Saxenda, 6 mg/ml 3 ml cartridges in syringe pens 3 pcs

Pharmacotherapeutic group
Hypoglycemic agent – analog of glucagon-like peptide-1 (GFP-1).
ATC code: A10BJ02.

Pharmacological properties

Pharmacodynamics

. Saxenda® active substance, liraglutide, is an acylated human GFP-1 analog produced by recombinant DNA biotechnology using Saccharomyces cerevisiae strain, which has 97% amino acid sequence homology to endogenous human GFP-1. Liraglutide binds to and activates the GFP-1 receptor (GFP-1P). Liraglutide is resistant to metabolic breakdown; its half-life from plasma after subcutaneous administration is 13 h. The pharmacokinetic profile of liraglutide, which allows its administration to patients once daily, is the result of self-association, resulting in delayed absorption of the drug; binding to plasma proteins; and resistance to dipeptidyl peptidase-4 (DFP-4) and neutral endopeptidase (NEP).
PPP-1 is a physiological regulator of appetite and food intake, and PPP-1P is located in several brain regions involved in appetite regulation processes. In animal studies, peripheral administration of liraglutide resulted in drug uptake in specific brain regions, including the hypothalamus, where liraglutide through specific activation of GFP-1P increased satiety signals and attenuated hunger signals, thereby leading to weight loss.
GFP-1P is also present in specific areas of the heart, blood vessels, immune system and kidneys. In experiments on mice with atherosclerosis, liraglutide prevented further development of aortic plaques and reduced inflammation in them. In addition, liraglutide had a favorable effect on plasma lipids. Liraglutide did not reduce the size of existing plaques.
Liraglutide reduces body weight in humans primarily by reducing the weight of adipose tissue. The decrease in body weight is due to a decrease in food intake. Liraglutide does not increase 24-hour energy expenditure. Liraglutide regulates appetite by increasing the feeling of a full stomach and satiety, while reducing the feeling of hunger and reducing anticipated food intake.
Liraglutide stimulates insulin secretion and reduces unnecessarily high glucagon secretion in a glucose-dependent manner, and improves pancreatic beta cell function, resulting in lower fasting and post-meal glucose concentrations. The mechanism of glucose concentration reduction also includes a slight delay in gastric emptying.
In long-term clinical trials (LC) with the participation of overweight and obese patients, the use of Saxenda® in combination with a low-calorie diet and increased physical activity resulted in significant weight reduction.

Effects on appetite, caloric intake and energy expenditure, gastric emptying and glucose concentration at fasting and after meals
The pharmacodynamic effects of liraglutide were studied in a five-week pharmacological QI involving 49 obese patients (body mass index (BMI) 30-40 kg/m2) without diabetes mellitus (DM).

Appetite, caloric intake and energy expenditure
It is believed that body weight reduction with Saxenda® is associated with regulation of appetite and food intake. Appetite was assessed before and within 5 h after a standardized breakfast; unrestricted food intake was assessed during the subsequent lunch. Compared with placebo, Saxenda® increased feeling of fullness and gastric filling after a meal and decreased feeling of hunger and estimated amount of estimated food intake, as well as decreased unrestricted food intake. No therapy-related increase in 24-hour energy expenditure was noted in the respiratory chamber assessment.

Gastric Emptying
Administration of Saxenda® resulted in a slight delay in gastric emptying during the first hour after ingestion, resulting in a decreased rate of glucose elevation as well as a decreased total blood glucose concentration after ingestion.

