Preparation Tresiba FleksTach – human insulin analog extremely long action produced by recombinant DNA biotechnology using the strain Saccharomyces cerevisiae.
The mechanism of action
Insulin degludek specifically binds to a receptor of the human endogenous insulin and, interacting with it, realize its pharmacological effect similar to the effect of human insulin.
Degludek hypoglycemic action of insulin due to an increase in glucose utilization tissue upon binding of insulin receptors of muscle and fat cells and simultaneous reduction in hepatic glucose production speed.
Tresiba FleksTach drug is an analogue of human insulin basal extremely long action; after s / c injection of soluble multigeksamery it forms a subcutaneous depot, from which there is a continuous and prolonged absorption of insulin into the bloodstream degludek providing sverhdlitelnyh flat profile of action and stable hypoglycemic effect of the drug. Within 24 hours of preparation hypoglycemic action monitoring period in patients degludek insulin dose was administered 1 time / day, the drug Tresiba FleksTach, unlike insulin glargine demonstrated uniform Vd between the action of the first and second 12-hour periods (AUCGIR.0- 12h, SS / AUCGIR, total, SS = 0.5).
The duration of drug action Tresiba FleksTach is more than 42 hours within the therapeutic dosage range. Css drug in the blood plasma is reached 2-3 days after dosing.
Insulin degludek in Css state demonstrates significantly less (4 times) in comparison with insulin glargine variability in daily profiles hypoglycemic action, which is estimated by the value variation coefficient (CV) for the study the hypoglycemic effect of the drug within one dosing interval (AUCGIR, t, SS) and within a time period of from 2 to 24 hours (AUCGIR2-24h, SS).
Table 1. The variability of the daily profiles of the drug hypoglycemic Tresiba FleksTach and insulin glargine in the state of equilibrium concentrations in patients with type 1 diabetes
(N = 26)
(N = 27) (CV%) Variability profiles daily hypoglycemic action during one dosing interval (AUCGIR, t, SS) 2082Variabelnost daily profiles hypoglycemic action during the time interval from 2 to 24 hours (AUCGIR2-24h, SS ) 2292
CV: coefficient intraindividual variability in%.
SS: drug concentration in the equilibrium state.
AUCGIR2-24h: metabolic effect in the last 22 hours of the dosing interval (i.e., there is no influence on it entered I / insulin run-in period for Clamp-study).
Proved linear correlation between increasing dose and Tresiba FleksTach general hypoglycemic action.
Both forms release drug Tresiba FleksTach – 100 U / ml and 200 U / ml demonstrate comparable between a common hypoglycemic effect when administered each of the two dosages of the drug in the same total dose.
The studies revealed no clinically significant differences in the pharmacodynamics of the drug Tresiba FleksTach between elderly patients and younger adult patients.
Clinical efficacy and safety
Conducted 11 international randomized, open-label clinical studies Treat-to-Target (strategy “treat to target ‘) lasting 26 and 52 weeks, conducted in parallel groups, which included, a total of 4275 patients (1102 patients with type 1 diabetes and 3173 patients with type 2 diabetes mellitus), receiving the drug Tresiba FleksTach.
Efficacy Tresiba FleksTach studied in patients with type 1 diabetes who have not received before insulin, and type 2 diabetes treated with insulin therapy, in a fixed or flexible dosing regimen preparation Tresiba FleksTach. It proved the absence superiority comparisons of drugs (insulin detemir and insulin glargine) above preparation Tresiba FleksTach in reducing NbA1c indicator from power before the end of the study. The exception was the drug sitagliptin, in comparison with which the drug Tresiba FleksTach showed its statistically significant superiority in reducing the index NbA1c.
Results of clinical studies (strategy “treat to target”) on initiating insulin therapy in patients with type 2 diabetes showed a decrease by 36% the frequency of episodes of confirmed nocturnal hypoglycemia (defined as hypoglycemia episodes occurred during the time of day between 0 hours and 6 a.m. confirmed by the result of measurement of blood plasma glucose concentration
Results of a prospective meta-analysis of data obtained during the seven-designed on the principle of “treat to target ‘clinical studies in patients with diabetes mellitus type 1 and 2, demonstrated the benefits of therapy with Tresiba FleksTach against lower in comparison with the therapy insulin glargine the incidence in patients episodes of confirmed hypoglycemia and nocturnal hypoglycemia episodes confirmed. Reducing the frequency of episodes of hypoglycemia during treatment with the drug Tresiba FleksTach it has been achieved at a lower average of blood glucose fasting plasma than when treated with insulin glargine.
