Levemir FlexPen solution for subcutaneous injection 100 IU/ml 3 ml cartridges in syringe pens, 5 pcs.

Composition

Active ingredient:

detemir insulin 100 UNITS;

Auxiliary substances:

glycerol;

phenol;

metacresol;

zinc acetate;

sodium hydrophosphate dihydrate;

sodium chloride;

hydrochloric acid or sodium hydroxide;

water for injection;

Pharmacological action

Levemir ® FlexPen® is produced by recombinant DNA biotechnology using the Saccharomyces cerevisiae strain. It is a soluble analog of long-acting basal human insulin with a flat action profile.

The action profile of Levemir ® FlexPen® is significantly less variable compared to isofan-insulin and insulin glargine.

The prolonged effect of Levemir ® FlexPen® is due to the pronounced self-association of detemir insulin molecules at the injection site and the binding of the drug molecules to albumin through a connection with the fatty acid side chain. Detemir insulin is delivered to peripheral target tissues more slowly than isophane insulin. These combined delayed distribution mechanisms provide a more reproducible absorption and action profile of Levemir FlexPen compared to isofan-insulin.

For doses of 0.2-0.4 U / kg,50% of the maximum effect of the drug occurs in the range from 3-4 to 14 hours after administration. The duration of action is up to 24 hours, depending on the dose, which allows for a single or double daily administration. With double administration, C_ss of the drug is achieved after 2-3 doses of the drug are administered.

After subcutaneous administration, a pharmacodynamic response proportional to the administered dose was observed (maximum effect, duration of action, overall effect).

Long-term studies have demonstrated low levels of variability in fasting plasma glucose concentrations from day to day when patients are treated with Levemir® FlexPen® in contrast to isofan-insulin.

In long-term studies in patients with diabetes mellitus type 2 treated with basal insulin in combination with oral hypoglycemic drugs has been demonstrated that glycemic control (in terms of glycosylated hemoglobin HbA_1C) during therapy with Levemir® Flexpen® was comparable in the treatment of isophane-insulin and insulin glargine, there was a low increase of body weight.

In studies, the use of combination therapy with Levemir ® FlexPen® and oral hypoglycemic drugs resulted in a 61-65% reduction in the risk of developing mild nocturnal hypoglycemia compared to the use of isofan-insulin.

An open-label randomized clinical trial was conducted in patients with type 2 diabetes mellitus who did not reach the target glycemic values during therapy with oral hypoglycemic drugs. The study began with a 12-week preparatory period, during which patients received combination therapy with liraglutide in combination with metformin, and against which 61% of patients achieved HbA1c_with FlexPen® in a single daily dose; patients in the other group continued to receive liraglutide in combination with metformin for the next 52 weeks.

During this period, the treatment group receiving a single daily injection of Levemir FlexPen in addition to liraglutide with metformin showed a further decrease in HbA1c_from the initial 7.6% to 7.1% at the end of the 52-week period, with no episodes of severe hypoglycemia. When adding a dose of Levemir ® FlexPen® to liraglutide therapy, the advantage of the latter in terms of statistically significant weight loss in patients remained.

In long-term studies (≥6 months) involving patients with type 1 diabetes mellitus, the fasting plasma glucose level was better during treatment with Levemir ® FlexPen® compared to the use of isofan-insulin in basic bolus therapy. Glycemic control (HbA1c) with Levemir FlexPen was comparable to that with isofan-insulin, with a lower risk of nocturnal hypoglycemia and no weight gain with Levemir FlexPen.