The fasting and postmeal glucose, insulin, and glucagon concentrations
The fasting and postmeal glucose, insulin, and glucagon concentrations were assessed before and within 5 h of standardized meal intake. Compared to placebo, Saxenda® decreased fasting and postprandial glucose concentrations (AUC0-60 min) during the first hour after a meal, and decreased the 5-hour AUC of glucose and the rising glucose concentration (AUC0-300 min). In addition, compared to placebo, Saxenda® decreased postprandial glucagon (AUC0-300 min) and insulin (AUC0-60 min) concentrations and incremental insulin concentration (iAUC0-60 min) after a meal.
Fasting glucose and insulin concentrations and incremental glucose and insulin concentrations were also assessed during an oral glucose tolerance test (IGT) with 75 g glucose before therapy and after 1 year of therapy in 3731 overweight and obese patients and with the presence or absence of prediabetes. Compared to placebo, Saxenda® decreased fasting glucose concentration and increasing glucose concentration. The effect was more pronounced in patients with prediabetes. In addition, compared to placebo, Saxenda® decreased fasting insulin concentration and increased increasing insulin concentration.
After 160 weeks of continued therapy with liraglutide 3.0 mg, the AUC of plasma glucose decreased, while when using placebo it remained unchanged. Additionally, insulin AUC remained relatively stable during the 160-week period of liraglutide 3.0 mg treatment, whereas a decrease was observed with placebo. All studied effects of the therapy were statistically significant in favor of liraglutide 3.0 mg.

Effects on fasting glucose concentration and rising glucose concentration in patients with type 2 diabetes mellitus (DM2) with overweight and obesity
. Compared to placebo, Saxenda® reduced fasting glucose concentration and mean rising postprandial glucose concentration (90 minutes after a meal, mean value for 3 meals per day).

Pancreatic Beta Cell Function
CIs of up to one year with Saxenda® in patients with overweight and with or without DM have demonstrated improved and maintained pancreatic beta cell function. This was shown using measurement methods such as the homeostatic beta cell function assessment model (NOMA-B) and the ratio of proinsulin to insulin concentrations.

Clinical efficacy and safety
. The efficacy and safety of Saxenda® for long-term body weight correction in combination with a low-calorie diet and increased physical activity was studied in 4 randomized, double-blind, placebo-controlled phase 3 SCALE studies involving a total of 5,358 adult patients.

Body weight
. Compared to placebo, Saxenda® achieved greater reductions in body weight in obese/overweight patients in all study groups, including those with or without prediabetes, DM2 and moderate to severe obstructive sleep apnea. In addition, among the study population, a greater proportion of patients achieved weight reductions ≥ 5% and ˃ 10% with Saxenda® compared to placebo. Significant weight loss was also observed in a CI in which patients achieved an average weight loss of 6.0% using a low-calorie diet for 12 weeks prior to treatment with Saxenda®. In this study, more patients maintained the weight loss achieved before treatment with Saxenda® compared to placebo (81.4% and 48.9%, respectively).

In the 160-week CI, patients who received Saxenda® achieved greater weight loss compared to patients who received placebo. Most of the weight loss occurred in the first year and was maintained for 160 weeks.
In the 160-week QI, the mean percent change in body weight and the proportion of patients achieving weight loss from baseline to 160 weeks by at least 5% and more than 10% were also significant compared to placebo.

Weight loss after 12 weeks of therapy with Saxenda® (liraglutide 3.0 mg)
In two trials lasting 56 weeks, 67.5% and 50.4% of patients achieved weight loss of at least 5% after 12 weeks of therapy with Saxenda® in a 3.0 mg dose. The average weight loss in these patients who completed the study was 11.2% compared to the baseline value. In patients who achieved a weight loss of less than 5% after 12 weeks of therapy at the dose of 3.0 mg and completed the study (1 year), the average weight loss was 3.8%.

Glycemic control
Liraglutide therapy significantly improved glycemic parameters in the normoglycemic, prediabetes and DM2 subpopulations.
DM2 developed in 0.2% of patients treated with Saxenda® compared to 1.1% in the placebo group. 69.2% of patients with prediabetes reversed this condition with Saxenda® compared to 32.7% in the placebo group. At week 160, 3% of patients who received Saxenda® and 11% of patients who received placebo were diagnosed with DM2 while continuing treatment. Compared with placebo, the time to DM2 development was 2.7 times longer with liraglutide 3.0 mg and the relative risk (RR) of DM2 development with liraglutide was 0.2. At week 160 in the liraglutide 3.0 mg group, 65.9% of patients with prediabetes reversed this condition to normoglycemia compared with 36.3% in the placebo group.
In one study, 69.2% and 56.5% of obese and DM2 patients treated with Saxenda® achieved target HbA1c values of ˂ 7% and ≤6.5%, respectively, compared with 27.2% and 15.0% in patients treated with placebo.

