overdoses up to 4 mg in a single dose and up to 4 mg per week have been reported. The most common HP reported was nausea. All patients recovered without complications.

Treatment: There is no specific antidote for Ozempic overdose. In case of overdose, appropriate symptomatic therapy is recommended. Given the long half-life of the drug (approximately 1 week), a long period of observation and treatment of overdose symptoms may be required.

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OZEMPIC 0.25 mg
OZEMPIC 0.5 mg
OZEMPIC 1 mg 

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Drug Information

      

Pharmacokinetics

A half-life of semaglutide of approximately 1 week allows for a once-weekly dosing regimen of Ozempic.SuctionThe time to reach Cmax in plasma ranged from 1 to 3 days after a dose of the drug.The equilibrium concentration of the drug (AUCt / 24) was achieved after 4-5 weeks of a single weekly use of the drug. After s/c 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.Exposure for doses of semaglutide 0.5 mg and 1 mg increases in proportion to the administered dose.When semaglutide is injected subcutaneously into the anterior abdominal wall, thigh, or upper arm, a similar exposure is achieved.The absolute bioavailability of semaglutide after subcutaneous administration was 89%.DistributionThe average Vd of semaglutide in tissues after subcutaneous administration in patients with type 2 diabetes was approximately 12.5 liters. Semaglutide was highly bound to plasma albumin (>99%).MetabolismSemaglutide is metabolized through proteolytic cleavage of the peptide backbone of the protein and subsequent beta-oxidation of the side chain fatty acid.breedingThe 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 intestines.Approximately 3% of the administered dose is excreted by the kidneys as unchanged semaglutide.In patients with type 2 diabetes, the clearance of semaglutide was about 0.05 l/h. With an elimination T1 / 2 of approximately 1 week, semaglutide will be present in the general circulation for approximately 5 weeks after the last dose of the drug.Pharmacokinetics in special groups of patientsNo dose adjustment of semaglutide is required based on age, gender, race, ethnicity, body weight, or presence of renal or hepatic insufficiency.Age. Based on data obtained during phase 3a clinical studies, which included patients aged 20 to 86 years, it was shown that age did not affect the pharmacokinetics of semaglutide.Gender. Gender did not affect the pharmacokinetics of semaglutide.Race. Racial group (white, black or African American, Asian) did not affect the pharmacokinetics of semaglutide.Ethnicity. Ethnicity (Hispanic) did not affect the pharmacokinetics of semaglutide.Body mass. Body weight influenced semaglutide exposure. Higher body weight results in 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.Renal failure. Renal failure 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 dialysis patients) compared with patients with normal renal function in a single dose study of semaglutide 0.5 mg. This has also been shown in phase 3a clinical trials in patients with type 2 diabetes and renal insufficiency, although experience in patients with end-stage renal disease has been limited.Liver failure. Liver failure did not affect semaglutide exposure. The pharmacokinetic properties of semaglutide were evaluated in a single dose study of 0.5 mg semaglutide in patients with varying degrees of hepatic insufficiency (mild, moderate, severe) compared with patients with normal hepatic function.Children and teenagers. Studies of semaglutide in children and adolescents under the age of 18 years have not been conducted.

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Indication& Dosage

Ozempic pen is indicated for use in adults with type 2 diabetes during diet and exercise to improve glycemic control as:monotherapy;combination therapy with other oral hypoglycemic drugs – metformin, metformin and a sulfonylurea derivative, 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 therapy with Ozempic and metformin.Ozempic for weight loss is indicated to reduce the risk of major CV events* in patients with type 2 diabetes mellitus at high CV risk as an adjunct to standard CV treatment (based on analysis of time to first major CV event – see section “Pharmacological action”, subsection “Assessment of the effect on the cardiovascular system”).* Major CV events include: CV death, non-fatal myocardial infarction, non-fatal stroke.

