Instruction for use: Insulin degludec + Liraglutide (Insulinum degludecum + Liraglutidum)

Pharmacological group

Insulin in combination

Nosological classification (ICD-10)

E11 Non-insulin-dependent diabetes mellitus

Acetonuric diabetes, Decompensation of carbohydrate metabolism, Diabetes insulin-independent sugar, Diabetes sugar type 2, Type 2 Diabetes, Non-insulin-dependent diabetes, Non-insulin dependent diabetes mellitus, Non-insulin-dependent diabetes mellitus, Insulin resistance, Insulin resistant diabetes mellitus, Coma lactobacillus diabetic, Violation of carbohydrate metabolism, Type 2 diabetes mellitus, Diabetes mellitus type II, Diabetes mellitus in adulthood, Diabetes mellitus in old age, Diabetes insulin-independent, Diabetes mellitus type 2, Sugar insulin-independent diabetes type II

Characteristics

A hypoglycemic combination, consisting of insulin degludec and liraglutide (produced by the method of biotechnology of recombinant DNA (deoxyribonucleic acid) using the strain Saccharomyces cerevisiae), which have complementary mechanisms of action for improving glycemic control. Analogue of long-acting insulin.

Pharmacology

Pharmacological action - hypoglycemic.

Mechanism of action

Insulin degludec is a basal insulin that, after the SC administration, forms soluble multhexamers forming a depot in the subcutaneous fat, wherece there is a continuous and slow absorption of insulin into the bloodstream, providing an ultra-long, flat and stable hypoglycemic effect with low day-to-day variability.

Insulin degludec specifically binds to the human insulin receptor, providing the same pharmacological effect as human insulin.

The hypoglycemic effect of insulin degludec is due to the increased utilization of glucose by tissues after the binding of insulin to the receptors of muscle and fat cells and the simultaneous inhibition of glucose from the liver.

Liraglutide is an analog of human GLP-1 with 97% homology to human endogenous GLP-1, which binds and activates the GLP-1 receptor. The long-lasting action profile of liraglutide with n-to-c administration is provided by three mechanisms: self-association, which results in a delayed absorption; Binding to albumin; Higher resistance to DPP-4 and neutral endopeptidase (NEP), which leads to an increase in T1 / 2 from plasma.

The effect of liraglutide is due to a specific interaction with the GLP-1 receptors and to improve glycemic control by decreasing the fasting blood glucose and after eating. Liraglutide stimulates the secretion of insulin and reduces the excessively high secretion of glucagon in a glucose-dependent manner. With an increase in the concentration of glucose in the blood, stimulation of insulin secretion and inhibition of glucagon secretion occur. Conversely, during hypoglycemia, liraglutide reduces insulin secretion and does not interfere with the secretion of glucagon. The mechanism of reducing blood glucose is also associated with a slight delay in emptying the stomach. Liraglutide reduces body weight and fat tissue by mechanisms that reduce hunger and reduce energy consumption.

Pharmacodynamics

The combination of insulin degludec + liraglutide has a stable pharmacodynamic profile with a duration of action reflecting the combination of individual profiles of insulin degludec and liraglutide, which allows it to be administered once a day at any time, regardless of food intake. Improves glycemic control by persistent lowering of fasting blood glucose and after eating.

Decrease in postprandial glucose concentration was confirmed in a 4-hour follow-up with a standard breakfast in which patients with unsatisfactory glycemic control participated with metformin monotherapy or metformin therapy combined with pioglitazone. The combination of insulin degludec + liraglutide resulted in a significantly more pronounced decrease in the postprandial increase in plasma glucose concentration (mean for 4 hours compared to insulin). When comparing the combination of insulin degludec + liraglutide and liraglutide, close results were obtained.

Insulin secretion / function of pancreatic beta cells

The combination of insulin degludec + liraglutide improves the function of beta cells of the pancreas as compared to insulin degludec, as shown in the homeostatic model for assessing the function of beta cells of the pancreas (HOMA-beta). Improved insulin secretion compared with insulin degludec was demonstrated in a 4-hour sub-analysis with a standard breakfast in which patients with poor glycemic control were treated with metformin treated as monotherapy or in combination with pioglitazone for 52 weeks.

Clinical efficacy and safety

Addition to oral hypoglycemic drugs

Addition to therapy of metformin in the form of monotherapy or in combination with pioglitazone. The efficacy and safety of the combination of insulin degludec + liraglutide in comparison with insulin degludec and liraglutide with all drugs once a day was studied in a 26-week, randomized, controlled, open-label, open-label study with a 26-week prolongation period involving patients with Type 2 diabetes mellitus. The initial dose of a combination of insulin degludec + liraglutide and insulin degludec was 10 dose steps and 10 units respectively, the dose was adjusted 2 times a week by increasing or decreasing (2 insulin degludec units / 0.072 mg liraglutide) to a target plasma glucose concentration of 4-5 mmol / l in fasting plasma. In patients from the group of liraglutide, the initial dose was 0.6 mg, and an increase in the dose to a maintenance dose of 1.8 mg was carried out according to a fixed dose increase schedule of 0.6 mg once a week. The maximum dose of insulin degludec + liraglutide combination was 50 dose steps. In the insulin degludec group, the maximum dose was not established.