Cardiometabolic parameters
Compared with placebo, Saxenda® significantly improved systolic blood pressure (BP), waist circumference and fasting lipid concentration.
In a 160-week CI, the mean reduction in waist circumference was 8.2 cm with Saxenda® and 4.0 cm with placebo; the reduction in systolic and diastolic BP was 4.3 mmHg and 1.5 mmHg with Saxenda® and 2.7 mmHg and 1.8 mmHg, respectively. when using placebo, respectively; LDL cholesterol concentration decrease was 3.1 mmol/L when using Saxenda® and 0.7 mmol/L when using placebo; HDL cholesterol concentration increase was 2.3 mmol/L when using Saxenda® and 0.5 mmol/L when using placebo.

Apnea-Hypnea Index (AHI)
Compared to placebo, a significant decrease in the severity of obstructive sleep apnea was observed with Saxenda®, as assessed by the change in AHI relative to the baseline value.

Immunogenicity
Due to the potential immunogenic properties of protein and peptide drugs, patients may develop antibodies to liraglutide after therapy with Saxenda®. In the CI, 2.5% of patients treated with Saxenda® developed antibodies to liraglutide. Antibody formation did not reduce the efficacy of Saxenda®.

Evaluation of cardiovascular events
Major cardiovascular events (MACEs) were evaluated by a panel of external independent experts and defined as nonfatal myocardial infarction, nonfatal stroke and cardiovascular-related death. In 5 double-blind controlled phase 2 and 3 CIs with Saxenda®, there were 6 BSSS in patients receiving Saxenda® and 10 BSSS in patients receiving placebo. The OR with 95% CI was 0.33 for Saxenda® versus placebo. In the phase 3 CI, the mean increase in heart rate (HR) was 2.5 beats per minute in patients receiving Saxenda®. The greatest increase in HR was observed after 6 weeks of therapy. This increase was reversible and disappeared after discontinuation of liraglutide therapy.
A multicenter, placebo-controlled, double-blind study, “Effect and Effects of Liraglutide in Diabetes Mellitus: Assessment of Cardiovascular Risk” (LEADER®) was conducted.

Liraglutide 1.8 mg also significantly reduced the risk of advanced BCCS (primary BCCS, unstable angina leading to hospitalization, myocardial revascularization, or hospitalization due to heart failure) and other secondary end points.

Children and adolescents
In a double-blind QI comparing the effectiveness and safety of Saxenda® versus placebo for weight loss in obese adolescents aged 12 years and older, Saxenda® was superior to placebo in reducing the standard deviation of BMI (measured to assess weight loss) after 56 weeks of treatment. More patients achieved ≥5% and ≥10% reductions in BMI on liraglutide therapy than patients receiving placebo, with greater reductions in mean BMI and body weight. During the 26 weeks of follow-up without use of the drug, a recovery in body weight was observed with Saxenda® compared to placebo (assessed as change in standard deviation of BMI)
Based on tolerability, for most patients (82.4%) the drug dose was increased and they continued to receive the 3.0 mg dose; for the remaining patients the dose was increased and they continued to receive the drug in the 2.4 mg to 0.6 mg dose range.

Patient-determined scores
The drug Saxenda®, compared with placebo, improved patient-determined scores on several measures. There was a significant improvement in overall scores on the Simplified Body Weight Questionnaire for Quality of Life (IWQoL-Lite) and on all scales of the SF-36 Quality of Life Questionnaire, indicating a positive effect on the physical and psychological components of quality of life.

