Victoza, 18mg/ 3ml syringe pen, 2pcs

Composition

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1 ml of solution for subcutaneous use contains:

Active ingredient:

liraglutide 6 mg

. excipients:

sodium hydrophosphate dihydrate-1.42 mg;

propylene glycol-14 mg;

phenol-5.5 mg;

hydrochloric acid/sodium hydroxide-q. s. ;

water for injection-up to 1 ml

Pharmacological action

Pharmacotherapy group: Hypoglycemic agent-glucagon-like polypeptide receptor agonist. Code ATX-A 10 VH07.

Pharmacological properties

Mechanism of action

Liraglutide is an analog of human glucagon-like peptide-1 (GLP-1), produced by recombinant DNA biotechnology using the Saccharomyces cerevisiae strain, which has 97% homology with human GLP-1, which binds and activates GLP-1 receptors in humans. The GLP-1 receptor targets native GLP-1, the endogenous hormone incretin, which stimulates glucose-dependent insulin secretion in pancreatic beta cells. Unlike native GLP-1, the pharmacokinetic and pharmacodynamic profiles of liraglutide allow it to be administered to patients daily once a day.

The long-acting profile of liraglutide for subcutaneous injection is provided by three mechanisms: self-association, which results in delayed absorption of the drug; binding to albumin and a higher level of enzymatic stability with respect to dipeptidyl peptidase-4 (DPP-4) and the neutral endopeptidase (NEP) enzyme, which ensures a long half-life of the drug from plasma. Liraglutide acts by interacting with specific GLP-1 receptors, resulting in an increased level of cyclic adenosine monophosphate cAMP.

Under the action of liraglutide, glucose-dependent stimulation of insulin secretion occurs and the function of pancreatic beta cells improves. At the same time, liraglutide suppresses excessively high glucose-dependent glucagon secretion. Thus, when the concentration of blood glucose increases, insulin secretion is stimulated and glucagon secretion is suppressed. On the other hand, during hypoglycemia, liraglutide reduces insulin secretion, but does not inhibit glucagon secretion. The mechanism of lowering the level of glycemia also includes a slight delay in emptying the stomach. Liraglutide reduces body weight and reduces body fat mass through mechanisms that reduce hunger and reduce energy expenditure.

Studies in experimental animal models with prediabetes have shown that liraglutide slows down the development of diabetes mellitus. In vitro diagnostics showed that liraglutide is a powerful factor in specific stimulation of pancreatic beta cell proliferation and prevents the formation of cytokines and free fatty acids that induce beta cell death (apoptosis). In vivo, liraglutide increases insulin biosynthesis and increases beta cell mass in experimental animal models with diabetes mellitus. When glucose levels return to normal, liraglutide stops increasing the mass of pancreatic beta cells.

Pharmacodynamics

Liraglutide has a long-lasting 24-hour effect and improves glycemic control by reducing fasting and post-meal blood glucose concentrations in patients with type 2 diabetes mellitus.

Glucose-dependent insulin secretion

When the concentration of glucose in the blood increases, liraglutide increases the secretion of insulin. When using a stepwise glucose infusion, insulin secretion after a single dose of liraglutide is administered to patients with type 2 diabetes mellitus increases to a level comparable to that in healthy subjects.

Pancreatic beta cell function

Liraglutide improved the function of pancreatic beta cells, which is confirmed by the first and second phase of the insulin response and the maximum secretory activity of beta cells. Pharmacodynamic studies of patients with type 2 diabetes mellitus showed recovery of the first phase of insulin secretion (intravenous use of insulin), improvement of the second phase of insulin secretion (hyperglycemic clamp test) and maximum secretory activity of insulin (arginine stimulation test).

During the 52-week treatment with Victoza, there was an improvement in the function of pancreatic beta cells, which is confirmed by the assessment of the homeostatic model of pancreatic beta cell function (NOMA index) and the ratio of insulin to proinsulin.

Glucagon secretion:

Liraglutide, by stimulating the secretion of insulin and suppressing the secretion of glucagon, reduces the concentration of glucose in the blood. Liraglutide does not inhibit the glucagon response to low glucose concentrations. In addition, liraglutide was associated with lower endogenous glucose production.

Emptying the stomach:

Liraglutide causes a slight delay in gastric emptying, thus reducing the intensity of postprandial glucose intake into the blood.

Body weight, body composition, and energy expenditure:

In subjects with increased body weight included in long-term clinical studies of liraglutide, the latter caused a significant decrease in body weight. Scans using computed tomography (CT) and dual-energy X-ray absorptiometry (DERA) methods showed that the weight loss occurred primarily due to the loss of adipose tissue in patients. These results are explained by the fact that during liraglutide therapy, patients experience reduced hunger and energy expenditure.

