Welgia^® (Solution) Instructions for Use

ATC Code

A10BJ06 (Semaglutide)

Active Substance

Semaglutide (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Drug for the treatment of obesity – glucagon-like peptide-1 (GLP-1) receptor agonist

Pharmacotherapeutic Group

Drugs for the treatment of diabetes mellitus; hypoglycemic drugs, other than insulins; glucagon-like peptide-1 (GLP-1) analogues

Pharmacological Action

Mechanism of action

Semaglutide is a GLP-1 analogue with 94% homology to human GLP-1. Semaglutide acts as a GLP-1 receptor agonist, which selectively binds to and activates the GLP-1 receptor (the target of native GLP-1).

GLP-1 is a physiological regulator of appetite and calorie intake. GLP-1 receptors are localized in various areas of the brain involved in appetite regulation.

Animal studies have shown that Semaglutide affects the CNS through the GLP-1 receptor. Semaglutide has a direct effect on areas of the brain involved in the homeostatic regulation of food intake in the hypothalamus and brainstem. Semaglutide may influence the pleasure sensation from eating (hedonic regulation of eating behavior) through direct or indirect effects on brain structures, including the septum, thalamus, and amygdala.

Clinical studies have shown that Semaglutide reduces calorie intake, enhances feelings of satiety, fullness, and control over food intake, reduces hunger, as well as the frequency and intensity of food cravings. Furthermore, Semaglutide reduces the preference for high-fat foods.

Semaglutide affects the homeostatic and hedonic regulation of eating behavior by reducing appetite, cravings for high-calorie foods, pleasure from food consumption, and changing food preferences.

Furthermore, clinical studies have shown that Semaglutide reduces blood glucose levels through glucose-dependent stimulation of insulin secretion and reduction of glucagon secretion at elevated blood glucose levels. The mechanism of blood glucose reduction also includes a minor delay in gastric emptying in the early postprandial period. During hypoglycemia, Semaglutide reduces insulin secretion and does not affect glucagon secretion.

GLP-1 receptors are also present in the heart, vascular system, immune system, and kidneys. In clinical studies, Semaglutide had a beneficial effect on plasma lipid levels, reduced systolic blood pressure, and reduced inflammation. Animal studies have shown that Semaglutide suppresses the development of atherosclerosis and has an anti-inflammatory effect on the cardiovascular system.

Pharmacodynamic effects

Appetite, energy intake, and food choices

Semaglutide reduces appetite by enhancing satiety while reducing hunger and prospective food consumption. In a Phase I study, calorie intake during an ad libitum meal was 35% lower with semaglutide compared to placebo after 20 weeks of treatment. This was confirmed by improved control over eating, reduced food cravings, and a relative reduction in preference for high-fat foods. In the STEP 5 study, food cravings were assessed in more detail using the Control of Eating Questionnaire (CoEQ). At week 104, the results showed significant improvement in the semaglutide therapy group, both in terms of appetite control and cravings for savory and spicy foods, while no pronounced effect was observed for cravings for sweet foods.

Fasting and postprandial lipid levels

Semaglutide at a dose of 1 mg compared to placebo reduced fasting triglyceride (TG) and very-low-density lipoprotein (VLDL) concentrations by 12% and 21%, respectively. Postprandial TG and VLDL levels in patients after a high-fat meal were reduced by more than 40%.

Clinical efficacy and safety

The efficacy and safety of semaglutide for weight reduction in combination with reduced calorie intake and increased physical activity were evaluated in four double-blind, randomized, placebo-controlled Phase IIIa studies lasting 68 weeks (STEP 1-4). A total of 4684 adult patients were included in the studies (2652 of them were randomized to semaglutide treatment). Furthermore, in a double-blind, randomized, placebo-controlled Phase IIIb study (STEP 5), which included 304 patients (152 patients received Semaglutide), the efficacy and safety of semaglutide use compared to placebo were assessed over 2 years.

The superiority of semaglutide therapy, clinically significant and sustained weight reduction compared to placebo, was demonstrated in patients with obesity (BMI >30 kg/m²) or overweight (BMI from >27 kg/m² to < 30 kg/m²), and at least one comorbidity related to overweight. Furthermore, in all studies, Semaglutide enabled patients to achieve weight reduction of >5%, >10%, >15%, and >20% compared to placebo. Weight reduction occurred independently of the presence of gastrointestinal symptoms such as nausea, vomiting, or diarrhea.

Semaglutide treatment also showed a statistically significant reduction in waist circumference, improvement in systolic blood pressure, and physical condition compared to placebo.

Efficacy was demonstrated regardless of age, sex, race, ethnicity, baseline body weight, BMI, presence of T2DM, and level of kidney function. Differences in efficacy were observed across all subgroups. A relatively greater weight reduction effect was observed in women and patients without T2DM, as well as in patients with lower baseline body weight compared to patients with higher baseline body weight.

STEP 1: Weight control

In a 68-week double-blind study, 1961 patients with obesity (BMI >30 kg/m²) or overweight (BMI from >27 kg/m² to < 30 kg/m²) and at least one comorbidity related to overweight were randomized to groups using semaglutide or placebo. All patients followed a low-calorie diet and increased physical activity throughout the study.

Weight reduction occurred rapidly and continued throughout the study. By the end of treatment (week 68), weight reduction in the semaglutide group was superior and clinically significant compared to the placebo group (see Table 1 and Figure 1). With semaglutide therapy, patients managed to achieve weight reduction of >5%, >10%, >15%, and >20% compared to the placebo group (see Table 1 and Figure 1). In most patients with prediabetes at the start of the study, glycemic levels were normal at the end of semaglutide treatment compared to placebo (84.1% vs. 47.8%).

