Ozempic^® (Solution) Instructions for Use

Marketing Authorization Holder

Novo Nordisk A/S (Denmark)

Contact Information

NOVO NORDISK LLC (Russia)

ATC Code

A10BJ06 (Semaglutide)

Active Substance

Semaglutide (Rec.INN registered by WHO)

Dosage Form

Ozempic®

Solution for subcutaneous administration 1.34 mg/1 ml: cartridge in a pen-injector 1.5 ml (0.25 mg/dose or 0.5 mg/dose) and 3 ml (1 mg/dose)

Dosage Form, Packaging, and Composition

Solution for subcutaneous administration colorless or almost colorless, transparent.

Excipients: disodium phosphate dihydrate, propylene glycol, phenol, hydrochloric acid (for pH adjustment), sodium hydroxide (for pH adjustment), water for injection.

1.5 ml (0.25 mg/dose or 0.5 mg/dose) – glass cartridges (1) – disposable plastic pen-injectors (1) for multiple injections in a set with 6 disposable NovoFine^® Plus needles – cardboard packs.
3 ml (1 mg/dose) – glass cartridges (1) – disposable plastic pen-injectors (1) for multiple injections in a set with 4 disposable NovoFine^® Plus needles – cardboard packs.

Clinical-Pharmacological Group

Hypoglycemic agent. Glucagon-like peptide-1 (GLP-1) receptor agonist

Pharmacotherapeutic Group

Hypoglycemic agent – glucagon-like peptide-1 (GLP-1) analog

Pharmacological Action

Semaglutide is a GLP-1 receptor agonist (GLP-1RA) produced by recombinant DNA biotechnology using a Saccharomyces cerevisiae strain followed by purification.

Semaglutide is a GLP-1 analog with 94% homology to human GLP-1. Semaglutide acts as a GLP-1RA that selectively binds to and activates the GLP-1 receptor. The GLP-1 receptor is the target for native GLP-1.

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

Unlike native GLP-1, the prolonged half-life of semaglutide (approximately 1 week) allows for once-weekly subcutaneous administration. Binding to albumin is the main mechanism for the long-acting effect of semaglutide, which reduces its renal excretion and protects it from metabolic degradation. Furthermore, Semaglutide is stable against degradation by the dipeptidyl peptidase-4 enzyme.

Semaglutide reduces blood glucose through glucose-dependent stimulation of insulin secretion and suppression of glucagon secretion. Thus, when blood glucose rises, insulin secretion is stimulated and glucagon secretion is suppressed. The mechanism of glycemic reduction 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 fat mass by reducing energy intake. This mechanism involves an overall reduction in appetite, including enhanced satiety signals and weakened hunger signals, as well as improved control of food intake and reduced food cravings. Insulin resistance is also reduced, possibly due to weight loss. In addition, Semaglutide reduces the preference for high-fat food intake. Animal studies have shown that Semaglutide is taken up by specific areas of the brain and enhances key satiety signals and attenuates key hunger signals. By acting on isolated brain tissue areas, Semaglutide activates neurons associated with satiety and suppresses neurons associated with hunger.

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

In animal studies, Semaglutide suppressed the development of atherosclerosis, preventing further progression of aortic plaques and reducing inflammation in plaques.

Pharmacodynamics

All pharmacodynamic studies were conducted after 12 weeks of therapy (including the dose escalation period) at a steady-state semaglutide concentration of 1 mg once weekly.

Fasting blood glucose and postprandial blood glucose

Semaglutide reduces fasting glucose concentration and postprandial glucose concentration. Compared to placebo, therapy with semaglutide 1 mg in patients with type 2 diabetes (T2D) resulted in a reduction in glucose concentration in terms of absolute change from baseline (mmol/L) and relative reduction compared to placebo (%) for: fasting glucose concentration (1.6 mmol/L; 22%); 2-hour postprandial glucose concentration (4.1 mmol/L; 37%); mean daily glucose concentration (1.7 mmol/L; 22%) and postprandial glucose peaks over 3 meals (0.6-1.1 mmol/L). Semaglutide reduced fasting glucose concentration after the first dose.

Pancreatic β-cell function and insulin secretion

Semaglutide improves pancreatic β-cell function. After an intravenous glucose bolus in patients with T2D, Semaglutide compared to placebo improved the first and second phase insulin response with a three-fold and two-fold increase, respectively, and increased the maximum secretory capacity of pancreatic β-cells after an arginine stimulation test. Furthermore, compared to placebo, semaglutide therapy increased fasting insulin concentrations.

Glucagon secretion

Semaglutide reduces fasting glucagon concentration and postprandial glucagon concentration. In patients with T2D, Semaglutide results in a relative reduction in glucagon concentration compared to placebo: fasting glucagon concentration (8-21%), postprandial glucagon response (14-15%), and mean daily glucagon concentration (12%).

Glucose-dependent insulin secretion and glucose-dependent glucagon secretion

Semaglutide reduced high blood glucose by stimulating insulin secretion and reducing glucagon secretion in a glucose-dependent manner. The rate of insulin secretion after semaglutide administration in patients with T2D was comparable to that in healthy volunteers.

During induced hypoglycemia, Semaglutide compared to placebo did not alter the counterregulatory response of increased glucagon concentration, nor did it exacerbate the decrease in C-peptide concentration in patients with T2D.

Gastric emptying

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

Body weight and body composition

Greater weight loss was observed with semaglutide compared to the studied comparator drugs (placebo, sitagliptin, exenatide extended-release, dulaglutide, and insulin glargine) (see section “Clinical Efficacy and Safety”). Weight loss with semaglutide occurred primarily through loss of fat tissue, exceeding the loss of muscle mass by 3 times.

Appetite, calorie intake, and food choices

Compared to placebo, Semaglutide reduced calorie intake by 18-35% during three consecutive ad libitum meals. This was facilitated by semaglutide-induced suppression of appetite both fasting and postprandial, improved control of food intake, reduced food cravings, especially for high-fat foods.

Fasting lipids and postprandial lipids

Compared to placebo, Semaglutide reduced fasting triglyceride and VLDL cholesterol concentrations by 12% and 21%, respectively. The postprandial increase in triglyceride and VLDL cholesterol concentration in response to a high-fat meal was reduced by more than 40%.

Cardiac electrophysiology

The effect of semaglutide on the cardiac repolarization process was tested in a cardiac electrophysiology study. The use of semaglutide in doses exceeding therapeutic doses (at steady-state concentrations up to 1.5 mg) did not lead to prolongation of the corrected QT interval.