Electrophysiology of the heart (EFs): The effect of liraglutide on the repolarization process in the heart was tested in the EFs study. The use of liraglutide at steady-state concentrations in a daily dose of up to 1.8 mg does not produce prolongation of EFs.

Clinical efficacy

3992 patients with type 2 diabetes mellitus were randomized to participate in 5 double-blind clinical trials of safety and efficacy conducted to evaluate the effect of Victoza on glycemic control. Victoza therapy resulted in clinically and statistically significant improvements in HbA1c, fasting glucose, and postprandial glucose compared to placebo.

Glycemic control Victoza monotherapy for 52 weeks caused a statistically significant (p1) increase compared to the same indicator in patients receiving glimepiride therapy. At the same time, the marked decrease in HbA1c below 7% persisted for 12 months.

In patients with HbA1c above 9.5% at baseline, this indicator decreased by 2.1% against the background of Victoza monotherapy, while in patients participating in clinical trials with the combined use of Victoza, the average HbA1c decreased by 1.1-2.5%.

Victoza during 26-week combination therapy with metformin, sulfonylureas or metformin and thiazolidinedione caused a statistically significant p1c decrease compared to that in patients receiving placebo.

In patients who did not achieve adequate glycemic control on Victoza and metformin therapy, the addition of detemir insulin provided greater efficacy compared to Victoza and metformin therapy after 26 weeks of treatment (a 0.52% decrease in HbA1c).

The efficacy of Victoza at a dose of 0.6 mg in combination with sulfonylureas or metformin has been shown to be superior to placebo, but at the same time lower compared to doses of 1.2 mg and 1.8 mg.

Ratio of patients who achieved a reduction in HbA1c

During the 52-week study, the number of patients who achieved HBA1C1 with < 6.5% increased significantly (p < 0.0001) compared to the number of patients who received hypoglycemic drugs alone without the addition of Victoza during monotherapy.

In the groups of patients who did not achieve adequate glycemic control on Victoza and metformin therapy, the percentage of patients who achieved the HbA1c target(

During a 26-week study of the combined use of Victoza, it was possible to achieve the HbA1 index of fasting glycemic severity

Fasting glucose concentration decreased by 13-43.5 mg% (0.72-2.42 mmol/l) while taking Victoza as monotherapy or in combination with one or two oral hypoglycemic agents. This decrease was observed within the first two weeks after the start of treatment.

Postprandial glycemic level

The use of Victoza for three days of standard food intake helped to reduce the concentration of postprandial glucose by 31-49 mg% (1.68-2.71 mmol/l).

Body weight

52-week monotherapy with Victoza was associated with sustained weight loss. Throughout the clinical trial period, sustained weight loss was also associated with the use of Victoza in combination with metformin and in combination with a combination of metformin with sulfonylureas or a combination of metformin with thiazolidinedione.

Weight loss in patients receiving Victoza in combination with metformin was also observed after the addition of insulin detemir.

The greatest reduction in body weight was observed in patients who had an increased body mass index (BMI) at the initial point of the study. Monotherapy with Victoza for 52 weeks caused a decrease in the average waist size by 3.0-3.6 cm. Weight loss was observed in all patients treated with Victoza, regardless of whether or not they experienced an adverse reaction in the form of nausea.

The drug Victoza in combination therapy with metformin reduced the volume of subcutaneous fat by 13-17%.

Non-alcoholic steatohepatosis

Liraglutide reduces the severity of steatohepatosis in patients with type 2 diabetes mellitus.

Blood pressure indicators

Long-term clinical studies have shown that Victoza reduces systolic blood pressure by an average of 2.3-6.7 mm Hg in the first two weeks of treatment. A decrease in systolic blood pressure occurred before the onset of weight loss.

Other clinical data

In the comparative study of the efficacy and safety of the drug Victoza (at doses of 1.2 mg and 1.8 mg) and inhibitor of dipeptidyl peptidase-4 sitagliptin at a dose of 100 mg in patients who do not achieve adequate control on Metformin therapy, after 26 weeks of treatment proved a better reduction in HbA1 with the use of the drug Victoza in both doses compared with sitagliptin (-1,24%, -1,50% compared to -0,90%, R 1 to 7% with the use of the drug Victoza compared to sitagliptin (43.7% and 56,0% compared to 22.0%, p

Compared to patients receiving sitagliptin, patients receiving Victoza were more likely to experience nausea. However, the nausea was transient. The incidence of mild hypoglycemia did not differ significantly between Victoza and sitagliptin (0.178 and 0.161, compared to 0.106 cases/patient per year). The reduction in HbA1 C and the advantage of the drug Victoza compared with sitagliptin was observed after 26 weeks of treatment, Victoza (1.2 mg and 1.8 mg) and confirmed after 52 weeks of treatment (of -1.29% and -1,51% compared -0,88%, R 1 to 78 weeks of treatment (0,24% and 0.45%,95 CL: from 0.41 to -0,67 from 0.07 to 0.23).

