Saksenda - instructions for use, dose, side effects, contraindications

Active substanceLiraglutideLiraglutide

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Victoriza®

solution PC

Novo Nordisk A / S Denmark

Saxenda®

solution PC

Novo Nordisk A / S Denmark

Dosage form: & nbsphypodermic solution

Composition:

In 1 ml of the drug contains:

active substance: liraglutide 6 mg (in one pre-filled syringe pen contains 3 ml of solution, which corresponds to 18 mg of liraglutide);

Excipients: sodium hydrogen phosphate dihydrate 1.42 mg, phenol 5.5 mg, propylene glycol 14.0 mg; hydrochloric acid / sodium hydroxide (for pH correction), water for injection up to 1 ml.

Description:

A clear, colorless or almost colorless solution.

Pharmacotherapeutic group:A hypoglycemic agent, a glucagon-like receptor polypeptide, an agonist

ATX: & nbsp

A.10.B.X.07 Liraglutide

Pharmacodynamics:

Mechanism of action

The active substance of Saxenda®- lyraglutide - is an analog of human glucagon-like peptide-1 (GLP-1), produced by the method biotechnology of recombinant DNA using a strain Saccharomyces cerevisiae, having 97% homology of the amino acid sequence to endogenous human GLP-1. Liraglutide binds and activates the GLP-1 receptor (GLP-1R). Liraglutide is resistant to metabolic disintegration, its half-life from plasma after subcutaneous administration is 13 hours.The pharmacokinetic profile of liraglutide, allowing it to be administered to patients once a day, is the result of self-association, which results in a slow absorption of the drug; binding to plasma proteins; as well as resistance to dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidase (NEP).

GLP-1 is a physiological regulator of appetite and food intake. GLP-1P are found in several areas of the brain involved in regulating appetite. In animal studies, the administration of liraglutide led to its capture in specific areas of the brain, including the hypothalamus, where lyraglutide through specific activation, GLP-1P increased saturation signals and weakened signals of hunger, thereby leading to a decrease in body weight.

Liraglutide reduces body weight in humans primarily by reducing the mass of adipose tissue. The decrease in body weight occurs due to a decrease in food intake. Liraglutide does not increase the 24-hour power consumption. Liraglutide regulates appetite by strengthening the feeling of filling the stomach and saturation, while weakening the feeling of hunger and reducing the estimated consumption of food.

Liraglutide stimulates insulin secretion and reduces unreasonably high secretion of glucagon in a glucose-dependent manner, and also improves the function of beta cells of the pancreas, which leads to a decrease in fasting glucose and after eating. The mechanism for reducing glucose concentration also includes a slight delay in gastric emptying.

Pharmacodynamics

In long-term clinical trials involving patients with overweight or obesity, the use of Saxenda® in combination with a low-calorie diet and enhanced physical activity resulted in a significant reduction in body weight.

Influence on appetite, caloric intake, energy expenditure, gastric emptying and fasting glucose concentration and after eating

The pharmacodynamic effects of liraglutide were studied in a five-week study involving 49 obese patients (body mass index (BMI) of 30-40 kg / m²) without diabetes.

Appetite, calorie intake and energy consumption

It is believed that the decrease in body weight with Saxenda® is associated with the regulation of appetite and the amount of calories consumed.Appetite was evaluated before and within 5 hours after a standard breakfast; unlimited food intake was assessed during the subsequent lunch. Saksenda® drug increased the feeling of fullness and stomach fullness after a meal and decreases hunger, and the estimated number of prospective food consumption, as well as reduced the unlimited consumption of food as compared to placebo. When evaluating with a respiratory chamber, there was no associated increase in the 24-hour energy expenditure associated with therapy.

Emptying the stomach

Use of the drug Saksenda® resulted in a slight delay in gastric emptying in the first hour after a meal, resulting in decreased rate of increase in the concentration and the total concentration of blood glucose after meal.

The concentration of glucose, insulin and glucagon on an empty stomach and after meals

The concentration of glucose, insulin, and glucagon after fasting and food intake were assessed before and for 5 hours after a standardized meal. Compared to placebo, Saxenda® reduced blood glucose concentration on fasting and after meals (AUC₀_{-60 min}) during the first hour after eating, and also reduced the 5-hour AUC Glucose and an increasing concentration of glucose (AUC₀_{-300 min}) - In addition, Saxend® medication reduced postprandial glucagon concentration (AUC₀_{-300 min}) and insulin (AUC₀_{-60 min}) and an increasing concentration of insulin (iAUC₀_{-60 min}) after eating compared to placebo.

Fasting and increasing concentrations of glucose and insulin were also evaluated during an oral glucose tolerance test (PTTG) with 75 g of glucose before and after 1 year of therapy in 3731 obese patients and with impaired glucose tolerance and without impaired glucose tolerance. Compared to placebo, Saxenda® reduced fasting concentration and increasing glucose concentration. The effect was more pronounced in patients with impaired glucose tolerance. In addition, the Saxend® medication reduced fasting concentration and increased the increasing concentration of insulin compared with placebo.