Clinical Efficacy and Safety

Both improvement in glycemic control and reduction of cardiovascular morbidity and mortality are integral parts of T2D treatment.

The efficacy and safety of Ozempic^® at doses of 0.5 mg and 1 mg were evaluated in six randomized controlled phase 3a clinical trials. Of these, five clinical trials evaluated glycemic control efficacy as the primary objective, while one clinical trial evaluated cardiovascular outcome as the primary objective. In addition, two phase 3 clinical trials of Ozempic^® were conducted involving Japanese patients.

In addition, a phase 3b trial was conducted to compare the efficacy and safety of Ozempic^® at doses of 0.5 mg and 1 mg once weekly with dulaglutide 0.75 mg and 1.5 mg once weekly, respectively. A phase 3b clinical trial was also conducted to investigate the efficacy and safety of semaglutide as an add-on to sodium-glucose cotransporter-2 (SGLT2) inhibitor therapy.

Ozempic^® therapy demonstrated sustained, statistically superior, and clinically significant improvements in HbA_1c and reductions in body weight for up to 2 years compared to placebo and active control treatment (sitagliptin, insulin glargine, exenatide extended-release, and dulaglutide).

Age, sex, race, ethnicity, baseline BMI and body weight (kg), duration of diabetes (DM), and renal impairment did not affect the efficacy of Ozempic^®.

Monotherapy

Monotherapy with Ozempic^® at doses of 0.5 mg and 1 mg once weekly for 30 weeks compared with placebo resulted in statistically greater reductions in HbA_1c (-1.5%, -1.6% vs. 0%, respectively), fasting plasma glucose (FPG) (-2.5 mmol/L, -2.3 mmol/L vs. -0.6 mmol/L, respectively) and body weight (-3.7 kg, -4.5 kg vs. -1.0 kg, respectively).

Ozempic^® compared with sitagliptin, both in combination with 1-2 oral hypoglycemic drugs (metformin and/or thiazolidinedione drugs)

Therapy with Ozempic^® 0.5 mg and 1 mg once weekly for 56 weeks compared with sitagliptin resulted in sustained and statistically greater reductions in HbA_1c (-1.3%, -1.6% vs. -0.5%, respectively), FPG (-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 Ozempic^® 0.5 mg and 1 mg compared with sitagliptin significantly reduced systolic blood pressure from a baseline of 132.6 mm Hg (-5.1 mm Hg, -5.6 mm Hg vs. -2.3 mm Hg, respectively). There were no changes in diastolic blood pressure.

Ozempic^® compared with dulaglutide, both in combination with metformin

Therapy with Ozempic^® 0.5 mg compared with dulaglutide 0.75 mg, both once weekly for 40 weeks, resulted in sustained and statistically superior reductions in HbA_1c (-1.5% vs. -1.1%), FPG (-2.2 mmol/L vs. -1.9 mmol/L) and body weight (-4.6 kg vs. -2.3 kg), respectively.

Therapy with Ozempic^® 1 mg compared with dulaglutide 1.5 mg both once weekly for 40 weeks, resulted in sustained and statistically superior reductions in HbA_1c (-1.8% vs. -1.4%), FPG (-2.8 mmol/L vs. -2.2 mmol/L) and body weight (-6.5 kg vs. -3.0 kg), respectively.

Ozempic^® compared with exenatide extended-release, both in combination with metformin or metformin in combination with a sulfonylurea derivative

Therapy with Ozempic^® 1 mg once weekly for 56 weeks compared with exenatide extended-release 2.0 mg resulted in sustained and statistically greater reductions in HbA_1c (-1.5% vs. -0.9%), FPG (-2.8 mmol/L vs. -2.0 mmol/L) and body weight (-5.6 kg vs. -1.9 kg), respectively.

Ozempic^® compared with insulin glargine, both in combination with 1-2 oral hypoglycemic drugs (metformin monotherapy or metformin with a sulfonylurea derivative)

Therapy with Ozempic^® at doses of 0.5 mg and 1 mg once weekly compared with insulin glargine for 30 weeks resulted in statistically greater reductions in HbA_1c (-1.2%, -1.6% vs. -0.8%, respectively) and body weight (-3.5 kg, -5.2 kg vs. +1.2 kg, respectively).

The reduction in FPG was statistically greater for Ozempic^® 1 mg compared with insulin glargine (-2.7 mmol/L vs. -2.1 mmol/L). There was no statistically greater reduction in FPG for Ozempic^® 0.5 mg (-2.0 mmol/L vs. -2.1 mmol/L).

The proportion of patients who experienced severe or confirmed (<3.1 mmol/L) hypoglycemic episodes was lower with Ozempic^® 0.5 mg (4.4%) and Ozempic^® 1 mg (5.6%) compared with insulin glargine (10.6%).

More patients achieved HbA_1c<7% without severe or confirmed hypoglycemic episodes and without weight gain with Ozempic^® 0.5 mg (47%) and Ozempic^® 1 mg (64%) compared with insulin glargine (16%).

Ozempic^® compared with placebo, both in combination with basal insulin

Therapy with Ozempic^® at doses of 0.5 mg and 1 mg compared with placebo for 30 weeks resulted in statistically greater reductions in HbA_1c (-1.4%, -1.8% vs. -0.1%, respectively), FPG (-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 rate of severe or confirmed hypoglycemic episodes did not differ significantly between Ozempic^® and placebo. The proportion of patients with a screening HbA_1c ≤8% who reported severe or confirmed (<3.1 mmol/L) hypoglycemic episodes was higher with Ozempic^® compared with placebo and was comparable in patients with a screening HbA_1c >8%.

Ozempic^® compared with placebo as an add-on to SGLT2 inhibitor therapy (as monotherapy or in combination with a sulfonylurea derivative or metformin).

Therapy with Ozempic^® at a dose of 1 mg once weekly as an add-on to SGLT2 inhibitor therapy (as monotherapy or in combination with a sulfonylurea derivative or metformin) compared with placebo once weekly for 30 weeks resulted in a statistically significant reduction in HbA_1c (-1.5% vs. -0.1%, respectively), FPG (-2.2 mmol/L vs. 0 mmol/L, respectively) and body weight (-4.7 kg vs. -0.9 kg, respectively).

Combination with sulfonylurea derivative monotherapy

At week 30 of clinical trials (see subsection “Cardiovascular Outcome Assessment”), a subgroup of 123 patients on sulfonylurea derivative monotherapy was evaluated. At week 30, HbA_1c decreased by 1.6% and 1.5% with Ozempic^® 0.5 mg and 1 mg, respectively, and increased by 0.1% with placebo.