Table 1. STEP 1 results at week 68

* p< 0.0001 (unadjusted 2-sided) for proof of superiority.
¹ Estimated using an ANCOVA model with MI (multiple imputation) based on all data, regardless of discontinuation of study therapy or initiation of other obesity treatment drugs or bariatric surgery.
²During the study, 17.1% and 22.4% of patients randomized to the semaglutide 2.4 mg and placebo groups, respectively, completely discontinued the study drug. Assuming all randomized patients continued treatment and did not receive additional obesity therapy, the estimated changes in body weight from randomization to week 68 based on an MMRM analysis, including all observations until the first treatment discontinuation, were -16.9% and -2.4% for semaglutide 2.4 mg and placebo, respectively.
³Estimated using a binary regression model based on the same data imputation method as the primary analysis.

Figure 1. STEP 1: Mean change in body weight (%) from baseline to week 68

After the 68-week study, an additional 52-week treatment-free study was conducted, which included 327 patients who completed the main therapeutic dose period of semaglutide or placebo. In the absence of treatment from week 68 to week 120, mean body weight increased in both treatment groups. However, in patients who had previously received Semaglutide during the main study period, weight remained 5.6% below baseline compared to 0.1% in the placebo group.

STEP 2: Weight control in patients with T2DM

In a 68-week double-blind study, 1210 patients with overweight or obesity (BMI ≥27 kg/m²) with T2DM were randomized to groups using semaglutide 2.4 mg once weekly, semaglutide 1 mg once weekly, or placebo. The patients included in the study had inadequately controlled diabetes (HbA_1c 7-10%) and were treated with either diet and exercise alone or 1-3 oral hypoglycemic drugs. All patients followed a reduced-calorie diet and maintained increased physical activity throughout the study.

Use of semaglutide for 68 weeks resulted in a clinically significant reduction in body weight and HbA_1c level compared to placebo (see Table 2 and Figure 2).

Table 2. STEP 2: Results at week 68

* < 0.0001 (unadjusted 2-sided) for proof of superiority.
** p< 0.05 (unadjusted 2-sided) for proof of superiority.
¹Estimated using an ANCOVA model with MI (multiple imputation) taking into account all data, regardless of discontinuation of study therapy or initiation of other obesity treatment drugs or bariatric surgery.
²During the study, 17.1% and 22.4% of patients randomized to the semaglutide 2.4 mg and placebo groups, respectively, completely discontinued the study drug. Assuming all randomized patients continued treatment and did not receive additional obesity therapy, the estimated changes in body weight from randomization to week 68 based on an MMRM analysis, including all observations until the first treatment discontinuation, were -16.9% and -2.4% for semaglutide 2.4 mg and placebo, respectively.
³Estimated using a binary regression model based on the same data imputation method as the primary analysis.

Figure 2. STEP 2: Mean change in body weight (%) from baseline to week 68

STEP 3: Weight control with behavioral psychotherapy

In a 68-week double-blind study, 611 patients with obesity (BMI ≥30 kg/m²) or overweight (BMI from ≥27 kg/m² to < 30 kg/m²) and the presence of at least one comorbidity related to overweight were randomized to groups using semaglutide or placebo. During the study, all patients underwent a course of behavioral psychotherapy, including a very strict diet, increased physical activity, and behavior modification. The use of semaglutide and behavioral psychotherapy for 68 weeks showed superiority and resulted in a clinically significant reduction in body weight in the semaglutide therapy group compared to placebo (see Table 3).

Table 3. STEP 3: Results at week 68

* p< 0.005 (unadjusted 2-sided) for proof of superiority.
¹Estimated using an ANCOVA model with the MI method taking into account all data, regardless of discontinuation of study therapy or initiation of other obesity treatment drugs or bariatric surgery.
²During the study, 16.7% and 18.6% of patients randomized to the semaglutide 2.4 mg and placebo groups, respectively, completely discontinued the study therapy. Assuming all randomized patients continued treatment and did not receive additional obesity therapy, the calculated changes in body weight from randomization to week 68 using MMRMs, including all observations until the first treatment discontinuation, were -17.6% and -5.0% for semaglutide 2.4 mg and placebo, respectively.
³Estimated using a binary regression model based on the same data imputation method as the primary analysis.

STEP 4: Weight control on maintenance therapy

A 68-week double-blind study included 902 patients with obesity (BMI ≥30 kg/m²) or overweight (BMI from ≥27 kg/m² to 30 kg/m²) and the presence of at least one comorbidity related to overweight. All patients followed a reduced-calorie diet and maintained increased physical activity throughout the study. All patients received Semaglutide from week 0 to week 20 (run-in phase). At week 20 (baseline), patients who reached the maintenance dose of 2.4 mg were randomized to groups continuing treatment or switching to placebo. At week 0 (start of the run-in phase), the mean patient body weight was 107.2 kg, and the mean BMI was 38.4 kg/m².

Patients who reached the maintenance dose of 2.4 mg at week 20 (baseline) and continued using semaglutide for 48 weeks (weeks 20-68) continued to lose weight, showing superiority and a clinically significant reduction in body weight compared to patients receiving placebo (see Table 4 and Figure 3). Body weight steadily increased from week 20 to week 68 in patients who switched to placebo at week 20 (baseline). However, the mean body weight at week 68 was lower than at the start of the run-in phase (week 0) (see Figure 3). In patients receiving Semaglutide from week 0 (run-in phase) to week 68 (end of treatment), a mean change in body weight of ≥5% was achieved by 87.8%, ≥10% by 78.0%, ≥15% by 62.2%, and ≥20% by 38.6% of patients.

Table 4. STEP 4: Results from Week 20 to Week 68

P< 0.0001 (unadjusted 2-sided) for superiority.
¹Baseline data = week 20.
²Estimated using an ANCOVA model with the MI method using all data, regardless of trial product discontinuation or initiation of other obesity pharmacotherapy or bariatric surgery.
³During the trial, 5.8% and 11.6% of patients randomised to semaglutide 2.4 mg and placebo, respectively, completely discontinued the trial product. Assuming all randomised patients remained on treatment and received no additional obesity therapy, the estimated changes in body weight from randomisation to week 68 based on an MMRM including all observations until first treatment discontinuation were -8.1% and 6.5% for semaglutide 2.4 mg and placebo, respectively.

