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

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Dosage form: & nbspRAzvor for subcutaneous administration.

Composition:

In 1 ml of the drug contains:

active substances: insulin degludec 100 ED (3.66 mg), liraglutide 3.6 mg;

Excipients: phenol 5.7 mg, glycerol 19.7 mg, zinc 55.0 μg (as zinc acetate), hydrochloric acid / sodium hydroxide (for pH correction), water for injection up to 1 ml. The pH of the solution is 8.15.

One unit of insulin degloudek is equivalent to 0.0366 mg of anhydrous, insoluble insulina degludec.

In one pre-filled syringe pene contains 3 ml of solution, which corresponds to 300 units of insulin degludec and 10.8 mg of liraglutide.

Description:A colorless or almost colorless, clear solution.

Pharmacotherapeutic group:hypoglycemic agent - long-acting insulin analog

ATX: & nbsp

Insulin degludec and liraglutide

Pharmacodynamics:

Mechanism of action

Sultofay® is a combined preparation that consists of insulin degludec and liraglutide (produced by the biotechnology of recombinant DNA using a strain Saccharomyces cerevisiae), which have complementary mechanisms of action to improve glycemic control.

Insulin degludec is a basal insulin that, after subcutaneous administration, forms soluble multi-hexamers that form a depot in the subcutaneous fat,from which there is a continuous and slow absorption of insulin into the bloodstream, which provides a super-long, flat and stable hypoglycemic effect of the drug with low day-to-day variability.

Insulin deglucose 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 analogue of human glucagon-like peptide-1 (GLP-1) with 97% homology to human endogenous GLP-1, which binds and activates the GLP-1 receptor. The long-acting profile of liraglutide with subcutaneous administration is provided by three mechanisms: self-association, which results in a slow absorption of the drug; binding to albumin; higher resistance to dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidase (NEP), which leads to an increase in the half-life of the drug from the blood 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 increasing blood glucose concentration, stimulation of insulin secretion and inhibition of glucagon secretion occur. And, conversely, during hypoglycemia lyraglutide reduces the secretion of insulin 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 reduces the mass of fat tissue through mechanisms that reduce hunger and reduce energy consumption.

Pharmacodynamics

The drug Sultofay® has a stable pharmacodynamic profile with a duration of action that reflects the combination of individual insulin action profiles of deglucose and liraglutide, which allows the administration of Sultofay® once a day at any time, regardless of food intake.The drug Sultophain® improves the control of glycemia by persistent lowering of blood glucose concentration on an empty stomach and after eating.

Decrease in postprandial glucose concentration was confirmed in a 4-hour study with a standard breakfast, in which patients with poor glycemic control took part with metformin monotherapy or with metformin therapy in combination with pioglitazone. The drug Sultofay® led to a significantly more pronounced decrease in the postprandial increase in the plasma glucose concentration (mean for 4 hours) compared with insulin deglucose. Similar results were obtained when comparing the drug Sultofay® and liraglutide.

Insulin secretion / function of pancreatic beta cells

Sultophain® 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-β). Improved insulin secretion compared with insulin degludec was demonstrated in a 4-hour sub-analysis with a standard breakfast,in which patients with unsatisfactory glycemic control took part in the treatment of metformin in the form of 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 Sultophay® in comparison with insuline degludec and liraglutide with all preparations 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 diabetes mellitus 2 types. The initial dose of Sultofay® and insulin degludec was 10 dose steps and 10 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 fasting plasma glucose concentration 4, 0 to 5.0 mmol / l. 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 Sultofay® was 50 doses.In the insulin degludec group, the maximum dose was not established.

When using the drug Sultofay® reduction HbA₁_c at 26 weeks compared with the initial value of 1.9%, which demonstrates a higher efficacy compared with liraglutide (difference of -0.64%, p <0.0001) and no less effective than insulin degludec (difference -0 , 47%, p <0.0001). The body weight was reduced by 0.5 kg with the use of the Sultofay® preparation, the difference between the Sultofay® preparation and the insulin deglucose -2.22 kg (p <0.0001), which confirms a higher efficacy compared with insulin deglucose. With the use of the drug Sultofay®, a significant reduction in the overall risk of hypoglycemia was demonstrated compared with insulin deglucose. As shown in Figure 1, with the use of Sultophay®, the incidence of hypoglycemia in the entire range of values HbA₁_c was less in comparison with the use of insulin degludec.

80.6% of the patients receiving Sultophain® achieved the target value HbA₁_c<7% after 26 weeks of treatment. The result was statistically significantly greater than that observed both for insulin degludec (65.1%) and for liraglutide (60.4%), p <0.0001.The fasting plasma glucose concentration decreased from 9.2 mmol / L to 5.6 mmol / L with the Sultofay®, from 9.4 mmol / L to 5.8 mmol / L with insulin deglucose, from 9.0 mmol / l to 7.3 mmol / l with the use of liraglutide. Decrease was similar with Sultofay® 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 Sultofay® preparation and 53 units for insulin deglucose (difference -14.90, p <0.0001).