Combination with premixed insulin ± 1-2 oral hypoglycemic drugs

At week 30 of clinical trials (see subsection “Cardiovascular Outcome Assessment”), a subgroup of 867 patients on premixed insulin therapy (in combination with or without two oral hypoglycemic drugs) was evaluated. At week 30, HbA_1c decreased by 1.3% and 1.8% with Ozempic^® 0.5 mg and 1 mg, respectively, and decreased by 0.4% with placebo.

Proportion of patients achieving target HbA_1c reduction

Up to 79% of patients achieved treatment goals for HbA_1c reduction <7%, and the proportion of such patients was significantly greater with Ozempic^® compared with patients receiving sitagliptin, exenatide extended-release, insulin glargine, dulaglutide, and placebo.

The proportion of patients achieving HbA_1c less than 7% without severe or confirmed hypoglycemic episodes and without weight gain was significantly greater with Ozempic^® 0.5 mg and 1 mg (up to 66% and 74%, respectively) compared with patients receiving sitagliptin (27%), exenatide extended-release (29%), insulin glargine (16%), dulaglutide 0.75 mg (44%) and dulaglutide 1.5 mg (58%).

Body weight

Monotherapy with Ozempic^® 1 mg or therapy in combination with 1-2 drugs resulted in statistically greater weight loss (loss of up to 6.5 kg) compared with therapy with placebo, sitagliptin, exenatide extended-release, insulin glargine, or dulaglutide. Weight reduction was sustained for up to 2 years.

After one year of therapy, a greater number of patients receiving Ozempic^® 0.5 mg (46% and 13%) and 1 mg (up to 62% and 24%) achieved weight loss ≥5% and ≥10%, compared with patients on active comparator therapy sitagliptin and exenatide extended-release (up to 18% and up to 4%).

In a 40-week clinical trial, a greater number of patients receiving Ozempic^® 0.5 mg (44% and 14%) achieved weight loss ≥5% and ≥10%, compared with patients receiving dulaglutide 0.75 mg (23% and 3%). A greater number of patients receiving Ozempic^® 1 mg (up to 63% and 27%) achieved weight loss ≥5% and ≥10%, compared with patients receiving dulaglutide 1.5 mg (30% and 8%).

In the cardiovascular clinical trial, a greater number of patients receiving Ozempic^® 0.5 mg (36% and 13%) and 1 mg (47% and 20%) achieved weight loss ≥5% and ≥10%, compared with patients receiving placebo 0.5 mg (18% and 6%) and 1 mg (19% and 7%).

FPG and postprandial glucose increase

During all three daily meals, Ozempic^® 0.5 mg and 1 mg showed a significant reduction in FPG of up to 2.8 mmol/L and a reduction in postprandial glucose increment of up to 1.2 mmol/L (difference between pre- and post-meal values obtained after three meals) (additionally see subsection “Pharmacodynamics” above).

Pancreatic β-cell function and insulin resistance

During therapy with Ozempic^® 0.5 mg and 1 mg, an improvement in pancreatic β-cell function and a reduction in insulin resistance occurred, as confirmed by the assessment of homeostatic models of pancreatic β-cell function (HOMA-B) and insulin resistance (HOMA-IR) (for additional information, see the subsection “Pharmacodynamics” above).

Lipids

During clinical trials of Ozempic^®, an improvement in the fasting blood lipid profile was observed, primarily in the group receiving the 1 mg dose (for additional information, see the subsection “Pharmacodynamics” above).

Cardiovascular safety assessment

3297 patients with type 2 diabetes and high cardiovascular risk were randomized into a 104-week double-blind clinical trial to receive Ozempic^® 0.5 mg or 1 mg once weekly or placebo 0.5 mg or 1 mg in addition to standard cardiovascular disease therapy over the subsequent two years.

Treatment with Ozempic^® led to a 26% reduction in the risk of the primary composite outcome, which included cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. This was primarily driven by a significant reduction in the incidence of non-fatal stroke (39%) and a non-significant reduction in the incidence of non-fatal myocardial infarction (26%), but with no change in the incidence of cardiovascular death.

The risk of myocardial or peripheral artery revascularization was significantly reduced, while the risk of unstable angina requiring hospitalization and the risk of hospitalization for heart failure were reduced non-significantly. Microcirculatory outcomes included 158 new or worsening cases of nephropathy. The relative risk for the time to nephropathy (new onset of persistent macroalbuminuria, persistent doubling of serum creatinine, need for continuous renal replacement therapy, and death due to renal disease) was 0.64.

In addition to standard cardiovascular disease therapy, treatment with Ozempic^® at doses of 0.5 mg and 1 mg compared to placebo 0.5 mg and 1 mg over 104 weeks led to a significant and sustained reduction from baseline in HbA_1c (-1.1% and -1.4% versus -0.4% and -0.4%, respectively).

Blood pressure

A significant reduction in mean systolic blood pressure was observed with the use of Ozempic^® 0.5 mg (3.5-5.1 mmHg) and Ozempic^® 1 mg (5.4-7.3 mmHg) in combination with oral hypoglycemic drugs or basal insulin. No significant difference in diastolic blood pressure parameters was noted between Ozempic^® and comparator drugs.

Pharmacokinetics

The T_1/2 of semaglutide of approximately 1 week allows for the once-weekly dosing regimen of Ozempic^®.

Absorption

The time to reach C_max in plasma was 1 to 3 days after administration of the dose.

Steady-state concentration of the drug (AUC_t/24) was achieved after 4-5 weeks of once-weekly use of the drug. After subcutaneous administration of semaglutide at doses of 0.5 mg and 1 mg, the mean steady-state concentrations in patients with type 2 diabetes were approximately 16 nmol/L and 30 nmol/L, respectively.

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

Similar exposure is achieved with subcutaneous administration of semaglutide in the abdomen, thigh, or upper arm.

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

Distribution

The mean V_d of semaglutide in tissue after subcutaneous administration to patients with type 2 diabetes was approximately 12.5 L. Semaglutide is largely bound to plasma albumin (>99%).

Metabolism

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

Elimination

The gastrointestinal tract and kidneys are the main routes of elimination for semaglutide and its metabolites. Two-thirds of the administered semaglutide dose is excreted by the kidneys, and one-third via 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 T_1/2 of approximately 1 week, semaglutide will be present in the systemic circulation for approximately 5 weeks after the last dose is administered.