Influence on fasting concentration and increasing glucose concentration in patients with type 2 diabetes mellitus with excessive body weight or obesity

The Saxenda® drug reduced the fasting glucose concentration and the average increasing postprandial glucose concentration (90 minutes after ingestion,the mean value for 3 meals per day) compared with placebo.

Function of beta cells of pancreas

In clinical studies of up to one year with the use of Saxenda® in patients with or overweight or obese with or without diabetes mellitus, improvement and preservation of beta-cell function of the pancreas was demonstrated using measurement methods such as the homeostatic model for assessing beta function -cells (HOMA-B) and the ratio of the concentrations of proinsulin and insulin.

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 trials (3 studies of 56 weeks and 1 study of 32 weeks). The studies included a total of 5358 patients of 4 different populations: 1) patients with obesity or overweight, as well as with one of the following conditions / diseases: impaired glucose tolerance,arterial hypertension, dyslipidemia; 2) patients with obesity or overweight with insufficiently controlled type 2 diabetes mellitus (value of HbA_1c in the range 7-10%), before the study for correction of HbA_1c in these patients used: diet and exercise, metformin, preparations of sulfonylurea, glitazone, individually or in any combination; 3) patients with obesity with obstructive apnea of moderate or severe degree; 4) patients with obesity or overweight and concomitant arterial hypertension or dyslipidemia who achieved a body weight loss of at least 5% with a low-calorie diet.

Body mass

A more pronounced weight loss was achieved in obese / overweight patients receiving Saxend®, compared to placebo-treated patients in all the groups studied, including the presence or absence of impaired glucose tolerance, type 2 diabetes mellitus and obstructive apnea of moderate or severe degree. In Study No. 1 (obese and overweight patients with or without glucose tolerance impairment), weight loss was 8.0% in patients receiving Saxenda®, compared with 2.6% in the placebo group.In Study No. 2 (obese and overweight patients with type 2 diabetes), weight loss was 5.9% in patients receiving Saxenda®, compared with 2.0% in the placebo group. In Study No. 3 (patients with obesity and overweight with obstructive apnea of moderate or severe degree), weight loss was 5.7% in patients receiving Saxenda®, compared with 1.6% in the placebo group. In the study number 4 (patients with obesity and overweight after the previous loss of body weight of not less than 5%), further reduction in body weight was 6.3% in patients receiving Saxend®, compared with 0.2% in the placebo group. In Study No. 4, more patients retained weight loss, which was achieved before Saxend® treatment with placebo compared to placebo (81.4% and 48.9%, respectively). In addition, in all the populations studied, the majority of patients receiving Saxenda® achieved weight loss of at least 5% and more than 10% compared to patients receiving placebo.

In the study number 1 (patients with obesity and overweightbody with the presence or absence of impaired glucose tolerance), a decrease in body weight of not less than 5% at 56 weeks of therapy was noted in 63.5% of patients receiving Saxenda®, compared with 26.6% in the placebo group. The ratio of patients who decreased body weight at 56 weeks of therapy to more than 10% was 32.8% in the group of patients receiving Saxend®, compared with 10.1% in the placebo group. Overall, weight loss occurred in approximately 92% of patients receiving Saxend®, compared with approximately 65% in the placebo group.

Weight loss after 12 weeks of therapy with Saxend®

Patients with an early response to therapy were identified as patients who achieved a body weight loss of at least 5% after 12 weeks of therapy (4 weeks of dose increase and 12 weeks of therapy at a dose of 3 mg).

In two studies (patients with obesity or overweight without and type 2 diabetes mellitus), 67.5% and 50.4% of patients achieved a weight loss of at least 5% after 12 weeks of therapy. With the continuation of therapy with Saxend® (up to 1 year), 86.2% of these patients achieved a decrease in body weight by at least 5% and 51% by at least 10%.The average weight loss in these patients who completed the study was 11.2% compared with baseline. In patients who achieved a weight loss of less than 5% after 12 weeks of therapy at a dose of 3 mg and completed the study (1 year), the average weight loss was 3.8%.

Control of glycemia

Saxenda® therapy significantly improved glycemic parameters in subpopulations with normoglycemia, impaired glucose tolerance (mean decrease in HbA_1c - 0.3%) and type 2 diabetes mellitus (mean decrease of HbA_1c - 1.3%) compared with placebo (mean decrease in HbA_1c - 0.1% and - 0.4%, respectively). In a study involving patients with impaired glucose tolerance, Type 2 diabetes mellitus developed in fewer patients who received Saxend®, compared with the placebo group (0.2% and 1.1%, respectively). In a larger number of patients with impaired glucose tolerance, this state was reversed compared to the placebo group (69.2% and 32.7%, respectively).