In a comparative study of the efficacy and safety of Victoza (1.8 mg) and exenatide (10 micrograms twice daily) in patients who did not achieve adequate control on metformin and/or sulfonylurea derivatives, after 26 weeks of Victoza use, a greater decrease in HbA1c compared to exenatide was observed (-1.12% compared to -0.79%, p1c lower than 7% on Victoza compared to exenatide (54.2% compared to exenatide). compared to 43.4%, p=0.0015).

Both therapies showed an average weight loss of approximately 3 kg. The number of patients reporting nausea was lower in the Victoza group compared to exenatide. The incidence of mild hypoglycemia was significantly lower in the Victoza group compared to exenatide (1,932 versus 2,600 cases / patient per year, p=0.01). After 26 weeks of exenatide treatment, patients were transferred to Victoza, which resulted in an additional decrease in HbA1c at the 40th week of treatment (-0.32%, p1c below 7%. Treatment with Victoza for 52 weeks improved insulin sensitivity compared to that of sulfonylureas, which was revealed using the HOMA-IR homeostatic model for assessing insulin resistance.

Pharmacokinetics

Absorption and absorption of liraglutide after subcutaneous use is slow, the time to reach the maximum plasma concentration is 8-12 hours after the dose of the drug. The maximum concentration (Cmax) of liraglutide in plasma after subcutaneous injection in a single dose of 0.6 mg is 9.4 nmol/l. When liraglutide is administered at a dose of 1.8 mg, the average steady-state plasma concentration (AUC?/24) reaches approximately 34 nmol/l. Liraglutide exposure increases in proportion to the administered dose. After use of liraglutide in a single dose, the intrapopulation coefficient of variation of the area under the concentration-time curve AUC is 11%. The absolute bioavailability of liraglutide after subcutaneous use is approximately 55%.

Distribution The apparent volume of distribution of liraglutide in tissues after subcutaneous use is 11-17 liters. The average volume of distribution of liraglutide after intravenous use is 0.07 l / kg. Liraglutide binds significantly to plasma proteins (>98%). Metabolism For 24 hours after use of a single dose of radiolabeled [3H]-liraglutide to healthy volunteers, the main component of plasma remained unchanged liraglutide. Two metabolites were detected in the plasma (≤ 9% and ≤ 5% of the total radioactivity level in the blood plasma). Liraglutide is metabolized endogenously like large proteins, without involving any specific organ as a route of elimination.

Excretion After use of a dose of [3H]-liraglutide, unchanged liraglutide was not detected in the urine or feces. Only a small fraction of the administered radioactivity in the form of liraglutide-related metabolites (6% and 5%, respectively) was eliminated by the kidneys or through the intestine. Radioactive substances are mainly excreted by the kidneys or through the intestines during the first 6-8 days after use of the drug dose, and represent three metabolites. The average clearance from the body after subcutaneous use of liraglutide in a single dose is approximately 1.2 l / h with an elimination half-life of approximately 13 hours.

Special patient GROUPSOLD age: Data from pharmacokinetic studies in a group of healthy volunteers and analysis of pharmacokinetic data obtained in the patient population (from 18 to 80 years) indicate that age does not have a clinically significant effect on the pharmacokinetic properties of liraglutide. Gender: A population-based pharmacokinetic analysis of data obtained in the study of the effect of liraglutide in female and male patients, and data from pharmacokinetic studies in a group of healthy volunteers indicate that gender does not have a clinically significant effect on the pharmacokinetic properties of liraglutide.

Ethnicity: A population-based pharmacokinetic analysis of the data obtained in the study of the effect of liraglutide in subjects of white, black, Asian and Latin American racial groups indicates that ethnicity does not have a clinically significant effect on the pharmacokinetic properties of liraglutide. Obesity: A population pharmacokinetic analysis of the data indicates that body mass index (BMI) does not have a clinically significant effect on the pharmacokinetic properties of liraglutide.

Liver failure:The pharmacokinetic properties of liraglutide were studied in a clinical study of a single dose of the drug in subjects with varying degrees of hepatic insufficiency. Patients with mild hepatic insufficiency (according to the Child Pugh classification, disease severity 5-6 points) and severe hepatic insufficiency (according to the Child Pugh classification, disease severity >9 points) were included in the study. Liraglutide exposure in the group of patients with impaired liver function was not higher than that in the group of healthy subjects, indicating that liver failure does not have a clinically significant effect on the pharmacokinetics of liraglutide.

