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

Active substanceLiraglutideLiraglutide

Similar drugsTo uncover

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 with 3 ml volume contains 18 mg of liraglutide);

Excipients: sodium hydrogen phosphate dihydrate 1.42 mg, propylene glycol 14.0 mg, phenol 5.5 mg, hydrochloric acid / sodium hydroxide q.s, water for injection up to 1 ml.

Description:

A colorless or almost colorless, clear 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

Liraglutide is an analog of human glucagon-like peptide-1 (GLP-1), produced by the method of biotechnology of recombinant DNA using a strain Saccharomyces cerevisiae, 97% homologous with human GLP-1, which binds and activates the human GLP-1 receptor. The GLP-1 receptor serves as a target for native GLP-1, the endogenous hormone of incretin, which stimulates glucose-dependent insulin secretion in beta cells of the pancreas.In contrast to native GLP-1, the pharmacokinetic and pharmacodynamic profiles of liraglutide allow it to be administered to patients once a day.

The long-acting profile of liraglutide with subcutaneous injection is provided by three mechanisms: self-association, which results in a slow absorption of the drug, binding to albumin and a higher level of enzymatic stability with respect to dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidase (NEP) enzyme, for thereby ensuring a long half-life of the drug from the plasma. The action of liraglutide is carried out through interaction with specific receptors of GLP-1, as a result of which the concentration of cyclic adenosine monophosphate (cAMP) increases. Under the influence of liraglutide glucose-dependent stimulation of insulin secretion and improvement of beta-cell function of the pancreas occur. At the same time, under the action of liraglutide glucose-dependent suppression of excessively high secretion of glucagon occurs. Thus, with increasing blood glucose concentration, stimulation of insulin secretion and suppression of glucagon secretion occur.On the other hand, during hypoglycemia lyraglutide reduces the secretion of insulin, but does not inhibit the secretion of glucagon. The mechanism of lowering the level of glycemia also includes a slight delay in gastric emptying.

Лираглутид reduces weight of a body and reduces fatty weight of a body by means of the mechanisms causing decrease of feeling of hunger and decrease in the charge of energy.

GLP-1 is the physiological regulator of appetite and caloric intake, and the GLP-1 receptors are located in several areas of the brain involved in the processes of regulating appetite.

In animal studies, peripheral administration of liraglutide led to the capture of the drug in specific areas of the brain, including the hypothalamus, where lyraglutide by specific activation of the GLP-1 receptors, increased saturation signals and attenuated the hunger signals, thereby leading to a decrease in body weight.

Studies in experimental animal models with pre-diabetes showed that lyraglutide slows the development of diabetes. Diagnostics in vitro showed that lyraglutide is a potent factor specifically stimulating the proliferation of beta cells of the pancreas andprevents the death of beta-cells (apoptosis), induced by cytokines and free fatty acids. In vivo liraglutide increases the biosynthesis of insulin and increases the mass of beta cells in experimental animal models with diabetes mellitus. When the glucose concentration is normalized, lyraglutide ceases to increase the mass of beta cells of the pancreas.

Pharmacodynamics

The drug Victoria® has a long 24-hour action and improves glycemic control by lowering fasting blood glucose and after eating in patients with type 2 diabetes.

Glucose-dependent insulin secretion

When the concentration of glucose in the blood increases, the preparation Victoria® increases the secretion of insulin. With the use of a stepwise infusion of glucose, the secretion of insulin after the administration of a single dose of the preparation Victoria® to patients with type 2 diabetes grows to a level comparable to that of healthy subjects (Figure 1).

Function of beta cells of the pancreas

The drug Victoria® improved the function of beta cells of the pancreas, 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 showed restoration of the first phase of insulin secretion (intravenous insulin administration), improvement of the second phase of insulin secretion (hyperglycemic clamp test) and maximum secretory activity of insulin (arginine stimulation test).

During the 52-week therapy with Victoria®, there was an improvement in the function of pancreatic beta cells, as evidenced by an evaluation of the homeostatic model of the pancreatic beta-cell function (HOMA-index) and the ratio of insulin to proinsulin.

Glucagon secretion

The drug Victoria®, stimulating the secretion of insulin and suppressing the secretion of glucagon, reduces the concentration of glucose in the blood. The drug Victoria® does not suppress the glucagon response to a low concentration of glucose. In addition, against the background of the preparation Victoria®, a lower production of endogenous glucose was observed.

Emptying the stomach

The drug Victoria® causes a slight delay in the emptying of the stomach, which leads to a decrease in the rate of entry of postprandial glucose into the blood.