When using the combination of insulin degludec + liraglutide, the decrease in HbA1c at the 26th week was 1.9% compared to the baseline value, which demonstrates a higher efficacy compared with liraglutide (difference -0.64%, p <0.0001) and not less Effectiveness compared with insulin degludec (difference -0.47%, p <0.0001). Body weight was reduced by 0.5 kg with the combination of insulin degludec + liraglutide, the difference between the combination of insulin degludec + liraglutide and insulin degludec -2.22 kg (p <0.0001), which confirms a higher efficacy compared with insulin degludec . When using the combination of insulin degludec + liraglutide, a significant reduction in the overall risk of hypoglycemia was demonstrated in comparison with insulin degludec. It was shown that when using the combination of insulin degludec + liraglutide, the frequency of hypoglycemia development in the whole range of HbA1c values was less in comparison with the use of insulin degludec.

80.6% of patients who received the insulin degludec + liraglutide combination achieved the target HbA1c <7% after 26 weeks of treatment. The result was statistically significantly greater than that observed for both insulin degludec (65.1%) and liraglutide (60.4%), p <0.0001. The fasting plasma glucose concentration decreased from 9.2 to 5.6 mmol / L with the combination of insulin degludec + liraglutide, from 9.4 to 5.8 mmol / L with insulin degludec, from 9 to 7.3 mmol / L with the use of liraglutide. The decrease was similar with the combination of insulin degludec + liraglutide and insulin degludec, but was significantly higher than with liraglutide (difference -1.76 mmol / l, p <0.0001). The insulin dose at the end of the study was 38 units for the combination of insulin degludec + liraglutide and 53 units for insulin degludec (difference -14.9, p <0.0001).

After 26 weeks of therapy, 60.4% of patients who received the insulin degludec + liraglutide combination achieved the target HbA1c <7% without confirmed * hypoglycemia episodes. The proportion of patients was significantly higher than in the group of insulin degludec (40.9%), and similar to that in the group of liraglutide (57.7%). The incidence of confirmed episodes of hypoglycemia when using the combination of insulin degludec + liraglutide was less than with the use of insulin degludec, regardless of glycemic control.

* Confirmed hypoglycemia is defined as severe (episode requiring the help of another person) and / or mild (plasma glucose concentration <3.1 mmol / L, regardless of symptoms).

The indicator of the frequency of development of severe hypoglycemia, defined as an episode requiring the help of another person, was 0.01 (2 patients out of 825) for the patient-year of exposure with the use of insulin degludec + liraglutide, 0.01 (2 patients out of 412) Insulin degludec and 0 (0 patients out of 412) with the use of liraglutide. The frequency of development of nocturnal hypoglycemia was the same when using the combination of insulin degludec + liraglutide and insulin degludec.

In patients who received the combination of insulin degludec + liraglutide, overall, there were fewer side effects on the part of the gastrointestinal tract than in patients receiving liraglutide. This may be due to a slower increase in the dose of liraglutide at the beginning of therapy with a combination of insulin degludec + liraglutide compared with that at the beginning of therapy with liraglutide.

The efficacy and safety of the combination of insulin degludec + liraglutide persisted until the 52nd week of therapy. The decrease in HbA1s for 52 weeks compared with the baseline value was 1.84% when using the combination of insulin degludec + liraglutide, the difference compared to liraglutide is -0.65% (p <0.0001) and -0.46% compared to insulin Degludec (p <0.0001). Body weight was reduced by 0.4 kg with the combination of insulin degludec + liraglutide, the difference compared to insulin degludec -2.8 kg (p <0.0001), and the incidence of confirmed hypoglycemia remained 1.8 events per patient Year exposure, supporting a significant reduction in the risk of confirmed hypoglycemia compared with insulin degludec.