Figure 3. STEP 4: Mean change in body weight (%) from week 0 to week 68

STEP 5: 2-year trial

In a 104-week double-blind trial, 304 patients with obesity (BMI ≥30 kg/m²) or overweight (BMI from ≥27 kg/m² to 30 kg/m²) with at least one weight-related comorbidity were randomised to semaglutide or placebo. All patients followed a reduced-calorie diet and increased physical activity throughout the trial. At baseline, the mean patient BMI was 38.5 kg/m², and mean body weight was 106.0 kg.

Treatment with semaglutide for 104 weeks demonstrated superiority and a clinically significant reduction in body weight compared to placebo. Mean body weight decreased from baseline to week 68 in the semaglutide group, after which a plateau was reached. With placebo, mean body weight decreased more slowly, and a plateau was reached at approximately 20 weeks of treatment (see Table 5 and Figure 4). In patients treated with Semaglutide, the mean change in body weight was – 15.2%, with body weight reduction of ≥5% achieved by 74.7%, ≥10% by 59.2%, and ≥15% by 49.7% of patients.

Among patients who had prediabetes at the start of the trial, 80% and 37% showed a normal glycaemic status by the end of semaglutide and placebo treatment, respectively.

Table 5. STEP 5: Results at Week 104

* p< 0.0001 (unadjusted 2-sided) for superiority.
¹ Estimated using an ANCOVA model with MI using all data, regardless of trial product discontinuation or initiation of other obesity pharmacotherapy or bariatric surgery.
² During the trial, 13.2% and 27.0% of patients randomised to semaglutide and placebo, respectively, completely discontinued the trial product. Assuming all randomised patients remained on treatment and received no additional obesity therapy, the estimated changes in body weight from randomisation to week 68 based on an MMRM including all observations until first treatment discontinuation were -16.7% and -0.6% for semaglutide and placebo, respectively.
³ Estimated using a binary regression model based on the same data imputation method as the primary analysis.

Figure 4. STEP 5: Mean change in body weight (%) from week 0 to week 104

STEP 6: Semaglutide compared to liraglutide

In a 68-week randomised, open-label, paired placebo-controlled trial, 338 patients with obesity (BMI ≥30 kg/m²) or overweight (BMI from ≥27 kg/m² to 30 kg/m²) with at least one weight-related comorbidity were randomised to once-weekly semaglutide, liraglutide 3 mg once daily, or placebo. The trial with once-weekly semaglutide and liraglutide 3 mg was open-label, but within each active treatment group, a double-blind comparison with placebo administered at the same frequency was conducted. All patients followed a reduced-calorie diet and increased physical activity throughout the trial. At baseline, the mean patient BMI was 37.5 kg/m², and mean body weight was 104.5 kg.

Treatment with once-weekly semaglutide for 68 weeks demonstrated superiority and a clinically significant reduction in body weight compared to liraglutide. Mean body weight decreased from baseline to week 68 with semaglutide. In the liraglutide group, mean body weight decreased more slowly (see Table 6). 37.4% of patients receiving Semaglutide lost ≥ 20% of body weight compared to 7.0% of patients receiving liraglutide. Table 6 presents the results for the confirmatory endpoints of ≥10%, ≥15%, and ≥20% body weight loss.

Table 6. STEP 6: Results of the 68-week trial comparing semaglutide to liraglutide

* p< 0.005 (unadjusted 2-sided) for superiority.
¹ Estimated using an ANCOVA model with MI using all data, regardless of trial product discontinuation or initiation of other obesity pharmacotherapy or bariatric surgery.
²During the trial, 13.5% and 27.6% of patients randomised to semaglutide and liraglutide, respectively, completely discontinued the trial product.
Assuming all randomised patients remained on treatment and received no additional obesity therapy, the estimated changes in body weight from randomisation to week 68 based on an MMRM analysis including all observations until first treatment discontinuation were -16.7% and -6.7% for semaglutide and liraglutide, respectively.
3 Estimated using a binary regression model based on the same data imputation method as the primary analysis.

Effect on body composition

In a substudy of STEP 1 (N=140), body composition was assessed using dual-energy X-ray absorptiometry (DEXA). The DEXA assessment results showed that treatment with semaglutide led to a greater reduction in fat mass than in muscle mass, resulting in improved body composition compared to placebo at 68 weeks. Furthermore, this reduction in total fat mass was accompanied by a decrease in visceral fat. These results indicate that the reduction in total body weight was due to a decrease in adipose tissue, including visceral fat.

Improvement in physical function

Semaglutide demonstrated a small improvement in physical function scores. Physical function was assessed using both the general health-related quality of life questionnaire “Short Form-36v2 Health Survey (SF-36)” and the obesity-specific clinical trial questionnaire “Impact of Weight on Quality of Life” (IWQOL-Lite-CT).

Cardiovascular assessment

In the SUSTAIN 6 trial, 3297 patients with inadequately controlled T2D and high risk of cardiovascular complications were randomised to semaglutide 0.5 mg or 1 mg once weekly or placebo in addition to standard care. The treatment duration was 104 weeks. The mean patient age was 65 years, and the mean BMI was 33 kg/m².

The primary endpoint was the time from randomisation to the first major adverse cardiovascular event (MACE), such as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. The total number of MACE was 254, including 108 (6.6%) with semaglutide and 146 (8.9%) with placebo.