Body weight, body composition and energy consumption

In subjects with high body weight, included in the long-term clinical studies of the drug Victoria®, the latter caused a significant decrease in body weight. Scanning with computer tomography (CT) and dual energy X-ray absorptiometry (DEPA) showed that weight loss occurred primarily due to fat loss in patients. These results are explained by the fact that during the treatment with the drug Victoria® patients feel hungry and consumes energy.

Electrophysiology of the heart (EFS)

The effect of the preparation Victoria® on the process of repolarization in the heart was tested in the EFS study. The use of the preparation Victoria in the equilibrium concentration in a daily dose of up to 1.8 mg does not produce an elongation of the adjusted interval QT.

Clinical efficacy

3992 patients with type 2 diabetes were randomized to 5 double-blind clinical safety and efficacy studies to evaluate the effect of Vitisa® on glycemic control. Therapy with Victoria® caused a clinically and statistically significant improvement in HbA_1C, fasting glucose and postprandial glucose compared with placebo. These studies included 3,978 patients who received therapy (2,501 patients were treated with Victoria®), 53.7% of men and 46.3% of women, and 797 patients (508 received Victoria®) aged ≥65 years, 113 patients 66 received therapy with the drug Victoria®) age was ≥ 75 years.

Glycemic control

The preparation Victoria ® in the form of monotherapy for 52 weeks caused a statistically significant (p <0.0014) and a prolonged decrease in the HbA_1C compared with the same index in patients treated with glimepiride. The observed decrease in HbA_1C below 7% persisted for 12 months (Figure 2).

In patients with HbA_1C above 9.5% at baseline, this indicator decreased by 2.1% against the background of monotherapy with Victoria®, while in patients participating in clinical trials of combined use of the drug Victoria®, the average HbA_1C decreased by 1.1-2.5%.

The drug Victoria® during a 26-week combination therapy with metformin, sulfonylurea preparations or metformin and thiazolidinedione caused a statistically significant (p <0.0001) and prolonged declineindicator HbA_1C compared with that of patients treated with placebo.

In patients who did not achieve adequate glycemic control for therapy with Victoria® and metformin, the addition of insulin detemir resulted in greater efficacy compared with therapy with Victoria® and metformin after 26 weeks of treatment (a decrease in HbA_1C by 0.52%).

It has been proven that the efficacy of a 0.6 mg preparation of Victoria® in combination with sulfonylureas or metformin is superior to placebo, but at the same time lower in comparison with doses of 1.2 mg and 1.8 mg.

Ratio of patients who achieved a decrease in the indicator HbA_1C

Against the backdrop of monotherapy with Victoria® during the 52-week study, the number of patients who reached the HbA_1C <7%, statistically significantly increased (p ≤ 0.0007) compared with the number of patients who received glimepiride. At the 26th week of the use of the preparation Victoria ® in combination with metformin, preparations of sulfonylurea derivatives or a combination of metformin with thiazolidinedione, the number of patients who reached the HbA_1C ≤ 6.5%, statistically significantly increased (p ≤ 0.0001) in relation to the number of patients who received oral hypoglycemic therapy without the addition of the preparation Victoria®.

In the groups of patients who did not achieve adequate glycemic control for therapy with Victoria® and metformin, the percentage of patients who achieved the target HbA_1C (<7% and ≤ 6,5%), was significantly higher with therapy insulin detemir + lyraglutide 1.8 mg + metformin, compared with therapy lyraglutide 1.8 mg + metformin (p ≤ 0,0001 / p = 0,0016).

During a 26-week study of the combined use of the preparation, Victoria® managed to achieve the HbA_1C <7% in the larger number of patients who received the drug as a combination therapy, compared with the number of patients who received it as a monotherapy.

Use in patients with impaired renal function

In a double-blind study of the efficacy and safety of Victoria® ® 1.8 mg versus placebo as an adjunct to insulin and / or oral hypoglycemic agents in patients with type 2 diabetes and a moderate degree of renal dysfunction, Victoria® was more effective in reducing level HbA_1C in 26 weeks (-1.05% compared to -0.38%, p <0.0001). Significantly more patients achieved the value of HbA_1C less than 7% with the use of the drug Victoria ®, but compared with the use of placebo (52.8% compared with 19.5%, p <0.0001). Patients treated with Victoria® had a statistically significant decrease in body weight compared to patients receiving placebo (-2.41 kg compared to -1.09 kg, p = 0.0052). The risk of developing episodes of hypoglycemia between the two treatment groups was comparable. The safety profile of the preparation Victoria® was, in general, similar to that found in other studies of the drug Victoria®.

Level of fasting glycemia

The fasting glucose concentration decreased by 13-43.5 mg% (0.72-2.42 mmol / l) against the background of the use of the preparation Victoria® both in monotherapy and in combination with one or two oral hypoglycemic drugs. This decrease was observed already during the first two weeks of treatment.