After 26 weeks of therapy, 60.4% of patients receiving Sultophay® received the target HbA_1C <7% without confirmed episodes of hypoglycemia. The proportion of patients was significantly higher than in the insulin degludec group (40.9%), and similar to that in the liraglutide group (57.7%). The incidence of confirmed episodes of hypoglycemia in the use of Sultofay® was less than with insulin deglucose, regardless of glycemic control, see Figure 1.

Picture 1. The mean value of HbA_1C (%) for weeks of therapy (top) and the incidence of confirmed hypoglycemia * per patient-year exposure, depending on the mean HbA_1C (%) (bottom) in patients with type 2 diabetes mellitus with poor glycemic control against metformin monotherapy or metformin therapy in combination with pioglitazone

* Confirmed hypoglycemia is defined as severe hypoglycemia (episode requiring the help of another person) and / or mild hypoglycemia (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) in the case of Sultofay®, 0.01 (2 patients out of 412) with insulin deglucose and 0.00 (0 patients out of 412) with the use of liraglutide. The frequency of development of nocturnal hypoglycemia was the same with the use of the drug Sultofay® and insulin degludec.

Patients treated with Sultofay® generally had fewer side effects on the gastrointestinal tract than those who received lyraglutide. This may be due to a slower increase in the dose of liraglutide in Initiation of therapy with Sultofay® compared with that at the beginning of therapy with liraglutide.

The efficacy and safety of the Sultofay® drug persisted for up to 52 weeks of therapy.Decrease of HbA |_FROM at week 52, compared with the baseline, was 1.84% when using the Sultofay® preparation, the difference compared to liraglutide was 0.65% (p <0.0001) and -0.46% compared with insulin degludec (p < 0.0001). The body weight was reduced by 0.4 kg with the use of the Sultofay® preparation, the difference compared to insulin değludec -2,80 kg (p <0,0001), and the incidence of confirmed hypoglycemia remained equal to 1.8 events per patient-year exposure, supporting a significant reduction in the risk of developing confirmed hypoglycemia compared with insulin degludec.

Addition to monotherapy by a drug from the group of sulfonylurea derivatives or to a combination of metformin and sulfonylurea derivatives

The efficacy and safety of the SulThOfAy® drug when added to a sulfonylurea treatment in the form of 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 with diabetes mellitus 2 types, of which 289 received the preparation Sultofay®. Initial dose of Sultophay®was 10 steps of the dose; the dose was adjusted 2 times a week by increasing or decreasing the dose (2 units of insulin degludec / 0.072 mg liraglutide) to the target plasma glucose concentration on an empty stomach 4.0-6.0 mmol / l by 2 steps.

When using the drug Sultofay® reduction HbA₁_c at 26 weeks was 1.45% compared with baseline, which demonstrates greater efficacy compared with placebo (difference -1.02%, p <0.0001). Body weight with the use of the drug Sultofay® increased by 0.5 kg, the difference between the preparation Sultofay® and placebo 1.48 kg (p <0.0001). With the use of the drug Sultofay®, 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 receiving Sultophay® achieved the target HbA_1C <7% after 26 weeks of treatment compared with 28.8% of patients receiving placebo (p <0.0001). The concentration of fasting plasma glucose decreased from 9.1 mmol / L to 6.6 mmol / L with the use of the Sultofay® preparation, from 9.1 mmol / L to 8.8 mmol / L when applied placebo (difference -2.30 mmol / l, p <0.0001). The insulin dose for the Sultofay® drug at the end of the study was 28 units.

The index of the frequency of development of severe hypoglycemia in the patient-year of exposure was 0.02 (2 patients out of 288) with the use of Sultofay® and 0.00 (0 patients out of 146) with placebo.

Transfer from basal insulin therapy

The efficacy and safety of Sultophay® in comparison with insulin degludec once a day was studied in a 26-week, randomized, double-blind study with the concept of "treatment to the target", involving patients with type 2 diabetes mellitus with poor glycemic control against therapy basal insulin (20-40 units) and metformin alone or in combination with the sulfonylurea preparation / clayides. Basal insulin and sulfonylurea / clay were discontinued with randomisation. The initial dose of the drug Sultofay® 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 4.0 - 5.0 mmol / l. The maximum permitted dose of the Sultofay® preparation was 50 dose steps, and insulin degludec was 50 units.

Decrease HbA₁_c at the end of the study, compared with the initial value when using the Sultofay® preparation was 1.9%, which demonstrates a higher efficacy in comparison with insulin deglucose at a maximum dose of 50 units (difference -1.05%, p <0.0001). Body weight decreased by 2.7 kg with the use of the Sultofay® preparation, which indicates a significant decrease in the insulin level compared to insulin (a difference of -2.51 kg, p <0.0001), and the overall risk of hypoglycemia was similar with the use of the drug Sultofay ® and insulin degludec, despite lower values of HbA_1C at the end of the study with the use of the drug Sultofay®.

60.3% of patients who received the drug Sultofay® achieved the target HbA₁_c<7% after 26 weeks of treatment compared with 23.1% of patients receiving insulin degluedek, p <0.0001. The fasting plasma glucose concentration decreased from 9.7 mmol / L to 6.2 mmol / L with the use of the Sultofay® preparation and from 9.6 mmol / L to 7.0 mmol / L with the use of insulin degludec (difference -0.73 mmol / l, p <0.05). The insulin dose for both the Sultofay® preparation and insulin deglucose at the end of the study was 45 units.