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Action

Semaglutide is a GLP-1 (GLP-1R) receptor agonist produced by recombinant DNA biotechnology using a strain of Saccharomyces cerevisiae with subsequent purification.Semaglutide is a GLP-1 analogue with 94% homology to human GLP-1. Semaglutide acts as a GLP-1R agonist that selectively binds to and activates GLP-1R. GLP-1R serves as a target for native GLP-1.GLP-1 is a physiological hormone with several effects on glucose regulation and appetite, as well as on the cardiovascular system. The effect on glucose concentration and appetite is specifically mediated by GLP-1R, located in the pancreas and brain. Pharmacological concentrations of semaglutide reduce blood glucose concentration and body weight through a combination of effects described below. GLP-1Rs are also present in specific areas of the heart, blood vessels, immune system, and kidneys, where their activation may have cardiovascular and microcirculatory effects.Unlike native GLP-1, the prolonged T1 / 2 of semaglutide (about 1 week) allows you to use it s / c 1 time per week. Binding to albumin is the main mechanism for the 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 against cleavage by the enzyme dipeptidyl peptidase-4.Semaglutide reduces blood glucose levels 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 for lowering glycemic levels 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 by reducing energy intake. This mechanism involves a general decrease in appetite, including an increase in satiety signals and a decrease in hunger signals, as well as improved control of food intake and a decrease in food cravings. Insulin resistance is also reduced, possibly due to weight loss. In addition, semaglutide reduces the preference for high-fat meals. In animal studies, semaglutide has been shown to be taken up by specific areas of the brain and increase key satiety signals and attenuate key hunger signals. By acting on isolated areas of brain tissue, semaglutide activates neurons associated with satiety and suppresses neurons associated with hunger.In clinical studies, semaglutide had a positive effect on plasma lipids, lowered systolic blood pressure and reduced inflammation.In animal studies, semaglutide inhibits the development of atherosclerosis by preventing further development of aortic plaques and reducing inflammation in the plaques.

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Interaction

In vitro studies with semaglutide have shown a very low likelihood of inhibition or induction of enzymes of the cytochrome P450 (CYP) system and inhibition of drug transporters.Delayed gastric emptying with semaglutide may interfere with the absorption of concomitant oral medicinal products. Semaglutide should be used with caution in patients receiving oral medicinal products requiring rapid absorption from the gastrointestinal tract.ParacetamolWhen evaluating the pharmacokinetics of paracetamol during a standardized food intake test, semaglutide was found to delay gastric emptying. With the 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 the simultaneous administration of semaglutide and paracetamol, dose adjustment of the latter is not required.Oral hormonal contraceptivesSemaglutide is not expected to reduce the effectiveness of oral hormonal contraceptives. With the 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; a 20% increase in exposure to levonorgestrel at steady state was observed. Cmax has not changed for any of the components.AtorvastatinSemaglutide did not alter the systemic exposure of atorvastatin following a single dose of atorvastatin (40 mg). Cmax of atorvastatin decreased by 38%. This change was regarded as clinically insignificant.DigoxinSemaglutide did not change the systemic exposure or Cmax of digoxin after a single dose of digoxin (0.5 mg).MetforminSemaglutide did not change the systemic exposure or Cmax of metformin after the use of metformin at a dose of 500 mg 2 times / day for 3.5 days.WarfarinSemaglutide did not change the systemic exposure or Cmax of the R- and S-isomers of warfarin after a single dose of warfarin (25 mg). Based on the determination of INR, there were also no clinically significant changes in the pharmacodynamic effects of warfarin.IncompatibilitySubstances added to Ozempic may cause degradation of semaglutide. Ozempic must not be mixed

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Adverse Effect &Precautions

The most commonly reported adverse reactions (HP) during clinical trials were gastrointestinal disturbances, including nausea, diarrhea, and vomiting. In general, these reactions were mild or moderate in severity and short-lived.