Addition to monotherapy with a drug from the sulfonylurea derivatives group or a combination of metformin and sulfonylurea derivatives. The efficacy and safety of the combination of insulin degludec + liraglutide when added to treatment with the drug sulfonylurea as monotherapy or in combination with metformin was studied in a 26-week, randomized, placebo-controlled, double-blind study with the concept of "treatment to the goal," in which 435 patients Type 2 diabetes mellitus, of which 289 received a combination of insulin degludec + liraglutide. The initial dose of the combination was 10-step doses; The dose was adjusted 2 times a week by increasing or decreasing by 2 steps of the dose (2 units of insulin degludec / 0.072 mg of liraglutide) to the target plasma glucose concentration on an empty stomach of 4-6 mmol / l. When using the combination of insulin degludec + liraglutide, the decrease in HbA1s at week 26 was 1.45% compared to baseline, which is more effective than placebo (difference -1.02%, p <0.0001) . Body weight with the combination of insulin degludec + liraglutide increased by 0.5 kg, the difference between the combination and placebo was 1.48 kg (p <0.0001). Using a combination of insulin degludec + liraglutide, a statistically significantly higher incidence of confirmed hypoglycemia was observed compared with placebo (3.52% compared with 1.35% of patients, a ratio of 3.74, p <0.0001).

79.2% of patients who received the insulin degludec + liraglutide combination achieved the HbA1c target <7% after 26 weeks of treatment, compared with 28.8% of patients receiving placebo (p <0.0001). The fasting plasma glucose concentration decreased from 9.1 to 6.6 mmol / L with the combination of insulin degludec + liraglutide, from 9.1 to 8.8 mmol / L with placebo (difference 2.3 mmol / L, p < 0.0001). The insulin dose for the combination of insulin degludec + liraglutide at the end of the study was 28 units.

The rate of development of severe hypoglycemia in the patient-year of exposure was 0.02 (2 patients out of 288) with the combination of insulin degludec + liraglutide and 0 (0 patients out of 146) with placebo.

Transfer from basal insulin therapy

The efficacy and safety of the combination of insulin degludec + liraglutide compared with insulin degludec once a day was studied in a 26-week randomized double-blind study with the concept of "treatment to the goal" involving patients with type 2 diabetes mellitus with poor glycemic control in the background Basal insulin therapy (20-40 units) and metformin alone or in combination with a sulfonylurea / clay preparation. Basal insulin and sulfonylureas / clay preparations were discontinued when randomized. The initial dose of a combination of insulin degludec + liraglutide and insulin degludec was 16 dose steps and 16 units, respectively; The dose was adjusted 2 times a week by increasing or decreasing by 2 steps of the dose (2 units of insulin degludec / 0.072 mg liraglutide) to the target plasma glucose concentration on an empty stomach 4-5 mmol / l. The maximum allowed dose of the combination insulin degludec + liraglutide was 50 steps of the dose, and insulin degludec - 50 units.

The decrease in HbA1c at the end of the study compared to the baseline value when using the combination of insulin degludec + liraglutide was 1.9%, which demonstrates a higher efficacy compared with insulin degludec at a maximum dose of 50 units (-1.05% difference, p <0, 0001). Body weight decreased by 2.7 kg with the use of insulin degludec + liraglutide combination, which indicates a significant decrease in the insulin level of degludec (difference -2.51 kg, p <0.0001), and the overall risk of developing hypoglycemia was the same when applied Combinations of insulin degludec + liraglutide and insulin degludec, despite lower values of HbA1c at the end of the study when the combination was used.

60.3% of patients who received the insulin degludec + liraglutide combination achieved the target HbA1c <7% after 26 weeks of treatment, compared with 23.1% of patients receiving insulin degludec, p <0.0001. The fasting plasma glucose concentration decreased from 9.7 to 6.2 mmol / L with the combination of insulin degludec + liraglutide and from 9.6 to 7 mmol / L with insulin degludec (difference -0.73 mmol / L, p <0 , 05). The insulin dose for both the combination of insulin degludec + liraglutide and insulin deglucose at the end of the study was 45 units.

After 26 weeks of therapy, the target HbA1c <7% was achieved in 48.7% of patients without episodes of confirmed hypoglycemia, which was significantly greater than in the group of insulin degludec (15.6%).

The incidence of severe hypoglycemia was 0.01 (1 patient out of 199) with insulin degludec plus liraglutide and 0 (0 patients out of 199) with insulin degludec. The frequency of development of nocturnal hypoglycemia was the same when using the combination of insulin degludec + liraglutide and insulin degludec.

Other clinical data

Arterial hypertension. In patients with unsatisfactory control of glycemia against metformin in the form of monotherapy or in combination with pioglitazone, the combination of insulin degludec + liraglutide reduced the average SAD by 1.8 mm Hg. Art. Compared with a decrease of 0.7 mm Hg. Art. When using insulin degludec and at 2.7 mm Hg. Art. When using liraglutide. In patients with unsatisfactory control of glycemia, when taking sulfonylureas in the form of monotherapy or in combination with metformin, the reduction was 3.5 mm Hg. Art. When using a combination of insulin degludec + liraglutide and 3.2 mm Hg. Art. (Millimeter of mercury) with placebo. The difference was statistically insignificant. In patients with unsatisfactory glycemic control against basal insulin therapy, the mean SAD decrease was 5.4 mm Hg. Art. When using a combination of insulin degludec + liraglutide and 1.7 mm Hg. Art. When using insulin degludec, a statistically significant difference was -3.71 mm Hg. Art. (P = 0.0028).