After 26 weeks of therapy, 48.7% of patients achieved the target value HbA₁_c <7% without episodes of confirmed hypoglycemia, which was significantly greater than in the group of insulin degludec (15.6%).

The incidence of severe hypoglycaemia was 0.01 (1 patient out of 199) with Sultofay® and 0.00 (0 patients out of 199) with insulin degludec. The frequency of development of nocturnal hypoglycemia was the same with the use of the drug Sultofay® and insulin degludec.

Other clinical data

Arterial hypertension

In patients with poor glycemic control against metformin in the form of monotherapy or in combination with pioglitazone, the Sultofay® drug reduced the mean systolic blood pressure 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 poor glycemic control, a reduction of 3.5 mm Hg was observed when taking sulfonylureas in the form of monotherapy or in combination with metformin. Art. when using the drug Sultofay® and 3.2 mm Hg. Art. when using a placebo. The difference was statistically insignificant. In patients with unsatisfactory glycemic control against basal insulin therapy, the mean systolic blood pressure decrease was 5.4 mm Hg. Art.when using the drug Sultofay® and 1.7 mm Hg. Art. when using insulin degludec, the statistically significant difference was -3.71 mm Hg. Art. (p = 0.0028).

Nausea

The proportion of patients who reported nausea at any time with Sultofay® 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 hazard to humans.

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

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 Degloudek

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

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

Liraglutide

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

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

In animal studies, there was no direct adverse effect of the drug on fertility, but there was a slight increase in the incidence of early embryonic death with the highest possible doses of the drug. 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 of the drug. It is not known what caused such a decrease in the growth of newborn rats: a decrease in the consumption of milk by newborns due to exposure GLP-1 or a decrease in the production of milk by maternal individuals due to a decrease in their intake of calories.

Pharmacokinetics:

In general, the pharmacokinetics of insulin degludec and liraglutide with the administration of the Sultofay® preparation did not clinically change significantly in comparison with individual injections of insulin degludec and liraglutide.

Below are the pharmacokinetic properties of the Sultofay® preparation, unless it is indicated that the data presented were obtained by administering insulin degludec or liraglutide separately.

Suction

The total exposure of insulin degludec was the same after administration of the Sultofay® and insulin degludec alone, while the maximum concentration (C_max) was higher by 12%. The total exposure of liraglutide was the same after the administration of Sultofay® and liraglutide separately, while C_mOh was lower by 23%. The difference was regarded as clinically insignificant, since the initial dose of the Sultofay® preparation and the dose adjustment depend on the target glucose concentration in the particular patient.

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

The pharmacokinetic profile of the Sultofay® preparation allows the drug to be administered once a day, and the equilibrium concentration of insulin degludec and liraglutide is reached after 2-3 days of daily administration.

Distribution

Insulin Degloodec and lyraglutide are significantly associated with blood plasma proteins (> 99% and> 98%, respectively).

Metabolism

Insulin Degloudek

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

Liraglutide

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

Excretion

The half-life of insulin degludec is approximately 25 hours, the half-life of liraglutide is approximately 13 hours.

Special patient groups

Elderly patients

According to the results of population pharmacokinetic data analysis, including data on patients receiving Sultophay® before the age of 83, the age had no clinically significant effect on the pharmacokinetics of the Sultofay® preparation.

Floor

According to the results of the population pharmacokinetic analysis, sex had no clinically significant effect on the pharmacokinetics of the Sultofay® preparation.

Ethnicity

According to the results of the population pharmacokinetic analysis, which included data on patients of European, Negroid, Asian and Hispanic and Indian descent, ethnicity does not have a clinically significant effect on the pharmacokinetics of the Sultofay® preparation.

Patients with impaired hepatic function

Insulin Degloudek

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. Patients with impaired hepatic function from mild (5-6 points by classification Child Pugh) to a severe degree (> 9 points by classification Child Pugh). Exposure was not increased in patients with impaired liver function compared with healthy thus, a violation of liver function did not exert any clinically significant effect on the pharmacokinetics of liraglutide.

Patients with renal insufficiency

Insulin Degloudek

There were no clinically significant differences in the pharmacokinetics of insulin deglucal 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 clearance of creatinine 50-80 ml / min) to a severe degree (calculated creatinine clearance <30 ml / min) and patients with terminal stage of chronic kidney disease requiring dialysis were included in the study. Impaired renal function did not exert any clinically significant effect on the pharmacokinetics of liraglutide.

Children

Studies of the efficacy and safety of Sultophay® in children and adolescents under the age of 18 have not been conducted.

Indications:

Sultophay® is indicated for achieving glycemic control in adults with type 2 diabetes mellitus in combination with oral hypoglycemic drugs.

Contraindications:

Hypersensitivity to insulin degludec, liraglutide or any of the auxiliary components of the drug.