The results of clinical studies evaluating the basic bolus regimen of insulin therapy indicate a comparable incidence of hypoglycemia in general with Levemir® FlexPen® and isofan-insulin therapy. Analysis of the development of nocturnal hypoglycemia in patients with diabetes mellitus type 1 showed a significantly lower incidence of hypoglycemia and light night on the background of the use of Levemir® Flexpen®(when the patient is able to resolve the condition of hypoglycemia, and hypoglycemia confirmed by the measurement result of the concentration of glucose in capillary blood — less than 2.8 mmol/l glucose in the blood plasma of less than 3.1 mmol/l), compared to that when using isophane-insulin; however, between the two studied drugs showed no differences in frequency of occurrence of episodes of light night of hypoglycemia in patients with diabetes mellitus type 2.

The nocturnal glycemic profile is flatter and more even in Levemir FlexPen compared to isofan-insulin, which is reflected in a lower risk of nocturnal hypoglycemia.

Antibody production was observed when Levemir ® FlexPen® was used. However, this fact does not affect glycemic control in any way.

Pregnancy

A randomized controlled clinical trial involving 310 pregnant women with type 1 diabetes mellitus evaluated the efficacy and safety of Levemir FlexPen in a basic bolus regimen (152 patients), compared with isofan-insulin, in combination with insulin aspart (158 patients), used as prandial insulin.

The results of the study showed that patients treated with Levemir ® FlexPen® showed a similar decrease in the HbA1c index at 36 weeks of pregnancy compared to the group receiving isofan-insulin. The group of patients treated with Levemir®FlexPen® and the group treated with isofan-insulin showed similarity in the overall HbA1c profile throughout pregnancy_.

The target level_{of HbA1c with} FlexPen® and in 32% of patients in the isofan-insulin therapy group.

Fasting glucose concentrations at 24 and 36 weeks of pregnancy were significantly lower in the group of women taking Levemir FlexPen compared to the group receiving isofan-insulin therapy.

During the entire pregnancy period, there were no statistically significant differences in the frequency of hypoglycemic episodes between patients treated with Levemir FlexPen and isofan-insulin.

Both groups of pregnant women treated with Levemir FlexPen and isofan-insulin showed similar results in the incidence of adverse events during the entire pregnancy period; however, it was found that in quantitative terms, the incidence of serious adverse events in patients during the entire pregnancy period (61 (40%) vs.49 (31%), in children during the period of intrauterine development and after birth (36 (24%) vs.32 (20%) was higher in the Levemir FlexPen group isofan-insulin therapy group.

The number of live births to mothers who became pregnant after being randomly assigned to treatment groups to receive one of the test drugs was 50 (83%) in the Levemir® FlexPen® treatment group and 55 (89%) in the isofan — insulin treatment group. The number of children born with congenital malformations was 4 (5%) in the Levemir FlexPen group and 11 (7%) in the isofan — insulin group. Of these, serious congenital malformations were observed in 3 (4%) children in the Levemir FlexPen group and 3 (2%) in the isofan-insulin group.

Children and teenagers

Efficacy and safety of Levemir ® FlexPen® In children, the study was conducted in two 12-month controlled clinical trials involving adolescents and children over the age of 2 years with type 1 diabetes (694 patients in total); one of these studies included a total of 82 children with type 1 diabetes in the two-to five-year-old age group. The results of these studies demonstrated that glycemic control (HbA1c) during Levemir FlexPen therapy was comparable to that during isofan-insulin treatment, when they were prescribed in basic bolus therapy. In addition, there was a lower risk of nocturnal hypoglycemia (based on the plasma glucose values measured by the patients themselves) and no weight gain (standard deviation for body weight adjusted for gender and age of the patient) during treatment with Levemir ® FlexPen®, compared with the use of isofan-insulin.One of the clinical trials was extended for an additional 12 months (a total of 24 months of clinical data were obtained) in order to obtain a more complete database for evaluating the formation of antibodies in patients during long-term treatment with Levemir FlexPen.

The results obtained during the study indicate that during the first year of treatment, while taking Levemir® FlexPen®, there was an increase in the level of antibodies to insulin detemir; however, by the end of the second year of treatment, the level of antibody formation to Levemir® FlexPen® decreased in patients to a level slightly higher than the initial level at the time of starting Levemir® FlexPen®therapy. Thus, it was proved that the formation of antibodies in patients with diabetes mellitus during treatment with Levemir ® FlexPen® does not adversely affect the level of glycemic control and the dose of insulin detemir.