Kidney failure:The pharmacokinetics of liraglutide were studied in patients with varying degrees of renal insufficiency in a single-dose study. This study included subjects with varying degrees of renal impairment, ranging from mild (estimated creatinine clearance 50-80 ml / min) to severe (estimated creatinine

clearance in Children:The study of the drug Victoza in children was not conducted. Data from preclinical safety studiesresults of preclinical toxicological studies with repeated doses of the drug, including genotoxicity, showed that the use of liraglutide does not pose a threat to human health. Tumors of C-cells of the thyroid gland of rats and mice were detected during two-year studies of the drug’s carcinogenicity in rodents and did not lead to a fatal outcome. The non-toxic dose (NOAEL) in rats has not been established. The appearance of such tumors in monkeys treated with liraglutide for 20 months was not observed. The results obtained in rodent studies are related to the fact that rodents are particularly sensitive to a non-genotoxic specific mechanism mediated by the GLP-1 receptor. The significance of the data obtained for humans is low, but cannot be completely excluded. The appearance of any 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 fetal death when treated with the highest dose of the drug. use of Victoza to rats in the middle of the gestation period caused a decrease in the mother’s body weight and embryo growth with an unknown effect on the ribs, and in the rabbit group – deviations in the skeletal structure.

The growth of newborns in the rat group decreased during Victoza therapy, and this decrease persisted steadily in the period after the end of breastfeeding in the group of models receiving high doses of liraglutide. It is not known whether this decrease in the growth of newborn rats is due to a decrease in their consumption of breast milk due to the direct influence of GLP-1, or insufficient production of breast milk by maternal rats due to a decrease in their caloric intake.

Indications

Victoza is indicated in adult patients with type 2 diabetes mellitus on the background of diet and exercise to achieve glycemic control as a dietary supplement. :

• Monotherapy options
• Combined therapy with one or more oral hypoglycemic drugs (with metformin, sulfonylurea derivatives or thiazolidinediones), in patients who did not achieve adequate glycemic control on previous therapy.
• Combined therapy with basal insulin in patients who did not achieve adequate glycemic control on treatment with Victoza®and metformin.

Use during pregnancy and lactation

Adequate data on the use of Victoza in pregnant women are not available. Animal studies have demonstrated the reproductive toxicity of the drug. The potential risk to humans is unknown.

The drug Victozanel should not be used during pregnancy, instead it is recommended to carry out treatment with insulin. If the patient is preparing for pregnancy or pregnancy has already occurred, treatment with Victoza should be stopped immediately.

It is not known whether liraglutide is excreted in the breast milk of women. Animal studies have shown that the penetration of liraglutide and metabolites of a close structural bond into breast milk is low. There is no experience of using Victozau in nursing women. The use of the drug during breastfeeding is contraindicated.

Recommendations for use

Instructions for the patient

Please read these instructions carefully before using the Victoza® pen.

The Victoza ® pen contains 18 mg of liraglutide. The patient can choose any of three possible dosages: 0.6,1.2 and 1.8 mg. The Victoza ® syringe pen is designed for use with NovoFine® or NovoTvist® disposable needles up to 8 mm long and up to 32G (0.25/0.23 mm) thick.

Victoza®syringe Pen

Needle (example)

Preparing the pen for injection

Check the name and color code on the label of the pen to make sure it contains liraglutide. Using the wrong medication can be harmful to the patient’s health.

A. Remove the cap from the pen.

B. Remove the paper sticker from the disposable needle. Carefully and tightly screw the needle onto the syringe handle.

C. Remove the outer needle cap and set it aside without discarding it.

D. Remove the inner needle cap and discard it.

Important information. Always use a new needle for each injection. Such a measure will prevent contamination, infection, leakage of the drug from the syringe pen, clogging of needles and guarantees the accuracy of dosing. Take precautions when handling the needle to avoid bending or damaging the needle before using it.

Important information. Never put the inner cap back on the needle. This will prevent the risk of accidental needle pricks.

Care of the syringe handle

– do not attempt to repair the syringe handle yourself or take it apart;

– protect the syringe handle from dust, dirt and all types of liquids;

– the syringe handle can be cleaned with a cloth moistened with a mild detergent. Do not immerse the pen in liquid, wash or lubricate it, as this may damage the machine.

Important Information

The pen is intended for individual use and should not be passed on to others. Keep the pen out of the reach of everyone, especially children.

Checking the operation of a new syringe pen

Important information

Always check the operation of the pen as shown below before using a new pen for injection.

If the patient is already using a pen, they should proceed to step H “Dose adjustment”.

E. Rotate the dose selector until the operation check symbol is aligned with the dose indicator in the display window.

F. While holding the pen with the needle facing up, tap the cartridge several times with your finger so that the air bubbles move to the top of the cartridge.