Contraindicated use of the drug Sultofay ® due to the lack of data on efficacy and safety in the following groups of patients:

- children's age till 18 years;

- period of pregnancy and breastfeeding;

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

- abnormal liver function;

- impaired renal function of a serious degree;

- type 1 diabetes mellitus, diabetic ketoacidosis;

- Inflammatory bowel disease and diabetic gastroparesis.

Carefully:

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

Care should be taken when using the drug in patients with thyroid disease, as well as in patients with a history of chronic pancreatitis (see the section "Special instructions").

Pregnancy and lactation:

Pregnancy

Clinical experience of the use of the drug Sultofay®, insulin degludec or liraglutide in pregnant women is absent. The use of Sultophay® during pregnancy is contraindicated. When planning or onset of pregnancy, therapy with Sultofay® 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. In studies of liraglutide on animals, reproductive toxicity was demonstrated, see the section "Preclinical data but safety. " The potential risk to humans is unknown.

Breastfeeding period

Clinical experience of the use of the drug Sultofay® during breastfeeding is absent. It is not known whether the lyraglutide or insulin degluedek in human milk. Due to the lack of experience in the use of the drug, SulTOPAI® is contraindicated during breastfeeding.

In rats insulin degluedek penetrates into breast milk; the concentration of the drug in breast milk was lower than in blood plasma.In animal studies, it has been demonstrated that penetration of liraglutide and metabolites of a close structural bond into breast milk is low.

Dosing and Administration:

Mode of application

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

Sultophay® is administered once a day. Sultophay® can be administered at any time of the day, preferably at the same time.

It should be injected into the abdomen, hip or shoulder area. You should constantly change injection sites within the same anatomical area to reduce the risk of developing lipodystrophy.

Read the information in the "Instructions for use" section.

Doses

The dosage of Sultophay® is determined according to the individual needs of the patient. To optimize the control of glycemia, it is recommended to select a dose based on the fasting plasma glucose concentration.

As with all insulin preparations, the patient may need to adjust the dose in the event of increased physical activity, changes in the normal diet or during co-morbidities.

Patients who forget to enter the drug are advised to enter the dose as soon as they remember, and then return to the usual schedule of a daily single dose of the drug. The interval between injections should be at least 8 hours. This also applies to situations where it is not possible to administer the drug at the same time.

The drug Sultophay® is administered by the dose steps. One step of the dose contains 1 unit of insulin degludec and 0.036 mg of liraglutide. Pre-filled syringe pen allows you to enter from 1 to 50 steps of a dose in one injection in increments of 1. The maximum daily dose of Sultofay® is 50 dose steps (50 units of insulin degludec and 1.8 mg of liraglutide). The dose counter on the syringe-pen shows the number of dose steps.

Addition to oral hypoglycemic drugs (PGHP)

The recommended initial dose of Sultofay® is 10 steps of the dose (10 units of insulin degludec and 0.36 mg of liraglutide).

The drug Sultofay® can be added to the already used therapy of PGHP. When Sultophair® is added to therapy with sulfonylureas, the dose of sulfonylurea should be considered (for information on hypoglycemia, see section Special instructions).

Transfer from basal insulin therapy

Basal insulin therapy should be discontinued prior to the initiation of therapy with Sultofay®. When transferring from basal insulin therapy, the recommended initial dose of Sultofay® is 16 steps of the dose (16 units of insulin degludec and 0.6 mg of liraglutide, see sections "Special instructions" and "Pharmacodynamic properties "). Do not exceed the recommended initial dose. During the transfer and subsequent weeks, careful monitoring of glycemia is recommended.

Special patient groups

Patients of advanced age (≥65 years)

The drug Sultofay® can be used in elderly patients. Enhanced glycemic control and individual dose adjustment are necessary.

Patients with renal insufficiency

When using the drug Sultofay® in patients with impaired renal function of mild or moderate degree, increased glycemic control and individual dose adjustment are necessary. The use of Sultofay® in patients with impaired renal function of a severe degree, including patients with terminal stage of chronic kidney disease, is contraindicated (see "Pharmacokinetic properties ").

Patients with impaired hepatic function

Currently, the experience with the use of Sultophay® in patients with impaired liver function is limited, so the use of the drug in this group of patients is contraindicated (see "Pharmacokinetic properties ").

Children and teens

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

Side effects:

The program of clinical studies of the SulThOfAy® preparation showed no increase in the incidence of specific undesired reactions compared with the individual components of the drug: insulin degludec and liraglutide. Hypoglycaemia and gastrointestinal disturbances were the most frequently noted adverse reactions during therapy with SulTOPAI® (see section "Description of individual adverse reactions ").

Undesirable reactions associated with the use of the Sultofay® preparation are listed below in accordance with the classification of organ systems and frequency of occurrence. Categories 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 ≥ 1/10 000 to <1/1000); very rarely (<1/10 000) and unknown (the frequency can not be determined from the available data).