Absorption

of_cmax in the blood serum is achieved in 6-8 hours after administration. With a double daily regimen of administration, C_ss is achieved after 2-3 injections.

Intra-individual absorption variability is lower in Levemir ® FlexPen® compared to other basal insulin preparations. There were no clinically significant sex-to-sex differences in the pharmacokinetics of Levemir FlexPen.

Distribution

The average Vd of Levemir FlexPen (approximately 0.1 l / kg) indicates that a high proportion of detemir insulin is circulating in the blood.

Metabolism

Inactivation of Levemir FlexPen is similar to that of human insulin preparations; all resulting metabolites are inactive.

The results of protein binding studies in vitro and in vivo show no clinically significant interactions between insulin detemir and fatty acids or other protein-binding drugs.

Deduction

The terminal T_1/2 after subcutaneous injection is determined by the degree of absorption from subcutaneous tissue and is 5-7 hours, depending on the dose.

Linearity

With subcutaneous administration, plasma concentrations were proportional to the administered dose (_Cmax, degree of absorption). There was no pharmacokinetic or pharmacodynamic interaction between liraglutide and Levemir FlexPen, at steady state, when Levemir FlexPen in a single dose of 0.5 U /kg and liraglutide in a dose of 1.8 mg were administered concomitantly to patients with type 2 diabetes mellitus.

Special patient groups

The pharmacokinetic properties of Levemir FlexPen were studied in children (6-12 years) and adolescents (13-17 years) and compared with the pharmacokinetic properties in adults with type 1 diabetes mellitus. No differences were found.

There were no clinically significant differences in the pharmacokinetics of Levemir FlexPen between elderly and young patients, or between patients with impaired renal and hepatic function and healthy patients.

Data from preclinical safety studies

In vitro studies in a human cell line, including studies on binding to insulin receptors and IGF-1 (insulin-like growth factor), have shown that insulin detemir has a low affinity for both receptors and has little effect on cell growth compared to human insulin. Preclinical data based on conventional studies of pharmacological safety, repeated dose toxicity, genotoxicity, carcinogenic potential, toxic effects on reproductive function, did not reveal any danger to humans.

Indications

Diabetes mellitus in adults, adolescents, and children over 2 years of age.

Use during pregnancy and lactation

When using Levemir® FlexPen® during pregnancy, it is necessary to consider how much the benefits of its use outweigh the possible risks.

One randomized controlled clinical trial involving pregnant women with type 1 diabetes mellitus, which examined the efficacy and safety of Levemir FlexPen plus insulin aspart (152 pregnant women) compared with isofan-insulin plus insulin aspart (158 pregnant women), did not reveal a difference in the overall safety profile during pregnancy, in pregnancy outcomes, or effects on fetal and neonatal health (see “Pharmacodynamics”, “Pharmacodynamics”, “Pregnancy safety”, “Pregnancy safety”, “pregnancy safety”, “pregnancy safety”, “pregnancy safety”, “Pregnancy safety”, “Pregnancy safety”, “Pregnancy safety”, “Pregnancy safety”, “Pregnancy safety”, “Pregnancy safety”, “Pregnancy safety”, “Pharmacokinetics”).

Additional data on the efficacy and safety of Levemir®FlexPen® treatment, obtained from approximately 300 pregnant women during post-marketing use, indicate that there are no undesirable side effects of detemir insulin, leading to the occurrence of congenital malformations and malformative or feto/neonatal toxicity.

Studies of reproductive function in animals did not reveal a toxic effect of the drug on the reproductive system (see “Pharmacodynamics”, “Pharmacokinetics”).