The cardiovascular safety of treatment with semaglutide 0.5 or 1 mg was confirmed: the hazard ratio (HR) for semaglutide compared to placebo was 0.74, [0.58, 0.95] [95% CI], driven by a reduction in the incidence of non-fatal myocardial infarction or non-fatal stroke with no difference in cardiovascular death (see Figure 5).

Figure 5. Kaplan-Meier plot of time to first occurrence of the composite outcome: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (SUSTAIN 6 clinical trial)

Non-clinical safety data

Non-clinical data based on safety pharmacology, repeat-dose toxicity, and genotoxicity studies revealed no risk to humans.

Non-lethal tumours originating from thyroid C-cells observed in rodents are effects characteristic of the GLP-1 receptor agonist class. In a 2-year carcinogenicity study in rats and mice, Semaglutide at clinically relevant exposure levels caused the occurrence of thyroid C-cell tumours. No other tumours considered related to treatment were observed. C-cell tumours in rodents are due to a specific non-genotoxic GLP-1 receptor-mediated mechanism to which rodents are particularly sensitive.

This risk is considered low for humans but cannot be completely excluded.

In fertility studies in rats, Semaglutide did not affect mating ability or fertility in males. In female rats, an increase in the estrous cycle length and a minor reduction in the number of corpora lutea (ovulations) were observed at doses accompanied by a reduction in female body weight.

In embryo-foetal development studies in rats, Semaglutide had embryotoxic effects at exposures below clinically relevant levels. Semaglutide caused a marked reduction in female body weight and decreased embryo survival and growth parameters. Foetuses exhibited major skeletal and visceral malformations, including changes in long bones, ribs, vertebrae, tail bones, blood vessels, and brain ventricles. A mechanistic assessment indicated that the embryotoxicity involves a GLP-1 receptor-mediated disruption of nutrient delivery to the embryo via the rat yolk sac. Due to species differences in yolk sac anatomy and function, and due to insufficient GLP-1 receptor expression in the yolk sac of non-human primates, this mechanism is considered unlikely for humans. However, the possibility of a direct effect of semaglutide on the foetus cannot be ruled out.

In developmental toxicity studies in rabbits and cynomolgus monkeys at clinically relevant exposure levels, an increased incidence of pregnancy loss and some increase in foetal abnormalities were observed. Such outcomes coincided with marked maternal body weight loss, reaching 16%. It is unknown whether these effects are related to reduced maternal food intake due to the direct GLP-1 effect.

Postnatal growth and development were assessed in cynomolgus monkeys. Offspring were slightly smaller at birth, but their body weight recovered during the nursing period.

In juvenile rats, Semaglutide caused a delay in sexual maturation in both males and females. Such delays did not affect fertility and reproductive performance in either sex, nor the ability of females to maintain pregnancy.

Pharmacokinetics

Unlike native GLP-1, Semaglutide has a long T_1/2of about 1 week, allowing for once-weekly subcutaneous administration.

The primary mechanism for the long action of semaglutide is albumin binding, which reduces its renal clearance and protects it from metabolic degradation.

Furthermore, Semaglutide has hydrolytic stability due to its physicochemical properties, protecting it from hydrolysis by the dipeptidyl peptidase-4 (DPP-4) enzyme.

Absorption

After subcutaneous administration of the maintenance therapeutic dose of semaglutide, its mean steady-state concentration was approximately 75 nmol/L in patients with overweight (BMI from >27 kg/m² to < 30 kg/m²) or obesity (BMI >30 kg/m²) based on phase IIIa trial data, where 90% of patients had a mean concentration ranging from 51 nmol/L to 110 nmol/L. With doses from 0.5 mg to 2.4 mg once weekly, semaglutide exposure increased proportionally with the dose. Drug exposure was stable, estimated up to week 68. No effect of injection site on semaglutide exposure was identified, as similar pharmacokinetic parameters were achieved with subcutaneous injection of semaglutide in the abdomen, thigh, or upper arm.

The absolute bioavailability of semaglutide was 89%.

Distribution

After subcutaneous administration in patients with overweight or obesity, the mean V_dof semaglutide was approximately 12.4 L. Semaglutide is largely bound to plasma albumin (>99%).

Metabolism

Semaglutide is extensively metabolised via proteolytic cleavage of the peptide backbone and sequential β-oxidation of the fatty acid side chain, followed by elimination from the body. The majority of semaglutide is metabolised by neutral endopeptidase (NEP).

Elimination

The main routes of elimination for semaglutide-related material are renal and enterohepatic elimination. Approximately 3% of the administered semaglutide dose was excreted unchanged in the urine.

In patients with overweight (BMI from ≥27 kg/m² to < 30 kg/m²) or obesity (BMI ≥30 kg/m²), the clearance of semaglutide was approximately 0.05 L/h. With a T_1/2of about 1 week, traces of semaglutide are present in the circulation for about 7 weeks after the last 2.4 mg dose is administered.

Pharmacokinetics in special patient groups

Renal impairment. Renal impairment does not affect the pharmacokinetics of semaglutide in a clinically significant manner. Based on clinical trials where Semaglutide was administered as a single 0.5 mg dose in patients with varying degrees of renal impairment (mild, moderate, severe, or patients on dialysis), no clinically significant effect of semaglutide on pharmacokinetics was identified in patients with renal impairment compared to patients with normal renal function.

These results were also confirmed in phase IIIa clinical trials in patients with overweight (BMI ≥27 kg/m² to < 30 kg/m²) or obesity (BMI ≥30 kg/m²) and mild or moderate renal impairment.

Elderly. In phase III clinical trials including patients aged 18 to 86 years, no effect of age on the pharmacokinetics of semaglutide was demonstrated.

Gender, race and ethnicity. Data from phase IIIa clinical trials showed no effect of gender, race (Caucasian, Black or Asian), or ethnicity (Hispanic or Latino, not Hispanic or Latino) on the pharmacokinetics of semaglutide.