Postprandial level of glycemia

With the use of the drug, Victoria, there was a decrease in the concentration of postprandial glucose after each of the three daily meals by 31-49 mg% (1.68-2.71 mmol / l).

Body mass

The 52-week monotherapy with Victor® was associated with a sustained reduction in body weight.

Throughout the period of the clinical study, a sustained reduction in body weight was also associated with the use of the preparation Victoria in combination with metformin and in combination with a combination of metformin with sulfonylurea derivatives or a combination of metformin and thiazolidinedione.

The decrease in body weight in patients receiving the preparation of Victoria ® in combination with metformin, was also observed after the addition of insulin detemir.

The greatest decrease in body weight was observed in patients who had an elevated body mass index (BMI) at the starting point of the study.

Monotherapy with Victoria® preparation for 52 weeks caused a decrease in the average waist circumference by 3.0-3.6 cm.

Weight loss was observed in all patients treated with Victoria®, regardless of whether or not they experienced a side effect in the form of nausea.

The drug Victoria ® as a part of combined therapy with metformin reduced the volume of subcutaneous fat by 13-17%.

Nonalcoholic steatohepatosis

The drug Victoria® reduces the severity of steatohepatosis in patients with type 2 diabetes mellitus.

Immunogenicity

Given the possibility of immunogenic effects of protein and peptide drugs, the use of the drug Victoria in patients can lead to the formation of antibodies to liraglutide. The formation of antibodies is observed on average in 8.6% of patients. The formation of antibodies does not lead to a decrease in the effectiveness of the drug Victoria®.

Evaluation of the effect on the cardiovascular system

Long-term clinical studies have shown that the preparation Victoria® lowers systolic blood pressure by an average of 2.3-6.7 mm Hg. in the first two weeks of treatment. The drug Victoria® lowered the incidence of metabolic syndrome development in accordance with the definition III of the report of the expert group on adult therapy (APRIII). Reduction of systolic blood pressure occurred before weight loss.

In a retrospective analysis of serious adverse cardiovascular events (death due to cardiovascular disease, myocardial infarction, stroke), according to all long-term studies and studies of mean duration of II and III phases (lasting from 26 to 100 weeks),including 5,607 patients (3651 patients receiving the preparation of Victoria®), there was no increase in cardiovascular risk (the incidence ratio was 0.75 (95% CI 0.35, 1.63) for the combined endpoint with the use of Victoria® compared with all drugs of comparison (metformin, glimepiride, rosiglitazone, insulin glargine, placebo)). Patients with high cardiovascular risk were excluded from the study and the incidence of serious cardiovascular events in the study was low (6.02 per 1,000 patient-years in patients receiving the Victoria® drug and 10.45 in patients receiving all of the reference drugs) which prevents unambiguous conclusions.

Other clinical data

In an open study comparing efficacy and safety of the drug Victoria® at a dose of 1.8 mg and lixisenatide at a dose of 20 μg in 404 patients with poor glycemic control against metformin therapy (mean HbA_1C 8.4%), the preparation Victoria® more effectively reduced the level of HbA_1C compared with lixisenatide after 26 weeks of therapy (-1.83% compared to -1.21%, p <0.0001). In a significantly larger number of patients, the value of HbA_1C less than 7% with the use of the preparation Victoria® as compared with lixisenatide (74.2% versus 45.5%, p <0.0001), and also the target value of HbA_1C 6.5% or less (54.6% compared to 26.2%, p <0.0001). A significantly more pronounced decrease in fasting plasma glucose was achieved with the use of the preparation Victoria® as compared with lixisenatide (-2.85 vs. -1.70 mmol / L, p <0.0001). A decrease in body weight was noted in both treatment groups (-4.3 kg with Victoriaz® and -3.7 kg with lixisenatide). The safety profile of the drug, Victoria® and lixisenatide, was generally comparable. No new safety information was revealed with the use of the drug Victoria®.

In a comparative study of the efficacy and safety of the preparation of Victoria® (in doses of 1.2 mg and 1.8 mg) and the inhibitor of dipeptidyl peptidase-4 sitagliptin at a dose of 100 mg in patients who did not achieve adequate control for metformin therapy, after 26 weeks of treatment the best reduction indicator HbA_1C when using the drug