Table 2. Undesirable reactions recorded during controlled trials Phase 3

System of organs	Frequency
Immune system disorders	Infrequently - Hives Rarely - Hypersensitivity Unknown - Anaphylactic reactions
Disorders from the metabolism and nutrition	Often - Hypoglycaemia Often - Reduced appetite Infrequently - Dehydration
Disorders from the gastrointestinal tract	Often - Nausea, diarrhea, vomiting, constipation, dyspepsia, gastritis, abdominal pain, flatulence, gastroesophageal reflux, bloating Unknown - Pancreatitis (including necrotizing pancreatitis)
Disturbances from the skin and subcutaneous tissues	Infrequently - Rash, itching Rarely - Acquired lipodystrophy
General disorders and disorders at the site of administration	Often - Reactions at the site of administration Infrequently - Peripheral edema
Laboratory and instrumental data	Unknown - Increased heart rate (heart rate)

Description of individual undesirable reactions:

Hypoglycaemia

Hypoglycemia can develop if the dose of the Sultofai® drug exceeds what is needed.Severe hypoglycemia may lead to loss of consciousness and / or convulsions, temporary or permanent impairment of the cerebral function, or even death. Symptoms of hypoglycemia, as a rule, develop suddenly. They may include cold sweats, pale skin, fatigue, irritability, or tremor, anxiety, unusual tiredness or weakness, confusion, difficulty in concentration, drowsiness, expressed the feeling of hunger, blurred vision, headache, nausea and palpitations.

AllergenIchereactions

Allergic reactions (manifested signs and symptoms such as urticaria, skin rashes, itching and / or swelling of the tongue and lips) were observed with insulin degludek and liraglutide two components Sultofay® preparation. Several instances of anaphylactic reactions with additional symptoms such as hypotension, palpitations, shortness of breath and peripheral edema were noted during application of the post-registration liraglutide. Anaphylactic reactions can potentially be life threatening.

Undesirable reactions from the gastrointestinal tract

In patients receiving Sultophay®, undesirable gastrointestinal symptoms were noted, including nausea, diarrhea, vomiting, constipation, dyspepsia, gastritis, abdominal pain, flatulence, gastroesophageal reflux, bloating, and decreased appetite. These adverse gastrointestinal events may occur more frequently during the initiation of therapy with Sultofay®, and their manifestations usually decrease within a few days or weeks as the therapy continues.

Reactions at the site of administration

The patients receiving Sultophay® received reactions at the injection site (hematoma at the injection site, pain, hemorrhage, erythema, nodules, swelling, skin discoloration, pruritus, 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 (including lipohydrophy, lipoatrophy) can develop. Adherence to the rules of changing the injection site within one anatomical area can help reduce the risk of developing this reaction.

Increase in heart rate

In clinical studies with the use of Sultofay®, there was an increase in heart rate in comparison with baseline by an average of 2-3 beats per minute. Long-term clinical effects of increased heart rate have not been established.

Overdose:

Data on the overdose of Sultophay® are limited.

When a dose of Sultophain® is administered that exceeds the required dose, the patient may develop hypoglycemia:

- Hypoglycemia of mild degree 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 a patient is unable to help himself, can be stopped by intramuscular or subcutaneous administration of glucagon (0.5-1 mg) by a trained person or by intravenous injection of a dextrose solution by a medical professional. It is necessary to inject intravenously a solution of dextrose if within 10-15 minutes there is no response to the introduction of glucagon. After recovery of consciousness, the patient is recommended to take a carbohydrate-rich food to prevent relapse.

Interaction:

Pharmacodynamic interaction

Studies of interaction with the preparation of SulTOPHAY® were not conducted.

A number of substances affect the metabolism of glucose and may require a dose adjustment of the drug Sultofay®.

The need for Sultofay® reduces hypoglycemic drugs, monoamine oxidase inhibitors (MAO), nonselective beta adrenoblockers, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids and sulfonamides.

The need for Sultofay® increases oral hormonal contraceptives, thiazides, 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 the SulTOPAI® preparation.

Alcohol and ethanol-containing medications can both enhance and reduce the hypoglycemic effect of the Sultofay® preparation.

Pharmacokinetic interaction

In vitro demonstrated a very low ability of liraglutide and insulin degludec to pharmacokinetic interactions with other drugs associated with the cytochrome P450 system (CYP) and binding to plasma proteins.

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

Warfarin and other coumarin derivatives

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

Paracetamol (acetaminophen)

Liraglutide did not affect the total exposure of paracetamol after the administration of a single dose of 1000 mg. FROM_max paracetamol was reduced by 31%, and the median t_max increased by 15 minutes. Correction of the dose with the concomitant use of paracetamol is not required.

Atorvastatin

Liraglutide did not change the total exposure of atorvastatin 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. When using liraglutide C_mOh Atorvastatin was reduced by 38%, and the median t_max increased from 1 hour to 3 hours.

Griseofulvin

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

Digoxin

The introduction of a single dose of digoxin 1 mg in combination with liraglutide resulted in a decrease AUC digoxin by 16% and a decrease in C_mOh by 31%. Median time to achieve maximum concentration (t_max) was increased from 1 hour to 1.5 hours. In view of these results, correction of the dose of digoxin is not required.