Nausea. The proportion of patients who reported nausea at any time of therapy with the combination of insulin degludec + liraglutide was less than 4%; Nausea was transient in most patients.

Preclinical safety data

The preclinical research program for insulin degludec / liraglutide included basic toxicity studies of up to 90 days in one animal species (Wistar rats). Local tolerance was assessed in rabbits and pigs.

Preclinical data based on repeated dose toxicity studies did not reveal any danger to humans.

Local responses in two studies on rabbits and pigs were limited to mild inflammatory responses.

Studies using a combination of insulin degludec + liraglutide to assess carcinogenesis, mutagenesis and fertility disorders have not been conducted. The following data are based on the results of individual studies of insulin degludec and liraglutide.

Insulin Degludec

Preclinical data based on pharmacological safety studies, repeated dose toxicity, carcinogenic potential and reproductive toxicity did not reveal any danger to humans.

The ratio of metabolic and mitogenic activity of insulin deglucose is similar to that of human insulin.

Liraglutide

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

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

In animal studies, there was no direct adverse effect of liraglutide on fertility, but there was a slight increase in the incidence of early embryonic death with the highest dose applied. The administration of liraglutide in the middle of the gestational period caused a decrease in the body weight of the mother and fetal growth with an unexplained effect on the ribs in rats, and in rabbits - abnormalities in the structure of the skeleton. The growth of newborns was reduced in rats during therapy with liraglutide, and this decrease persisted after the end of breastfeeding in the group receiving high doses. It is not known what caused such a decrease in the growth of newborn rats: a decrease in milk consumption by newborns due to the effect of GLP-1 or a decrease in milk production by maternal individuals due to a reduction in their caloric intake.

Pharmacokinetics

In general, the pharmacokinetics of insulin degludec and liraglutide with the administration of insulin degludec + liraglutide combination did not clinically change significantly compared to individual injections of insulin deglucose and liraglutide.

The pharmacokinetic properties of the combination of insulin degludec + liraglutide are given below unless indicated that the data presented are obtained by administering insulin degludec or liraglutide separately.

Suction

The total exposure of insulin degludec was the same after administration of a combination of insulin degludec + liraglutide and insulin degludec alone, while Cmax was 12% higher. The total exposure of liraglutide was the same after administration of a combination of insulin degludec + liraglutide and liraglutide alone, while Cmax was lower by 23%. The difference was regarded as clinically insignificant, since the initial dose of the insulin degludec + liraglutide combination and dose adjustment depend on the target glucose concentration in the particular patient.

Based on the results of the population pharmacokinetic analysis, the exposure of insulin degludec and liraglutide increased in proportion to the dose of insulin degludec + liraglutide in the entire dose range.

The pharmacokinetic profile of the combination of insulin degludec + liraglutide allows it to be administered once a day, and Css of insulin degludec and liraglutide is achieved after 2-3 days of daily administration.

Distribution

Insulin degludec and liraglutide largely bind to blood plasma proteins (> 99% and> 98%, respectively).

Metabolism

Insulin Degludec. The breakdown of insulin degludec is similar to that of human insulin; All formed metabolites are inactive.

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

Excretion

T1 / 2 (half-life) of insulin degludec is approximately 25 hours, T1 / 2 liraglutide is approximately 13 hours.

Special patient groups

Patients of advanced age

According to the results of population pharmacokinetic analysis of data, including data on the combination of insulin degludec + liraglutide in patients under 83 years of age, the age did not have a clinically significant effect on the pharmacokinetics of the combination.

Gender

According to the results of population pharmacokinetic analysis, sex had no clinically significant effect on the pharmacokinetics of the combination of insulin degludec + liraglutide.

Ethnicity

According to the results of the population pharmacokinetic analysis, which included data on patients of Caucasoid, Negroid, Asian and Hispanic and Indian descent, ethnicity does not have a clinically significant effect on the pharmacokinetics of the combination of insulin degludec + liraglutide.

Impaired liver function

Insulin Degludec. There were no clinically significant differences in the pharmacokinetics of insulin deglucal between patients with impaired hepatic function and healthy individuals.

Liraglutide. The pharmacokinetics of liraglutide were evaluated in patients with varying degrees of impaired liver function in a single-dose study. The study included patients with impaired liver function from mild (5-6 points according to Child Pugh classification) to severe degree (> 9 points according to Child Pugh classification). Exposure was not increased in patients with impaired hepatic function in comparison with healthy individuals, thus, a violation of liver function did not exert any clinically significant effect on the pharmacokinetics of liraglutide.