In general, it is necessary to carefully monitor pregnant women with diabetes throughout pregnancy, as well as during pregnancy planning. The need for insulin usually decreases in the first trimester of pregnancy, then increases in the second and third trimesters. Soon after giving birth, the need for insulin quickly returns to pre-pregnancy levels.

It is not known whether insulin detemir is excreted in breast milk. It is assumed that insulin detemir does not affect the metabolic reactions in the body of newborns/children during breastfeeding, since it belongs to the group of peptides that are easily broken down in the digestive tract into amino acids and absorbed by the body.

In nursing women, it may be necessary to adjust the dose of insulin and diet.

Contraindications

Increased individual sensitivity to insulin detemir or any of the components of the drug; it is not recommended to use Levemir® FlexPen® in children under 2 years of age, because clinical studies in children under 2 years of age have not been conducted.

Side effects

From the immune system: allergic reactions, potentially allergic reactions, hives, skin rashes, skin rashes; anaphylactic reactions;

From the side of metabolism and nutrition: hypoglycemia;

Nervous system disorders: peripheral neuropathy (acute pain neuropathy);

From the side of the visual organ: refractive errors; diabetic retinopathy;

Skin and subcutaneous tissue disorders: lipodystrophy;

General disorders and disorders at the injection site: injection site reactions; edema;

Interaction

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

The hypoglycemic effect of insulin is enhanced by oral hypoglycemic drugs, MAO inhibitors, ACE inhibitors, carbonic anhydrase inhibitors, non-selective beta-blockers, bromocriptine, sulfonamides, anabolic steroids, tetracyclines, clofibrate, ketoconazole, mebendazole, pyridoxine, theophylline, cyclophosphamide, fenfluramine, lithium preparations, salicylates.

The hypoglycemic effect of insulin is weakened by oral contraceptives, corticosteroids, iodine-containing thyroid hormones, somatropin, thiazide diuretics, heparin, tricyclic antidepressants, sympathomimetics, danazol, clonidine, BCC, diazoxide, morphine, phenytoin, nicotine.

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

Beta-blockers can mask the symptoms of hypoglycemia and delay recovery from hypoglycemia.

Alcohol can both increase or decrease the hypoglycemic effect of insulin.

Incompatibility

Some drugs, such as those containing thiol or sulfite groups, when added to Levemir ® Flexpen®, can cause the destruction of detemir insulin. Levemir®Flexpen® do not add to infusion solutions. This drug should not be mixed with other drugs.

How to take, course of administration and dosage

Subcutaneously.

Dosage of Levemir® FlexPen® It is determined individually on a case-by-case basis based on the patient’s needs.

Overdose

There is no specific dose that causes an overdose of insulin, but hypoglycemia can develop gradually if the dose is too high for a particular patient.

Treatment: the patient can eliminate mild hypoglycemia by taking glucose, sugar, or carbohydrate-rich foods inside. Therefore, people with diabetes are advised to carry sugar, sweets, cookies or sweet fruit juice at all times.

In the case of severe hypoglycemia, when the patient is unconscious,0.5 to 1 mg of glucagon should be administered intravenously or subcutaneously (can be administered by a trained person) or intravenously 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 recommended to eat a carbohydrate-rich diet to prevent the recurrence of hypoglycemia.

Special instructions

Levemir ® FlexPen® is a soluble basal insulin analog with a prolonged action (up to 24 hours).

Unlike other insulin preparations, basic bolus therapy with Levemir ® FlexPen® does not lead to weight gain.

Treatment with Levemir ® FlexPen® provides a smaller increase in body weight compared to the use of isofan-insulin and insulin glargine.

The lower risk of nocturnal hypoglycemia compared to isofan-insulin allows for more intensive titration of the dose in order to achieve the target blood glucose level in basic bolus therapy.

Compared to other insulins, in particular with isofan-insulin, the lower risk of mild nocturnal hypoglycemia episodes allows for more intensive dose selection in order to achieve the target blood glucose level during treatment with Levemir® FlexPen® in combination with oral hypoglycemic drugs.