Victoria® in both doses compared to sitagliptin (-1.24%,-1.50% compared to -0 .90%, p <0.0001). A significantly larger number of patients reached the HbA_1C lower than 7% with the use of the preparation Victoria® as compared to sitagliptin (43.7% and 56.0% compared to 22.0%, p <0.0001). The decrease in body weight in patients receiving the preparation of Victoria® was significantly more than in patients receiving sitagliptin (- 2.9 kg and - 3.4 kg in comparison with - 1.0 kg, p <0.0001). Compared with patients receiving sitagliptin, patients who received the preparation of Victoria® were more likely to experience nausea. However, the nausea was transitory. The incidence of mild hypoglycemia was slightly different when treated with Victoria® and sitagliptin (0.178 and 0.161, compared with 0.106 cases / patient per year). Decrease in HbA_1C and the advantage of the preparation Victoria® as compared to sitagliptin, observed after 26 weeks of treatment with Victoria® (1.2 mg and 1.8 mg), remained after 52 weeks of treatment (-1.29% and 1.51% vs. - 0.88%, p <0.0001). After 52 weeks of the use of sitagliptin, the patients were transferred to the preparation of Victoria®, which led to an additional and statistically significant decrease in the HbA_1C at the 78th week of treatment (0.24% and 0.45%, 95 CI: from 0.41 to 0.07 and from -0.67 to 0.23), but the control group of patients was not available.

In a comparative study of the efficacy and safety of the drug Victoria® (at a dose of 1.8 mg) and exenatide (at a dose of 10 μg twice daily)who did not achieve adequate control on the therapy with metformin and / or sulfonylureas, after 26 weeks of administration of the preparation, a greater decrease in HbA_1C in comparison with exenatide (-1.12% versus 0.79%, p <0.0001). A significantly larger number of patients reached the HbA_1C less than 7% for therapy with the preparation of Victoria® as compared with exenatide (54.2% compared with 43.4%, p = 0.0015). Both therapies showed an average weight loss of about 3 kg. The number of patients reporting nausea was lower in the group of patients treated with Victoria®, compared with exenatide. The incidence of mild hypoglycemia was significantly lower in the group of patients treated with Victoria®, compared with exenatide (1.932 vs. 2,600 cases / patient per year, p = 0.01). After 26 weeks of exenatide, patients were transferred to the preparation of Victoria®, which led to an additional decrease in HbA_1C at the 40th week of treatment (-0.32%, p <0.0001), with 13% of patients achieving HbA_1Cbelow 7%.

Therapy with Victoria® for 52 weeks improved insulin sensitivity compared to that of sulfonylurea preparations,which was revealed using a homeostatic model of insulin resistance assessment HOMA-IR.

Pharmacokinetics:

Absorption

Absorption of liraglutide after subcutaneous administration is slow, the time to reach the maximum concentration in the plasma is 8-12 hours after the dose of the drug is administered. The maximum concentration (C_mOh) of liraglutide in plasma after subcutaneous injection in a single dose of 0.6 mg is 9.4 nmol / l. With the administration of liraglutide at a dose of 1.8 mg, the average value of its equilibrium concentration in plasma (AUC_{t / 24}) reaches about 34 nmol / l. The exposure of liraglutide is increased proportionally to the administered dose. After the administration of liraglutide in a single dose, the intra-individual coefficient of area variation under the "concentration-time" curve AUC is 11%. The absolute bioavailability of liraglutide after subcutaneous administration is approximately 55%.

Distribution

The apparent volume of distribution of liraglutide in tissues after subcutaneous administration is 11-17 liters. The average volume of distribution of liraglutide after intravenous administration is 0.07 l / kg. Liraglutide is largely associated with plasma proteins (> 98%).

Metabolism

Within 24 hours after the administration of a single dose of radioactive isotope labeled to healthy volunteers [³H] -liraglutide remained the main component of the plasma unchanged lyraglutide. Two metabolites in plasma were detected (≤ 9% and ≤ 5% of the level of total radioactivity in the blood plasma). Liraglutide is metabolized endogenously like large proteins, without involving any specific organ as a route of excretion.

Excretion

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

Special patient groups

Elderly age: Data of pharmacokinetic studies in the group of healthy volunteers and analysis of pharmacokinetic data obtained in the patient population (18 to 80 years),indicate that age does not have a clinically significant effect on the pharmacokinetic properties of liraglutide.

Floor: Population pharmacokinetic analysis of data from Investigating the effects of liraglutide in female and male patients, and the data from pharmacokinetic studies in healthy volunteers indicate that gender does not have a clinically meaningful effect on the pharmacokinetics of liraglutide.

Ethnicity: Population pharmacokinetic analysis of data obtained in the study of the action of liraglutide in subjects of white, black, Asian and Latin American racial groups, suggests that ethnicity has no clinically meaningful effect on the pharmacokinetics of liraglutide.

Obesity: Population pharmacokinetic analysis suggests that body mass index (BMI) has no clinically meaningful effect on the pharmacokinetics of liraglutide.