Renal insufficiency

Insulin Degludec. There were no clinically significant differences in the pharmacokinetics of insulin deglucose between patients with impaired renal function and healthy subjects.

Liraglutide. The pharmacokinetics of liraglutide were evaluated in patients with varying degrees of renal dysfunction in a single-dose study. Patients with impaired renal function from mild (calculated Cl creatinine 50-80 ml / min) to severe (calcu lar creatinine <30 ml / min) and patients with terminal stage of chronic kidney disease requiring dialysis were included in the study. Disturbance of renal function did not exert any clinically significant effect on the pharmacokinetics of liraglutide.

Children

Studies of the efficacy and safety of the combination of insulin degludec + liraglutide in children and adolescents under the age of 18 have not been conducted.

Indications

The combination of insulin degludec + liraglutide is indicated for achieving glycemic control in adults with type 2 diabetes mellitus in combination with oral hypoglycemic agents.

Contraindications

Hypersensitivity to insulin degludec or liraglutide; Contraindicated use due to lack of data on efficacy and safety in the following groups of patients: children under 18 years of age; Period of pregnancy and breastfeeding; Chronic heart failure III-IV functional class (according to the NYHA classification); Impaired liver function; Impaired renal function of severe severity; Diabetes mellitus type 1, diabetic ketoacidosis; Inflammatory bowel disease and diabetic gastroparesis.

Restrictions for use

Chronic heart failure class I-II according to the NYHA classification (experience of use is limited); Thyroid gland diseases; Chronic pancreatitis in anamnesis (see "Precautions").

pregnancy and lactation

The clinical experience of using a combination of insulin degludec + liraglutide, insulin degludec or liraglutide in pregnant women is absent. The use of a combination of insulin degludec + liraglutide during pregnancy is contraindicated. When planning or onset of pregnancy, therapy with a combination of insulin degludec + liraglutide should be discontinued.

In studies of reproductive function in animals, there was no difference between insulin degludec and human insulin in terms of embryotoxicity and teratogenicity. Reproductive toxicity was demonstrated in animal studies of liraglutide (see Preclinical Safety Data). The potential risk to humans is unknown.

The clinical experience of using the combination of insulin degludec + liraglutide during breastfeeding is absent. It is not known whether liraglutide or insulin degloodec penetrates into human breast milk. In connection with the lack of experience of application, the combination of insulin degludec + liraglutide is contraindicated during breastfeeding.

In rats, insulin deglutec penetrates into breast milk, its concentration in breast milk was lower than in blood plasma. In animal studies, it has been demonstrated that the penetration of liraglutide and metabolites of a similar structure into breast milk is low.

Side effects

The clinical studies of the combination of insulin degludec + liraglutide showed no increase in the incidence of specific adverse reactions compared to the individual components of the combination: insulin degludec and liraglutide. Hypoglycemia and gastrointestinal disturbances were the most frequently observed undesirable reactions during therapy with a combination of insulin degludec + liraglutide (see "Selected adverse reactions").

Undesired reactions associated with the use of the combination of insulin degludec + liraglutide are listed below in accordance with the classification of organ systems and frequency of occurrence. Categories of frequency of occurrence are defined as follows: very often (≥1 / 10); Often (from ≥1 / 100 to <1/10); Infrequently (from ≥1 / 1000 to <1/100); Rarely (from ≥1 / 10000 to <1/1000); Very rarely (<1/10000) and unknown (the frequency can not be determined from the available data).

Unwanted reactions recorded during phase 3 controlled trials

From the immune system: infrequently - hives; Rarely - hypersensitivity; Unknown - anaphylactic reactions.

From the side of metabolism and nutrition: very often - hypoglycemia; Often - decreased appetite; Infrequently - dehydration.

From the gastrointestinal tract: often - nausea, diarrhea, vomiting, constipation, dyspepsia, gastritis, abdominal pain, flatulence, gastroesophageal reflux, bloating; Unknown - pancreatitis (including necrotizing pancreatitis).

From the skin and subcutaneous tissues: infrequently - rash, itching; Rarely - acquired lipodystrophy.

General disorders and disorders at the injection site: often - reactions at the injection site; Infrequent peripheral edema.

Laboratory and instrumental data: unknown - increased heart rate.

Individual undesirable reactions

Hypoglycemia. Hypoglycemia can develop if the dose of a combination of insulin degludec + liraglutide exceeds what is needed. Severe hypoglycemia can lead to loss of consciousness and / or convulsions, temporary or irreversible impairment of brain function or even death. Symptoms of hypoglycemia tend to develop suddenly. They may include cold sweat, pale skin, fatigue, irritability or tremor, anxiety, unusual fatigue or weakness, confusion, difficulty concentrating, drowsiness, severe hunger, visual impairment, headache, nausea and palpitations.