HP are distributed by system organ classes in accordance with MedDRA, indicating the frequency of their occurrence according to WHO recommendations: very often (≥1 / 10); often (≥1/100 to <1/10); infrequently (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000) and very rare (<1/10000). In each group, the incidence of HP is presented in order of decreasing severity.Table 1. HP identified during phase 3a clinical trialsVery often Often Infrequently RarelyFrom the side of the immune systemHypersensitivityc Anaphylactic reactionsAngioedemaFrom the side of metabolism and nutritionHypoglycemiaa when co-administered with insulin or a sulfonylurea Hypoglycemiaa when co-administered with other oral hypoglycemic agentsDecreased appetiteFrom the side of the nervous systemDizziness DysgeusiaFrom the organ of visionComplications of diabetic retinopathybFrom the side of the heartIncrease in heart rateFrom the gastrointestinal tractNauseaDiarrhea VomitingAbdominal painBloatingConstipationDyspepsiaGastritisGastroesophageal reflux diseaseBelchingFlatulence Acute pancreatitisFrom the side of the liver and biliary tractCholelithiasisGeneral disorders and disorders at the injection siteFatigue Reactions at the injection siteLaboratory and instrumental dataIncreased lipase activityIncreased amylase activityWeight lossa Hypoglycemia defined as severe (requiring help from another person) or symptomatic in association with plasma glucose <3.1 mmol/L.b Complications of diabetic retinopathy are a combination of: the need for retinal photocoagulation, the need for intravitreal administration of drugs, vitreous hemorrhage, the development of blindness associated with diabetes.The frequency is based on a study of cardiovascular outcomes.c A group term that also includes adverse reactions associated with hypersensitivity, such as rash and urticaria.d HP from post-marketing sourcesTwo-Year Study of Cardiovascular Outcomes and SafetyIn a population of patients with a high risk of developing cardiovascular diseases, the HP profile was similar to that in other phase 3a clinical studies (described in the subsection “Clinical efficacy and safety”).Description of individual HPhypoglycemiaDuring monotherapy with Ozempic, no episodes of severe hypoglycemia were observed. Severe hypoglycemia has mainly been observed with the use of Ozempic in combination with a sulfonylurea derivative or insulin. Several episodes of severe hypoglycemia have been observed with the use of Ozempic in combination with other, with the exception of a sulfonylurea derivative, oral hypoglycemic drugs.American Diabetes Association hypoglycemia was observed in 11.3% (0.3 cases/patient-year) of patients when semaglutide 1.0 mg was added 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 tractDuring therapy with Ozempic at doses of 0.5 mg and 1 mg, patients experienced nausea, diarrhea and vomiting. Most reactions were mild to moderate and short-term. HP caused premature withdrawal from clinical trials in 3.9% and 5.9% of patients, respectively. Most often, HP was reported in the first months of therapy.Low body weight patients treated with semaglutide may experience more gastrointestinal adverse events.In clinical studies with the simultaneous use of an SGLT2 inhibitor and semaglutide, constipation and gastroesophageal reflux disease were observed in 6.7% and 4% of patients receiving semaglutide 1.0 mg, respectively, compared with no events in patients receiving placebo. The prevalence of these events has not decreased over time.Acute pancreatitisThe incidence of peer-reviewed acute pancreatitis in phase 3a studies was 0.3% with semaglutide and 0.2% with the comparator. In a two-year study of cardiovascular outcomes, the incidence of acute pancreatitis, confirmed by the results of peer review, was 0.5% with semaglutide and 0.6% with placebo (see section “Special Instructions”).Complications of diabetic retinopathyComplications of diabetic retinopathy are a combination of: the need for photocoagulation of the retina, the need for intravitreal administration of drugs, vitreous hemorrhage, the development of blindness associated with diabetes.The frequency is based on a study of cardiovascular outcomes.c A group term that also includes adverse reactions associated with hypersensitivity, such as rash and urticaria.d HP from post-marketing sourcesTwo-Year Study of Cardiovascular Outcomes and SafetyIn a population of patients with a high risk of developing cardiovascular diseases, the HP profile was similar to that in other phase 3a clinical studies (described in the subsection “Clinical efficacy and safety”).Description of individual HPhypoglycemiaDuring