Levemir FlexPen, 100 me/ml 3 ml cartridges in syringe pens 5 pcs

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

The profile of action of Levemir^® FlexPen^® is much less variable than isophan insulin and insulin glargine.

The prolonged action of Levemir^® FlexPen^® is due to the marked self-association of insulin detemir molecules at the injection site and the binding of drug molecules to albumin via a side-chain fatty acid bond. Insulin detemir is slower to reach peripheral target tissues than isophan insulin. These combined delayed-distribution mechanisms provide a more reproducible absorption and action profile of Levemir^® FlexPen^® compared to isophane insulin.

For doses of 0.2-0.4 IU/kg, 50% of the drug’s maximum effect occurs between 3 and 4 and 14 hours after administration. The duration of action is up to 24 hours, depending on the dose, which provides the possibility of single and double daily administration. When administered twice daily, C_ss of the drug is achieved after administering 2-3 doses of the drug.

After p/q administration, a pharmacodynamic response proportional to the dose administered was observed (maximal effect, duration of action, overall effect).

Long-term studies have demonstrated low day-to-day variability in fasting plasma glucose concentrations when treating patients with Levemir^® FlexPen^® compared to isophane insulin.

In long-term studies in patients with type 2 diabetes who received basal insulin therapy in combination with oral hypoglycemic agents, it has been demonstrated that glycemic control (as measured by glycosylated hemoglobin – HbA_1C) on therapy with Levemir^® FlexPen^® was comparable to that on treatment with isophane insulin and insulin glargine, with a low increase in body weight.

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

An open randomized clinical trial was conducted involving patients with type 2 diabetes mellitus who did not achieve glycemic targets on therapy with oral hypoglycemic agents. The study began with a 12-week preparatory period, during which patients received liraglutide combination therapy with metformin, during which 61% of patients reached their HbA_1c ® FlexPen^® at a daily single dose; patients in the other continued to receive liraglutide in combination with metformin for the next 52 weeks.

While this period, the treatment group that received in addition to liraglutide therapy with metformin a daily single injection of Levemir^®FlexPen^®, demonstrated a further decrease in HbA_1c from an initial 7.6% to 7.1% at the end of the 52-week period, with no episodes of severe hypoglycemia. When a dose of Levemir^® FlexPen^® was added to liraglutide therapy, the advantage of the latter in terms of statistically significant weight reduction in patients persisted.

In long-term studies (≥6 months) involving patients with type 1 diabetes mellitus, fasting plasma glucose concentrations were better on treatment with Levemir^® FlexPen^® compared to the use of isofan-insulin in base-bolus therapy. Glycemic control (HbA_1c) on therapy with Levemir^®FlexPen^® was comparable to that of isofan-insulin treatment, with a lower risk of nocturnal hypoglycemia and no increase in body weight on Levemir^® FlexPen®.

The results of clinical studies evaluating the basal bolus mode of insulin therapy, indicate a comparable incidence of hypoglycemia in general on therapy with Levemir^® FlexPen^® and isophane insulin. Analysis of the development of nocturnal hypoglycemia in patients with type 1 diabetes demonstrated a significantly lower incidence of mild nocturnal hypoglycemia with Levemir^® FlexPen^®(when the patient is able to resolve hypoglycemia independently and hypoglycemia is confirmed by measuring capillary blood glucose concentration less than 2.8 mmol/L or plasma glucose less than 3.1 mmol/L) compared to that with isofan-insulin; and no differences were found between the two studied drugs in the frequency of occurrence of mild nocturnal hypoglycemic episodes in type 2 diabetic patients.

The nocturnal glycemic profile is flatter and flatter with Levemir^® FlexPen^{® compared to isophane insulin, which is reflected in a lower risk of nocturnal hypoglycemia.}

When using Levemir^® FlexPen^® antibody production was observed. However, this fact has no effect on glycemic control.

Pregnancy

A randomized controlled clinical trial including 310 pregnant women with type 1 diabetes evaluated the efficacy and safety of Levemir^® FlexPen^® in a baseline-bolus regimen of therapy (152 patients), compared with isophane insulin in combination with insulin aspart (158 patients) used as prandial insulin.

The results of the study showed that patients who received Levemir^® FlexPen^®, a similar decrease in the HbA_1c index at 36 weeks of pregnancy was observed compared to the group receiving isofan-insulin. The group of patients treated with Levemir^®FlexPen^® and the group treated with isofan-insulin showed similar overall HbA_1c profile throughout pregnancy.

Target HbA_1c ® FlexPen^® and 32% of patients in the isophane-insulin therapy group.

The fasting glucose concentration at gestational ages 24 and 36 weeks was statistically significantly lower in the group of women who received Levemir^® FlexPen^® compared to the group receiving isofan-insulin therapy.

There were no statistically significant differences between patients treated with Levemir^® FlexPen^® and isophan-insulin in the incidence of hypoglycemic episodes throughout pregnancy.