Lisinopril

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

Oral hormonal contraceptives

After applying a single dose of oral contraceptive lyraglutide led to a decrease in C_mOh ethinylestradiol and levonorgestrel by 12% and 13%, respectively, t_max 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, it is not expected to influence the contraceptive effect in the combined use of oral hormonal contraceptives and liraglutide.

Incompatibility

Substances added to the Sultofay® preparation may cause destruction of the active ingredients.

The drug Sultophay® can not be added to infusion solutions.

This drug should not be mixed with other medicinal products.

Special instructions:

Hypoglycaemia

Hypoglycemia can occur if too much of the patient's dose of Sultophay® is administered. To hypoglycemia may result in a skipping meal or an unplanned active physical activity. When combined with the drug 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 Sultofay®. Patients with significant improvement in glycemic control (for example, with intensified therapy) may experience a change in common 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 preparations containing basal insulin, the prolonged effect of the Sultofay® preparation may 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 Sultofay®, 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, rapid urination, nausea, vomiting, drowsiness, congestion and dryness of the skin, dry mouth, loss of appetite, and the smell of acetone in the exhaled air. In a 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.

The simultaneous use of drugs of the thiazolidinedione group and insulin preparations Cases of chronic heart failure in the treatment of patients with thiazolidinediones in combination with insulin preparations have been reported, especially if such patients have risk factors for developing chronic heart failure. This fact should be taken into account when appointing patients a combination therapy with thiazolidinediones and the Sultofay® preparation. In the appointment of such combination therapy, it is necessary to conduct a medical examination of patients to identify signs and symptoms of chronic heart failure,increase in body weight and the presence of peripheral edema. If the symptoms of heart failure worsen in patients, treatment with thiazolidinediones should be discontinued.

Visual disturbances

Intensification of insulin therapy (a component of the Sultofay® preparation) 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 Sultophay® can lead to the formation of antibodies to insulin deglucose and / or liraglutide. In rare cases, the formation of antibodies may require a dose adjustment of the Sultofay® preparation to prevent the development of hyperglycemia or hypoglycemia. In a very small number of patients, therapy with Sultophay® 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 Sultofay® preparation.

Acute pancreatitis

The use of GLP-1 receptor agonists was associated with the risk of developing acute pancreatitis. In clinical studies and post-marketing use, reports of acute pancreatitis were reported using lyraglutide, a component of the Sultofay® preparation. Patients should be informed of the characteristic symptoms of acute pancreatitis. In case of suspected development of pancreatitis, the use of Sultophay® should be discontinued; In case of confirmation of acute pancreatitis, therapy with Sultophay® should not be resumed. Care should be taken when using the drug in patients with pancreatitis in history.

Thyroid gland diseases

In clinical studies using GLP-1 receptor agonists, including lyraglutide, component of the Sultofay® preparation, undesirable reactions from the thyroid gland were noted, including an increase in calcitonin concentration in the blood, goitre and thyroid nasal tumors, especially in patients with an existing thyroid disease. In this regard, the drug Sultofay ® in these patients should be used with caution.

Inflammatory bowel disease and diabetic gastroparesis

The experience of using the Sultofay® preparation in patients with inflammatory bowel diseases and diabetic gastroparesis is absent. In this regard, the use of the drug Sultofay ® in such patients is contraindicated.

Dehydration

In clinical trials, signs and symptoms of dehydration, including renal dysfunction and acute renal failure, were noted in patients receiving GLP-1 receptor agonists, including, lyraglutide, a component of Sultofay®. Patients receiving Sultophay® should be informed of the potential risk of dehydration associated with side effects from the gastrointestinal tract and should take precautions to prevent hypovolemia.

Electrophysiology of the heart (QTc)

Investigations of the influence of Sultophay® on the interval QTc did not conduct.

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

Fertility

Clinical experience with the use of Sultofay® in relation to fertility is absent. If the patient wishes to become pregnant, then the treatment with Sultofay® should be discontinued.

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 in lieu of Sultofay®.

Populations in which no studies were conducted

Studies on the transition to the drug Sultofay® 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 Sultophay® in combination with inhibitors of dipeptidyl peptidase 4 (DPP-4), clay or prandial insulin have not been performed.

Instructions for use

Follow the detailed instructions supplied with the pre-filled syringe pen.

The pre-filled syringe pen is designed for use with NovoFine® or NovoTvist® disposable needles up to 8 mm in length and up to 32G. The syringe-pen with the preparation Sultofay® is intended only for individual use.

The preparation Sultophay® can not be used if the solution does not look transparent and colorless.

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

The patient should discard the injection needle after each injection.

All unused medicinal product or waste should be disposed of in accordance with local requirements.

Instructions for patients on the use of the drug SulTOPAI® solution for subcutaneous administration 100 U / ml + 3.6 mg / ml

Read these instructions carefully Before using a pre-filled syringe handle with Sultofay®.

Use the syringe pen only after you have learned how to use it under the guidance of a doctor or nurse.

Check the label on the syringe pen label to make sure that it contains the preparation Sultophay 100 ED / ml + 3.6 mg / ml, and then carefully examine the illustrations below, which show the details of the syringe and the needle.