G. While holding the syringe handle with the needle facing up, press the start button until 0 mg appears in the indicator window opposite the dose indicator. A drop of the drug should appear at the end of the needle. If the drop does not appear, repeat operations E–G until a drop of liraglutide appears at the end of the needle. If after 4 repetitions of these operations, a drop of the drug at the end of the needle has not appeared, change the needle to a new one and repeat operations E-G again. If a drop of the drug does not appear at the end of the needle, it means that the pen is defective and the patient should use a new pen.

Important information. If the patient drops the pen on a hard surface or has doubts about its complete functionality, a new disposable needle should be attached and the pen should be checked before starting to administer the drug.

Setting the dose

First of all, you need to make sure that in the indicator window “0 mg” is located opposite the dose indicator.

H. Turn the dose selector until the patient’s desired dose (0.6,1.2 or 1.8 mg) in the display window is aligned with the dose indicator (mg means mg). You can correct an incorrectly set dose by turning the dose selector forward or backward until the appropriate dose numbers in the display window are aligned with the dose indicator. When turning the dose selector back, be careful not to accidentally push the trigger button to avoid releasing a dose of liraglutide. If the dose selector stops before the patient’s desired dose appears in the display window opposite the dose indicator, it means that there is not enough liraglutide left in the pen to administer the full dose. In this case, you should perform one of the two actions described below.

Enter the desired dose in two divided doses

Rotate the dose selector in any direction until the dose of 0.6 or 1.2 mg is opposite the dose indicator. Make an injection. Prepare a new pen for the second injection and enter the remaining dose of the drug (in milligrams)to complete the full dose. You can divide the dose of the drug between a used and new pen only if the patient has been trained or recommended by a doctor. You must use a calculator to plan your doses. If the patient divides the dose incorrectly, they may inject insufficient or too large amounts of liraglutide.

Inject the full dose of the drug with a new syringe pen

If the dose selector has stopped before the numbers 0.6 mg appear in the indicator window opposite the dose indicator, prepare a new pen for injection and enter the full dose of the drug using the new pen.

Important information. Do not attempt to select doses other than those of 0.6,1.2, or 1.8 mg. The numbers in the indicator window should be exactly opposite the dose indicator-this position ensures that the patient receives the correct dose of the drug.

The dose selector clicks when rotated. Do not use these clicks to measure the dose of liraglutide that the patient needs for injection.

Do not use the cartridge scale to measure the dose of liraglutide for injection — it shows insufficiently accurate values.

Introduction of the drug

Insert the needle under the skin using the injection technique recommended by your doctor or nurse. Then follow the instructions given below:

I. Press the start button all the way down until “0 mg”appears in the display window opposite the dose indicator. Care must be taken: do not touch the indicator window with your fingers or press the dose selector — this may cause the pen mechanism to lock. Keep the trigger button pressed all the way down and the needle under the skin for at least 6 seconds. This will ensure that the full dose of the drug is administered.

J. Remove the needle from under the skin. The patient may see a drop of liraglutide on the end of the needle. This is a normal phenomenon that does not affect the dose of the drug that was just administered.

K. Insert the end of the needle inside the outer cap of the needle, without touching the needle and the outer cap.

L. When the needle is in the cap, gently push the outer cap of the needle forward so that the needle is fully inserted into it. Then unscrew the needle. Discard the needle carefully and cover the pen with the cap. If the pen is empty, unscrew the needle and discard the empty pen without the needle. Observe local regulations for the disposal of used medical materials.

Important information. Remove the used needle after each injection and do not store the pen with the needle attached. This will help prevent contamination, infection, and leakage of liraglutide from the pen and clogged needles. This will also ensure accurate dosing.

Important information. Caregivers should handle used needles with extreme care to avoid accidental injections and cross-infection.

Contraindications

• hypersensitivity to the Active ingredient or other components included in the composition of the drug;
• pregnancy and breastfeeding;
• diabetes mellitus, type 1;
• diabetic ketoacidosis;
• severe impairment of renal function;
• the liver;
• heart failure III–IV functional class (according to NYHA classification);
• inflammatory bowel disease;
• paresis of the stomach;
• the age of 18.

With caution: heart failure of functional class I–II (according to NYHA classification); moderate renal impairment; age 75 years and older  The experience of using the drug in patients of these categories is limited.

Side effects

In clinical trials, the most frequently reported gastrointestinal side effects were nausea and diarrhea (reported in >10% of patients); vomiting, constipation, abdominal pain, and dyspeptic symptoms (reported in ≥1%, but < 10% of patients).

At the beginning of Victoza therapy, these gastrointestinal side effects may occur more frequently, but as treatment continues, the reactions usually decrease within a few days or weeks. Adverse reactions in the form of headache and upper respiratory tract infections were relatively common (1-10% of patients). In addition, hypoglycemic conditions may develop, especially when Victoza is used in combination with sulfonylureas (reported in > 10% of patients). Severe hypoglycemia mainly develops against the background of combined use of Victoza with sulfonylurea derivatives.