Pharmacokinetics

absorption
Absorption of liraglutide after subcutaneous administration is slow, with a time to reach maximum concentration (tmax) of approximately 11 h after administration. In obese patients (BMI 30-40 kg/m2) the average equilibrium concentration of liraglutide (AUCτ/24) reaches approximately 31 nmol/L after administration of 3.0 mg liraglutide. In the dose range of 0.6 mg to 3.0 mg, liraglutide exposure increases in proportion to the dose. The absolute bioavailability of liraglutide after subcutaneous administration is approximately 55%.

Distribution
The average apparent volume of distribution after subcutaneous administration of liraglutide at a dose of 3.0 mg is 20-25 L (in persons with a body weight of approximately 100 kg). Liraglutide is largely bound to plasma proteins (> 98%).

Metabolism
For 24 h after administration of a single dose of [3H]liraglutide to healthy volunteers, unchanged liraglutide remained the major component in plasma. Two metabolites (≤ 9% and ≤ 5% of total plasma radioactivity) were detected.

Elimation
Liraglutide is metabolized endogenously like large proteins without involvement of any specific organ as the primary excretion route. After administering a dose of [3H]-liraglutide, unaltered liraglutide was not detected in the urine or feces. Only a minor portion of the administered radioactivity in the form of liraglutide metabolites was excreted by the kidneys or through the intestine (6% and 5%, respectively). The radioactivity is excreted by the kidneys or through the intestine mainly during the first 6-8 days and represents 3 metabolites.
The average clearance after subcutaneous administration of 3.0 mg liraglutide is approximately 0.9 1.4 L/h and the elimination half-life is approximately 13 h.

Special patient groups

Elderly patients
No dose adjustment for age is required. According to the results of a population pharmacokinetic analysis in overweight and obese patients aged 18 to 82 years, age had no clinically significant effect on the pharmacokinetics of liraglutide when administered subcutaneously at a dose of 3.0 mg.

Gender
Based on population pharmacokinetic analysis data, women have a 24% lower body weight-adjusted clearance of liraglutide after subcutaneous administration at a dose of 3.0 mg than men. Based on the drug response data, no gender-adjusted dose is required.

Ethnicity
. According to a population pharmacokinetic analysis that included data from studies in overweight and obese patients of Caucasoid, non-Hispanic, Asian, and Hispanic racial groups, ethnicity had no clinically significant effect on the pharmacokinetics of liraglutide when administered subcutaneously at the 3.0 mg dose.

Body weight
Exposure to liraglutide decreases with increasing baseline body weight. Administration of liraglutide at a dose of 3.0 mg daily provides adequate exposure in the body weight range of 60-234 kg, according to the evaluation of the response to systemic exposure to the drug in the CI. Exposure to liraglutide in patients with body weights greater than 234 kg was not studied.

Patients with hepatic impairment
The pharmacokinetics of liraglutide were evaluated in patients with varying degrees of hepatic impairment in a single-dose (0.75 mg) study. A 13-23% reduction in liraglutide exposure was observed in patients with mild to moderate hepatic impairment and a significant reduction in liraglutide exposure (44%) in patients with severe hepatic impairment (> 9 Child-Pugh score) compared to healthy volunteers.

Patients with renal impairment
In a single-dose study (0.75 mg), liraglutide exposure was lower in patients with renal impairment compared with individuals with normal renal function. Exposure to liraglutide was lower by 33%, 14%, 27%, and 26%, respectively, in patients with mild (creatinine clearance (CK) 50 to 80 mL/min), moderate (CK 30 to 50 mL/min), severe (CK < 30 mL/min), and in patients with end-stage renal failure requiring hemodialysis.

Children and adolescents
The pharmacokinetic properties of liraglutide 3.0 mg were evaluated in clinical studies in obese adolescents aged 12 years to 18 years (134 patients, body weight 62-178 kg). The exposure of liraglutide in adolescents aged 12 to 18 years was comparable to that observed in adult obese patients.

Pharmacokinetic properties were also evaluated in a clinical pharmacology study involving obese children aged 7 to 11 years (13 patients, body weight 54-87 kg). Exposure to liraglutide 3.0 mg in children aged 7 years to 11 years was comparable to that observed in adult patients after adjustment for body weight.