In a study involving patients with type 2 diabetes mellitus, 69.2% and 56.5% of patients treated with Saxenda® achieved the target HbA_1c <7% and <6.5%, respectively, compared with 27.2% and 15.0% in patients receiving placebo.

Cardiometabolic parameters

In a study involving patients with obesity or overweight with or without impaired glucose tolerance, a significant reduction in systolic blood pressure (4.3 points versus 1.5 points) was observed with Saxend®, a diastolic blood pressure (by 2.7 point versus 1.8 points), waist circumference (by 8.2 cm vs. 4.0 cm) and a significant change in fasting lipid concentration (a 3.2% decrease in total cholesterol compared with 0.9%, a decrease in lipoproteins low density by 3.1% against 0.7%; increase in high-density lipoproteins by 2.3% vs. 0.5%; decreased triglycerides by 13.6% compared to 4.8%) compared with placebo.

Apnea-hypnosis index

With the use of Saxend®, a significant decrease in obstructive sleep apnea compared with placebo was observed, which was estimated by a decrease in the apnea-hypnoea index (YAG) by 12.2 cases per hour and 6.1 cases per hour, respectively.

Immunogenicity

Given the potential immunogenic properties of protein and peptide drugs, antibodies to liraglutide may appear in patients after Saxend® therapy.In clinical studies, antibodies to liraglutide appeared in 2.5% of patients receiving Saxend®. The formation of antibodies did not lead to a decrease in the effectiveness of Saxend®.

Evaluation of cardiovascular events

Significant adverse cardiovascular events (MACE) were evaluated by a group of external independent experts and defined as non-fatal myocardial infarction, non-fatal stroke and death due to cardiovascular pathology. In all long-term clinical trials using Saxend®, 6 MACE were observed in patients receiving Saxend® and 10 MACE in placebo-treated patients. The risk ratio and 95% CI when comparing Saxend® and placebo were 0.31 [0.10; 0.92]. In clinical trials of Phase 3, there was an increase in the heart rate (heart rate) by an average of 2.5 beats per minute (1.6 to 3.6 beats per minute in separate studies) in patients receiving Saxend®. The greatest increase in heart rate was observed after 6 weeks of therapy. This increase was reversible and disappeared after discontinuation of therapy with liraglutide.

Patient evaluation results

The Saxenda® preparation, in comparison with placebo, improved patient-defined estimates for individual indicators. There was a significant improvement in the overall assessment of the Simplified Questionnaire of the Effect of Body Weight on Quality of Life (IWQoL-Lite) and on all scales of the questionnaire for assessing the quality of life SF-36, which indicates a positive effect on the physical and psychological components of the quality of life.

Preclinical data Pon security

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

In a two-year study of carcinogenicity, rats and mice were diagnosed with tumor C-cells of the thyroid gland, which did not lead to death. Non-toxic dose (NOAEL) in rats it is not established. Monkeys who received therapy for 20 months, the development of these tumors was not observed. The results obtained from rodent studies are due to the fact that rodents show special sensitivity to the receptor-mediated GLP-1 non-genotoxic specific mechanism.The significance of the data obtained for a person is low, but can not be completely ruled out. The appearance of other neoplasms associated with the therapy was not noted.

In animal studies, there was no direct adverse effect of the drug on fertility, but there was a slight increase in the frequency of early embryonic death with the highest doses of the drug. The introduction of liraglutide in the middle of the gestational period caused a decrease in the mother's body weight and fetal growth with an unexplained effect on the ribs in rats, and in rabbits - abnormalities in the structure of the skeleton. The growth of newborns was reduced in rats during therapy with liraglutide, and this decrease persisted after the end of breastfeeding in the group receiving high doses of the drug. It is not known what caused such a decline in the growth of newborn rats - a decrease in caloric intake by maternal individuals or a direct effect of GLP-1 on fetuses / newborns.

Pharmacokinetics:

Suction

The absorption of liraglutide after subcutaneous administration is slow, the time to reach the maximum concentration (t_max) - about 11 hours after administration. In patients with obesity (BMI 30-40 kg / m²) after the administration of liraglutide in a dose of 3 mg, the average equilibrium concentration of liraglutide (AUC_t_/24) reaches approximately 31 nmol / l. In the dose range from 0.6 mg to 3 mg, the exposure of liraglutide 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 in a dose of 3 mg is 20-25 liters (in individuals with a body weight of about 100 kg). Liraglutide is largely associated with plasma proteins (> 98%).

Metabolism

During 24 hours after the administration of a single dose to healthy volunteers [³H] -liraglutide remained the main component in the plasma unchanged lyraglutide. Two metabolites were detected (≤ 9% and ≤ 5% of the level of total radioactivity in the blood plasma).