Allergic reactions. Allergic reactions (manifested by such signs and symptoms as hives, rashes, itching and / or tongue and lips) were noted with the use of insulin degludec and liraglutide, the two components of the combination. Several cases of anaphylactic reactions with such additional symptoms as arterial hypotension, palpitations, dyspnea and peripheral edema were noted during the post-marketing application of liraglutide. Anaphylactic reactions can potentially be life threatening.

Undesirable reactions from the gastrointestinal tract. In patients receiving the combination of insulin degludec + liraglutide patients, undesirable gastrointestinal events were noted, including nausea, diarrhea, vomiting, constipation, dyspepsia, gastritis, abdominal pain, flatulence, gastroesophageal reflux, bloating, and decreased appetite. These unwanted gastrointestinal symptoms may occur more often during the initiation of therapy with the combination of insulin degludec + liraglutide, and their manifestations usually decrease within a few days or weeks with continued therapy.

Reactions at the site of administration. The patients receiving insulin degludec + liraglutide combination had reactions at the injection site (hematoma at the injection site, pain, hemorrhage, erythema, nodules, swelling, discoloration, itching, hyperemia and compaction at the injection site). These reactions, as a rule, were mild and transitory and in most cases were resolved during continued therapy.

Lipodystrophy. At the injection site lipodystrophy can develop (including lipogypertrophy, lipoatrophy). Adherence to the rules for changing the injection site within one anatomical area can help reduce the risk of developing this reaction.

Increase in heart rate (heart rate). In clinical studies using the combination of insulin degludec + liraglutide, there was an increase in heart rate in comparison with baseline by an average of 2-3 beats per minute (beat per minute). Long-term clinical effects of increased heart rate have not been established.

Interaction

Pharmacodynamic interaction

Studies of interaction with the combination of insulin degludec + liraglutide were not conducted.

A number of substances affect the metabolism of glucose and may require a dose adjustment combination of insulin degludec + liraglutide.

The need for a combination of insulin degludec + liraglutide reduces other hypoglycemic agents, MAO inhibitors (monoamine oxidase), nonselective beta adrenoblockers, ACE inhibitors (angiotensin converting enzyme), salicylates, anabolic steroids and sulfonamides.

The need for a combination of insulin degludec + liraglutide increases oral hormonal contraceptives, thiazides, GCS (glucocorticosteroids), thyroid hormone preparations, sympathomimetics, somatropin and danazol. Beta-blockers can mask symptoms of hypoglycemia.

Octreotide / lanreotide can both increase or decrease the need for a combination of insulin degludec + liraglutide.

Alcohol and ethanol containing drugs can both enhance and reduce the hypoglycemic effect of the combination of insulin degludec + liraglutide.

Pharmacokinetic interaction

In vitro, a very low ability of liraglutide and insulin degludec to pharmacokinetic interactions with other drugs associated with the cytochrome P450 system and binding to plasma proteins was demonstrated. A slight delay in gastric emptying with the use of liraglutide can affect the absorption of concomitantly used oral medications. In the interaction studies, no clinically significant delay in absorption was demonstrated.

Warfarin and other coumarin derivatives. No interaction studies were conducted. Clinically significant interaction with active substances with low solubility or narrow therapeutic index, such as warfarin, can not be ruled out. After initiating therapy with the combination of insulin degludec + liraglutide in patients receiving warfarin or other coumarin derivatives, more frequent monitoring of MHO is recommended.

Paracetamol. Liraglutide did not affect the total exposure of paracetamol after the administration of a single dose of 1000 mg. The amount of paracetamol was reduced by 31%, and the median Tmax was increased by 15 min. Correction of the dose with concomitant application of paracetamol is not required.

Atorvastatin. Liraglutide did not change the total exposure of atorvastatin to a clinically significant extent after a single dose of atorvastatin 40 mg. Therefore, correction of the dose of atorvastatin when used in combination with liraglutide is not required. At application ëèðàãëóòèäà Ñmàõ atorvastatin has been lowered on 38%, and median Tmàh is increased from 1 up to 3 ch.

Griseofulvin. Liraglutide did not change the total exposure of griseofulvin after a single dose of 500 mg. The griseofulvin age was increased by 37%, while the median Tmax did not change. Correction of the dose of griseofulvin and other compounds with low solubility and high penetrating power is not required.

Digoxin. The introduction of a single dose of digoxin 1 mg in combination with liraglutide led to a decrease in AUC digoxin by 16% and a decrease of Cmax by 31%. The median time to reach Cmax was increased from 1 to 1.5 hours. In view of these results, correction of the dose of digoxin is not required.

