Tresib Penfill - instructions for use, dose, side effects, contraindications

Active substanceInsulin DegloudekInsulin Degloudek

Similar drugsTo uncover

Tresiba® Penphill®

solution PC

Novo Nordisk A / S Denmark

Tresiba® FlexTech®

solution PC

Novo Nordisk A / S Denmark

Dosage form: & nbsphypodermic solution

Pharmacotherapeutic group:hypoglycemic agent - long-acting insulin analog

ATX: & nbsp

A.10.A.E. Insulins and their long-acting analogues

A.10.A.E.06 Insulin degludek

Pharmacodynamics:

Insulin degloudec binds specifically to the human endogenous insulin receptor and, interacting with it, realizes its pharmacological effect in a manner similar to that of 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 a simultaneous decrease in the rate of production of glucose by the liver.

The drug Tresiba® Penfill® is a basal analogue of human insulin of super-long action; after subcutaneous injection, it forms soluble multiexamers in the subcutaneous depot, from which there is a continuous and prolonged absorption of insulin degludec into the bloodstream, providing an ultra-long, flat profile and stable hypoglycemic effect of the drug (see Figure 1).During the 24-hour monitoring period of the hypoglycemic effect of the drug in patients who received insulin degludec once a day, Tresiba® Penphill®, in contrast to insulin glargine, showed a uniform volume of distribution between action in the first and second 12-hour periods (AUC_GIR_,0-₁₂_{h, ss}/ AUC_GIR_{, total, ss}= 0,5)

(see pIs. 1. The 24-hour average profile of glucose infusion rate is the equilibrium concentration of insulin degludec 100 U / ml 0.6 U / kg (study 1987)).

The duration of the drug Tresiba Penfill® is more than 42 hours within the therapeutic range of doses. The equilibrium concentration of the drug in the blood plasma is achieved 2-3 days after the administration of the drug.

Insulin degludec in a state of equilibrium concentration demonstrates a significantly lower (4-fold) comparison with insulin glargine variability in daily profiles of hypoglycemic action, which is estimated from the value of the coefficient of variabilityCV) for the study of the hypoglycemic effect of the drug during a single dosing interval (AUCgir.τ.ss) and in within the time frame of 2 to 24 hours (AUC_GIR_,₂_-₂₄_h,ss) , see Table 1.

Table 1.The variability of the daily profiles of the hypoglycemic action of the drug Tresib® and insulin glargine in a state of equilibrium concentration in patients with type 1 diabetes mellitus.

Insulin

degloudek

(N26)

(CV%)

Insulin

glargine

(N27)

(CV%)

Variability of daily profiles of hypoglycemic action during one dosage interval (AUC_GIR_,_t_,_ss)

Variability of daily profiles of hypoglycemic action during the time interval from 2 to 24 hours (AUC_GiR_,₂_-₂₄_h)

CV: coefficient of intra-individual variability in%

SS: Concentration of the drug in the equilibrium state

AUC_GiR_,₂_-₂₄_h: a metabolic effect in the last 22 hours of the dosing interval (i.e., there is no effect on it of intravenous insulin administered during the introductory period of the clamp study).

A linear relationship between the increase in the dose of Tresib® Penfill® and its general hypoglycemic effect has been proved.

In the studies, there was no clinically significant difference in the pharmacodynamics of the drug Tresib ® between elderly patients and older patients of a young age.

Clinical efficacy and safety

11 international randomized open clinical trials were conducted Treat-to-Target ("cure to goal" strategy) of 26 and 52 weeks in parallel groups, which included a total of 4,275 patients (1102 patients with type 1 diabetes and 3,173 patients with type 2 diabetes) who received Tresiba® .

The efficacy of Tresib® was studied in patients with type 1 diabetes who had not previously received insulin and with type 2 diabetes mellitus who received insulin therapy in a fixed or flexible dosage regimen of the Tresib® drug. The lack of superiority of the reference drugs (insulin detemir and insulin glargine) over the drug Tresiba® in relation to the reduction in the HbA_1C from the moment of inclusion to the end of the study. The exception was the drug sitagliptin, in comparison with which the preparation of Tresiba® demonstrated its statistically significant superiority in the reduction of HbA₁_c.