Excretion

Liraglutide is metabolized endogenously like large proteins without the participation of any specific organ as the main pathway of excretion. After dosing [³N] - liraglutide unchanged lyraglutide not detected in urine or feces. Only a small part of the introduced radioactivity in the form of metabolites of liraglutide was excreted by the kidneys or through the intestine (6% and 5%, respectively).Radioactive substances are secreted by the kidneys or through the intestines, mainly during the first 6-8 days and represent 3 metabolites.

The average clearance after subcutaneous administration of liraglutide is approximately 0.9 to 1.4 l / h, the half-life is approximately 13 hours.

Special patient groups

Patients of elderly increase

Dose adjustment with age is not required. According to the results of population pharmacokinetic analysis in obese or overweight patients aged 18-82 years age had no clinically significant effect on the pharmacokinetics of liraglutide when administered subcutaneously at a dose of 3 mg.

Floor

Based on the data of the population pharmacokinetic analysis, in women, the corrected for body weight clearance of liraglutide after subcutaneous injection at a dose of 3 mg is 24% less than in men. Based on the data on the response to the effect of the drug, dose adjustment with regard to sex is not required.

Ethnicity

According to the results of population pharmacokinetic analysis, which included data from studies in patients with obesity or overweight of Caucasoid, Negroid, Asian and Latin American racial groups, ethnic accessory did not have a clinically significant effect on the pharmacokinetics of liraglutide when administered subcutaneously at a dose of 3 mg.

Body mass

The exposure of liraglutide decreases with an increase in the initial body weight. The use of liraglutide at a dose of 3 mg daily provides adequate exposure in the body weight range of 60-234 kg, according to the evaluation of the response to the systemic exposure of the drug in clinical studies. Exposure of liraglutide in patients with a body weight of more than 234 kg was not studied.

Patients with impaired hepatic function

The pharmacokinetics of liraglutide were evaluated in patients with varying degrees of impaired hepatic function in a single dose study (0.75 mg). The exposure of liraglutide was 23% and 13% less in patients with impaired liver function of mild or moderate severity, respectively, compared with healthy volunteers. Exposure was significantly less (by 44%) in patients with impaired hepatic function (> 9 points by classification Child Pugh).

Patients with renal insufficiency

In the study of a single dose (0.75 mg), the exposure of liraglutide was less in patients with renal insufficiency compared to those with normal renal function.Exposure of liraglutide was less by 33%, 14%, 27% and 26%, respectively, in patients with renal insufficiency of lung (creatinine clearance 50 - 80 ml / min), medium (30-50 ml / min), severe (< 30 ml / min) and in patients with terminal stage of renal failure who need hemodialysis.

Children

Clinical studies of the efficacy and safety of Saxende® in children have not been conducted.

Indications:

Saxenda® is indicated as a supplement to a low-calorie diet and increased physical exertion for long-term use to correct body weight in adult patients with BMI:

- ≥30 kg / m² (obesity) or

- ≥ 27 kg / m² up to <30 kg / m (overweight) in the presence of at least one associated comorbid disease, such as impaired glucose tolerance, type 2 diabetes, arterial hypertension, dyslipidemia, or obstructive sleep apnea syndrome.

Contraindications:

- hypersensitivity to liraglutide or any of the auxiliary components of the drug;

- medullary thyroid cancer in history, including in the family;

- multiple endocrine neoplasia of type 2;

- severe depression, suicidal thoughts or behavior, including in the anamnesis.

Contraindicated in the following groups of patients and with the following conditions / diseases due to lack of data on efficacy and safety:

- impaired renal function of a serious degree;

- a severe liver function disorder;

- children's age till 18 years;

- period of pregnancy and breastfeeding;

- heart failure III-IV functional class (according to the classification NYHA (New York Heart Association));

- simultaneous use of other drugs to correct body weight;

- simultaneous use with insulin;

- secondary obesity against the background of endocrinological diseases or eating disorders, or against the background of the use of medications that can lead to an increase in body weight.

The experience of using Saxend® in patients with inflammatory bowel diseases and diabetic gastric ulcer is limited. The use of liraglutide in such patients is not recommended, since it is associated with transient undesirable reactions from the gastrointestinal tract, including nausea, vomiting and diarrhea.

Carefully:

In patients with chronic heart failure class I-II in accordance with the classification NYHA, impaired liver function of mild or moderate severity, history of pancreatitis, thyroid disorders; in patients aged ≥ 75 years.

Pregnancy and lactation:

Pregnancy

Data on the use of Saxend® in pregnant women are limited. In animal studies, reproductive toxicity was demonstrated (see section Preclinical data but safety). The potential risk to humans is unknown.

The use of Saxend® during pregnancy is contraindicated. When planning or onset of pregnancy, therapy with Saxend® should be discontinued.

Breastfeeding period

It is not known whether the lyraglutide in human milk. In animal studies, it has been demonstrated that the penetration of liraglutide and structurally related metabolites into breast milk is low. In preclinical studies, therapy-related growth retardation in newborn rats breastfed (see section Preclinical safety data). Due to the lack of experience with the application, Saxende® is contraindicated during breastfeeding.