Body weight. Clinical trials showed a significant effect of body weight on semaglutide exposure. Thus, higher body weight leads to lower exposure; a 20% difference in body weight between patients leads to an approximately 18% difference in exposure. The semaglutide weekly dose of 2.4 mg provides sufficient systemic exposure across the body weight range of 54.4-245.6 kg, which was assessed considering the exposure-response in clinical trials.

Hepatic impairment.Hepatic impairment did not affect the exposure of semaglutide. The effect of hepatic impairment on the pharmacokinetic parameters of semaglutide was evaluated in clinical studies following a single dose of semaglutide equal to 0.5 mg in patients with varying degrees of hepatic impairment (mild, moderate, severe) compared to patients with normal liver function.

Prediabetes and diabetes. In phase IIIa clinical studies, the presence of prediabetes or diabetes mellitus in patients did not have a clinically significant effect on the exposure of semaglutide.

Immunogenicity. During treatment with semaglutide, the formation of antibodies to semaglutide was rare (see section ” Adverse Reactions“), and this reaction did not affect the pharmacokinetics of semaglutide.

Indications

• As an adjunct to a low-calorie diet and increased physical activity for weight control, including weight loss and weight maintenance, in adults from 18 years of age with an initial body mass index (BMI):
  • ≥30 kg/m² (obesity) or
  • ≥27 kg/m² to < 30 kg/m² (overweight)

In the presence of at least one weight-related comorbidity, such as prediabetes or type 2 diabetes mellitus (T2DM), hypertension, dyslipidemia, obstructive sleep apnea syndrome, or cardiovascular disease.

ICD codes

Dosage Regimen

Solution

The recommended starting dose is 0.25 mg once a week.

The maximum maintenance (therapeutic) dose of semaglutide is 2.4 mg once a week.

To reduce the likelihood of gastrointestinal adverse reactions, the dose should be increased over 16 weeks, starting from a dose of 0.25 mg to a maintenance therapeutic dose of 2.4 mg once a week according to the following dose escalation scheme (see Table 7). In case of serious gastrointestinal symptoms, consider delaying the dose increase or reducing to the previous dose until the symptoms resolve. Administration of more than 2.4 mg per week is not recommended.

Table 7. Dose escalation scheme

Patients with type 2 diabetes mellitus

When prescribing semaglutide to patients with T2DM, consider reducing the dose of insulin or drugs that increase insulin secretion (e.g., sulfonylureas) to reduce the risk of hypoglycemia (see section ” Special Instructions“).

Missed dose

If a dose is missed, the drug Wegovy^® eco should be administered as soon as possible within 5 days of the scheduled administration time. If the duration of the miss is more than 5 days, the missed dose should not be administered. The next dose of Wegovy^® eco should be administered as usual on the scheduled day. In each case, patients can resume their usual once-weekly administration schedule. If more doses are missed, consider reducing the dose to the initial dose for re-initiation of treatment.

Special patient groups

Elderly patients (≥65 years)

Dose adjustment is not required. Experience with the drug in patients aged ≥75 years is limited. Increased sensitivity to semaglutide in some elderly individuals cannot be ruled out.

Patients with renal impairment

Patients with mild or moderate renal impairment do not require dose adjustment. Experience with semaglutide in patients with severe renal impairment is limited. Semaglutide is not recommended for use in patients with severe renal impairment (eGFR < 30 ml/min/1.73 m²), including patients with end-stage renal disease (see sections ” Special Instructions“, ” Adverse Reactions” and ” Pharmacokinetics“).

Patients with hepatic impairment

Patients with mild or moderate hepatic impairment do not require dose adjustment. Experience with semaglutide in patients with severe hepatic impairment is limited. Semaglutide is not recommended for use in patients with severe hepatic impairment and should be used with caution in patients with mild or moderate hepatic impairment (see sections ” Special Instructions” and ” Pharmacokinetics“).

Children

The drug Wegovy^® eco is contraindicated in children and adolescents aged 0 to 18 years.

Method of administration

The drug Wegovy^® eco is intended for subcutaneous administration. The drug Wegovy^® eco must not be administered intravenously or intramuscularly.

The drug is administered once a week at any time, regardless of meals.

The drug should be administered subcutaneously into the abdomen, thigh, or upper arm. The injection site can be rotated.

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, continue administration once a week.

Patients should be advised to carefully read the instructions for use of the syringe, autoinjector, or pen provided in the package leaflet before administering the drug.

Instructions for using the Wegovy^® eco drug in a syringe

1. Preparation for use

Remove the protective cap by first twisting it and then pulling it straight off the protective case. Do not touch the needle after removing the cap and do not allow the needle to come into contact with any surfaces (Figure 1).

Figure 1

If air bubbles appear in the syringe, do not remove the air bubbles before injection – this may lead to loss of part of the drug. Before administration, hold the syringe as shown in Figure 2.

Figure 2

2. Performing the injection

The drug should be administered subcutaneously into the abdomen, thigh, or upper arm. The injection site can be rotated. Clean the injection site with an alcohol wipe. With one hand, pinch the skin fold cleaned with the alcohol wipe, holding it with the thumb and forefinger until the end of drug administration (Figure 3).

Figure 3

Administer the drug at a 45°C (113°F) or 90°C (194°F) angle to the skin surface depending on the skin thickness and the prominence of the subcutaneous fat layer (Figure 4). With a prominent subcutaneous fat layer, the injection should be performed at a 90° angle.

Figure 4

Insert the syringe needle under the skin as shown in Figure 4. Then press the syringe plunger and inject the entire solution with a slow, constant pressure over 2-5 seconds (Figure 5).

Figure 5

When the syringe is empty, remove the needle from the skin without changing the position of the syringe (Figure 6). Gently press the injection area with a dry sterile napkin or cotton ball, but do not rub the area where the injection was performed.