The results of the clinical study (the "treat to the target" strategy) for the initiation of insulin therapy in patients with type 2 diabetes mellitusshowed a 36% decrease in the incidence of confirmed episodes of nocturnal hypoglycemia (defined as episodes of hypoglycemia that occurred between zero hours and six o'clock in the morning, confirmed by measuring the plasma glucose concentration <3.1 mmol / l or evidence that the patient for the restoration of the condition, third-party help was required) against the background of the daily administration of Tresib® once daily in combination with oral hypoglycemic agents (PGHP) compared with The use of insulin glargine also in combination with PGHP. The results of the clinical study (the "treat up to the target" strategy) for baseline bolus insulin regimens in patients with type 2 diabetes showed a lower overall risk for hypoglycemic episodes and night hypoglycemia compared with the use of Tresib® as compared with insulin glargine .

The results of a prospective meta-analysis of the data obtained from seven clinically designed "treat to the end" clinical trials involving patients with type 1 and type 2 diabetes mellitus,demonstrated the advantages of Tresiba therapy with respect to the lower incidence of episodes of confirmed hypoglycemia and episodes of confirmed nocturnal hypoglycemia compared with insulin glargine. A decrease in the incidence of episodes of hypoglycemia during treatment with Tresiba® was achieved with a lower average fasting plasma glucose than with insulin glargine.

Table 2 Results of meta-analysis of data on episodes of hypoglycemia

The calculated risk ratio (insulin degludec / insulin glargine)	Episodes of confirmed hypoglycemia^a
	Total	Night
Diabetes mellitus type 1 + type 2 (general data)	0,91*	0,74*
Dose maintenance period ^b	0,84*	0,68*
Elderly patients> 65 years of age	0,82	0,65*
Type 1 diabetes mellitus	1,10	0,83
Dose maintenance period ^b	1,02	0,75*
Diabetes mellitus type 2	0,83*	0,68*
Dose maintenance period ^b	0,75*	0,62*
Only basal therapy in patients who had not previously received insulin	0,83*	0,64*

* Statistically significant

^a Confirmed hypoglycemia is an episode of hypoglycemia, confirmed by a blood glucose concentration measurement of <3.1 mmol / l, or evidence that the patient needed third-party care to restore the condition.Confirmed night hypoglycemia is a hypoglycemia that occurred during the time of day between zero hours and six o'clock in the morning.

^b Episodes of hypoglycemia after the 16th week of therapy.

There was no clinically significant formation of antibodies to insulin after treatment with the drug Tresiba Penfill® for an extended period.

Pharmacokinetics:

Absorption

The super-long action of insulin degludec is due to the specially created structure of its molecule. After subcutaneous injection, the formation of soluble stable multi-hexamers, which create a depot of insulin in the subcutaneous fat. Multiexameres gradually dissociate, releasing insulin degludec monomers, resulting in a slow and prolonged delivery of the drug into the blood.

The equilibrium concentration of the drug Tresiba in blood plasma is achieved 2-3 days after the administration of the drug.

The effect of insulin degludec for 24 hours with its daily administration once a day is evenly distributed between the first and second 12-hour intervals (AUC_{GiR, 0-12h, ss}/ AUC_GIR_{, t, ss} = 0,5).

Distribution

The relationship of insulin degludec with plasma proteins (albumin) is> 99%.

Metabolism

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

Excretion

The half-life after subcutaneous injection of the drug Tresiba Penfill® is determined by the rate of its absorption from the subcutaneous tissue. The half-life of Tresib® Penfill® is approximately 25 hours and is dose independent.

Linearity

With subcutaneous administration, the total plasma concentrations were proportional to the administered dose in the therapeutic dose range.

Special patient groups

There were no differences in the pharmacokinetic properties of the drug Tresiba Penfill®, depending on the sex of patients.

Patients of advanced age, patients of different ethnic groups, patients with impaired renal or hepatic function

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.

Children and teens

The pharmacokinetic properties of insulin degludec when tested in children (6-11 years) and adolescents (12-18 years) with type 1 diabetes 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 dose of the drug in children and adolescents is higher in comparison with that in adult patients.

Pre-clinical safety data

Preclinical data based on studies of pharmacological safety, toxicity of repeated doses, carcinogenic potential, toxic effect on reproductive function, did not reveal any hazard of insulin deglucose for humans. The ratio of metabolic and mitogenic activities of insulin deglucose is similar to that of human insulin.

Indications:

Diabetes mellitus in adults.

Contraindications:

Increased individual sensitivity to the active substance or any of the auxiliary components of the drug.

Children under the age of 18, the period of pregnancy and breastfeeding (clinical experience of the drug in children, women during pregnancy and breastfeeding is absent).

Pregnancy and lactation:Pregnancy

The use of the drug Tresiba Penfill® during pregnancy is contraindicated, since the clinical experience of its use during pregnancy is absent.

Studies of reproductive function in animals showed no difference between insulin degludec and human insulin in terms of embryotoxicity and teratogenicity.