Dosing and Administration:

Mode of application

The Saxenda® preparation is intended only for subcutaneous administration. It can not be administered intravenously or intramuscularly.

Saxenda® is administered once a day at any time, regardless of food intake. It should be injected into the abdomen, hip or shoulder area. Place and time of injection can be changed without dose adjustment. Nevertheless, it is advisable to do injections at about the same time of day after choosing the most convenient time.

Doses

The initial dose is 0.6 mg per day. The dose is increased to 3 mg per day, adding 0.6 mg at intervals of at least one week to improve gastrointestinal tolerance (see Table 1). If, with increasing doses, a new dose is poorly tolerated by the patient for 2 consecutive weeks, consideration should be given to discontinuing therapy. The use of the drug in a daily dose of more than 3 mg is not recommended.

Table 1 Scheme of dose increase

	Dose	Weeks
Dose increase for 4 weeks	0.6 mg	1
	1.2 mg	1
	1.8 mg	1
	2.4 mg	1
Therapeutic dose	3 mg

Therapy with Saxend® should be discontinued if, after 12 weeks of using the drug at a dose of 3 mg per day, the loss in body weight is less than 5% of the initial value. The need to continue therapy should be reviewed annually.

Missing dose

If, after a normal dose, less than 12 hours have elapsed, the patient should administer the dose as soon as possible. If there is less than 12 hours left before the usual dose of the next dose, the patient should not inject the missed dose, but should resume the drug at the next scheduled dose. Do not add or increase the dose to compensate for the missed dose.

Patients with type 2 diabetes mellitus

Saxenda® should not be used in combination with other EPP-E receptor agonists

At the beginning of therapy with Saxenda®, it is recommended to reduce the doses of simultaneously used insulin secretagogues (such as sulfonylureas) to reduce the risk of developing hypoglycemia.

Special patient groups

Patients of advanced age (≥65 years)

Dose adjustment with age is not required.Experience in the use of the drug in patients ≥ 75 years of age is limited, it is necessary to apply the drug in such patients with caution.

Patients with renal insufficiency

In patients with impaired renal function of mild or moderate degree (creatinine clearance ≥ 30 ml / min), dose adjustment is not required. There is limited experience with Saxend® in patients with severe renal dysfunction (creatinine clearance <30 mL / min). The use of Saxend® in these patients, including patients with terminal stage of renal failure, is contraindicated.

Patients with impaired hepatic function

In patients with impaired liver function of light or moderate severity, dose adjustment is not required. In patients with impaired liver function of mild or moderate severity, the drug should be used with caution. The use of Saxend® in patients with impaired liver function is severely contraindicated.

Children

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

Side effects:

The Saxenda® clinical study program consists of 5 completed clinical trials involving 5813 obese or overweight patients and at least one associated with an overweight associated disease. In general, gastrointestinal disorders were the most frequently reported side effects during Saxenda® therapy (see section "Description of individual adverse reactions").

Table 2 shows a list of adverse reactions recorded during clinical trials. Undesirable reactions are grouped according to organ systems MedDRA and frequency. The frequency is defined as follows: very often (≥ 1/10); often (≥ 1/100 to <1/10); infrequently (≥ 1/1000 to <1/100); rarely (≥ 1/10 000 to <1/1000); very rarely (<1/10 000).

Table 2 Unwanted reactions recorded during controlled trials 2 and 3 of the phase

System of organs	Frequency
Immune system disorders	Anaphylactic reactions - Rarely
Disorders from the metabolism and nutrition	Hypoglycemia * - Frequently Dehydration - infrequently
Disorders of the psyche	Insomnia ** - Frequently
Disturbances from the nervous system	Dizziness , Dysgeusia - Often
Heart Disease	Tachycardia - Infrequently
Infringements from gastrointestinal tract	Nausea, vomiting, diarrhea, constipation - Very often Dry mouth, dyspepsia, gastritis, gastroesophageal reflux, pain in the upper abdomen, flatulence, belching, bloating - Often Pancreatitis *** - Infrequently
Disturbances from the liver and bile ducts	Cholithiasis * - Frequently Cholecystitis * - Infrequently
Disturbances from the skin and subcutaneous tissues	Hives - infrequently
Disorders from the kidneys and urinary tract	Acute renal failure, impaired renal function - Rarely
General disorders and disorders at the site of administration	Reactions at the injection site, asthenia , fatigue - Often Malady ** - Infrequently

* Hypoglycemia (based on patient-noted symptoms, not confirmed measurements of blood glucose concentration), noted in patients without type 2 diabetes who received the Saxenda® preparation in combination with diet and exercise. For detailed information, see "Description of individual adverse reactions".