Pharmacokinetics in special patient populations

No dose adjustment of semaglutide is required based on age, sex, race and ethnicity, body weight, or the presence of renal or hepatic impairment.

Age. Based on data from phase 3a clinical trials including patients aged 20 to 86 years, age was shown not to affect the pharmacokinetics of semaglutide.

Sex. Sex did not affect the pharmacokinetics of semaglutide.

Race. Race 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 weight. Body weight affected the exposure to semaglutide. Higher body weight leads to lower exposure. Semaglutide doses of 0.5 mg and 1 mg provide sufficient drug exposure across a body weight range of 40 to 198 kg.

Renal impairment. Renal impairment did not have a clinically significant effect on the pharmacokinetics of semaglutide. This was shown in patients with varying degrees of renal impairment (mild, moderate, severe, or patients on dialysis) compared to patients with normal renal function in a single-dose study of semaglutide 0.5 mg. This was also shown based on data from phase 3a clinical trials for patients with type 2 diabetes and renal impairment, although experience in patients with end-stage renal disease was limited.

Hepatic impairment. Hepatic impairment did not affect the exposure to semaglutide. The pharmacokinetic properties of semaglutide were evaluated in a single-dose study of semaglutide 0.5 mg in patients with varying degrees of hepatic impairment (mild, moderate, severe) compared to patients with normal liver function.

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

Indications

Ozempic^® is indicated for use in adult patients with type 2 diabetes mellitus in conjunction with 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 a thiazolidinedione, in patients who have not achieved adequate glycemic control with prior therapy;
• Combination therapy with insulin in patients who have not achieved adequate glycemic control on therapy with Ozempic^® and metformin.

Ozempic^® is indicated to reduce the risk of major adverse cardiovascular events* in patients with type 2 diabetes and high cardiovascular risk as an addition to standard cardiovascular disease treatment (based on the time-to-first major adverse cardiovascular event analysis – see section “Pharmacological Properties”, subsection “Cardiovascular safety assessment”).

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

ICD codes

Dosage Regimen

The initial dose of Ozempic^® is 0.25 mg once a week. After 4 weeks of use, the dose should be increased to 0.5 mg once a week. For further improvement in 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 Ozempic^® dose of 0.25 mg is not a therapeutic dose. Administration of more than 1 mg per week is not recommended.

Ozempic^® can be used as monotherapy or in combination with one or more hypoglycemic drugs (see section “Clinical Efficacy and Safety”).

When adding Ozempic^® to previous therapy with metformin and/or a thiazolidinedione, or an SGLT2 inhibitor, therapy with metformin and/or a thiazolidinedione, or an SGLT2 inhibitor can be continued at the same doses.

When adding Ozempic^® to ongoing therapy with a sulfonylurea derivative or insulin, a reduction in the dose of the sulfonylurea derivative or insulin should be considered to reduce the risk of hypoglycemia (see section “Special Instructions”).

The use of Ozempic^® does not require self-monitoring of blood glucose concentration. Self-monitoring of blood glucose is necessary for adjusting the dose of sulfonylurea and insulin, especially at the beginning of treatment with Ozempic^® and when reducing the insulin dose. A stepwise approach to reducing the insulin dose is recommended.

Missed dose

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

Special patient groups

No dose adjustment is required for elderly patients (≥65 years). Experience with semaglutide in patients aged 75 years and older is limited.

No dose adjustment is required for patients with hepatic impairment (see section “Pharmacokinetics”). Experience with semaglutide in patients with severe hepatic impairment is limited; the use of Ozempic^® in such patients is contraindicated.

No dose adjustment is required for patients with renal impairment. Experience with the drug in patients with end-stage renal failure is lacking; the use of Ozempic^® in such patients is contraindicated.

The use of Ozempic^® in children and adolescents under 18 years of age is contraindicated due to lack of safety and efficacy data.

Method of administration

Ozempic^® is used once a week at any time, regardless of meals. Ozempic^® is administered subcutaneously into the abdomen, thigh, or upper arm. The injection site can be changed without dose adjustment. Ozempic^® must 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 selecting a new administration day, administration once a week should be continued.

Instructions for use

The pre-filled Ozempic^® pen is supplied in two types

• Ozempic^® 0.25 mg/dose or 0.5 mg/dose solution for subcutaneous injection in a pre-filled pen allows for the administration of 0.25 mg or 0.5 mg doses. This pen is intended for dose escalation and maintenance of the 0.5 mg therapeutic dose. One pen contains 1.5 ml of solution.
• Ozempic^® 1 mg/dose solution for subcutaneous injection in a pre-filled pen allows for the administration of only 1 mg doses. This pen is intended only for maintenance of the 1 mg therapeutic dose. One pen contains 3 ml of solution.

NovoFine^® Plus needles are included in the Ozempic^® package.

The patient should be advised to discard the injection needle after each injection in accordance with local requirements.

The Ozempic^® pen is intended for single-person use only.

Ozempic^® must not be used if it looks different from a clear, colorless or almost colorless solution.

Ozempic^® must not be used if it has been frozen.

Ozempic^® can be administered using needles up to 8 mm in length. The pen is intended for use with disposable NovoFine^® injection needles.

Always remove the needle after each injection and store the Ozempic^® pen with the needle detached. This will help prevent needle blockages, contamination, infection, leakage of solution, and administration of an incorrect dose.

Patient instructions for using Ozempic^® 0.25 mg/dose or 0.5 mg/dose solution for subcutaneous injection in a pre-filled pen

Read these instructions carefully before using the pre-filled Ozempic^® pen.

Use the pen only after you have been trained on how to use it by your doctor or nurse.

Start by checking the pen to make sure it contains Ozempic^® 0.25 mg/dose or 0.5 mg/dose, then look at the illustrations below to familiarize yourself with the different parts of the pen and needle.

If you are blind or have severe vision problems and cannot see the numbers on the dose counter, do not use the pen without assistance. Get help from a sighted person trained in using the pre-filled Ozempic^® pen.

This pen is a pre-filled pen. It contains 2 mg of semaglutide and allows you to select doses of 0.25 mg or 0.5 mg. The pen is designed for use with disposable NovoFine^® needles up to 8 mm in length.

NovoFine^® Plus needles are included in the package.

Δ Important information

Pay special attention to information marked with such symbols, as it is very important for the safe use of the pen.

Pre-filled Ozempic^® pen and needle (example)

1. Preparing a new pen with a new needle for use

• Check the name and color code on the pen label to make sure it contains Ozempic^® 0.25 mg/dose or 0.5 mg/dose. This is especially important if you use more than one injectable medicine.
• Pull off the pen cap (Fig. A).