Serious side effects have been reported very rarely.

Table 1 shows information on side effects identified during long-term controlled phase III clinical trials of Victoza and in spontaneous (post-marketing) reports. Adverse reactions identified in long-term phase III clinical trials with a frequency of >5% are presented, provided that their frequency was higher in the group of patients receiving Victoza compared to that in the group of patients receiving comparison drugs. Also included are adverse reactions with a frequency of ≥1%, provided that their frequency was 2 or more times higher than the frequency of adverse reactions in the groups of patients receiving therapy with reference drugs.

The frequency of other spontaneous (post-marketing) reports was calculated based on their occurrence in phase III clinical trials. All of the following adverse reactions, based on data obtained during clinical trials and in the post-marketing period, are grouped according to the frequency of development in accordance with MedDRA and organ systems. The frequency of adverse reactions is defined as: very common (≥ 1/10); common (≥ 1/100 to

Table 1 Adverse reactions identified in long-term placebo-controlled phase III clinical trials and spontaneous (post-marketing) reports

Organs and systems/ Adverse reactionsfrequency of development Phase III Investigationsponta messages Metabolic and nutritional disorders Hypoglycemia Frequency Anorexicasto Reduced appetitechasto Disorders of the nervous systemscapular pain frequently Disorders of the gastrointestinal tract Nausea is very common Diarrhea is very common Vomiting often dyspepsia often Pain in the upper abdomen often constipated Gastritis frequently Flatulence is common Bloating is frequent Gastroesophageal reflux is common Belching often Disorders of the immune systemanaphylactic reactions Rare infections and invasions of the upper respiratory tract infrequently General disorders and reactions at the injection sitedisease Infrequent reactions at the injection site often Renal and urinary tract disorders Acute renal failure * Infrequent renal impairment* Infrequent metabolic and nutritional disorders Dehydration* Infrequent skin and subcutaneous tissue disorders Urticaria Infrequent placemark often itching Infrequently

N= 2501 patients receiving Victoza Gipoglycemia therapy

Most episodes of confirmed hypoglycemia reported in clinical trials were mild. No cases of severe hypoglycemia have been reported in clinical trials when Victoza is used as monotherapy. Severe hypoglycaemia may occur infrequently and is mainly observed when Victoza is used in combination with sulfonylureas (0.02 cases/patient per year). When Victoza was used in combination with other oral hypoglycemic drugs (not sulfonylureas), the development of hypoglycemia was very rare (0.001 cases/patient per year).

No cases of severe hypoglycaemia were reported during treatment with liraglutide 1.8 mg in combination with insulin detemir and metformin. The incidence of mild hypoglycemia was 0.228 cases/patient per year. In the groups of patients treated with liraglutide 1.8 mg and metformin, the incidence of mild hypoglycemia was 0.034 and 0.115 cases/patient per year, respectively.

Adverse reactions from the gastrointestinal tract In most cases, nausea was mild or moderate, was transient and rarely led to discontinuation of therapy. 20.7% of patients treated with Victoza in combination with metformin experienced at least one episode of nausea, and 12.6% experienced at least one episode of diarrhea. When taking Victoza in combination with sulfonylureas,9.1% of patients had at least one episode of nausea, and 7.9% had at least one case of diarrhea.

In long-term controlled clinical trials (26 weeks or more), the frequency of discontinuation of patients from the study due to the development of side effects was 7.8% in the group of patients receiving Victoza, and 3.4% in the group of patients receiving comparison drugs. The most common adverse reactions that led to discontinuation of Victoza were nausea (2.8% of patients) and vomiting (1.5%).

In patients over the age of 70 years, the incidence of adverse reactions from the gastrointestinal tract with the use of Victoza may be higher.

When using Victoza in patients with mild renal insufficiency (creatinine clearance ≤ 60-90 ml/min), the frequency of adverse reactions from the gastrointestinal tract may be higher.

Immunogenicity Taking into account the possibility of an immunogenic effect of protein and peptide drugs, the use of Victoza in patients may lead to the formation of antibodies to liraglutide. The formation of antibodies is observed in an average of 8.6% of patients. The formation of antibodies does not lead to a decrease in the effectiveness of Victoza.

Injection site reactionsin long-term (26 weeks or more) controlled studies, approximately 2% of patients treated with Victoza experienced injection site reactions. These reactions were usually mild in nature.

Pancreatitis Several cases of acute pancreatitis have been reported (

Thyroid side effects The overall incidence of thyroid side effects in all intermediate and long-term clinical trials using liraglutide, placebo, and comparison drugs is 33.5; 30.0, and 21.7 cases per 1000 patient – years of total exposure, respectively; and the incidence of serious side effects is 5.4; 2.1, and 1.2 cases, respectively.