Liver failure:

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

Renal insufficiency:

The pharmacokinetics of liraglutide was studied in patients with varying degrees of renal failure in a single dose study. Subjects with varying degrees of renal insufficiency were included in this study: from mild (creatinine clearance 50-80 ml / min) to severe (creatinine clearance <30 ml / min) and subjects with end-stage renal failure who need hemodialysis. Renal insufficiency did not have a clinically significant effect on the pharmacokinetics of liraglutide.

Children: The study of the drug Victoria® in children was not conducted.

Pre-clinical safety data

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, tumors of thyroid C-cells in rats and mice that did not lead to death were detected. Non-toxic dose (NOAEL) in rats is not established. The appearance of such tumors in monkeys that received liraglutide therapy for 20 months was not noted. The results obtained from rodent studies are related 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 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 embryonic death in the treatment with the highest dose of the drug.The introduction of the drug Victoria® to rats in the middle of the period of pregnancy caused them to reduce the body weight of the mother and the growth of the embryo with unexplained effect on the ribs, and in the group of rabbits - deviations in the skeletal structure. The growth of newborns in the group of rats during the treatment with Victoria® drug decreased, and this decline persisted steadily after the end of breastfeeding in the group of models receiving high doses of liraglutide. It is not known whether this effect is due to a decrease in caloric intake due to the direct effect of GLP-1.

Indications:

The drug Victoria® is indicated for use once a day in adult patients with type 2 diabetes on the background of diet and exercise to achieve glycemic control as:

- Monotherapy;

- Combination therapy with one or more oral hypoglycemic drugs (with metformin, sulfonylurea derivatives or thiazolidinediones), in patients who did not achieve adequate glycemic control in previous therapy;

- Combined therapy with basal insulin in patients who did not achieve adequate glycemic control on therapy with Victoria® and metformin.

Contraindications:

- Hypersensitivity to the active substance or other components included in the preparation;

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

- Multiple endocrine neoplasia of type 2.

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

- Type 1 diabetes mellitus; diabetic ketoacidosis (see section "Special instructions");

- pregnancy and the period of breastfeeding (see the section on "Application during pregnancy and during breast-feeding");

- severe renal dysfunction;

- violations of the liver function;

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

- Inflammatory bowel disease (see section "Special instructions");

- diabetic gastroparesis (see section "Special instructions");

- Children under 18 years of age (see section "Method of administration and dose").

Carefully:

Due to limited experience, it is recommended to use with caution in patients with chronic heart failure I-II functional class (according to the classification NYHA); at the age of 75 years and older (see sections "Special instructions", "Method of administration and dose"); for diseases of the thyroid gland (see section "Special instructions").

Pregnancy and lactation:

Pregnancy

Adequate data on the use of the drug Victoria ® in pregnant women are absent. Animal studies have demonstrated the reproductive toxicity of the drug (see section "Pre-clinical safety data"). The potential risk to people is unknown.

It is contraindicated to use the drug Victoria® during pregnancy, instead it is recommended to carry out treatment with insulin. If the patient is preparing for pregnancy, or the pregnancy has already begun, therapy with Victoria® should be stopped immediately.

Breastfeeding period

It is not known whether the lyraglutide in the breast milk of women. Animal studies have shown that penetration of liraglutide and metabolites of a close structural bond into breast milk is low. Experience with the use of the drug Victoria® in lactating women is absent; the use of the drug in the period of breastfeeding is contraindicated.

Dosing and Administration:

Preparation Viktoza® applied once a day at any time, regardless of the meal, it can be administered as a subcutaneous injection in the abdomen, thigh or shoulder.

Place and time of injection may vary 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 the preparation Victoria ® is contained in the section "Guidelines for use".

The drug Victoria® you can not enter intravenously and intramuscularly.

Doses

To improve gastrointestinal tolerance, the initial dose of the drug is 0.6 mg of liraglutide per day. After applying 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 a patient, and taking into account the clinical efficacy of the drug Viktoza® dose can be increased to 1.8 mg after its application in a dose of 1.2 mg for at least a week. The use of the drug in a daily dose of more than 1.8 mg is not recommended.

The drug Victoria® can be used in addition to existing metformin therapy or combined therapy with metformin with thiazolidinedione. Therapy with metformin and thiazolidinedione can be continued in the previous doses.

The drug Victoria® can be added to the current therapy with derivatives of sulfonylureas or to combined therapy with metformin with derivatives sulfonylureas. When adding the drug Victoria® 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 (see section "Special instructions").

When you add Victoria® to basal insulin therapy, you should consider reducing the dose of insulin in order to minimize the risk of hypoglycemia (see section "Special instructions").