• Make sure the solution in the pen is clear and colorless (Fig. B). Look through the pen window. If the solution is cloudy or not colorless, do not use the pen.

• Take a new needle and remove the protective sticker (Fig. C). If the protective sticker is damaged, do not use the needle, as sterility cannot be guaranteed in this case.

• Screw the needle onto the pen and turn it until it is firmly attached to the pen (Fig. D).

• Pull off the outer needle cap, but do not throw it away (Fig. E). You will need it after the injection is completed to safely remove the needle from the pen.

• Pull off and discard the inner needle cap (Fig. F). If you try to put the inner cap back on the needle, you may accidentally stick yourself with the needle.

A drop of solution may appear at the needle tip. This is normal, but you should still perform a flow check if you are using a new pen for the first time.

Do not attach a new needle until you are ready to make an injection.

Δ Always use a new needle for each injection. This can prevent needle blockages, contamination, infection, and administration of an incorrect dose.

Δ Never use a needle if it is bent or damaged.

2. Flow check

• Before the first injection with each new pen, perform a flow check. If the pen is already in use, proceed to step 3 “Setting the dose”.
• Turn the dose selector until the dose counter shows the flow check symbol (••—) (Fig. A).

• Hold the pen with the needle pointing upwards. Press and hold the dose button until the dose counter returns to “0” (Fig. B). The “0” must be aligned with the dose pointer. A drop of solution should appear at the needle tip.

A small drop may remain at the needle tip, but it will not be injected. If a drop of solution does not appear at the needle tip, repeat step “2” “Flow check”, but no more than 6 times. If a drop still does not appear, change the needle and repeat step “2” “Flow check” once more. If a drop still does not appear, dispose of the pen and use a new one.

Δ Always before using a new pen for the first time make sure that a drop of solution appears at the needle tip. This ensures the flow of the drug.

If a drop of solution does not appear, the drug will not be injected, even if the dose counter moves. This may indicate that the needle is blocked or damaged.

If you do not perform a flow check before the first injection with each new pen, you may not inject the required dose and the expected effect of Ozempic^® will not be achieved.

3. Setting the dose

• Turn the dose selector until it shows the required dose (0.25 mg or 0.5 mg) (Fig. A). If the wrong dose was selected, you can turn the dose selector forwards or backwards until the correct dose is set. The maximum dose that can be set is 0.5 mg.

The dose selector changes the dose. Only the dose counter and the dose pointer show the number of mg of the drug in the dose you have selected.

You can select up to 0.5 mg of the drug per dose. If the pen contains less than 0.5 mg, the dose counter will stop before “0.5” appears.

Each turn of the dose selector produces clicks; the sound of the clicks depends on the direction the dose selector is turned: forward, backward, or if the dialed dose exceeds the amount of mg of drug remaining in the pen. Do not count the pen clicks.

Δ Always before each injection, check how many mg of the drug you have dialed using the dose counter and the dose pointer.

Do not count the pen clicks.

Use the dose selector to select only doses of 0.25 mg or 0.5 mg. The selected dose must be exactly opposite the dose pointer – this position ensures that you receive the correct drug dose.

How much drug is left

To determine how much drug is left, use the dose counter (fig. A): turn the dose selector until the dose counter stops.

If it shows “0.5”, there is at least 0.5 mg of drug left in the pen. If the dose counter stopped before “0.5” appeared, it means there is an insufficient amount of drug left in the pen to deliver a full 0.5 mg dose.

Δ If there is an insufficient amount of drug left in the pen for a full dose, do not use the pen. Use a new Ozempic^® pen.

4. Injecting the drug

• Insert the needle under the skin using the injection technique recommended by your doctor or nurse (fig. A).
• Ensure the dose counter is within your line of sight. Do not touch the dose counter with your fingers – this may interrupt the injection.

• Press the injection button all the way in and hold it in this position until the dose counter shows “0” (fig. B). “0” must be exactly opposite the dose pointer. You may hear or feel a click.

• Keep the needle under the skin after the dose counter returns to “0” and slowly count to 6 (fig. C).
• If you remove the needle from under the skin too early, you may see drug leakage from the needle. In this case, an incomplete drug dose will be administered.

• Remove the needle from under the skin (fig. D). If blood appears at the injection site, gently press a cotton swab to the injection site. Do not rub the injection site.

After the injection is completed, you may see a drop of solution at the tip of the needle. This is normal and does not affect the drug dose you administered.

Δ Always check the dose counter reading to know how many mg of the drug you have injected. Hold the injection button until the dose counter shows “0”.

How to detect a blocked or damaged needle

• If “0” does not appear on the dose counter after holding the injection button for a long time, it may indicate a blocked or damaged needle.
• In this case, you did not receive the drug, even if the dose counter moved from the initial dose you set.

What to do with a blocked needle

Replace the needle as described in step 5 “After the injection is completed” and repeat all steps starting from step 1 “Preparing the pen with a new needle for use”. Make sure you set the full required dose.

Never touch the dose counter during drug administration. This may interrupt the injection.

5. After the injection is completed

• Place the outer needle cap on a flat surface and insert the needle end into the cap without touching the cap or the needle (fig. A).

• When the needle is inside the cap, carefully push the outer cap onto the needle (fig. B).
• Unscrew the needle and dispose of it safely.

• After each use, put the cap back on the pen to protect the solution inside from light (fig. C).

Always dispose of the needle after each injection to ensure a comfortable injection and avoid needle blockages. If the needle is blocked, you will not inject the drug. Dispose of the empty pen with the needle removed according to the recommendations given by your doctor, nurse, pharmacist, or according to local requirements.

Δ Never try to put the inner needle cap back on the needle. You may prick yourself.

Δ After each injection, always remove the needle from the pen immediately. This can prevent needle blockages, contamination, infection, solution leakage, and administration of an incorrect drug dose.

Δ Additional important information

• Always store the pen and its needles in a place inaccessible to all, and especially to children.
• Never share your pen and its needles with other people.
• Caregivers must handle used needles with special care to prevent needle sticks and cross-infection.

Pen care

Handle the pen with care. Careless handling or improper use may lead to incorrect drug dosing, which may result in high blood glucose or abdominal discomfort (nausea or vomiting).