Breastfeeding period

The use of the drug Tresiba® Penfill® during breastfeeding is contraindicated, since the clinical experience of its use in lactating women is absent.

Studies in animals have shown that in rats insulin degluedek 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 degluedek with breast milk of women.

Fertility

In animal studies, there was no adverse effect of insulin deglutecus on fertility.

Dosing and Administration:

The drug Tresiba® Penfill® is an analogue of insulin of super-long action.

The drug is administered subcutaneously once a day at any time of the day, but it is preferable to administer the drug at the same time every day.

In patients with type 2 diabetes mellitus the drug Tresiba® Penfill® can be used either as monotherapy or in combination with PGHP or with bolus insulin (see subsection "Pharmacodynamics ").

Patients with type 1 diabetes mellitus prescribe the drug Tresiba Penfill® in combination with short / ultrashort insulin to cover the need for prandial insulin.

The dose of Tresib® Penfill® should be determined individually according to the patient's needs. To optimize the control of glycemia, it is recommended to correct the dose of the drug based on the fasting plasma glucose values.

As with all insulin preparations, dose adjustment of the Tresib® Penfill® preparation may also be necessary if the patient's physical activity is increased, his usual diet changes or if he has a concomitant disease.

The initial dose of the drug Tresiba Penfill®

Patients with type 2 diabetes mellitus

The recommended initial daily dose of the drug Tresiba Penfill® is 10 units, with the subsequent selection of an individual dose of the drug.

Patients with type 1 diabetes mellitus

The drug Tresiba Penfill® is prescribed once a day in combination with prandial insulin, which is administered together with a meal, followed by the selection of an individual dose of the drug.

Translation from other insulin preparations

It is recommended that the blood glucose concentration be closely monitored during the transfer and in the first weeks of the appointment of the new drug. It may be necessary to correct the concomitant hypoglycemic therapy (dose and time of administration of insulin preparations of short and ultrashort action or dose of PGHP).

Patients with type 2 diabetes mellitus

When transferring Trisiba® Penfill® to patients with type 2 diabetes mellitus who are on basal or basal bolus insulin regimens, or on a regimen of ready-mixed insulin / self-mixed insulin preparations, the dose of Tresiba® Penphill® should be calculated on the basis of the dose of basal insulin , which the patient received before his transfer to a new type of insulin, according to the principle of "unit per unit," and then adjusted in accordance with the individual needs of the patient.

Patients with type 1 diabetes mellitus

In most patients with type 1 diabetes mellitus, when switching from any basal insulin to the Tresib® Penphill® preparation, the "unit per unit" principle is used based on the basal insulin dose that the patient received before the transition, then the dose is adjusted according to his individual needs.In patients with type 1 diabetes mellitus who, at the time of transfer to Tresib® Penfill®, were on insulin therapy with basal insulin in a twice daily schedule, or in patients with a HbA₁_c <8%, the dose of Tresib® Penfill® should be adjusted on an individual basis. It may be necessary to reduce the dose followed by an individual dose selection based on glycemic parameters.

Flexible dosing regimen

Based on the needs of the patient, the drug Tresiba Penfill® allows you to change the time of its administration (see subsection "Pharmacodynamics "). The interval between injections should be at least 8 hours.

Those patients who forget to enter the dose of insulin in time, it is recommended to enter the dose as soon as they have found it, and then return to their usual time of a daily single injection of the drug.

Special patient groups

Patients of advanced age (over 65 years)

The drug Tresiba Penfill® can be used in elderly patients. You should carefully monitor the concentration of blood glucose and adjust the dose of insulin individually (see section "Pharmacokinetics ").

Patients with kidney and liver failure

The drug Tresiba® Penfill® can be used in patients with kidney and liver failure. You should carefully monitor the concentration of blood glucose and adjust the dose of insulin individually (see section "Pharmacokinetics ").

Children and teens

Existing pharmacokinetic data are presented in subsection Pharmacokinetics, however, the efficacy and safety of Tresib® Penphyl® in children and adolescents have not been studied, and recommendations for the dose of the drug in children have not been developed.

Mode of application

The drug Tresiba Penfill® is intended only for subcutaneous administration.

The drug Tresiba Penfill® can not be administered intravenously, as this can lead to the development of severe hypoglycemia. The drug Tresiba Penfill® can not be administered intramuscularly, since in this case the absorption of the drug varies. The drug Tresiba® Penfill® can not be used in insulin pumps.

The drug Tresiba Penfill® is injected subcutaneously into the thigh, anterior abdominal wall or shoulder area. You should constantly change injection sites within the same anatomical area to reduce the risk of developing lipodystrophy.