To correct the dose of the drug, Victoria® does not require self-monitoring of blood glucose. However, at the beginning of therapy with the preparation Victoria® in combination with sulfonylurea derivatives or basal insulin, such self-monitoring of blood glucose may be required to correct the dose of sulfonylurea derivatives or basal insulin.

Missing dose

If a dose is missed, the preparation should be administered as soon as possible within 12 hours of the scheduled dose.

If the duration of the pass is more than 12 hours, the preparation Victoria® should be administered the next day at the scheduled time.

Do not administer the next day an additional or increased dose of Victoria® to compensate for the missed dose.

Special patient groups

Elderly age (> 65 years): No dosage adjustment is required depending on age. There is limited experience in the use of the drug in patients aged 75 years and older (see subsection "Pharmacokinetics").

Patients with renal insufficiency

No dose adjustment is required in patients with renal insufficiency of mild or moderate severity (creatinine clearance 60-90 ml / min and 30-59 ml / min, respectively). The experience of using the drug in patients with severe renal failure (creatinine clearance below 30 ml / min) is absent. Currently, the use of the drug Victoria® in patients with severe renal dysfunction, including in patients with terminal stage of renal failure, is contraindicated (cf.subsection "Pharmacokinetics").

Patients with hepatic insufficiency

Currently, there is limited experience with the use of the drug Victoria® in patients with liver failure, so it is contraindicated to use it patients with hepatic insufficiency of mild, moderate or severe degree (see subsection "Pharmacokinetics").

Children and teens

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

Side effects:

The most frequently reported adverse reactions during clinical trials were disorders of the gastrointestinal tract: nausea and diarrhea were recorded very often, and vomiting, constipation, abdominal pain and dyspepsia were frequent.

At the beginning of therapy with the drug Victoria® these undesirable phenomena from the gastrointestinal tract can occur more often; these reactions usually weaken within a few days or weeks on the background of continuation of therapy. Headache and upper respiratory tract infections were also recorded frequently. In addition, hypoglycemia was recorded frequently and very often with the use of the preparation Victoria® in combination with sulfonylurea derivatives.The expressed hypoglycemia was predominantly noted in combination therapy with sulfonylurea derivatives.

Table 1 lists the undesirable reactions noted in long-term controlled Phase III trials and spontaneous (post-registration) messages. The frequency for related spontaneous (post-registration) messages was calculated on the basis of their frequency in clinical studies of Phase IIa.

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

System of organs	Often	Often	Infrequently	Rarely	Rarely
Infections and invasions		Upper respiratory tract infection
Immune system disorders				Anaphylactic reactions
Metabolic and nutritional disorders		Hypoglycemia * Anorexia Decreased appetite	Dehydration^#
Disturbances from the nervous system		Headache
Heart Disease		Increase heart rate
Disorders from the gastrointestinal tract	Nausea Diarrhea	Vomiting Dyspepsia Pain in the upper abdomen Constipation Gastritis Flatulence Bloating Gastroesophageal reflux disease Belching			Pancreatitis (including pancreatic necrosis)
Disturbances from the skin and subcutaneous tissues		Rash	Hives Itching
Disorders from the kidneys and urinary tract			Impaired renal function^# Acute kidney failure^#
General disorders and reactions at the site of administration		Reactions at the site of administration	Malaise

N = 2501 patients treated with Victoria®

^*The phenomenon occurs very often when used in combination with insulin.

^# see section "Special instructions"

Description of individual adverse reactions

Hypoglycaemia

Most episodes of confirmed hypoglycemia recorded during clinical trials were mild.

During clinical trials with the use of the drug Victoria ® in the form of monotherapy, no cases of severe hypoglycemia were noted. Severe hypoglycemia can occur infrequently and is mainly observed with the use of the preparation Victoria in combination with sulfonylurea derivatives (0.02 cases / patient per year).When using the drug Victoria ® in combination with other oral hypoglycemic drugs (not derivatives of sulfonylureas), individual cases of hypoglycemia were observed (0.001 cases / patient per year).

With the treatment with the drug Victoria ® in a dose of 1.8 mg in combination with insulin detemir and metformin, no cases of severe hypoglycemia were noted. 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 cancellation of therapy.

The percentage of patients with adverse reactions in the form of nausea (weekly) in a long-term clinical trial is shown in Fig.

20.7% of patients who received the preparation of Victoria ® in combination with metformin, suffered a minimum of one nausea episode, and 12.6% - at least one episode of diarrhea. With the use of the preparation Victoria® in combination with sulfonylurea derivatives, at least one episode of nausea was noted in 9.1% of patients, and 7.9% of at least one case of diarrhea.