** Primarily noted during the first 3 months of therapy.

*** See the section Special instructions.

Description of individual undesirable reactions:

Hypoglycaemia the patients without diabetes mellitus 2 PIT

In clinical studies involving patients with excessive body weight or obesity without type 2 diabetes, who received Saxenda® therapy in combination with diet and exercise, severe hypoglycemia (requiring assistance by a third party) was not noted. Symptoms of hypoglycaemia were reported in 1.6% of patients receiving Saxend® and 1.1% of patients receiving placebo; however, these cases were not confirmed by measurements of blood glucose concentration. In most cases, slight hypoglycemia was noted.

Hypoglycaemia the patients with type 2 diabetes mellitus

In a clinical study involving patients with overweight or obesity and type 2 diabetes mellitus who received Saxenda® therapy in combination with diet and exercise, cases of severe hypoglycemia (requiring the assistance of a third party) were noted in 0.7% of patients, who received the drug Saxend®, and only in patients who were simultaneously receiving sulfonylurea therapy. Also in this group of patients, confirmed hypoglycemia (glucose concentration ≤ 3.9 mmol / l in combination with symptoms) was noted in 43.6% of patients receiving Saxend® and 27.3%who received a placebo. Among patients who did not simultaneously receive the sulfonylurea drug, confirmed hypoglycemia was noted in 15.7% of patients receiving Saxend® and 7.6% of patients receiving placebo.

Undesirable reactions from the gastrointestinal tract

Most of the reactions from the gastrointestinal tract were of mild or moderate severity, transient and, in most cases, did not lead to discontinuation of therapy. The reactions usually occurred during the first weeks of therapy, and their manifestations gradually decreased within a few days or weeks with continued therapy.

Patients aged ≥65 years may experience more severe adverse reactions from the gastrointestinal tract during Saxenda® therapy.

In patients with impaired renal function of mild or moderate severity (creatinine clearance ≥ 30 ml / min), more severe manifestations of adverse gastrointestinal reactions during Saxend® therapy may be observed.

Allergic reactions

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

Reactions at the site of administration

In patients receiving the Saxend® preparation, reactions at the site of administration were described. These reactions, as a rule, were of an easy degree, were transient in nature and in most cases disappeared with the continuation of therapy.

Tachycardia

In clinical trials, tachycardia was noted in 0.6% of patients receiving Saxend® and 0.1% of patients receiving placebo. Most of the phenomena were of mild or moderate severity. Phenomena were isolated and in most cases passed while continuing therapy with Saxenda®.

Overdose:

According to clinical studies and postagregational application of liraglutide, cases of overdose have been reported (72 mg dose was administered, which is 24 times more than recommended for body mass correction). One case was also recorded when a six-fold dose (18 mg per day) was administered for 7 months. According to patients, these cases of overdose were accompanied by severe nausea, vomiting and diarrhea, but in all cases the patients recovered without complications.In no case was severe hypoglycemia observed.

In case of an overdose, appropriate symptomatic therapy is necessary.

Interaction:

Evaluation of drug interactions in vitro

The very low ability of liraglutide to pharmacokinetic interactions with other active substances due to metabolism in the cytochrome P450 system has been demonstrated (CYP) and binding to plasma proteins.

Evaluation of drug interactions in vivo

A slight delay in gastric emptying with the use of liraglutide can affect the absorption of concomitantly used drugs for ingestion. In the interaction studies, no clinically significant slowing of absorption was demonstrated, so no dose adjustments are required.

Interaction studies were carried out using liraglutide at a dose of 1.8 mg. The effect on the rate of gastric emptying was the same when using liraglutide at a dose of 1.8 mg and 3 mg (AUC₀_{-300 min}paracetamol). Several patients who received lyraglutide, at least one episode of severe diarrhea was noted.Diarrhea can affect the absorption of concurrently used medications for ingestion.

Warfarin and other coumarin derivatives

No interaction studies were conducted. Clinically significant interaction with active substances with low solubility or with a narrow therapeutic index, such as warfarin, can not be ruled out. After initiation of Saxend® therapy in patients receiving warfarin or other coumarin derivatives, more frequent monitoring of the International Normalized Ratio (INR) is recommended.

Paracetamol (acetaminophen)

Liraglutide did not change the total exposure of paracetamol after the administration of a single dose of 1000 mg. The maximum concentration (C_m_Oh) of paracetamol was reduced by 31%, and the median t_max increased by 15 minutes. Correction of the dose with the concomitant use of paracetamol is not required.

Atorvastatin

Liraglutide did not change the total exposure of atorvastatin after a single dose of atorvastatin 40 mg. Therefore, correction of the dose of atorvastatin when used in combination with liraglutide is not required. FROM_m_Oh Atorvastatin was reduced by 38%, and the median t_max Increased from 1 hour to 3 hours when using liraglutide.

Griseofulvin

Liraglutide did not change the total exposure of griseofulvin after a single dose of griseofulvin 500 mg. FROM_m_Oh griseofulvin was increased by 37%, and the median t_max has not changed. Correction of the dose of griseofulvin and other compounds with low solubility and high penetrating power is not required.