Lysinopril. The use of a single dose of lisinopril 20 mg in combination with liraglutide led to a decrease in AUC of lisinopril by 15%, a decrease of C max by 27%. The median Tmax of lisinopril was increased from 6 to 8 hours. In view of these results, correction of the dose of lisinopril is not required.

Oral hormonal contraceptives. After applying a single dose of oral contraceptive, liraglutide led to a decrease in Cmax of ethinyl estradiol and levonorgestrel by 12 and 13%, respectively. Tmax of both compounds against the background of the use of liraglutide was increased by 1.5 hours. There was no clinically significant effect on the systemic exposure of ethinylestradiol or levonorgestrel. Thus, the effect on the contraceptive effect in the combined use of oral hormonal contraceptives and liraglutide is not expected.

Incompatibility

Substances added to the combination of insulin degludec + liraglutide in the form of a solution for SC administration may cause destruction of the active ingredients.

The combination of insulin degludec + liraglutide in the form of a solution for SC administration can not be added to infusion solutions.

This drug should not be mixed with other medicinal products.

Overdose

Data on an overdose of a combination of insulin degludec + liraglutide are limited.

Symptoms: when a dose of insulin degludec + liraglutide is added to the dose that exceeds the required dose, the patient may develop hypoglycemia.

Treatment: mild hypoglycemia can be stopped by ingestion of dextrose or other sugar-containing products. Therefore, patients are advised to always carry sugar-containing products.

Severe episodes of hypoglycemia, when the patient is unable to help himself, can be stopped in / m or by / by injecting glucagon (0.5-1 mg) by a trained person or / and injecting a dextrose solution by a medical professional. It is necessary in / in to enter a solution of dextrose, if within 10-15 minutes there is no response to the introduction of glucagon. After restoration of consciousness to the patient it is recommended to take the carbohydrate-rich food for prophylaxis of relapse.

Routes of administration

Subcutaneously

Precautions

Hypoglycaemia

Hypoglycemia can occur if a dose of insulin degludec + liraglutide is added too large in relation to the patient's need. To hypoglycemia may result in a skipping meal or an unplanned active physical activity. When combined with a drug of sulfonylurea, the risk of hypoglycemia can be reduced by reducing the dose of the sulfonylurea drug. Concomitant diseases of the kidneys, liver or disease with adrenal, thyroid or pituitary gland may require a change in the dose of insulin degludec + liraglutide. Patients with significant improvement in the control of glycemia (for example, with intensified therapy) may experience a change in the usual symptoms-precursors of hypoglycemia, which they should be appropriately informed about. In patients with prolonged course of diabetes mellitus, the usual symptoms-precursors of hypoglycemia may disappear. As with all products containing basal insulin, the prolonged effect of a combination of insulin degludec + liraglutide can lead to a delayed recovery after hypoglycemia.

Hyperglycaemia

The introduction of inadequate doses and / or discontinuation of hypoglycemic therapy can lead to the development of hyperglycemia and, possibly, the development of hyperosmolar coma. In the event of discontinuation of therapy with the combination of insulin degludec + liraglutide, instructions should be provided to initiate alternative hypoglycemic therapy. In addition, the development of hyperglycemia can lead to concomitant diseases, especially infectious, and thus cause an increase in the need for hypoglycemic therapy. Usually the first symptoms of hyperglycemia develop gradually, within a few hours or days. These include thirst, frequent urination, nausea, vomiting, drowsiness, congestion and dryness of the skin, dry mouth, loss of appetite, as well as the smell of acetone in the exhaled air. In the situation of severe hyperglycemia, you should introduce short-acting insulin. In the absence of therapy, hyperglycemia eventually leads to the development of hyperosmolar coma / diabetic ketoacidosis, which can lead to death.

Simultaneous use of drugs of the thiazolidinedione group and insulin preparations

Cases of CHF in the treatment of patients with thiazolidinediones in combination with insulin preparations have been reported, especially if such patients have risk factors for CHF. This fact should be taken into account when appointing patients combination therapy with thiazolidinediones and a combination of insulin degludec + liraglutide. When this combination therapy is prescribed, it is necessary to conduct a medical examination of patients to identify signs and symptoms of CHF, weight gain and the presence of peripheral edema. In case of worsening of symptoms of heart failure in patients, treatment with thiazolidinediones should be stopped.

Visual disturbances

Intensification of insulin therapy (a component of the insulin degludec + liraglutide combination) with a sharp improvement in glycemic control may be accompanied by a temporary deterioration in the manifestations of diabetic retinopathy, while a prolonged improvement in glycemic control reduces the risk of progression of diabetic retinopathy.