The Penfill® cartridge is designed for use with NovoFine® or NovoTvist® disposable needles and Novo Nordisk insulin delivery systems.

Side effects:

The most common side effect reported during the treatment with insulin degludec is hypoglycemia (see "Description of individual adverse reactions "). All of the side effects presented below, based on data from clinical trials, are grouped according to MedDRA and organ systems.

The incidence of side effects is defined as: very often (≥1 / 10); often (≥ 1/100 to <1/10); infrequently (≥1 / 1,000 to <1/100); rarely (≥1 / 10,000 to <1 / 1,000), very rarely (<1 / 10,000) and unknown (impossible to estimate based on available data).

System of organs	Frequency
Immune system disorders	Rarely - Hypersensitivity reactions
Immune system disorders	Rarely - Hives
Disorders from the metabolism and nutrition	Often - Hypoglycaemia
Disturbances from the skin and subcutaneous tissues	Infrequently - Lipodystrophy
General disorders and disorders at the site of administration	Often - Reactions at the site of administration
	Infrequently - Peripheral edema

Description of individual adverse reactions

Immune system disorders

With the use of insulin preparations, it is possible to develop allergic reactions. Allergic reactions of the immediate type to the insulin preparation itself or the auxiliary components that make up it can potentially threaten the life of the patient.

With the use of the drug Tresiba Penfill®, hypersensitivity reactions (including edema of the tongue or lips, diarrhea, nausea, fatigue and pruritus) and hives are rarely noted.

Hypoglycaemia

Hypoglycemia can develop if the dose of insulin is too high in relation to the patient's need for insulin. Severe hypoglycemia can lead to loss of consciousness and / or convulsions, temporary or irreversible impairment of brain function up to a lethal outcome. Symptoms of hypoglycemia, as a rule, develop suddenly. They include cold sweats, pale skin, increased fatigue, nervousness or tremor, anxiety, unusual fatigue or weakness, impaired orientation, decreased concentration, drowsiness, severe hunger, visual impairment, headache, nausea, palpitations.

Lipodystrophy

Lipodystrophy (including lipohydrophy, lipoatrophy) can develop at the injection site. Adherence to the rules of changing the injection site within one anatomical area helps reduce the risk of this side reaction.

Reactions at the site of administration

Patients treated with Tresiba Penfill® received reactions at the injection site (hematoma, pain, local hemorrhage, erythema, connective tissue nodules, swelling, skin discoloration, itching, irritation and compaction at the injection site). Most of the reactions at the site of administration are insignificant and temporary, and usually disappear when the treatment is continued.

Children and teens

Pharmacokinetic properties of the drug Tresiba Penfill® have been studied in children and adolescents under the age of 18 (see "Pharmacokinetics "). Studies of 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 between elderly patients and patients with impaired renal or hepatic function and the general population of patients have been identified.

Overdose:

A certain dose necessary for an insulin overdose has not been established, however hypoglycemia can develop gradually if the dose of the drug has been too high in comparison with the patient's need (see "Special instructions").

- Light hypoglycemia the patient can eliminate himself by taking glucose or sugar-containing foods inside. Therefore, patients with diabetes are encouraged to constantly carry with them sugar-containing foods.

- In case of severe hypoglycemiawhen the patient is unconscious, he should enter glucagon (from 0.5 to 1 mg) intramuscularly or subcutaneously (can be administered by a trained person), or intravenously a solution of dextrose (glucose) (can be administered only by a medical professional). It is also necessary to inject dextrose intravenously in the case if the patient does not regain consciousness 10 to 15 minutes after the administration of glucagon. After restoration of consciousness, the patient is recommended to take food rich in carbohydrates, to prevent the recurrence of hypoglycemia.

Interaction:

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

The need for insulin can reduce: oral hypoglycemic drugs, glucagon-like peptide-1 receptor agonists (GLP-1), monoamine oxidase inhibitors, non-selective beta-blockers, angiotensin converting enzyme inhibitors, salicylates, anabolic steroids and sulfonamides.

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

Beta-blockers can mask symptoms of hypoglycemia.

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

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

Incompatibility

Some drugs, when added to the Tresib® Penfill® preparation, can cause its destruction.

The drug Tresiba® Penfill® can not be added to infusion solutions.

Do not mix Tresib® Penfill® with other medications.

Special instructions:

Hypoglycaemia

If you miss a meal or an unplanned intensive physical exertion, the patient may develop hypoglycemia.Hypoglycemia can also develop if the insulin dose is too high in relation to the patient's need (see "Side effect" and "Overdose").