Digoxin

The use of a single dose of digoxin 1 mg in combination with liraglutide led to a decrease in the area under the concentration-time curve (AUC) digoxin by 16%, decrease in C_m_Oh by 31%. Median t_max increased from 1 hour to 1.5 hours. Given these results, correction of the dose of digoxin is not required.

Lisinopril

The use of a single dose of lisinopril 20 mg in combination with liraglutide resulted in a decrease AUC lisinopril by 15%, the decrease in C_m_Oh on 27%. Median t_max lisinopril increased from 6 hours to 8 hours. Taking into account these results, correction of the dose of lisinopril is not required.

Oral hormonal contraceptives

Liraglutide led to a decrease in C_m_Oh ethinyl estradiol and levonorgestrel by 12% and 13%, respectively, after applying a single dose of oral hormonal contraceptive. t_max of both medicinal substances against the background of the use of liraglutide increased by 1.5 hours. There was no clinically significant effect on the systemic exposure of ethinylestradiol or levonorgestrel. Thus, the influence on the contraceptive effect is not expected when combined with liraglutide.

Incompatibility

Medicinal substances added to the Saxenda® preparation may cause destruction of liraglutide. Due to the lack of compatibility studies, this medication should not be mixed with other medications.

Special instructions:

Patients with diabetes should not use Saxend® as an insulin replacement.

Cardiovascular failure

Experience in patients with chronic heart failure class I-II in accordance with the classification NYHA Limited, so Saxenda® should be used with caution.

Pancreatitis

The use of GLP-1 receptor agonists was associated with a risk of developing acute pancreatitis. Several cases of acute pancreatitis have been reported with the use of liraglutide.Patients should be informed of the characteristic symptoms of acute pancreatitis. In case of suspected development of pancreatitis, Saxend® should be discontinued; In case of confirmation of acute pancreatitis, therapy should not be resumed. Care should be taken when using the drug in patients with pancreatitis in history.

Cholithiasis and cholecystitis

In clinical trials, a higher incidence of cholelithiasis and cholecystitis was noted in patients receiving Saxenda® compared with placebo-treated patients. This may be partly explained by the fact that a decrease in body weight may increase the risk of developing cholelithiasis and therefore cholecystitis. Cholithiasis and cholecystitis can lead to hospitalization and cholecystectomy. Patients should be informed of the characteristic symptoms of cholelithiasis and cholecystitis.

Thyroid gland diseases

In clinical trials involving patients with type 2 diabetes mellitus, undesirable thyroid events were noted, including an increase in serum calcitonin concentration, goiter and thyroid neoplasm, especially in patients already having thyroid disease.In patients with thyroid disease, Saxenda® should be used with caution.

In the postmarketing period, patients who received lyraglutide, cases of medullary thyroid cancer were noted. The available data are insufficient to establish or exclude the causal relationship of the occurrence of medullary thyroid cancer with the use of liraglutide in humans. Saksenda® drug is contraindicated for use in patients with medullary thyroid cancer history, including a family, and multiple endocrine neoplasia type 2. It should inform the patient about the risk of medullary thyroid cancer and symptoms of thyroid tumors (seal in the neck, dysphagia, dyspnea, nagging hoarseness).

The current control of serum calcitonin concentration or ultrasound (ultrasound) of the thyroid gland is not significant for the early detection of medullary thyroid cancer in patients using Saxenda®. A significant increase in the concentration of calcitonin in the serum may indicate the presence of medullary cancerthyroid gland, patients with medullary thyroid cancer usually have a calcitonin concentration of more than 50 ng / l. If there is an increase in the concentration of calcitonin in the serum, a further examination of the patient is necessary. Patients with thyroid nodules identified by medical examination or ultrasound of the thyroid gland should also be further examined.

Heart Rate

In clinical studies, there was an increase in heart rate. The clinical significance of the increase in heart rate with Saxend®, especially in patients with cardiac and cerebrovascular diseases, remains unclear due to the limited experience of the drug in these patients. The heart rate should be monitored at intervals consistent with routine clinical practice. Patients should be informed of the symptoms of tachycardia (palpitations or a feeling of rapid heartbeat at rest). Patients with clinically significant permanent tachycardia at rest should discontinue therapy with Saxend®.

Dehydration

Signs and symptoms of dehydration, including renal dysfunction and acute renal failure, were noted in patients receiving GLP-1 receptor agonists.Patients receiving Saxend® should be informed of the the potential risk of dehydration associated with side effects from the gastrointestinal tract, and the need to prevent hypovolemia.

Hypoglycemia in patients with overweight or obesity and type 2 diabetes mellitus

The risk of developing hypoglycemia may be higher in patients with type 2 diabetes who receive the Saxenda® preparation in combination with sulfonyl urea derivatives. This risk can be reduced by reducing the dose of the sulfonylurea compound. The addition of Saxend® to therapy in patients receiving insulin was not evaluated.