Levemir ® FlexPen® provides better glycemic control (based on measurement of fasting plasma glucose) compared to the use of isofan-insulin.

Before a long trip involving jet lag, the patient should consult with their healthcare provider, as jet lag means that the patient must eat and administer insulin at a different time.

Insufficient dosage of the drug or discontinuation of treatment, especially in patients with type 1 diabetes, can lead to the development of hyperglycemia or diabetic ketoacidosis. As a rule, the first symptoms of hyperglycemia appear gradually, over several hours or days. These symptoms include thirst, rapid urination, nausea, vomiting, drowsiness, red and dry skin, dry mouth, loss of appetite, and the smell of acetone in the exhaled air. In type 1 diabetes without appropriate treatment, hyperglycemia leads to diabetic ketoacidosis and can lead to death.

Hypoglycemia can develop if the insulin dose is too high in relation to the need for insulin, if you skip a meal or if you have an unplanned intense physical activity. After compensation of carbohydrate metabolism, for example, with intensive insulin therapy, patients may change their typical symptoms-harbingers of hypoglycemia, which patients should be informed about.

The usual harbinger symptoms may disappear with a prolonged course of diabetes mellitus.

Concomitant diseases, especially those that are infectious and accompanied by fever, usually increase the body’s need for insulin.

Dose adjustment may also be necessary if the patient has concomitant kidney, liver, or adrenal, pituitary, or thyroid disorders.

Transfer of the patient from other insulin preparations. Transfer of the patient to a new type or preparation of insulin from another manufacturer should be carried out under strict medical supervision. If you change the concentration, manufacturer, type, type (human, analog of human insulin) and/or method of its production, you may need to adjust the dose. Patients switching to Levemir ® FlexPen® treatment with a different type of insulin may need to change the dose compared to the doses of previously used insulin preparations.

Dose adjustments can be made at the first dose or during the first few weeks or months of treatment.

Reactions at the injection site. As with other insulin medications, reactions at the injection site may develop, which may include pain, redness, hives, inflammation, bruising, swelling, and itching. Regularly changing the injection site in the same anatomical area can reduce symptoms or prevent the development of a reaction. Reactions usually disappear within a few days to several weeks. In rare cases, injection site reactions require discontinuation of treatment.

Simultaneous use of drugs of the thiazolidinedione group and insulin preparations. Cases of chronic heart failure have been reported when patients are treated with thiazolidinediones in combination with insulin preparations, especially when these patients have risk factors for developing chronic heart failure. This fact should be taken into account when prescribing combination therapy with thiazolidinediones and insulin preparations to patients. When prescribing such combination therapy, it is necessary to conduct medical examinations of patients for signs and symptoms of chronic heart failure, weight gain and the presence of edema. If the symptoms of heart failure worsen in patients, treatment with thiazolidinediones should be discontinued.

Influence on the ability to drive vehicles and work with mechanisms. Patients ‘ ability to concentrate and react quickly may be impaired due to hypoglycemia, which can be dangerous in situations where these abilities are particularly necessary (for example, when driving vehicles or working with machines and mechanisms). Patients should be advised to take measures to prevent the development of hypoglycemia when driving vehicles and working with mechanisms. This is especially important for patients with the absence or reduction of symptoms-harbingers of developing hypoglycemia or suffering from frequent episodes of hypoglycemia. In these cases, the feasibility of driving a vehicle or performing similar work should be considered.

Product form

solution for subcutaneous administration

Storage conditions

Store in a dark place at a temperature of 2-8 °C (do not freeze). To protect the pen from light, keep it with the cap on. A syringe pen containing the drug that is used or carried as a spare pen should be kept at room temperature.

Shelf life

30 months

Active ingredient

Detemir Insulin

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection

Weight

Weight: 145 g.