Figure 6

Cover the needle with the protective cap and dispose of it according to the recommendations of the attending physician.

Instructions for using the Wegovy^® eco drug in an autoinjector

1. Preparation for use

Do not shake the autoinjector. Immediately before injection, remove the cap from the autoinjector with one hand using slight force (Figure 2).

Figure 1

Do not twist the cap! Make sure you have removed the autoinjector cap together with the needle protective cap (it should remain inside the outer autoinjector cap) and the needle is accessible for administration (Figure 1).

Figure 2

2. Performing the injection

Clean the injection site with an alcohol wipe. With one hand, take the skin fold cleaned with the alcohol wipe and hold it throughout the entire injection procedure (Figure 3).

Figure 3

Take the autoinjector in the other hand, holding it by the body. Bring the autoinjector to the injection site at a 90° angle (Figure 4).

Figure 4

Press the autoinjector against the surface of the skin fold. This will trigger the drug administration. Monitor the drug administration by the movement of the plunger in the control window. When the entire drug dose has been administered, the plunger will be fully lowered and this will be accompanied by a corresponding sound (Figure 5).

Figure 5

After the injection is complete, remove the autoinjector; the needle will automatically close. (Figure 6).

Figure 6

3. Disposal

Put on the protective cap and dispose of the autoinjector. Reuse of the autoinjector is not possible; it will be locked.

Instructions for using the Wegovy^® eco drug in a pen

Figure 1

1. Preparation for use

A. Pull the pen cap to remove it. Do not remove the label from the pen.

B. Preparation and installation of the needle

• Use a new needle each time you administer the drug, as the needles are single-use and cannot be reused. Reuse may lead to infection and inability to administer the required drug dose.
• Take a new pen needle, check for the presence of the protective film (Figure 2).
• Make sure the protective film and the cap on the needle are fully closed; avoid using non-sterile needles.
• Remove the protective film (Figure 2).

Figure 2

• Screw the needle directly onto the cartridge holder (Figure 3).

Figure 3

• Remove the outer, then the inner needle caps (Figure 4).
• Keep the outer needle cap so that it can be used after the injection.
• Discard the inner needle cap so that children do not swallow it by mistake.
• Do not put the inner needle cap back on to avoid accidental needle sticks.

Figure 4

C. Turn the dose selector on the pen so that the symbol “-…” appears in the dose selector window and align it with the pointer (Figure 5).

Figure 5

Hold the pen with the needle pointing upwards, then press the trigger button and hold it until “0” appears in the dose selector window. Check if drops of the drug appear at the tip of the needle. If no drops appear, then repeat the steps according to point 1.C until the drug appears at the end of the needle (Figure 6).

Figure 6

The pen is now ready for use.

If drops do not appear after removing air 3 times, it is possible that the pen needle being used is blocked. You should discard this needle, replace it with a new one, and repeat the steps of point 1.C again.

2. Performing the injection

A. Make sure the pointer on the body of the pre-filled pen points to the zero mark in the dose selector window. By turning the dose selector, set the numerical value corresponding to the pen dose. For each pen, one of the following doses corresponds: 0.25 mg or 0.5 mg, or 1 mg, or 1.7 mg, or 2.4 mg. Do not set the dose by counting the number of clicks heard when turning the dose selector. Do not rely on clicks until the prescribed dose appears in the window.

For example, Figure 7 shows the numerical value “2.4”, which corresponds to a pen with a dose of 2.4 mg.

B. The drug should be administered subcutaneously into the abdomen, thigh, or upper arm. The injection site can be rotated. Clean the drug administration site with an alcohol wipe. Insert the needle into the chosen site and press the trigger button, continuing to press it until the dose pointer aligns with the value “0” in the dose selector window. Count to 10 and pull the needle out of the skin (Figure 7).

Figure 7

3. Disposal

Carefully put the outer cap on the needle, turn the outer needle cap counterclockwise and unscrew the needle clockwise. Then dispose of the pen (Figure 8).

Figure 8

Always check that the needle is disconnected. Put the pen cap back on. Disposal of used needles should be carried out in accordance with the recommendations of healthcare professionals and sanitary and epidemiological standards.

4. Needle replacement

Each time you replace the needle, follow points 1.B and 1.C.

Precautions

• The pen should only be used after consultation with your attending physician.
• If there is suspicion that the pen specimen being used is damaged, a new pen should be used.
• Before each injection, make sure the pen contains the correct drug prescribed by your attending physician.
• Read and follow the drug package leaflet. Always check that the pen is prepared for use according to the guide. Violation of the pen preparation procedure for use may lead to administration of an inaccurate drug dose.

Storage and disposal

• The pen must not be used if it has been out of the refrigerator for longer than the time specified in the package leaflet.
• Pens not in use should be stored in the refrigerator at a temperature from 2°C (35.6°F) to 8°C (46.4°F), but not near the freezer. Protect from light. Do not freeze. The drug is allowed to be stored in the original packaging (carton) for protection from light when in use at a temperature not exceeding 30°C (86°F) for no more than 28 days.
• Store pens out of the reach of children.
• Dispose of used needles in their puncture-resistant protective caps or as recommended by the attending physician or pharmacy staff.
• Empty pens must not be reused. Dispose of used pens without attached needles and in accordance with the recommendations of the attending physician.

All remaining drug and waste should be destroyed in accordance with established procedures.

Special precautions for the disposal of used drug or waste generated after the use of the drug and other handling of the drug

The drug should not be used if the solution has become cloudy or a precipitate has formed. The drug Wegovy^® eco should not be used if it has been frozen.

The drug Wegovy^® eco in a syringe, in a syringe with an autoinjector, or in a pen contains 1 dose: 0.25 mg, 0.5 mg, 1 mg, 1.7 mg, 2.4 mg of semaglutide.

The patient should be informed that a new single-use disposable syringe or a new single-use disposable autoinjector or a new single-use disposable pen must be used for each injection.