Indications

Age

(number of years)

Body mass index

30 kg/m2

Male sex

Female

12

26.02

26.67

12.5

26.43

27.24

13

26.84

27.76

13.5

27.25

28.20

14

27.63

28.57

14.5

27.98

28.87

15

28.30

29.11

15.5

28.60

29.29

16

28.88

29.43

16.5

29.14

29.56

17

29.41

29.69

17.5

29.70

29.84

18

30.00

30.00

Active ingredient

Composition

How to take, the dosage

Dose

Pancreatitis***, delayed gastric emptying**** – Infrequent

Liver and biliary tract disorders

Cholecithiasis*** – Often

Cholecystitis*** – Infrequent

Skin and subcutaneous tissue disorders

Urticaria – Infrequent

Renal and urinary tract disorders

Acute renal failure, impaired renal function – Rarely

General disorders and disorders at the injection site

Reactions at the injection site, asthenia**, fatigue** – Often

/p>

Malaise** – Infrequent

Laboratory Methods of Investigation

Increased lipase, increased amylase activity – Often

Interaction

Special Instructions

Contraindications

Side effects

The Saxenda® clinical trial program consists of 5 completed clinical trials involving 5,813 obese or overweight patients with at least one overweight-related comorbidity. Overall, gastrointestinal disorders were the most frequently reported adverse effects during therapy with Saxenda® (see section “Description of Individual Adverse Reactions”).

Description of individual adverse reactions:

Hypoglycemia in patients without type 2 diabetes

In clinical trials involving overweight or obese patients without type 2 diabetes who received therapy with Saxenda® in combination with diet and exercise, severe hypoglycemia (requiring third-party assistance) was not noted. Symptoms of hypoglycemia were reported in 1.6% of patients receiving Saxenda® and 1.1% of patients receiving placebo; however, these cases were not confirmed by blood glucose measurements. Mild hypoglycemia was observed in most cases.

Hypoglycemia in patients with type 2 diabetes

. In a clinical study involving overweight or obese patients with type 2 diabetes mellitus treated with Saxenda® in combination with diet and exercise, cases of severe hypoglycemia (requiring third-party care) were noted in 0.7% of patients treated with Saxenda® and only in patients receiving concurrent therapy with sulfonylurea derivatives.

Also in this group of patients, confirmed hypoglycemia (glucose concentration ≤ 3.9 mmol/L combined with symptoms) was noted in 43.6% of patients receiving Saxenda® and 27.3% of patients receiving placebo. Among patients who did not simultaneously receive sulfonylurea, confirmed hypoglycemia was noted in 15.7% of patients receiving Saxenda® and 7.6% of patients receiving placebo.

Indesirable gastrointestinal reactions

The majority of gastrointestinal reactions were mild to moderate in severity, transient and, in most cases, did not lead to discontinuation of therapy. Reactions usually occurred during the first weeks of therapy, and their manifestations gradually subsided over several days or weeks with continuation of therapy.

Patients aged ≥65 years may experience greater gastrointestinal adverse reactions during therapy with Saxenda®.

In patients with renal impairment of mild to moderate severity (creatinine clearance ≥ 30 ml/min), more severe adverse reactions from the gastrointestinal tract may be observed during Saxenda® therapy.

Allergic reactions

A few cases of anaphylactic reactions with symptoms such as arterial hypotension, palpitations, dyspnea or peripheral edema have been reported. Anaphylactic reactions can potentially be life-threatening.

Injection site reactions

In patients who have received Saxenda®, injection site reactions have been described. These reactions were generally mild, transient and in most cases disappeared with continued therapy.

Tachycardia

In clinical studies, tachycardia was reported in 0.6% of patients receiving Saxenda® and 0.1% of patients receiving placebo. Most events were mild to moderate in severity. The phenomena were isolated and in most cases resolved with continuation of therapy with Saxenda®.

Overdose

Pregnancy use