The formation of antibodies

The administration of a combination of insulin degludec + liraglutide can lead to the formation of antibodies to insulin degludec and / or liraglutide. In rare cases, the formation of antibodies may require a dose adjustment combination of insulin degludec + liraglutide to prevent the development of hyperglycemia or hypoglycemia. In a very small number of patients, combination therapy with insulin degludec + liraglutide can cause the formation of specific antibodies to insulin degludec; Antibodies cross-reacting with human insulin, or antibodies to liraglutide. The formation of antibodies is not associated with a decrease in the effectiveness of the combination of insulin degludec + liraglutide.

Acute pancreatitis

The use of GLP-1 receptor agonists was associated with a risk of developing acute pancreatitis. In clinical studies and post-registration use, reports of acute pancreatitis with the use of liraglutide, a component of the insulin degludec + liraglutide combination were obtained. Patients should be informed of the characteristic symptoms of acute pancreatitis. In case of suspected development of pancreatitis, the use of a combination of insulin degludec + liraglutide should be discontinued; In the case of confirmation of acute pancreatitis, therapy should not be restarted with a combination. Care should be taken when using a combination in patients with pancreatitis in history.

Thyroid gland diseases

In clinical studies using GLP-1 receptor agonists, including liraglutide, the insulin degludec + liraglutide combination component, undesirable thyroid reactions have been noted, including an increase in calcitonin concentration in the blood, goiter and thyroid neoplasm, especially in patients with an existing Thyroid disease. In this regard, the combination of insulin degludec + liraglutide in these patients should be used with caution.

Inflammatory bowel disease and diabetic gastroparesis

The experience of using the combination of insulin degludec + liraglutide in patients with inflammatory bowel disease and diabetic gastroparesis is absent. In this regard, the use of combination in such patients is contraindicated.

Dehydration

In clinical studies, signs and symptoms of dehydration, including renal dysfunction and acute renal failure, were noted in patients receiving GLP-1 receptor agonists, incl. Liraglutide, a component of a combination of insulin degludec + liraglutide. Patients receiving a combination of insulin degludec + liraglutide should be informed of the potential risk of dehydration associated with gastrointestinal side effects and observe precautionary measures to prevent hypovolemia.

Heart Electrophysiology (QTc)

Studies of the effect of the combination of insulin degludec + liraglutide on the QTc interval were not performed. The effect of liraglutide on myocardial repolarization was studied in the study with the determination of the QTc interval. Liraglutide at equilibrium concentration when administered at daily doses up to 1.8 mg did not lead to an extension of the QTc interval. With regard to insulin degludec, there was no statistically significant difference between insulin degludec and the reference preparation for changing the duration of the QTc interval compared to the baseline value based on ECG analysis in a 12-month clinical trial.

Fertility

The clinical experience of using the combination of insulin degludec + liraglutide with respect to fertility is absent. If the patient wishes to become pregnant, then treatment with insulin degludec + liraglutide should be stopped.

Prevention of erroneous introduction

Patients should be informed of the need to always check the label on the syringe pen prior to injection to avoid accidentally injecting another injectable drug to treat diabetes instead of a combination of insulin degludec + liraglutide.

Special patient groups

Patients of advanced age (≥65 years). The combination of insulin degludec + liraglutide can be used in elderly patients. Need increased glycemic control and individual dose adjustment.

Renal insufficiency. When using the combination of insulin degludec + liraglutide in patients with impaired renal function of mild or moderate degree, increased glycemic control and individual dose adjustment are necessary. The use of insulin degludec + liraglutide in patients with impaired renal function, including patients with terminal stage of chronic kidney disease, is contraindicated.

Violation of the function of the liver. At present, the experience of using the combination of insulin degludec + liraglutide in patients with impaired liver function is limited, and therefore its use in this group of patients is contraindicated.

Children and teenagers. The use of the combination of insulin degludec + liraglutide in children and adolescents under the age of 18 is contraindicated due to the lack of safety and efficacy data.

Populations in which no studies were conducted

Studies on switching to a combination of insulin degludec + liraglutide with basal insulin therapy in a dose> 40 units were not performed.

Studies on the transition from therapy with GLP-1 receptor agonists have not been conducted.

Studies using a combination of insulin degludec + liraglutide in combination with DPP-4 inhibitors, clay or prandial insulin have not been performed.

Influence on the ability to drive vehicles and mechanisms. When hypoglycemia, the ability of patients to concentrate and the speed of reaction may be compromised. This can be dangerous in situations where these capabilities are particularly necessary (for example, when driving vehicles or working with mechanisms).

Patients should be advised to take measures to prevent the development of hypoglycemia in the management of vehicles or work with mechanisms. This is especially important for patients with a lack or decrease in the severity of symptoms-precursors of hypoglycemia or frequent episodes of hypoglycemia. In these cases, consideration should be given to the desirability of driving a vehicle or performing such work.