After removal from the refrigerator, it is recommended to let the drug reach room temperature for at least 30 minutes before performing the subcutaneous injection, as with all injectable drugs for more comfortable administration.

Adverse Reactions

Summary of the safety profile

In four phase IIIa clinical studies, 2650 adult patients received treatment with semaglutide once a week. The duration of the studies was 68 weeks. The most frequently reported adverse reactions were gastrointestinal disorders, including nausea, vomiting, diarrhea, and constipation.

Tabulated summary of adverse reactions

Adverse reactions classified by organ system are listed below in descending order of frequency: very common (≥1/10), common (≥1/100, but <1/10), uncommon (≥1/1000, but <1/100), rare (≥1/10000, but <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from the available data).

Table 8. Adverse reactions reported in controlled phase IIIa studies in adult patients

^a See description of selected adverse reactions below.
^b Observed predominantly during the dose escalation period.
^c Grouped preferred terms.

Description of selected adverse reactions

Gastrointestinal disorders

During the 68-week study period, nausea was observed in 43.9% of patients receiving Semaglutide (16.1% in the placebo group), diarrhea in 29.7% (15.9% in the placebo group), and vomiting in 24.5% (6.3% in the placebo group). Most reactions were mild or moderate in severity and short-lived. Constipation occurred in 24.2% of patients receiving Semaglutide (11.1% in the placebo group), was mild or moderate in severity, and lasted longer. In patients receiving Semaglutide, the median duration of nausea was 8 days, vomiting 2 days, diarrhea 3 days, and constipation 47 days.

Patients with moderate renal impairment (eGFR ≥30 mL/min/1.73 m²) may experience more pronounced gastrointestinal adverse reactions when treated with semaglutide.

Gastrointestinal complications led to treatment discontinuation in 4.3% of patients.

Acute Pancreatitis

The incidence of confirmed acute pancreatitis reported in Phase IIIa clinical trials was 0.2% for semaglutide and < 0.1% for placebo, respectively.

Acute Gallstone Disease/Cholelithiasis

Cholelithiasis was reported in 1.6% and led to cholecystitis in 0.6% of patients receiving Semaglutide. Cholelithiasis and cholecystitis were reported in 1.1% and 0.3% of patients receiving placebo, respectively.

Hair Loss

Hair loss was reported in 2.5% of patients receiving Semaglutide and in 1.0% of patients receiving placebo. Cases were mostly mild, and most patients recovered by the end of therapy. Hair loss was reported more frequently in patients with greater weight loss (≥20%).

Palpitations

In Phase IIIa studies, patients receiving Semaglutide showed a mean increase in heart rate of 3 beats per minute from a baseline mean of 72 beats per minute. The proportion of patients with a heart rate increase from baseline of ≥10 beats per minute at any time during treatment was 67.0% in the semaglutide group versus 50.1% in the placebo group.

Immunogenicity

Due to the potential immunogenic properties of protein and peptide drugs, patients may develop antibodies to semaglutide after therapy. The proportion of patients with a positive test result for anti- semaglutide antibodies at any time after study initiation was low (2.9%), and no patient had antibodies neutralizing Semaglutide or antibodies with a neutralizing effect on endogenous GLP-1 at the end of the study. During treatment, high concentrations of semaglutide could reduce the sensitivity of assays; therefore, the risk of false-negative results cannot be excluded. However, in patients with a positive antibody test during and after treatment, the presence of antibodies was temporary and did not have a significant impact on efficacy and safety.

Hypoglycemia in Patients with T2D

In the STEP 2 trial, clinically significant hypoglycemia was observed in 6.2% (0.1 events per patient-year) of patients receiving Semaglutide compared to 2.5% (0.03 events per patient-year) of patients receiving placebo. Hypoglycemia with semaglutide administration was observed both with and without concomitant sulfonylurea use. One episode (0.2% of subjects, 0.002 events/patient-year) was reported as severe in a subject not concurrently receiving a sulfonylurea. The risk of hypoglycemia was increased with concomitant use of semaglutide and sulfonylurea drugs.

Diabetic Retinopathy in Patients with Diabetes Mellitus

A 2-year clinical trial investigated the use of semaglutide at doses of 0.5 mg/dose and 1 mg/dose compared with placebo in 3297 patients with T2D at high cardiovascular risk, with long duration of diabetes and poorly controlled blood glucose levels. In this study, confirmed cases of diabetic retinopathy complications occurred in a greater number of patients receiving Semaglutide (3.0%) compared with placebo (1.8%).

Cases were observed in insulin-treated patients with known diabetic retinopathy. The treatment difference emerged early and persisted throughout the study. In the STEP 2 trial, retinal disorders were reported by 6.9% of patients receiving Semaglutide at a dosage of 2.4 mg once weekly, 6.2% of patients receiving Semaglutide at a dose of 1 mg/dose, and 4.2% of patients receiving placebo. Most cases were reported as diabetic retinopathy (4.0%, 2.7%, and 2.7%, respectively) and non-proliferative retinopathy (0.7%, 0%, and 0%, respectively).

Reporting of Suspected Adverse Reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the drug’s benefit-risk balance. Healthcare professionals are recommended to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to semaglutide or to 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 (T1D);
• Diabetic ketoacidosis.

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

• Severe hepatic impairment;
• End-stage renal disease (CrCl < 15 mL/min);
• Chronic heart failure (CHF) functional class IV (according to the NYHA (New York Heart Association) classification).

With caution

• In patients with renal impairment;
• In patients with a history of pancreatitis;
• Aged 75 years and older (see section “Dosage Regimen”);
• In patients with mild and moderate hepatic impairment (see section “Dosage Regimen”);
• With diabetic gastroparesis.