• Do not leave the pen in a car or any other place where it may be exposed to very high or very low temperatures.
• Do not use Ozempic^® if it has been frozen. In this case, blood glucose may become too high or you may experience abdominal discomfort such as nausea or vomiting.
• Do not use Ozempic^® if it has been exposed to direct sunlight. In this case, blood glucose may become too high.
• Protect the pen from dust, dirt, and liquid.
• Do not wash, immerse in liquid, or lubricate the pen. If necessary, the pen can be cleaned with a damp cloth moistened with a mild detergent.
• Do not drop or knock the pen against a hard surface. If you drop the pen or doubt its proper function, attach a new needle and check the drug flow before making an injection.
• Do not attempt to refill the pen. The empty pen must be disposed of.
• Do not attempt to repair the pen or take it apart yourself.

Instructions for patients on the use of Ozempic^® 1 mg/dose solution for s.c. injection in a pre-filled pen

Read these instructions carefully before using the Ozempic^® pre-filled pen.

Use the pen only after you have been trained on how to use it under the guidance of a doctor or nurse.

Start by checking the pen to ensure it contains Ozempic^® 1 mg/dose, then look at the illustrations below to familiarize yourself with the different parts of the pen and needle.

If you are visually impaired or have serious vision problems and cannot read the numbers on the dose counter, do not use the pen without assistance. A sighted person trained in using the Ozempic^® pre-filled pen can help you.

This pen is a pre-filled pen. It contains 4 mg of semaglutide and allows you to select only a 1 mg dose. The pen is designed for use with disposable NovoFine^® needles up to 8 mm in length.

NovoFine^® Plus needles are included in the package.

Δ Important information

Pay special attention to information marked with such symbols, as it is very important for the safe use of the pen.

Pre-filled Ozempic^® pen and needle (example)

1. Preparing the pen with a new needle for use

• Check the name and color code on the pen label to ensure it contains Ozempic^® 1 mg/dose. This is especially important if you use more than one injectable drug.
• Remove the cap from the pen (fig. A).

• Make sure the solution in the pen is clear and colorless (fig. B). Look through the pen window. If the solution is cloudy or not colorless, do not use the pen.

• Take a new needle and remove the protective sticker (fig. C). If the protective sticker is damaged, do not use the needle, as sterility cannot be guaranteed in this case.

• Push the needle straight onto the pen and turn it until it is on tight (fig. D).

• Pull off the outer needle cap, but do not discard it (fig. E). You will need it after the injection is completed to safely remove the needle from the pen.

• Pull off and discard the inner needle cap (fig. F). If you try to put the inner cap back on the needle, you may accidentally prick yourself with the needle.

A drop of solution may appear at the needle tip. This is normal, however, you should still check the drug flow if you are using a new pen for the first time.

Do not attach a new needle until you are ready to make an injection.

Δ Always use a new needle for each injection. This can prevent needle blockages, contamination, infection, and administration of an incorrect drug dose.

Δ Never use a needle if it is bent or damaged.

2. Checking the drug flow

• Before the first injection with each new pen, check the drug flow. If the pen is already in use, proceed to step 3 “Setting the dose”.
• Turn the dose selector until the dose counter is aligned with the drug flow check symbol (••—) (fig. A).

• Hold the pen with the needle pointing upwards. Press the injection button and hold it in this position until the dose counter returns to “0” (fig. B). “0” must be opposite the dose pointer. A drop of solution should appear at the needle tip.

A small drop may remain at the needle tip, but it will not be injected.

If a drop of solution does not appear at the needle tip, repeat step “2” “Checking the drug flow”, but no more than 6 times. If a drop still does not appear, change the needle and repeat step “2” “Checking the drug flow” once more. If a drop still does not appear, dispose of the pen and use a new one.

Δ Always before using a new pen for the first time make sure that a drop of solution appears at the needle tip. This ensures drug flow.

If a drop of solution does not appear, the drug will not be injected, even if the dose counter moves. This may indicate that the needle is blocked or damaged.

If you do not check the drug flow before the first injection with each new pen, you may not inject the required dose and the expected effect of Ozempic^® will not be achieved.

3. Setting the dose

• Turn the dose selector to select a 1 mg dose (fig. A). Continue turning until the dose counter stops and shows “1”.

Only the dose counter and the dose pointer will show that 1 mg has been selected.

You can only select 1 mg of the drug per dose. If the pen contains less than 1 mg, the dose counter will stop before “1” appears.

Each turn of the dose selector produces clicks; the sound of the clicks depends on the direction the dose selector is turned: forward, backward, or if you try to dial a dose greater than 1 mg. Do not count the pen clicks.

Δ Always before each injection, check using the dose counter and dose pointer that 1 mg has been dialed.

Do not count the pen clicks.

Use the dose selector to select only a 1 mg dose. The 1 mg dose must be exactly opposite the dose pointer – this position ensures that you receive the correct drug dose.

How much drug is left

To determine how much drug is left, use the dose counter (fig. A): turn the dose selector until the dose counter stops.

If it shows “1”, there is at least 1 mg of drug left in the pen. If the dose counter stopped before the number “1” appeared, it means there is an insufficient amount of drug left in the pen to deliver a full 1 mg dose.

Δ If there is an insufficient amount of drug left in the pen for a full dose, do not use the pen. Use a new Ozempic^® pen.

4. Injecting the drug

• Insert the needle under the skin using the injection technique recommended by your doctor or nurse (fig. A).
• Ensure the dose counter is within your line of sight. Do not touch the dose counter with your fingers – this may interrupt the injection.

• Press the injection button all the way in and hold it in this position until the dose counter shows “0” (fig. B). “0” must be exactly opposite the dose pointer. You may hear or feel a click.

• Keep the needle under the skin after the dose counter returns to “0” and slowly count to 6 (fig. C). If you remove the needle from under the skin too early, you may see drug leakage from the needle. In this case, an incomplete drug dose will be administered.

• Remove the needle from under the skin (fig. D). If blood appears at the injection site, gently press a cotton swab to the injection site. Do not rub the injection site.

After the injection is completed, you may see a drop of solution at the tip of the needle. This is normal and does not affect the drug dose you administered.

Δ Always check the dose counter reading to know how many mg of the drug you have injected. Hold the injection button until the dose counter shows “0”.

How to detect a blocked or damaged needle

• If “0” does not appear on the dose counter after holding the injection button for a long time, it may indicate a blocked or damaged needle.
• In this case, you did not receive the drug, even if the dose counter moved from the initial dose you set.

What to do with a blocked needle

Replace the needle as described in step 5 “After the injection is completed” and repeat all steps starting from step 1 “Preparing the pen with a new needle for use”. Make sure you set the full required dose.

