Tresiba FlexTouch, 100 me/ml syringe pens 3 ml, 5 pcs.

Composition

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1 ml of the solution contains:

Active ingredient:

insulin degludec 100 units,

excipients:

glycerol,

phenol,

metacresol,

zinc (in the form of zinc acetate),

hydrochloric acid/sodium hydroxide (for pH correction),

water for injection.

Pharmacological action

Tresiba FlextAch is an ultra-long-acting human insulin analog produced by recombinant DNA biotechnology using the Saccharomyces cerevisiae strain.

Mechanism of action

Insulin degludec specifically binds to the human endogenous insulin receptor and, by interacting with it, implements its pharmacological effect similar to that of human insulin.

The hypoglycemic effect of insulin degludec is due to an increase in glucose utilization by tissues after binding of insulin to muscle and fat cell receptors and a simultaneous decrease in the rate of glucose production by the liver.

Pharmacodynamics

Tresiba FlextAch is a basal analogue of ultra-long-acting human insulin; after subcutaneous injection, it forms soluble multihexamers in the subcutaneous depot, from where continuous and prolonged absorption of degludec insulin into the bloodstream occurs, providing an ultra-long flat profile of action and a stable hypoglycemic effect of the drug. During the 24-hour period of monitoring the hypoglycemic effect of the drug in patients who received a dose of insulin degludec 1 time/day, Tresiba FlextAch, unlike insulin glargine, showed a uniform Vd between the action in the first and second 12-hour periods (AUCGIR.0-12h, SS/AUCGIR, total, SS = 0.5).

The duration of action of Tresiba FlextAch is more than 42 hours within the therapeutic dose range. Css of the drug in blood plasma is reached 2-3 days after administration of the drug.

Insulin degludec in the Css state demonstrates significantly lower (4 times) variability in daily hypoglycemic action profiles compared to insulin glargine, which is estimated by the value of the coefficient of variability (CV) for studying the hypoglycemic action of the drug during a single dosage interval (AUCGIR, t, SS) and within a time period from 2 to 24 hours (AUCGIR2-24h, SS).

Table 1. Variability of daily hypoglycemic profiles of Tresiba FlextAch and insulin glargine at steady-state concentrations in patients with type 1 diabetes mellitus

Insulin degludec(n=26) (CV%)Insulinglargine(n=27) (CV%)Variability of daily profiles of hypoglycemic action during a single dosage interval (AUCGIR, t, SS)2082 Variability of daily profiles of hypoglycemic action during a time interval from 2 to 24 hours (AUCGIR2-24h, SS) 2292

CV: coefficient of intra-individual variability in%.

SS: drug concentration at steady state.

AUCGIR2-24h: metabolic effect in the last 22 hours of the dosing interval (i. e. no effect of intravenous insulin administered during the introductory period of the clamp study).

A linear relationship was shown between increasing the dose of Tresiba FlextAch and its overall hypoglycemic effect.

Both forms of release of Tresiba FlextAch – 100 U/ml and 200 U/ml demonstrate a comparable overall hypoglycemic effect when each of the two dosages of the drug is administered in the same total dose.

The studies did not reveal a clinically significant difference in the pharmacodynamics of Tresiba FlextAch between elderly patients and young adult patients.

Clinical efficacy and safety

We conducted 11 international randomized open-label Treat-to-Target (treat-to-target strategy) clinical trials lasting 26 and 52 weeks, conducted in parallel groups, which included a total of 4,275 patients (1,102 patients with type 1 diabetes mellitus and 3,173 patients with type 2 diabetes mellitus) treated with Tresiba FlextAch.

The efficacy of Tresiba FlextAch was studied in patients with type 1 diabetes mellitus who had not previously received insulin, and with type 2 diabetes mellitus who received insulin therapy, in a fixed or flexible dosage regimen of Tresiba FlextAch. The absence of superiority of comparison drugs (insulin detemir and insulin glargine) over Tresiba FlextAch in terms of reducing the HbA1c index from the moment of inclusion to the end of the study was proved. The exception was the drug sitagliptin, in comparison with which the drug Tresiba FlextAch showed its statistically significant superiority in terms of reducing the HbA1c index.