If you are visually impaired or have serious vision problems, and You can not distinguish the numbers on the dose counter, do not use a syringe pen without help. To help you can a person without visual impairment, trained in the correct use of a pre-filled syringe pen.

The preparation Sultofay® contains insulin degluedek and lyraglutide.

The drug Sultofay® is administered by the dose steps. One dose step contains 1 unit of insulin degludec + 0.036 mg of liraglutide.

The pre-filled syringe pen contains 3 ml of Sultofay® and allows to set and enter a dose from 1 dose step to a maximum of 50 dose steps (50 units of insulin degludec + 1.8 mg of liraglutide).

The syringe pen allows you to set the dose in steps of 1 step dose.

No recalculation of the dose is required, in the dose counter window the number of dose steps you have scored is reflected.

The syringe pen is designed for use with NovoFine® or NovoTvist® disposable needles up to 8 mm in length and up to 32G.

Needles are not included in this package.

! Important information

Pay attention to the information marked with these icons, it is very important for the safe use of the syringe pen.

Pre-filled syringe pen with Sultofay preparation and needle (for example, see Figure 2.)

1. Preparation of a syringe-pen with a needle to use

- Check the name and color code on the label syringe-pens to make sure that it contains the drug Sultofay®.

This is especially important if you use different injections. Applying the wrong medication can be harmful to your health.

- Remove the cap from the syringe handle (Figure A).

- Make sure that the solution in the syringe pen is transparent and colorless (Figure B).

Look in the window of the balance scale. If the drug is cloudy, the pen can not be used.

- Take a new disposable needle and remove the protective sticker (Figure C).

- Put the needle on the syringe pen and rotate it so that the needle fits tightly on the syringe handle (Fig. D).

- Remove the outer cap of the needle, but do not throw it away (Figure E). You will need it after the injection is completed to safely remove the needle.

- Remove and discard the inner needle cap (Fig. F). If you try to put the inner cap back on the needle, you can prick.

A drop of solution may appear at the end of the needle.This is normal, however, you still need to check the receipt of the drug.

Do not attach a new needle until you are ready to inject.

! Always use a new needle for each injection, to avoid blockage of the needle, infection, infection and the introduction of an incorrect dose of the drug.

! Never use the needle if it is bent or damaged.

2. Check the receipt of the drug.

- Type 2 of the dose step drug by turning the dose selector (Fig. A). Make sure that the dose counter shows "2".

- The dose counter and dose indicator will show how many steps of the dose of the SulThOfA® preparation you have typed.

- Press and hold the start button in this position, until the dose counter returns to zero (Figure C).

"O" should stand in front of the dose indicator.

A drop of solution should appear at the end of the needle.

A small drop may remain at the end of the needle, but it will not be injected.

If a drop of solution at the end of the needle does not appear, It is necessary to repeat operations 2A-2C, but not more 6 time. If a drop of solution has not appeared, change the needle and repeat the steps 2A-2C again.

If a drop of Sultofay® solution did not appear, Dispose of the syringe pen and use a new one.

! Before each injection, make sure that a drop of solution appears on the tip of the needle. This ensures the receipt of the drug.

If a drop of solution does not appear, the dose will not be entered, even if the dosage counter will move. This may indicate that the needle is clogged or damaged.

! It is very important to always check the injection before injection. If you do not check the receipt of the drug, you can enter an insufficient dose of the drug or do not enter it at all, which can lead to an excessively high concentration of blood glucose.

3. Setting the dose

- Dial the desired dose by turning the dose selector (Figure A).

The dose counter shows the dose in the dose steps.

If the dose has not been set correctly, rotate the dose selector forwards or backwards until the correct dose is set.

The maximum dose that can be set is 50 steps of the dose.

The dose selector changes the number of dose steps.

Only the dose counter and dose indicator will show the number of dose steps in the dose you have taken.

You can dial up to 50 steps of the dose. If the syringe pen contains less than 50 dose steps, the dose counter will stop for the number of remaining dose steps.

At each turn of the dose selector, clicks are heard, the sound of clicks depends on which direction the dose selector is rotating (forward, backward, or if the dose collected exceeds the number of dose steps remaining in the syringe pen). Do not count these clicks.

! Before you enter the drug, check how many steps of the dose you have typed on the dose counter and the dose indicator.

Do not count the clicks of the syringe-pen. If you install and enter the wrong dose, the blood glucose concentration may become too high or low.

The residue scale shows the approximate amount of solution remaining in the syringe-pen, so it can not be used to measure the dose of the drug.

How much Sultofay® is left?

- The residue scale shows the approximate amount of the drug left in the syringe pen (Figure A).

- To determine exactly how much drug is left, use the dose counter (Figure B):

Rotate the dose selector until the dose counter stops.

If it shows "50", at least 50 steps of the drug dose remain in the syringe pen. If the dose counter shows less than "50", this is the number of dose steps that are left in the syringe pen.

If you need to inject more than the amount left in the syringe pen, you can enter the dose with two syringes.

! Be very careful when calculating the dose. If you are not sure how to properly divide the dose with two syringes, set and enter the full dose with a new syringe pen. If you mis-divide the dose, you will inject too little or too much of the drug, which can lead to too high or too low a blood glucose concentration.