The most common side effects from the thyroid gland were thyroid neoplasms, increased serum calcitonin concentrations, and goiter. The incidence of these events per 1000 patient-years of exposure was 6.8; 10.9 and 5.4 cases, respectively, in patients treated with liraglutide, compared with 6.4; 10.7 and 2.1 cases – in patients treated with placebo, and 2.4; 6.0 and 1.8 cases – in patients treated with comparison drugs.

Allergic reactions

Allergic reactions such as hives, rash, and pruritus have been reported in the post-marketing period. In the post-marketing period, when using the drug Victoza, several cases of anaphylactic reactions have been described, accompanied by symptoms such as arterial hypotension, rapid heartbeat, shortness of breath, and edema.

Interaction

Drug interaction assessment in vitro. Liraglutide showed a very low ability to pharmacokinetic interaction with drugs due to metabolism in the cytochrome P450 (CYP) system, as well as binding to plasma proteins.

Drug interaction assessment in vivo. A slight delay in gastric emptying when using liraglutide may affect the absorption of concomitant oral medications. Drug interaction studies have not shown any clinically significant slowing of the absorption of these drugs. Several patients treated with Victoza experienced at least one episode of acute diarrhea. Diarrhea may affect the absorption of oral medications that are used simultaneously with Victoza.

Paracetamol. A single 1000 mg dose of paracetamol combined with liraglutide does not cause a change in systemic exposure. The Cmax of paracetamol in plasma decreased by 31%, and the average Tmax in blood plasma increased by 15 minutes. When taking liraglutide and paracetamol at the same time, no dose adjustment of the latter is required.

Atorvastatin. A single 40 mg dose of atorvastatin combined with liraglutide does not cause a change in systemic exposure. Thus, no dose adjustment of atorvastatin is required while taking Victoza. Cmax of atorvastatin in plasma decreased by 38%, and the average value of Tmax in plasma against the background of taking liraglutide increased from 1 to 3 hours.

Griseofulvin. A single 500 mg dose of griseofulvin combined with liraglutide does not cause a change in systemic exposure. Cmax of griseofulvin increased by 37%, while the mean plasma Tmax value did not change. Dose adjustment of griseofulvin and other drugs with low solubility and high permeability is not required.

Digoxin. With simultaneous single use of digoxin at a dose of 1 mg and liraglutide, a decrease in digoxin AUC by 16% was observed; digoxin Cmax decreased by 31%. The mean plasma digoxin Tmax increased from 1 to 1.5 hours. Based on the results obtained, no dose adjustment of digoxin is required while taking liraglutide.

Lisinopril.A single 20 mg dose of lisinopril combined with liraglutide resulted in a 15% decrease in lisinopril AUC and a 27% decrease in lisinopril Cmax. The mean plasma Tmax of lisinopril during liraglutide use increased from 6 to 8 hours. Based on the results obtained, no dose adjustment of lisinopril is required while taking liraglutide.

Oral contraceptives. The cmax of ethinyl estradiol and levonorgestrel after their single use during liraglutide therapy decreased by 12 and 13%, respectively. The use of both drugs together with liraglutide was accompanied by an increase in the Tmax of these drugs by 1.5 hours. liraglutide does not have a clinically significant effect on the systemic exposure of ethinyl estradiol and levonorgestrel in the body. Thus, the expected contraceptive effect of both drugs on the background of liraglutide therapy does not change.

Warfarin and other coumarin derivatives. No interaction studies have been conducted. At the beginning of Victoza treatment in patients receiving warfarin or other coumarin derivatives, it is recommended to monitor MHO more frequently.

Insulin. There was no pharmacokinetic or pharmacodynamic interaction of liraglutide with insulin detemir, with a single application of insulin detemir at a dose of 0.5 U / kg with liraglutide at a dose of 1.8 mg in patients with type 2 diabetes mellitus.

Incompatibility. Substances added to Victoza may cause degradation of liraglutide. Victoza should not be mixed with other drugs, including infusion solutions.

How to take, course of use and dosage

The drug Victoza is used once a day at any time, regardless of food intake, it can be administered as a subcutaneous injection in the abdomen, hip or shoulder. The place and time of injection may change without dose adjustment. However, it is preferable to administer the drug at approximately the same time of day, at the most convenient time for the patient. Further information on the method of use of Victoza is contained in the section “Instructions for use”. Victoza should not be used for intravenous or intramuscular use.

Dosage The initial dose of the drug is 0.6 mg of liraglutide per day. After using the drug for at least one week, the dose should be increased to 1.2 mg. There is evidence that in some patients, the effectiveness of treatment increases with an increase in the dose of the drug from 1.2 mg to 1.8 mg. In order to achieve the best glycemic control in the patient and taking into account the clinical effectiveness, the dose of Victoza can be increased to 1.8 mg after using it at a dose of 1.2 mg for at least one week. The use of the drug in a daily dose above 1.8 mg is not recommended.