Never touch the dose counter during drug administration. This may interrupt the injection.

5. After the injection is completed

• Place the outer needle cap on a flat surface and insert the needle end into the cap without touching the cap or the needle (fig. A).

• When the needle is inside the cap, carefully push the outer cap onto the needle (fig. B).
• Unscrew the needle and dispose of it safely.

• After each use, put the cap back on the pen to protect the solution inside from light (fig. C).

Always dispose of the needle after each injection to ensure a comfortable injection and avoid needle blockages. If the needle is blocked, you will not inject the drug. Dispose of the empty pen with the needle removed according to the recommendations given by your doctor, nurse, pharmacist, or according to local requirements.

Δ Never try to put the inner needle cap back on the needle. You may prick yourself.

Δ After each injection, always remove the needle from the pen immediately. This can prevent needle blockages, contamination, infection, solution leakage, and administration of an incorrect drug dose.

Δ Additional important information

• Always store the pen and its needles in a place inaccessible to all, and especially to children.
• Never share your pen and its needles with other people.
• Caregivers must handle used needles with special care to prevent needle sticks and cross-infection.

Pen care

Handle the pen with care. Careless handling or improper use may lead to incorrect drug dosing, which may result in high blood glucose or abdominal discomfort (nausea or vomiting).

• Do not leave the pen in a car or any other place where it may be exposed to very high or very low temperatures.
• Do not use Ozempic^® if it has been frozen. In this case, blood glucose may become too high or you may experience abdominal discomfort such as nausea or vomiting.
• Do not use Ozempic^® if it has been exposed to direct sunlight. In this case, blood glucose may become too high.
• Protect the pen from dust, dirt, and liquid.
• Do not wash, immerse in liquid, or lubricate the pen. If necessary, the pen can be cleaned with a damp cloth moistened with a mild detergent.
• Do not drop or knock the pen against a hard surface. If you drop the pen or doubt its proper function, attach a new needle and check the drug flow before making an injection.
• Do not attempt to refill the pen. The empty pen must be disposed of.
• Do not attempt to repair the pen or take it apart yourself.

Adverse Reactions

The most frequently reported adverse reactions (ARs) during clinical trials were gastrointestinal disorders, including nausea, diarrhea, and vomiting. Overall, these reactions were mild or moderate in severity and short-term.

ARs are listed by system organ class according to MedDRA with the frequency of their occurrence indicated according to WHO recommendations: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000). Within each frequency group, ARs are presented in decreasing order of severity.

Table 1. ARs identified in phase 3a clinical trials

^a Hypoglycemia, defined as severe (requiring assistance from another person) or symptomatic in combination with a plasma glucose concentration <3.1 mmol/L.

^b Complications of diabetic retinopathy is a composite of: need for retinal photocoagulation, need for intravitreal pharmacotherapy, vitreous hemorrhage, development of diabetes-related blindness.

The frequency is based on the cardiovascular outcomes trial.

^cA grouped term that also includes hypersensitivity-related adverse reactions, such as rash and urticaria.

^dAdverse reactions from post-marketing sources

Two-year cardiovascular outcomes and safety trial

In the population of patients at high cardiovascular risk, the adverse reaction profile was similar to that in other phase 3a clinical trials (described in the “Clinical Efficacy and Safety” subsection).

Description of selected adverse reactions

Hypoglycemia

No episodes of severe hypoglycemia were observed during monotherapy with Ozempic^®. Severe hypoglycemia was mainly observed when Ozempic^® was used in combination with a sulfonylurea derivative or insulin. A few episodes of severe hypoglycemia were observed when Ozempic^® was used in combination with other oral hypoglycemic agents, excluding sulfonylurea derivatives.

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

Gastrointestinal adverse reactions

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 in severity and short-term. Adverse reactions led to premature discontinuation from clinical trials in 3.9% and 5.9% of patients, respectively. Adverse reactions were most frequently reported during the first months of therapy.

Patients with low body weight treated with semaglutide may experience more gastrointestinal adverse reactions.

In clinical trials with concomitant 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 to no events in patients receiving placebo. The prevalence of these events did not decrease over time.

Acute pancreatitis

The incidence of adjudicated acute pancreatitis in phase 3a trials was 0.3% with semaglutide and 0.2% with comparator. In the two-year cardiovascular outcomes trial, the incidence of adjudicated acute pancreatitis was 0.5% with semaglutide and 0.6% with placebo (see “Special Precautions” section).

Complications of diabetic retinopathy

In a two-year clinical trial involving patients with type 2 diabetes and high cardiovascular risk, long duration of diabetes, and inadequate glycemic control, adjudicated cases of diabetic retinopathy complications occurred in a greater number of patients receiving Ozempic^® (3.0%) compared to patients receiving placebo (1.8%). In patients with a history of diabetic retinopathy at the start of the trial, the absolute risk increase for complications was higher. In patients without a confirmed history of diabetic retinopathy, the number of events was similar with Ozempic^® and placebo.

In a clinical trial of up to 1 year duration, the frequency of adverse reactions related to diabetic retinopathy was similar in the Ozempic^® group and the comparator groups.

Discontinuation of treatment due to adverse reactions

The frequency of treatment discontinuation due to adverse reactions was 8.7% for patients receiving Ozempic^® 1 mg. The most common adverse reactions leading to treatment discontinuation were gastrointestinal disorders.

Injection site reactions

Injection site reactions (such as injection site rash, erythema) were reported in 0.6% and 0.5% of patients receiving semaglutide 0.5 mg and 1 mg, respectively. These reactions were generally mild.

Immunogenicity

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

Contraindications

• Hypersensitivity to semaglutide or any of the excipients of the drug;
• Personal or family history of medullary thyroid carcinoma;
• Multiple endocrine neoplasia (MEN) type 2;
• Type 1 diabetes mellitus (T1DM);
• Diabetic ketoacidosis.

The use of Ozempic^® is contraindicated in the following patient groups and for the following conditions/diseases due to lack of efficacy and safety data or limited experience of use

• Pregnancy;
• Breastfeeding period;
• Age under 18 years;
• Severe hepatic impairment;
• End-stage renal disease (CrCl <15 mL/min);
• Chronic heart failure (CHF) NYHA functional class IV.

Use with caution

Ozempic^® should be used with caution in patients with renal impairment and in patients with a history of pancreatitis (see “Special Precautions” section).

Use in Pregnancy and Lactation

Pregnancy

Animal studies have demonstrated reproductive toxicity of the drug (see “Preclinical Safety Data” section).