In long-term, controlled clinical trials (26 weeks or more), the incidence of discontinuation due to side effects was 7.8% in the group of patients treated with Victoria® and 3.4% in the comparator group . The most frequent adverse reactions that led to the withdrawal of the drug Victoria® 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 the drug Victoria® can be higher.

With the use of the preparation Victoria in patients with mild and moderate renal insufficiency (creatinine clearance 60-90 ml / min and 30-59 ml / min, respectively), the incidence of adverse reactions from the gastrointestinal tract may be higher.

Reactions at the site of administration

In long-term (26 weeks or more) controlled trials, approximately 2% of patients treated with Victoria® received reactions at the injection site. These reactions were, as a rule, easy in nature.

Pancreatitis

Several cases of acute pancreatitis (<0.2%) have been reported in long-term clinical trials.There are reports of cases of development of pancreatitis in the post-marketing period.

Allergic reactions

In the postgrade period, allergic reactions such as urticaria, rashes and itching were reported.

In the post-marketing period with the use of the drug Victoria ® described several cases of anaphylactic reactions, accompanied by symptoms such as arterial hypotension, palpitation, shortness of breath, peripheral edema.

Increase heart rate

There have been reports of an increase in the heart rate with the use of the drug Victoria®. In long-term clinical trials with the use of the preparation Victoria®, the average increase in the heart rate from the baseline was 2 to 3 beats per minute. Long-term clinical consequences have not been established.

Overdose:

According to clinical studies and postagregational application of liraglutide, overdose cases with an increase in dose up to the recommended dose of 40 times (72 mg) were recorded. One case of overdose was observed with a dose exceeding 10 times (18 mg daily) for 7 months.As a rule, patients noted severe nausea, vomiting and diarrhea, but recovered without residual effects. None of the patients had severe hypoglycemia.

In the case of an overdose of the drug, Victoria® recommended the appropriate symptomatic therapy.

Interaction:

Evaluation of the interaction of drugs in vitro

Viktoza® preparation showed very low ability to pharmacokinetic drug interaction caused metabolism in cytochrome P-450 (RMS), and binding to plasma proteins.

Evaluation of drug interactions in vivo

A slight delay in gastric emptying with the use of the drug Victoria® can have an effect on the absorption of concomitant oral medications. Studies of drug interaction did not show any clinically significant slowing of absorption of these drugs, so dose adjustment is not required. Several patients treated with Victoria® received at least one episode of acute diarrhea. Diarrhea can affect the absorption of oral medications that are used concomitantly with the preparation Victoria®.

Warfarin and other coumarin derivatives

Interaction studies have not been conducted. Clinically significant interaction with active substances with low solubility or a narrow therapeutic index, such as warfarin. At the beginning of treatment with the drug Victoria® in patients receiving warfarin or other coumarin derivatives, it is recommended to monitor the International Normalized Ratio (INR) more often.

Paracetamol

A single application of paracetamol in a dose of 1000 mg against the background of the use of the drug Victoria® does not cause a change in systemic exposure. FROM_mOh paracetamol in the plasma decreased by 31%, and the mean time to reach the maximum concentration in the blood plasma t_max increased by 15 minutes. With the simultaneous administration of the drug Victoria® and paracetamol, dose adjustment of the latter is not required.

Atorvastatin

A single application of atorvastatin in a dose of 40 mg against the background of the use of the drug Victoria® does not cause a change in systemic exposure. Thus, against the background of taking the drug, Victoria® dose correction atorvastatin is not required. FROM_mOh Atorvastatin in plasma decreased by 38%, and the mean t_max In plasma, with the reception of the drug, Victoria® increased from 1 to 3 hours.

Griseofulvin

A single application of griseofulvin in a dose of 500 mg against the background of the use of the drug Victoria® does not cause a change in systemic exposure. FROM_mOh griseofulvin increased by 37%, while the mean t_max in plasma has not changed. Correction of the dose of griseofulvin and other drugs that have low solubility and high permeability is not required.

Digoxin

With the simultaneous single administration of digoxin in a dose of 1 mg and the preparation of Victoria® there was a decrease in the area under the curve AUC digoxin by 16%; FROM_mOh digoxin decreased by 31%. Average value t_max digoxin in plasma increased from 1 to 1.5 hours. Based on the results obtained, correction of the dose of digoxin is not required.

Lisinopril

A single application of lisinopril in a dose of 20 mg against the background of the use of the preparation of Victoria® led to a decrease in the area under the curve AUC lisinopril by 15%; FROM_mOhlisinopril decreased by 27%. Average value t_max Lysinopril in plasma on the background of taking the drug Victoria® increased from 6 to 8 hours. Based on the results obtained, dose adjustment of lisinopril is not required.