monotherapy with Ozempic, no episodes of severe hypoglycemia were observed. Severe hypoglycemia has mainly been observed with the use of Ozempic injection in combination with a sulfonylurea derivative or insulin. Several episodes of severe hypoglycemia have been observed with the use of Ozempic in combination with other, with the exception of a sulfonylurea derivative, oral hypoglycemic drugs.American Diabetes Association hypoglycemia was observed in 11.3% (0.3 cases/patient-year) of patients when semaglutide 1.0 mg was added 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 tractDuring therapy with Ozempic at doses of 0.5 mg and 1 mg, patients experienced nausea, diarrhea and vomiting. Most reactions were mild to moderate and short-term. HP caused premature withdrawal from clinical trials in 3.9% and 5.9% of patients, respectively. Most often, HP was reported in the first months of therapy.Low body weight patients treated with semaglutide may experience more gastrointestinal adverse events.In clinical studies with the simultaneous use of an SGLT2 inhibitor and semaglutide, constipation and gastroesophageal reflux disease were observed in 6.7% and 4% of patients receiving semaglutide 1.0 mg, respectively, compared with no events in patients receiving placebo. The prevalence of these events has not decreased over time.Acute pancreatitisThe incidence of peer-reviewed acute pancreatitis in phase 3a studies was 0.3% with semaglutide and 0.2% with the comparator. In a two-year study of cardiovascular outcomes, the incidence of acute pancreatitis, confirmed by the results of peer review, was 0.5% with semaglutide and 0.6% with placebo (see section “Special Instructions”).Complications of diabetic retinopathyIn a two-year clinical study in patients with type 2 diabetes and a high cardiovascular risk, long-term course of diabetes and inadequate glycemic control, confirmed cases of complications of diabetic retinopathy developed in a greater number of patients treated with Ozempic (3.0%), compared with patients receiving placebo (1.8%). Patients with a history of diabetic retinopathy at baseline had a higher absolute risk of complications. In patients with no confirmed history of diabetic retinopathy, the number of events was similar between Ozempic and placebo.In a clinical study lasting up to 1 year, the frequency of HP associated with diabetic retinopathy was similar in the Ozempic and comparator groups.Termination of treatment due to HPThe treatment discontinuation rate due to HP was 8.7% for patients treated with Ozempic 1 mg. The most common HP leading to discontinuation of treatment were gastrointestinal disorders.Reactions at the injection siteInjection 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 1 mg, respectively. These reactions were usually mild.ImmunogenicityDue to the potential immunogenic properties of protein and peptide drugs, patients may develop antibodies to semaglutide after treatment with Ozempic Australia. At the end of the clinical study, the proportion of patients who had antibodies to semaglutide at any time point was low (1-2%) and no patients had neutralizing antibodies to semaglutide or antibodies with a neutralizing endogenous GLP-1 effect.Contraindications for useHypersensitivity to semaglutide or any of the excipients of the drug;history of medullary thyroid cancer, incl. in the family;multiple endocrine neoplasia (MEN) type 2;type 1 diabetes mellitus (DM1);diabetic ketoacidosis.The use of Ozempic 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;breastfeeding period;age up to 18 years;severe liver failure;terminal stage of renal failure (CC <15 ml / min);chronic heart failure (CHF) IV functional class (according to the NYHA classification).CarefullyOzempic pen 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 lactationPregnancyAnimal studies have demonstrated the reproductive toxicity of the drug (see section “Preclinical safety data”).Data on the use of semaglutide in pregnant women are limited. Semaglutide is contraindicated during pregnancy. Women of reproductive potential are advised to use contraception during therapy with semaglutide. If the patient is preparing for pregnancy, or pregnancy has already occurred, semaglutide therapy should be discontinued. Due to the long T1 / 2, semaglutide therapy must be stopped at least 2 months before the planned onset of pregnancy (see the Pharmacokinetics section).breastfeeding periodIn lactating rats, semaglutide was excreted into milk. A risk to a breastfed child cannot be excluded. Semaglutide is contraindicated during breastfeeding.FertilityThe 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 the body