Victoza is recommended to be used in addition to existing metformin therapy or combination therapy with metformin and thiazolidinedione. Metformin and thiazolidinedione therapy can be continued at the same doses. Victoza is recommended to be added to ongoing therapy with sulfonylurea derivatives or to combination therapy with metformin and sulfonylurea derivatives. When adding Victozac to therapy with sulfonylurea derivatives, a reduction in the dose of sulfonylurea derivatives should be considered in order to minimize the risk of undesirable hypoglycemia.

No self-monitoring of blood glucose is required to adjust the dose of Victoza. However, at the beginning of Victoza therapy in combination with sulfonylurea derivatives, such self-monitoring of blood glucose may be required to adjust the dose of sulfonylurea derivatives. Special patient groupsold age (>65 years): No age-specific dose adjustment is required. There is limited experience of using the drug in patients aged 75 years and older.

Patients with renal insufficiency No dose adjustment is required for patients with mild renal insufficiency. There is limited experience with the drug in patients with moderate renal insufficiency. Currently, the use of Victoza in patients with severe renal impairment, including patients with end-stage renal insufficiency, is contraindicated Patients with hepatic insufficiency Currently, there is limited experience with the use of Victoza in patients with hepatic insufficiency, so it is contraindicated to use it in patients suffering from mild, moderate or severe hepatic insufficiency.

Children and adolescents The lack of data on the use of Victoza in patients under 18 years of age does not allow us to recommend it for the treatment of patients in this group.

Overdose

Symptoms: during clinical trials and post-marketing period, cases of Victoza use in doses up to 40 times higher than the average recommended dose (72 mg) were reported, which was accompanied by the development of severe nausea and vomiting. There were no cases of severe hypoglycemia. All patients recovered completely without complications.

Treatment: Appropriate symptomatic therapy is recommended.

Special instructions

Victoza should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Victoza does not replace insulin. use of liraglutide to patients already receiving insulin has not been studied.

The experience of using Victozau in patients with heart failure of functional classes I–II in accordance with the NYHA functional classification of chronic heart failure is limited. There is no experience of using Victoza in patients with heart failure of functional classes III–IV in accordance with the NYHA classification of chronic heart failure.

Experience with the use of Victoza in patients with inflammatory bowel diseases and diabetic gastric paresis is limited, so the use of Victoza in these groups of patients is contraindicated. The use of Victoza is associated with the development of transient adverse reactions from the gastrointestinal tract, such as nausea, vomiting and diarrhea.

The use of other GLP-1 agonists was associated with a risk of pancreatitis. Several cases of acute pancreatitis have been reported. Patients should be informed about the characteristic symptoms of acute pancreatitis: persistent severe abdominal pain. If pancreatitis is suspected, treatment with Victoza and other potentially dangerous drugs should be stopped immediately.

In clinical trials of Victoza, thyroid side effects have been reported in selected patients (in particular, in patients with pre-existing thyroid diseases), including increased serum calcitonin, goiter, and thyroid neoplasms.

Signs and symptoms of dehydration and renal failure have been reported in patients treated with Victoza in clinical trials. Patients receiving Victoza should be warned about the possible risk of dehydration due to side effects from the gastrointestinal tract and the need to take precautions to avoid the development of hypovolemia.

Patients receiving Victoza in combination with sulfonylurea derivatives have an increased risk of hypoglycemia. The risk of hypoglycemia can be reduced by reducing the dose of sulfonylurea derivatives.

Influence on the ability to drive vehicles and work with mechanisms. Studies on the effect of Victoza on the ability to drive vehicles and work with mechanisms have not been conducted. It is unlikely that liraglutide can affect the ability to drive vehicles or work with mechanisms. Patients should be warned to take precautions to avoid developing hypoglycemia while driving vehicles and when working with machinery, especially when using Victoza in combination with sulfonylurea derivatives.

Usage Guide

Victoza should not be used if it looks different from a clear and colorless or almost colorless liquid.

Victoza should not be used if it has been frozen.

Victoza can be administered with needles up to 8 mm long and up to 32 g thick. The pen is designed for use in combination with NovoFine or NovoTvist disposable injection needles.

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 the syringe pen should not be stored with the needle attached. Such a measure will prevent contamination, infection and leakage of the drug from the syringe pen and guarantee the accuracy of dosing.

Form of production

Solution for subcutaneous use

Storage conditions

At a temperature of 2-8 °C (do not freeze)

Shelf life

30 months

Active ingredient

Liraglutide

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection

Purpose

For adults as directed by your doctor

Indications

Type 2 Diabetes