Oral contraceptives

FROM_mOh ethinyl estradiol and levonorgestrel after their single use on the background of therapy with the drug Victoria® decreased by 12% and 13%, respectively. The use of both drugs together with the preparation of Victoria® was accompanied by an increase t_max of these medicines for 1.5 hours. Clinically significant effect on the systemic exposure of ethinylestradiol and levonorgestrel in the body lyraglutide does not render. Thus, the expected contraceptive effect of both drugs against the background of therapy with the preparation of Victoria® does not change.

Insulin

There was no pharmacokinetic or pharmacodynamic interaction of the drug Victoria® with insulin detemir with a single application of insulin detemir in a dose of 0.5 U / kg with a preparation of Victoria® at a dose of 1.8 mg in patients with type 2 diabetes.

Incompatibility

Substances added to the preparation of Victoria® can cause degradation of liraglutide. The drug Victoria® should not be mixed with other medicines, including infusion solutions.

Special instructions:

The use of the drug Victoria® is contraindicated in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

The drug Victoria® does not replace insulin.

Experience with the use of the preparation Victoria in patients with chronic heart failure I-II functional classes in accordance with the functional classification of chronic heart failure NYHA limited, so in these patients the drug should be used with caution. There is no experience with the use of the preparation Victoria in patients with chronic heart failure III-IV functional classes in accordance with the classification of chronic heart failure NYHA. The use of the drug Victoria ® in these patients is contraindicated.

The experience with the use of the drug Victoria ® in patients with inflammatory bowel diseases and diabetic gastroparesis is limited. The use of the drug Victoria® in these groups of patients is contraindicated, because is associated with the development of transient adverse reactions from the gastrointestinal tract, such as nausea, vomiting and diarrhea.

Acute pancreatitis

The use of GLP-1 agonists was associated with a risk of developing acute pancreatitis. It was reported on the development of acute pancreatitis during clinical trials and post-registration period.Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, therapy with Victoria® should be discontinued immediately; In case of confirmation of acute pancreatitis, therapy with Vitza® should not be resumed. Care should be taken when using the drug in patients with pancreatitis in history.

Thyroid gland diseases

During the clinical trials of the preparation Victoria®, certain patients (in particular, patients already having thyroid disease) reported side effects from the thyroid gland, including an increase in serum calcitonin concentration, goitre and thyroid nodules, in connection with this preparation of Victoria ® in these patients should be used with caution (see the section "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.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).

Hypoglycaemia

Patients receiving the preparation Victoria ® in combination with derivatives of sulfonylureas or basal insulin have an increased risk of developing hypoglycemia (see section "Side effect"). The risk of developing hypoglycemia can be reduced by reducing the dose of sulfonylurea derivatives or basal insulin.

Dehydration

Clinical studies reported the appearance of signs and symptoms of dehydration and renal failure in patients taking the drug Victoria®. Patients receiving the Vitaza® preparation should be warned about the possible risk of dehydration due to side effects from the gastrointestinal tract and the need for them to take precautions to avoid the development of hypovolemia.

Fertility

With the exception of a small decrease in the number of live implants, no evidence of adverse effects on fertility has been obtained in animal studies.

Instructions for Use

The Vitza® pen is only for individual use. The drug Victoria® can not be used if it looks different than a clear and colorless or almost colorless liquid.

The drug Victoria® can not be used if it has been frozen.

The drug Victoria® can be administered with needles up to 8 mm in length and up to 32G. The syringe pen is intended for use in combination with disposable needle injectors 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 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:

Studies of the influence of the drug Victoria® on the ability to drive vehicles and work with mechanisms have not been conducted. It is unlikely that the drug Victoria® can affect the ability to drive vehicles or work with mechanisms.Patients should be warned that they should take precautions to avoid developing hypoglycemia during driving and handling mechanisms, especially with the use of the preparation Victoria in combination with sulfonylureas or basal insulin.

Form release / dosage:Solution for subcutaneous administration, 6 mg / ml.

Packaging:

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

The cartridge is sealed in a plastic disposable syringe pen for multiple injections.

For 1, 2 or 3 plastic disposable syringe-pens for multiple injections together with instructions for use in a cardboard pack.

Each syringe-pen (3 ml) contains 30 doses of 0.6 mg, 15 doses of 1.2 mg or 10 doses of 1.8 mg of liraglutide.

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.

For the syringe pen in use: use within 1 month.Store at temperatures no higher than 30 ° C or 2 ° C to 8 ° C (in the refrigerator). Do not freeze. Close the syringe handle with a cap to protect it from light.

The drug Victoria® should be protected from the effects of excessive heat and light.

Shelf life:

30 months.

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

Terms of leave from pharmacies:On prescription

Registration number:LSR-004405/10

Date of registration:18.05.2010

Expiration Date:Unlimited

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