The results of a clinical trial (“treat to target” strategy) for initiating insulin therapy in patients with type 2 diabetes mellitus showed a 36% reduction in the incidence of episodes of confirmed nocturnal hypoglycemia (defined as episodes of hypoglycemia that occurred during the time of day between 0 h and 6 h in the morning, confirmed by the measurement of blood glucose concentration

The results of a prospective meta-analysis of data obtained from seven treat-to-target clinical trials involving patients with type 1 and type 2 diabetes mellitus demonstrated the benefits of Tresiba FlextAch therapy with respect to the lower frequency of confirmed hypoglycemia episodes and confirmed nocturnal hypoglycemia episodes in patients compared to insulin glargine therapy. A reduction in the frequency of hypoglycaemic episodes during treatment with Tresiba FlextAch was achieved with a lower average fasting plasma glucose level than during treatment with insulin glargine.

Table 2. Results of a meta-analysis of data on hypoglycemic episodes

Calculated risk ratio (insulin degludec/insulin glargine)Episodesof confirmedhypoglycemiaTotalNightly eventsType 1+type 2 diabetes mellitus (general data)0.91*0.74*Dose maintenance periodb0.84*0.68*Elderly patients ≥65 years 0.820.65*Type 1 diabetes mellitus1.10.83 Dose maintenance periodb1.020.75*Type 2 diabetes mellitus0.83*0.68*Dose maintenance periodb0.75*0.62*Basal therapy only in patients who have not previously received insulin 0.83*0.64*

* Statistically significant.

a Confirmed hypoglycemia is an episode of hypoglycemia that is confirmed by measuring the blood glucose concentration.

 Episodes of hypoglycemia after the 16th week of therapy.

There was no clinically significant formation of insulin antibodies after treatment with Tresiba FlextAch for an extended period of time.

Pharmacokinetics

Suction

The ultra-long action of insulin degludec is due to the specially designed structure of its molecule. After subcutaneous injection, soluble stable multihexamers are formed, which create an insulin depot in the subcutaneous adipose tissue. The multihexamers gradually dissociate, releasing the monomers of insulin degludec, resulting in a slow and prolonged supply of the drug to the blood.

Css of Tresiba in blood plasma is reached 2-3 days after administration of the drug.

The effect of insulin degludec for 24 hours with its daily administration 1 time/day is evenly distributed between the first and second 12-hour intervals (AUCGIR.0-12h, SS/AUCGIR, t, SS= 0.5).

Distribution

The binding of insulin degludec to plasma proteins (albumin) is >99%.

Metabolism

Degradation of insulin degludec is similar to that of human insulin; all metabolites produced are inactive.

Elimination

of T 1/2 after subcutaneous injection of Tresiba FlextAch is determined by the rate of its absorption from subcutaneous tissue, is approximately 25 hours and does not depend on the dose.

Linearity

When administered subcutaneously, the total plasma concentrations were proportional to the administered dose in the therapeutic dose range. Direct comparison of both forms of release of Tresiba FlextAch-100 U / ml and 200 U/ml-resulted in data on the compliance of their bioequivalence with the established requirements (based on the data obtained for AUCIDeg. t. SS and Cmax, IDeg, SS).

Pharmacokinetics in special patient groups

There were no differences in the pharmacokinetic properties of Tresiba FlextAch depending on the gender of patients.

There were no clinically significant differences in the pharmacokinetics of insulin degludec between elderly and young patients, between patients of different ethnic groups, between patients with impaired renal and hepatic function and healthy patients.

The pharmacokinetic properties of insulin degludec in a study in children (6-11 years) and adolescents (12-18 years) with type 1 diabetes mellitus are comparable to those in adult patients. Against the background of a single administration of the drug to patients with type 1 diabetes mellitus, it was demonstrated that the total effect of the drug dose in children and adolescents is higher compared to that in adult patients.

Preclinical data based on studies of pharmacological safety, repeated dose toxicity, carcinogenic potential, toxic effects on reproductive function, did not reveal any danger of insulin degludec for humans.

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

Indications

Diabetes mellitus in adults.

Use during pregnancy and lactation

The use of Tresiba FlextAch during pregnancy is contraindicated, since there is no clinical experience of its use in pregnant women.

Studies of reproductive function in animals did not reveal any differences between degludec insulin and human insulin in terms of embryotoxicity and teratogenicity.

The use of Tresiba FlextAch during breastfeeding is contraindicated, since there is no clinical experience of its use in nursing women.

Animal studies have shown that in rats, insulin degludec is excreted in breast milk, the concentration of the drug in breast milk is lower than in blood plasma. It is not known whether insulin degludec is excreted in breast milk of women.