Use in Pregnancy and Lactation

Women of childbearing potential

Women of childbearing potential are recommended to use reliable methods of contraception during treatment with semaglutide (see section “Drug Interactions”).

Pregnancy

Animal studies have shown reproductive toxicity (see subsection “Non-clinical safety data”). Data on the use of semaglutide in pregnant women are limited. Therefore, Semaglutide should not be used during pregnancy. If a patient is planning a pregnancy or if pregnancy occurs, therapy with semaglutide must be discontinued. Due to the long half-life, therapy with semaglutide must be discontinued at least 2 months before a planned pregnancy (see section “Pharmacokinetics”).

Breastfeeding period

In animal studies, Semaglutide was excreted in the milk of lactating rats. A risk to the breastfed child cannot be excluded. Semaglutide should not be used 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 duration of the estrous cycle and a slight decrease in the number of ovulations were observed at doses associated with a reduction in female body weight.

Use in Hepatic Impairment

Semaglutide is not recommended for patients with severe hepatic impairment and should be used with caution in patients with mild or moderate hepatic impairment. No dose adjustment is required for patients with mild or moderate hepatic impairment.

Use in Renal Impairment

Semaglutide is not recommended for patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²), including patients with end-stage renal disease. No dose adjustment is required for patients with mild or moderate renal impairment.

Pediatric Use

The drug Welgia^® eco is contraindicated in children and adolescents aged 0 to 18 years.

Geriatric Use

Experience with the drug in patients aged ≥75 years is limited. Increased sensitivity to semaglutide in some elderly individuals cannot be ruled out.

Special Precautions

Dehydration

The use of GLP-1 receptor agonists may be associated with gastrointestinal adverse reactions, which can cause dehydration, which in rare cases may lead to worsening of renal function.

Patients should be informed about the potential risk of dehydration associated with gastrointestinal adverse reactions and take precautions to avoid fluid loss.

Acute Pancreatitis

Cases of acute pancreatitis have been observed with the use of GLP-1 receptor agonists (see section “Adverse Reactions”). Patients should be informed about the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, the use of semaglutide should be discontinued. If the diagnosis of acute pancreatitis is confirmed, the use of semaglutide should not be resumed. Caution should be exercised in patients with a history of pancreatitis.

In the absence of other signs and symptoms of acute pancreatitis, an increase in pancreatic enzyme activity alone is not indicative of acute pancreatitis.

Cholecystitis

Treatment with semaglutide may increase the risk of cholecystitis and, consequently, lead to the development of cholangitis and cholestatic jaundice. During treatment with semaglutide, symptoms associated with the development of cholecystitis should be monitored.

Patients with T2D

Semaglutide should not be used as a substitute for insulin in patients with T2D.

Semaglutide should not be used in combination with other GLP-1 receptor agonist drugs. The efficacy of semaglutide in combination with other GLP-1 agonists has not been evaluated. There is an increased risk of adverse reactions associated with overdose.

Hypoglycemia in Patients with T2D

Insulin and sulfonylurea drugs are known to cause hypoglycemia. In patients receiving Semaglutide in combination with sulfonylurea drugs or insulin, the risk of hypoglycemia may be increased. The risk of hypoglycemia can be reduced by lowering the dose of sulfonylurea drugs or insulin at the start of treatment with Welgia^® eco.

Diabetic Retinopathy in Patients with T2D

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

There is no experience with semaglutide in patients with T2D with uncontrolled or potentially unstable diabetic retinopathy. The use of the drug Welgia^® eco in such patients is not recommended.

Aspiration Pneumonia

In patients receiving GLP-1 agonists, including Semaglutide, a risk of aspiration or aspiration pneumonia has been identified during surgical interventions under general anesthesia or deep sedation due to delayed gastric emptying and the presence of residual gastric contents.

Excipients

The drug Welgia^® eco contains less than 1 mmol (23 mg) of sodium per dose, i.e., it is essentially sodium-free.

Effect on the Ability to Drive and Use Machines

Semaglutide has no or negligible influence on the ability to drive and use machines. However, dizziness may occur during the dose escalation period. If dizziness occurs, caution should be exercised when driving or operating machinery.

Patients with T2D

When using semaglutide in combination with sulfonylurea drugs or insulin, patients should be advised to take precautions to avoid hypoglycemia while driving and using machines (see section “Special Precautions”).

Overdose

Symptoms overdose with semaglutide may manifest as gastrointestinal disorders, which can lead to dehydration.

Treatment in case of overdose, the patient should be observed for clinical signs and appropriate symptomatic treatment should be initiated.

Drug Interactions

Semaglutide delays gastric emptying and may potentially affect the absorption of concomitantly administered oral medications. When taking semaglutide at a dose of 2.4 mg, no clinically significant effect on the rate of gastric emptying was observed. Semaglutide should be used with caution in patients receiving 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 at a dose of 1 mg, the AUC_{0-60 min} and C_max of paracetamol decreased by 27% and 23%, respectively. The overall exposure of paracetamol (AUC_{0-5 h}) did not change. No dose adjustment of paracetamol is required when used concomitantly with semaglutide.

Oral Contraceptive Drugs

Semaglutide is not expected to reduce the effectiveness 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 of ethinylestradiol and levonorgestrel. The exposure of ethinylestradiol was not affected. A 20% increase in the steady-state exposure of levonorgestrel was observed. C_max did not change 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 at a dose of 500 mg twice daily for 3.5 days.

Warfarin and Other Coumarin Derivatives

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. However, after initiation of semaglutide treatment in patients taking warfarin or other coumarin derivatives, frequent monitoring of INR is recommended.

Children

Interaction studies have only been performed in adults.

Storage Conditions

The drug should be stored in the original packaging (carton) to protect from light at a temperature of 2°C (35.6°F) to 8°C (46.4°F) (in a refrigerator), but not near the freezer. Do not freeze.

Shelf Life

Shelf life – 2 years.

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.