Suicidal thoughts and behavior

In clinical trials, 6 (0.2%) of the 3,384 patients receiving Saxenda® reported suicidal thoughts, one of the patients attempted suicide. In patients (1941 people) who received a placebo, this was not noted. Patients should be monitored for the appearance or deterioration of depression, suicidal thoughts or behavior, and / or any unexpected changes in mood or behavior.In patients with suicidal thoughts or behavior, Saxend® should be discontinued.

It is contraindicated to use Saxende® in patients with suicidal attempts or active suicidal thoughts in an anamnesis.

Breast Cancer

Clinical studies reported confirmed breast cancer in 14 (0.6%) of 2379 women receiving Saxenda®, compared with 3 (0.2%) of the 1,300 women who received placebo, including invasive cancer (11 cases in women who received the Saxenda® preparation and 3 cases in women receiving placebo) and intra-cellular carcinoma in situ (3 cases in women receiving Saxenda® and 1 in women receiving placebo). Most cases of cancer have been estrogen- and progesterone dependent. It is impossible to determine whether these cases were associated with the use of Saxend® because of too few of them. In addition, there is insufficient data to determine whether the Saxend® medication influences already existing breast tumors.

Papillary thyroid cancer

In clinical trials, confirmed papillary thyroid carcinoma was reported in 7 (0.2%) of the 3291 patients receiving Saxenda®, compared to the absence of it in the group of patients,who received placebo (1,843 patients). Of all the cases, 4 carcinomas were less than 1 cm in the largest diameter and 4 were diagnosed by histology after a medical thyroidectomy.

Colon and colon neoplasia

Clinical studies reported confirmed colon and rectal benign neoplasms (predominantly adenomas of the colon) in 17 (0.5%) of 3291 patients receiving Saxenda®, compared with 4 (0.2%) of 1,843 patients, who received a placebo. Two confirmed cases of colorectal carcinoma of the colorectal and rectum (0.1%) in the patients receiving the Saxend® preparation were recorded and none of the patients receiving the placebo.

Cardiac conduction abnormalities

In clinical trials, 11 (0.3%) of 3384 patients receiving the Saxend® preparation reported the development of cardiac conduction abnormalities, such as atrioventricular blockade of the 1st degree, blockade of the right leg of the bundle, or blockade of the left bundle of the bundle. Patients (1941 people) who received a placebo did not report the development of cardiac conduction abnormalities.

Fertility

With the exception of a slight decrease in the number of live embryos, the results of animal studies do not indicate an adverse effect on fertility (see section Preclinical safety data).

Application Guide

Saxenda® can not be used if it looks different than a clear and colorless or almost colorless liquid.

Saxenda® can not be used if it has been frozen.

The Saxenda® preparation can be administered with needles up to 8 mm in length. The syringe pen is intended for use with disposable needles NovoFine® or NovoTvist®.

Injection needles are not included in the package.

The patient should be informed that the used needle should be discarded after each injection, and that it is impossible to store the syringe pen with the attached needle. Such a measure will prevent blockage of the needles, contamination, infection and leakage of the drug from the syringe pen and ensures the accuracy of dosing.

Effect on the ability to drive transp. cf. and fur:The Saxenda® preparation does not or does not significantly affect the ability to drive vehicles and mechanisms.In connection with the risk of hypoglycemia in the use of the drug, especially when combined with sulfonylureas in patients with diabetes mellitus 2, caution should be exercised when managing vehicles and mechanisms.

Form release / dosage:A solution for subcutaneous administration of 6 mg / ml.

Packaging:

3 ml in cartridges of glass 1 of hydrolytic class, sealed with discs of brombutyl rubber / polyisoprene on one side and pistons of bromobutyl rubber on the other.

The cartridge is sealed in a plastic multi-dose disposable syringe pen for multiple injections. 5 multi-dose disposable syringes with instructions for use in a cardboard pack.

Storage conditions:

Keep out of the reach of children.

Store at temperatures between 2 ° C and 8 ° C (in the refrigerator), but not near the freezer. Do not freeze.

The used syringe handle with the drug should be stored at a temperature not exceeding 30 ° C or in a refrigerator (at a temperature of 2 ° C to 8 ° C). Do not freeze. Use within 1 month.

Close the syringe handle with a cap to protect it from light.

Shelf life:

30 months.Do not use after the expiration date indicated on the label of the syringe pen and the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003491

Date of registration:09.03.2016

Expiration Date:09.03.2021

The owner of the registration certificate:Novo Nordisk A / SNovo Nordisk A / S Denmark

Manufacturer: & nbsp

NOVO NORDISK, A / S Denmark

Representation: & nbspNOVO NORDISK TOVNOVO NORDISK TOVDenmark

Information update date: & nbsp28.06.2016