No adverse effects of insulin degludec on fertility were found in animal studies.

Contraindications

• pregnancy;
• lactation (breastfeeding);
• children and adolescents under 18 years of age;
• increased individual sensitivity to the Active ingredient or any of the auxiliary components of the drug.

Side effects

The most common side effect reported during treatment with insulin degludec is hypoglycemia.

Organ SystemFrequencyImmune system disorders infrequently-hypersensitivity reac-tions infrequently-urticaria Metabolic and nutritional disorders very often-hypoglycemia Skin and subcutaneous tissue disorders infrequently-lipodystrophy General disorders and disorders at the injection site infrequently-injection site reactions infrequently-peripheral edema

Description of individual adverse reactions

Immune system disorders

When using insulin preparations, allergic reactions may develop. Immediate allergic reactions to the insulin preparation itself or its auxiliary components can potentially endanger the patient’s life.

Hypersensitivity reactions (including swelling of the tongue or lips, diarrhea, nausea, fatigue, and pruritus) and urticaria have rarely been reported with Tresiba FlextAch.

Hypoglycemia

Hypoglycemia may occur if the insulin dose is too high relative to the patient’s insulin requirements. Severe hypoglycemia can lead to loss of consciousness and / or seizures, temporary or permanent impairment of brain function up to death. Symptoms of hypoglycemia usually develop suddenly. These include “cold sweats”, pale skin, increased fatigue, nervousness or tremors, feelings of anxiety, unusual tiredness or weakness, disorientation, decreased concentration, drowsiness, severe hunger, visual disturbances, headache, nausea, palpitations.

Lipodystrophy

Lipodystrophy (including lipohypertrophy, lipoatrophy) can develop at the injection site. Following the rules for changing the injection site within one anatomical area helps to reduce the risk of developing this adverse reaction.

Injection site reactions

Reactions at the injection site (hematoma, pain, local hemorrhage, erythema, connective tissue nodules, swelling, discoloration of the skin, itching, irritation and compaction at the injection site) were observed in patients treated with Tresiba FlextAch. Most of the reactions at the injection site are minor and temporary and usually disappear with continued treatment.

Children and adolescents

The pharmacokinetic properties of Tresiba FlextAch were studied in children and adolescents under 18 years of age. Studies on the efficacy and safety of insulin degludec in children and adolescents have not been conducted.

Special patient groups

In clinical trials, no differences in the frequency, type or severity of adverse reactions were found between elderly patients and patients with impaired renal or hepatic function and the general patient population.

Interaction

There are a number of medications that affect the need for insulin.

The need for insulin can be reduced: oral hypoglycemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists, MAO inhibitors, non-selective beta-blockers, ACE inhibitors, salicylates, anabolic steroids and sulfonamides.

The need for insulin may increase: oral hormonal contraceptives, thiazide diuretics, corticosteroids, thyroid hormones, sympathomimetics, somatropin and danazol.

Beta-blockers can mask the symptoms of hypoglycemia.

Octreotide / lanreotide can both increase and decrease the body’s need for insulin.

Ethanol (alcohol) can both enhance and decrease the hypoglycemic effect of insulin.

Incompatibility

Some medications when added to Tresiba FlextAch may cause it to break down.

Tresiba FlextAch should not be added to infusion solutions.

Do not mix Tresiba FlextAch with other medications.

Overdose

A specific dose required for an insulin overdose has not been established, but hypoglycemia may develop gradually if the dose of the drug is too high compared to the patient’s need.

Treatment: the patient can eliminate mild hypoglycemia by taking glucose or sugar-containing products inside. Therefore, patients with diabetes are advised to carry sugar-containing products at all times.

In case of severe hypoglycemia, when the patient is unconscious, he should be administered glucagon (0.5 to 1 mg) i / m or subcutaneously (can be administered by a trained person) or I / v dextrose (glucose) solution (can only be administered by a medical professional). It is also necessary to inject dextrose intravenously if the patient does not regain consciousness 10-15 minutes after glucagon administration. After regaining consciousness, the patient is advised to eat a carbohydrate-rich diet to prevent relapse.

Storage conditions

Store in a dry dark place and out of reach of children at a temperature of 2 to 8°C.

Shelf life

30 months

Active ingredient

Insulin degludec

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection

Purpose

Children as prescribed by a doctor, Adults as prescribed by a doctor

Indications

Type 1 Diabetes, Type 2 Diabetes

Weight

Weight: 202 g.