Table 2. Results of meta-analysis of episodes of hypoglycemia data
Estimated risk ratio (degludek insulin / insulin glargine) Episodes
gipoglikemiia Total Night Diabetes mellitus type 1 + 2 type (general data) 0.91 * 0.74 * sustain period dozyb0.84 * 0.68 * elderly patients ≥65 let0.820.65 * type 1 diabetes 1.10.83Period maintain dozyb1.020.75 * < strong> type 2 diabetes 0.83 * 0.68 * sustain period dozyb0.75 * 0.62 * Only basal therapy in patients with previously untreated insulin0.83 * 0.64 *
* Statistically significant.
a Confirmed hypoglycemia – is an episode of hypoglycemia, confirmed the result of the measurement of plasma glucose concentrations
b episodes of hypoglycaemia after 16 weeks of therapy.
There were no clinically significant formation of antibodies to insulin after treatment Tresiba FleksTach over an extended period of time.
Sverhdlitelnyh degludek insulin action due to a specially designed structure of its molecule. After n / a soluble injection, the formation of stable multigeksamerov that create a depot of insulin in adipose tissue. Multigeksamery gradually dissociate releasing insulin monomers degludek, resulting in a slow and sustained delivery of the drug in the blood.
Css Tresiba drug in the blood plasma is reached 2-3 days after dosing.
Insulin action degludek for 24 hours when administered daily one time / day uniformly distributed between the first and second 12-hour intervals (AUCGIR.0-12h, SS / AUCGIR, t, SS = 0.5).
Degludek insulin binding to plasma proteins (albumin) is > 99%.
Disintegration insulin degludek similar to that of human insulin; all metabolites formed are inactive.
T1 / 2 when s / c injection of the drug Tresiba FleksTach subcutaneous tissue is determined from its rate of absorption is approximately 25 hours and is independent From dose.
For n / to a total plasma concentration are proportional to administered dose in the therapeutic dose range. In a direct comparison of the two forms of the drug release Tresiba FleksTach – 100 U / ml and 200 units / ml obtained data according bioequivalence established requirements (based on the received AUCIDeg.t.SS and Cmax data, IDeg, SS).
Pharmacokinetics in special patient groups
There were no differences in the pharmacokinetic properties of the drug Tresiba FleksTach depending on the sex of the patient.
There were no clinically significant differences in the pharmacokinetics of insulin degludek between young and elderly patients, patients between different ethnic groups, among patients with impaired renal and hepatic function and healthy patients.
The pharmacokinetic properties of insulin degludek in the study in children (6-11 years) and adolescents (12-18 years) with type 1 diabetes compared to those of adult patients. Against the background of a single administration of the drug to patients with type 1 diabetes have demonstrated that the net effect of the dose in children and adolescents is higher compared to that in adult patients.
Preclinical data based on studies of pharmacological safety, toxicity of repeated doses, a carcinogenic potential toxic effects on the reproductive function, have not revealed any risk to human insulin degludek.
The ratio of the metabolic and mitogenic activity of insulin degludek is similar to that of human insulin.
Novo Nordisk A / S, Denmark
1 ml solution contains:
the active substance:
degludek insulin 100 units,
Zinc (in the form of zinc acetate),
hydrochloric acid / sodium hydroxide (to correct for pH),
water for injections.
Diabetes mellitus in adults.
- lactation (breastfeeding);
- childhood and adolescence to 18 years;
- heightened individual sensitivity to the active agent or any of the auxiliary components of the preparation.
The most common side effects that were reported during treatment with insulin degludek is hypoglycemia.