Data on the use of semaglutide in pregnant women are limited. Semaglutide is contraindicated during pregnancy. Women of childbearing potential are advised to use contraception during semaglutide therapy. If a patient is planning pregnancy or becomes pregnant, semaglutide therapy should be discontinued. Due to the long half-life, semaglutide therapy should be discontinued at least 2 months before a planned pregnancy (see “Pharmacokinetics” section).

Breastfeeding

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

Fertility

The effect of semaglutide on human fertility is unknown. Semaglutide did not affect fertility in male rats. In female rats, an increase in the estrous cycle and a slight decrease in the number of ovulations were observed at doses accompanied by a reduction in female body weight.

Use in Hepatic Impairment

No dose adjustment is required in patients with hepatic impairment.

The use of the drug is contraindicated in severe hepatic impairment.

Use in Renal Impairment

The drug should be used with caution in patients with renal impairment.

The use of the drug is contraindicated in patients with end-stage renal disease (CrCl <15 mL/min).

Pediatric Use

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

Geriatric Use

No dose adjustment is required in elderly patients (≥65 years).

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

Special Precautions

The use of Ozempic^® is contraindicated in patients with T1DM or for the treatment of diabetic ketoacidosis.

Ozempic^® is not a substitute for insulin. Diabetic ketoacidosis has been reported in insulin-dependent patients who had rapid discontinuation or reduction of insulin dose upon initiation of GLP-1 receptor agonist therapy (see “Dosage and Administration” section).

Gastrointestinal reactions

The use of GLP-1 receptor agonists may be associated with gastrointestinal adverse reactions. This should be considered when treating patients with renal impairment, as nausea, vomiting, and diarrhea can lead to dehydration and worsening of renal function.

Acute pancreatitis

Cases of acute pancreatitis have been observed with the use of GLP-1 receptor agonists. Patients should be informed about the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, therapy with Ozempic^® should be discontinued; if acute pancreatitis is confirmed, therapy with Ozempic^® 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, elevated pancreatic enzyme levels are not predictive of developing acute pancreatitis.

Hypoglycemia

Patients receiving Ozempic^® in combination with a sulfonylurea derivative or insulin may have an increased risk of hypoglycemia. At the initiation of Ozempic^® treatment, the risk of hypoglycemia can be reduced by lowering the dose of the sulfonylurea derivative or insulin.

Diabetic retinopathy

An increased risk of diabetic retinopathy complications was observed in patients with diabetic retinopathy receiving therapy with insulin and semaglutide (see “Adverse Reactions” section). Caution should be exercised when using semaglutide in patients with diabetic retinopathy receiving insulin therapy. Such patients should be monitored continuously and treated according to clinical guidelines. Rapid improvement in glycemic control has been associated with a temporary worsening of diabetic retinopathy, but other causes cannot be excluded.

Heart failure

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

Thyroid disorders

Cases of medullary thyroid carcinoma (MTC) have been reported in the post-marketing period for another GLP-1 analogue, liraglutide. The available data are insufficient to establish or exclude a causal relationship between the occurrence of MTC and the use of GLP-1 analogues. Patients should be informed about the risk of MTC and about the symptoms of thyroid tumors (appearance of a mass in the neck, dysphagia, dyspnea, persistent hoarseness). A significant increase in plasma calcitonin concentration may indicate MTC (in patients with MTC, plasma calcitonin values are usually >50 ng/L). If an elevated plasma calcitonin concentration is detected, further examination of the patient should be performed. Patients with thyroid nodules detected on physical examination or thyroid ultrasound should also be further evaluated.

The use of semaglutide is contraindicated in patients with a personal or family history of MTC or with MEN type 2 syndrome.

Preclinical safety data

Preclinical data based on general pharmacology, repeated dose toxicity, and genotoxicity studies did not reveal any specific hazard for humans.

In two-year carcinogenicity studies in rats and mice at clinically relevant exposures, semaglutide caused non-lethal C-cell thyroid tumors. The non-lethal C-cell thyroid tumors observed in rats are typical for the class of GLP-1 analogues. This risk is considered low for humans but cannot be completely excluded.

Effect on ability to drive and use machines

Ozempic^® has no or negligible influence on the ability to drive and use machines. Patients should be cautioned to take precautions to avoid hypoglycemia while driving and operating machinery, especially when Ozempic^® is used in combination with a sulfonylurea derivative or insulin.

Overdose

Symptoms In clinical trials, overdoses of up to 4 mg as a single dose and up to 4 mg per week have been reported. The most commonly reported adverse reaction was nausea. All patients recovered without complications.

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

Drug Interactions

In vitro studies with semaglutide indicated a very low potential for inhibition or induction of cytochrome P450 (CYP) enzymes and inhibition of drug transporters.

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

Paracetamol

Assessment of the pharmacokinetics of paracetamol during a standardized meal test revealed that semaglutide delays gastric emptying. With concomitant use of semaglutide 1 mg, the AUC_{0-60 min} and C_max of paracetamol decreased by 27% and 23%, respectively. The overall exposure to paracetamol (AUC_{0-5 h}) was unchanged. No dose adjustment of paracetamol is required when taken concomitantly with semaglutide.

Oral hormonal contraceptives

Semaglutide is not expected to reduce the efficacy of oral hormonal contraceptives. With concomitant use of a combined oral hormonal contraceptive (0.03 mg ethinylestradiol/0.15 mg levonorgestrel) and semaglutide, the latter did not have a clinically significant effect on the overall exposure to ethinylestradiol and levonorgestrel. Exposure to ethinylestradiol was not affected; a 20% increase in exposure to levonorgestrel at steady state was observed. C_max was unchanged for either component.

Atorvastatin

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

Digoxin

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

Metformin

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

Warfarin

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

Incompatibility

Substances added to Ozempic^® may cause degradation of semaglutide. Ozempic^® must not be mixed with other medicinal products, including infusion solutions.

Storage Conditions

Store out of the reach of children at a temperature between 2°C (35.6°F) and 8°C (46.4°F) (in a refrigerator), but not near the freezer; protect from light; do not freeze. Protect from excessive heat and light.

Shelf Life

The shelf life is 3 years. Do not use after the expiry date stated on the pen label and packaging.

The pen in use or carried as a spare should be stored at a temperature not exceeding 30°C (86°F) or at a temperature between 2°C (35.6°F) and 8°C (46.4°F) (in a refrigerator) for 6 weeks. Do not freeze. After use, close the pen with the cap to protect from light.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.