weight of the female.Application for violations of liver functionDose adjustment is not required in patients with hepatic impairment.The use of the drug in severe liver failure is contraindicated.Application for violations of kidney functionThe drug is recommended to be used with caution in patients with renal insufficiency.The use of the drug in patients with end-stage renal failure (CC <15 ml / min) is contraindicated.Use in childrenThe use of the drug under the age of 18 is contraindicated.Use in elderly patientsDose adjustment is not required in elderly patients (≥65 years).Experience with the use of semaglutide in patients aged 75 years and older is limited.special instructionsThe use of Ozempic is contraindicated in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.Ozempic is not a substitute for insulin. Diabetic ketoacidosis has been reported in insulin-dependent patients who experienced a rapid discontinuation of treatment or a decrease in insulin dose when starting treatment with a GLP-1R agonist (see section “Dosage regimen”).Reactions from the gastrointestinal tractThe use of GLP-1R agonists may be associated with HP from the gastrointestinal tract. This should be taken into account when treating patients with renal insufficiency, because. nausea, vomiting, and diarrhea can lead to dehydration and poor kidney function.Acute pancreatitisWith the use of GLP-1R agonists, cases of acute pancreatitis have been observed. Patients should be informed about the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, Ozempic therapy should be discontinued; If acute pancreatitis is confirmed, Ozempic should not be restarted. 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 predictor of the development of acute pancreatitis.hypoglycemiaPatients receiving Ozempic in combination with a sulfonylurea or insulin may be at an increased risk of hypoglycemia. At the start of treatment with Ozempic, the risk of hypoglycaemia can be reduced by reducing the dose of the sulfonylurea or insulin.diabetic retinopathyThere was an increased risk of developing 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 monitored closely and treated according to clinical guidelines. A rapid improvement in glycemic control has been associated with a temporary worsening of diabetic retinopathy, but other causes cannot be ruled out.Heart failureThere is no experience with the use of Ozempic vs Wegovy in patients with NYHA functional class IV chronic heart failure. The use of the drug in such patients is contraindicated.Thyroid diseasesIn the post-registration period of use of another GLP-1 analogue, liraglutide, cases of medullary thyroid cancer (MTC) have been noted. The available data are insufficient to establish or rule out a causal relationship in the occurrence of MTC with the use of GLP-1 analogues. It is necessary to inform the patient about the risk of MTC and about the symptoms of a thyroid tumor (appearance of induration in the neck, dysphagia, shortness of breath, persistent hoarseness). A significant increase in plasma calcitonin concentration may indicate MTC (in patients with MTC, plasma calcitonin concentrations are 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 physical 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 MTC or MEN type 2 is contraindicated.Preclinical safety dataPreclinical data based on pharmacological safety studies, repeated dose toxicity and genotoxicity did not reveal any hazard to humans.In two-year carcinogenicity studies in rats and mice at clinically relevant concentrations, semaglutide caused non-fatal thyroid C-cell tumors. Non-fatal thyroid C-cell tumors observed in rats are characteristic of the group of GLP-1 analogues. In humans, this risk is considered to be low, but cannot be completely ruled out.Influence on the ability to drive vehicles and mechanismsThe drug Ozempic does not affect or slightly affects the ability to drive vehicles or work with mechanisms. Patients should be advised to take precautions to avoid hypoglycaemia while driving or operating machinery, especially when using Ozempic in combination with a sulfonylurea or insulin.OverdoseSymptoms: In clinical studies, overdoses up to 4 mg in a single dose and up to 4 mg per week have been reported. The most common HP reported was nausea. All patients recovered without complications.Treatment: There is no specific antidote for Ozempic overdose. In case of overdose, appropriate symptomatic therapy is recommended. Given the long half-life of the drug (approximately 1 week), a long period of observation and treatment of overdose symptoms may be required.

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