System opganov Frequency Violations of the immune sistemyredko – reaction giperchuvstvitelnostiredko – krapivnitsaNarusheniya with metabolic side and pitaniyaochen often – gipoglikemiyaNarusheniya with the skin side and subcutaneous tkaneynechasto – lipodistrofiyaObschie disorders and in place vvedeniyachasto – site reactions vvedeniyanechasto – peripheral edema
Description of individual adverse reactions
Violations of the immune system
In applying insulin preparations may develop allergic reactions. Allergic reactions of immediate type in itself insulin preparation or auxiliary components are included in it could potentially threaten the patient’s life.
In applying the drug Tresiba FleksTach hypersensitivity reactions (including swelling of the tongue or lips, diarrhea, nausea, fatigue and pruritus) and urticaria have been observed rarely.
Hypoglycemia can develop if the insulin dose is too high in relation to the patient’s need for insulin. Severe hypoglycemia may lead to loss of consciousness and / or convulsions, temporary or permanent impairment of brain function or death. Symptoms of hypoglycaemia usually develop suddenly. They include a “cold sweat”, pale skin, fatigue, nervousness or tremor, anxiety, unusual tiredness or weakness, disorientation, poor concentration, drowsiness, expressed the feeling of hunger, blurred vision, headache, nausea, palpitations.
Lipodystrophy (including lipohypertrophy, lipoatrophy) may occur at the injection site. Compliance with the rules change the injection site within the same anatomical region helps to reduce the risk of this adverse reaction.
The reactions at the injection site
Patients receiving the drug Tresiba FleksTach, marked reactions in the injection site (hematoma, pain, local bleeding, erythema, nodules of the connective tissue, swelling, changes in skin color, itching, irritation and induration at the injection site). Most injection site reactions are minor and of a temporary nature and usually disappear with continued treatment.
Children and adolescents
The pharmacokinetic properties of the drug Tresiba FleksTach been studied in children and adolescents up to 18 years. Research on the effectiveness and safety degludek insulin in children and adolescents have not been conducted.
Special patient groups
In clinical trials no differences in the incidence, type, and severity of adverse reactions between elderly patients and patients with impaired renal or hepatic function, and the general population of patients not detected.
In a dry and dark place inaccessible to children at 2 to 8 ° C.
There are a number of drugs that affect insulin requirements.
Insulin requirements may decrease: oral hypoglycemic agents, receptor agonists, glucagon-like peptide-1 (GLP-1), MAO inhibitors, 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, growth hormone and danazol.
Beta-blockers may mask the symptoms of hypoglycemia.
Octreotide / lanreotide may either increase or decrease the body’s need for insulin.
Ethanol (alcohol) can both enhance and decrease the hypoglycemic effect of insulin.
Some drugs, when added to the drug Tresiba FleksTach can cause its destruction.
Preparation Tresiba FleksTach can not be added to infusion solutions.
You can not mix preparation Tresiba FleksTach with other drugs.
Pregnancy and lactation
Use of the drug Tresiba FleksTach in pregnancy is contraindicated because clinical experience of its use in pregnant women is absent.
Reproduction studies in animals did not reveal any differences between insulin degludek and human insulin in terms of embryo toxicity and teratogenicity.
Use of the drug Tresiba FleksTach during breastfeeding contraindicated because clinical experience of its use in lactating women is not available.
Studies in animals have shown that in the rat insulin degludek excreted in breast milk, the drug concentration in breast milk is lower than in blood plasma. It is unknown whether insulin degludek excreted in breast milk of women.
In animal studies have found adverse effects of insulin degludek fertility.
Particular dose required for insulin overdose is not established, but may develop hypoglycemia gradually if introduced too high compared to the need of the patient dose.
Treatment: light hypoglycaemia the patient can remove himself, taking into glucose or sugar products. Therefore, patients with diabetes are advised to routinely carry sugar products.
In case of severe hypoglycemia when the patient is unconscious, he should enter glucagon (0.5 to 1 mg) / m or m / k (may be administered trained person) or on / in dextrose (glucose) (can only enter a medical worker ). It is also necessary in / dextrose enter if after 10-15 minutes after administration of glucagon, the patient did not regain consciousness. After recovery of consciousness the patient is advised to take food rich in carbohydrates for the prevention of relapse.