4. Dosing Introduction

- Insert the needle under the skin, using the injection technique recommended by a doctor or nurse (Figure A).

- Make sure that the dose counter is in your field of vision. Do not touch the dose counter with your fingers - this may interrupt the injection.

- Press the start button all the way down and hold it in this position until the dose counter shows "O" (Figure B).

"O" should be exactly opposite the dose indicator. In this case, you can hear or feel a click.

- Hold the needle under the skin, After the dose counter has returned to zero, and slowly count to 6 (Figure C).

If you remove the needle from under the skin before, you will see how the drug flows out of the needle.In this case, an incomplete dose of the drug will be introduced, and you will have to check the concentration of blood glucose more often.

- Remove the needle from under the skin (Fig. D).

If blood appears at the injection site, gently press a cotton swab into the injection site. Do not massage the injection site.

After completing the injection, you can see a drop of solution on the end of the needle.

This is normal and does not affect the dose of the drug you entered.

! Always check with the dose counter to know how many steps of the Sultofai® dose you have entered.

Hold the button until the dose counter shows "O". If the dose counter stopped before the "O" showed, a complete dose of the drug was not administered, which could lead to a too high concentration of blood glucose.

How can I detect clogging or damage to the needle?

- If, after a long press of the start button on the dose counter, "O" does not appear, it may mean a blockage or damage to the needle.

- This means that you did not receive the drug, even if the dose counter changed the position from the initial dose that you set.

What to do with a clogged needle?

Remove the needle as described in step 5 "After the injection is complete" and repeat all steps from step 1 "Preparing the syringe pen and new needle". Be sure to set the dose you need.

Never touch the dose counter during the injection. This can interrupt the injection.

5. After the injection is completed

- By placing the outer cap of the needle on a flat surface, insert the tip of the needle inside the cap, without touching it or the needle (Fig. A).

- When the needle enters the cap, Carefully place the cap on the needle (Fig. AT).

- Unscrew the needle and discard it, observing the precautions, according to the instructions of the doctor or nurse.

- After each injection put a cap on the syringe-pen, to protect the solution contained in it from the effects of light (Figure C).

Always throw out the needle after each injection, to ensure the use of an acute needle and to avoid clogging of needles. If the needle is clogged, you can not enter imagine a drug.

Dispose of an empty syringe pen with a disconnected needle, as recommended by your doctor, nurse, pharmacist or according to local requirements.

! To avoid accidental pricking with a needle, never try to put the inner cap back on the needle.

!! Always remove the needle from the syringe pen after each injection.

This will prevent clogging of the needle, infection, infection, leakage of solution and introduction of an incorrect dose of the drug.

! Important information

- Always carry a spare syringe pen and new needles in case of their loss or damage.

- Store the syringe pen and needle in the inaccessible to all, and especially for children, a place.

- Never give its syringe-pen with the drug to others. This can damage their health.

- Never give its syringe-pen and needles to it to other persons. This can lead to cross infection.

- Persons caring for the patient, should handle the used needles with extreme caution, to avoid accidental injections and infection.

Care of the syringe pen

- Do not leave a syringe pen in the car or any other place where it can be exposed to too high or too low temperatures.

- Do not store your syringe handle at temperatures above 30 ° C.

- Protect the pen from falling on it dust, dirt and all kinds of liquids.

- Do not wash the syringe handle, do not immerse it in liquid and do not lubricate it. When the syringe pen can be cleaned with a damp cloth moistened with a mild detergent.

- Do not drop or bump syringe-pen on a firm surface.

If you drop a syringe pen or doubt its serviceability, attach a new needle and check the drug intake before injecting.

- Do not refill the syringe pen. Empty syringe pen should be immediately discarded.

- Do not attempt to repair the syringe pen by yourself. or take it apart.

Effect on the ability to drive transp. cf. and fur:

In patients with hypoglycemia, the ability of patients to concentrate and the reaction rate may be impaired. 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 with frequent episodes of hypoglycemia. In these cases, the desirability of driving a vehicle or performing such work should be considered.

Form release / dosage:Solution for subcutaneous administration, 100 units / ml + 3.6 mg / ml.

Packaging:

By 3 ml in cartridges of glass 1 of hydrolytic class, sealed with disks of halobutyl rubber / polyisoprene on one side and pistons of halobutyl rubber on the other.

The cartridge is sealed in a polypropylene multi-dose disposable syringe pen for multiple injections.

5 multi-dose disposable syringes with instructions for use in a cardboard pack.

Storage conditions:

Keep out of the reach of children.

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

The used syringe pen with the drug should be stored at a temperature not exceeding 30 ° C or in a refrigerator (at a temperature of 2 ° C to 8 ° C). Do not freeze. Use within 21 days.

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

Shelf life:2 years.

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:LP-003554

Date of registration:11.04.2016

Date of cancellation:2021-04-11

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

Manufacturer: & nbsp

NOVO NORDISK, A / S Denmark

Representation: & nbspNOVO NORDISK TOVNOVO NORDISK TOVDenmark

Information update date: & nbsp16.06.2016