After the compensation of carbohydrate metabolism (for example, with intensified insulin therapy), the symptoms typical for them-precursors of hypoglycemia may change in patients, which patients should be informed about. Common symptoms-precursors can disappear with prolonged course of diabetes. Concomitant diseases, especially infectious and accompanied by fever, usually increase the body's need for insulin. Correction of the dose of the drug may also be required if the patient has concomitant diseases of the kidneys, liver or adrenal, pituitary or thyroid gland disorders.

As with other basal insulin preparations, recovery from hypoglycemia with Tresib® Penfill® may be delayed.

Hyperglycaemia

An insufficient dose of the drug or discontinuation of treatment can lead to the development of hyperglycemia or diabetic ketoacidosis.In addition, concomitant diseases, especially infectious diseases, can promote the development of hyperglycemic conditions and, accordingly, increase the body's need for insulin.

Typically, the first symptoms of hyperglycemia appear gradually, within a few hours or days. These symptoms include: thirst, rapid urination, nausea, vomiting, drowsiness, redness and dryness of the skin, dry mouth, loss of appetite, odor of acetone in the exhaled air. With type 1 diabetes mellitus without appropriate treatment, hyperglycemia leads to the development of diabetic ketoacidosis and can lead to death.

For the treatment of severe hyperglycemia, it is recommended that rapid insulin be administered.

Transfer of a patient from other insulin preparations

Transfer of a patient to a new type or preparation of insulin of a new brand or other manufacturer should occur under strict medical supervision. The translation may require a dose adjustment.

The simultaneous use of drugs of the thiazolidinedione group and insulin preparations

There have been reports of cases of development of chronic heart failure in the treatment of patients with thiazolidinediones in combination with drugsinsulin, especially if such patients have risk factors for developing chronic heart failure. This fact should be taken into account when appointing patients with combined therapy with thiazolidinedione and Tresiba® Penphill®. In the appointment of such combination therapy, it is necessary to conduct medical examinations 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.

Disturbances on the part of the organ of sight

Intensification of insulin therapy with a sharp improvement in carbohydrate metabolism control may lead to a temporary deterioration in the state of diabetic retinopathy, while a prolonged improvement in glycemic control reduces the risk of progression of diabetic retinopathy.

Prevention of accidental entanglement of insulin preparations

The patient should be instructed to check the labeling on the label before each injection to avoid accidental administration of another dose or other insulin.

It is necessary to inform visually impaired or visually impaired people that they always need help from those who do not have vision problems and are trained to work with the injector.

Antibodies to insulin

With the use of insulin, the formation of antibodies is possible. In rare cases, the formation of antibodies may require a dose adjustment of insulin to prevent cases of hyperglycemia or hypoglycemia.

Instructions for use

The Penfill® cartridge is designed for use with Novo Nordisk insulin injection systems and NovoFine® or NovoTvist® needles up to 8 mm in length.

The drug Tresiba Penfill® and needles are for individual use only. Do not refill the cartridge.

Do not use the drug if the solution has ceased to be clear and colorless. Do not use the drug if it has been frozen.

Discard the needle after each injection.

Observe local requirements for disposal of used medical materials.

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

The ability of patients to concentrate and the reaction rate may be disturbed during hypoglycemia,which can be dangerous in situations where this ability is especially necessary (for example, when driving vehicles or machinery).

Patients should be advised to take measures to prevent the development of hypoglycemia in the management of vehicles. This is especially important for patients with absence or reduction in the severity of symptoms-harbingers of developing hypoglycemia or frequent episodes of hypoglycaemia. In these cases, the desirability of driving a vehicle should be considered.

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

Packaging:

In the Penfill® cartridge.

3 ml in cartridges of glass I of hydrolytic class, sealed with stoppers with discs of halobutyl rubber / polyisoprene on one side and pistons of halobutyl rubber on the other side.

5 cartridges per blister of PVC / aluminum foil.

1 blister with instructions for use in a cardboard box.

Storage conditions:

Store at a temperature of 2 to 8 ° C (in the refrigerator), but not next to the freezer. Do not freeze.

Store the cartridges in a cardboard box to protect them from light.

For use or as a replacement cartridge: do not store in the refrigerator. Store at a temperature of no higher than 30 ° C for 8 weeks.

Keep out of the reach of children.

Shelf life:

30 months.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002233

Date of registration:18.09.2013

Date of cancellation:2018-09-18

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: & nbsp25.10.2015

Illustrated instructions

Instructions

Tresiba® Penphill® (TRESIBA® Penfill®)