The two groups of pregnant women treated with Levemir^® FlexPen^® and isophan-insulin showed similar results on the frequency of their adverse events throughout the pregnancy; However, the rates of serious adverse events were found to be quantitatively higher in patients throughout pregnancy (61 (40%) versus 49 (31%), in children during fetal development and after birth (36 (24%) versus 32 (20%)) in the Levemir treatment group.sup>® FlexPen^® compared to the isophane-insulin therapy group.

The number of live-born children from mothers who became pregnant after they were randomized to therapy groups to receive treatment with one of the test drugs was 50 (83%) in the Levemir treatment group^® FlexPen^® and 55 (89%) in the isophane-insulin treatment group. The number of children born with congenital malformations was 4 (5%) in the Levemir^® FlexPen^® treatment group and 11 (7%) in the isophane-insulin treatment group. Of these, serious congenital malformations were noted in 3 (4%) children in the Levemir^® FlexPen^® treatment group and 3 (2%) in the isophane-insulin treatment group.

Children and adolescents

The efficacy and safety of Levemir^® FlexPen^® in children was studied in two controlled 12-month clinical studies involving adolescents and children over 2 years of age with type 1 diabetes (694 patients in total); one of these studies included a total of 82 children with type 1 diabetes between the ages of two and five years. The results of these studies demonstrated that glycemic control (HbA_1c) on therapy with Levemir^®FlexPen^® was comparable to that of isophane insulin when given as basal bolus therapy. In addition, a lower risk of nocturnal hypoglycemia (based on patients’ self-measured plasma glucose concentrations) and no weight gain (standard deviation for body weight adjusted for patient gender and age) was noted during treatment with Levemir^® FlexPen^®, compared to the use of isophane insulin. One of the clinical studies was extended for an additional 12 months (a total of 24 months of clinical data were obtained) to provide a more complete database to evaluate patient antibody formation during long-term treatment with Levemir^® FlexPen^®.

The results obtained in the study indicate that during the first year of treatment with 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 antibodies to Levemir^® FlexPen^® decreased in patients to a level slightly higher than the baseline level at the start of therapy with Levemir^® FlexPen®. Thus, it is proved that antibody formation in diabetic patients against the background of treatment with Levemir^®FlexPen^® has no adverse effect on the level of glycemic control and the dose of insulin detemir.

Pharmacokinetics

Absorption

The C_max in serum is reached 6-8 h after administration. With twice daily administration, C_ss is reached after 2-3 administrations.

Interindividual variability in absorption is lower with Levemir^® FlexPen^® compared to other basal insulin preparations. No clinically significant intersex differences in the pharmacokinetics of Levemir^® FlexPen^® were found.

Distribution

The mean V_d of Levemir^® FlexPen^® (approximately 0.1 L/kg) indicates that a high proportion of insulin detemir is circulating in the blood.

Metabolism

The inactivation of Levemir^® FlexPen is similar to that of human insulin preparations; all metabolites produced are inactive.

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

Elimination

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

Linearity

When administered p/k, plasma concentrations were proportional to the dose administered (C_max, degree of absorption). No pharmacokinetic or pharmacodynamic interaction between liraglutide and Levemir^® FlexPen^® was detected., in equilibrium, when Levemir^® FlexPen^® was administered simultaneously to patients with type 2 diabetes at a single dose of 0.5 U/kg and liraglutide at a dose of 1.8 mg.

Particular patient groups

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

There were no clinically significant differences in the pharmacokinetics of Levemir^® FlexPen^® between elderly and younger patients or between patients with renal and hepatic impairment and healthy patients.

Preclinical safety data

In vitro studies in human cell lines, including insulin and IGF-1 (insulin-like growth factor) receptor binding studies, have shown that insulin detemir has low affinity for both receptors and little effect on cell growth compared to human insulin. Preclinical data based on routine studies of pharmacological safety, repeated-dose toxicity, genotoxicity, carcinogenic potential, and toxic effects on reproduction showed no danger to humans.

Indications

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

Active ingredient

Composition

Active ingredient:

Detemir insulin 100 IU;

Auxiliary substances:

Glycerol;

Phenol;

methacresol;

zinc acetate;

sodium hydrophosphate dihydrate;

Sodium chloride;

Hydrochloric acid or sodium hydroxide;

water for injection;

How to take, the dosage

Subcutaneously.

The dose of Levemir® FlexPen® is determined on a case-by-case basis based on the patient’s needs.

Interaction

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

. Hypoglycemic effect of insulin is enhanced by oral hypoglycemic drugs, MAO inhibitors, ACE inhibitors, carbohydrate inhibitors, non-selective beta-adrenoblockers, bromocriptine, sulfonamides, anabolic steroids, tetracyclines, clofibrate, ketoconazole, mebendazole, pyridoxine, theophylline, cyclophosphamide, phenfluramine, lithium preparations, salicylates.

The hypoglycemic effects of insulin are impaired by oral contraceptives, GCS, iodine containing thyroid hormones, somatropin, thiazide diuretics, heparin, tricyclic antidepressants, sympathomimetics, danazol, clonidine, BKK, diazoxide, morphine, phenytoin, nicotine.

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

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

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

Incompatibilities

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

Special Instructions

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

In contrast to other insulin drugs, basal bolus therapy with Levemir®FlexPen® does not lead to weight gain.

The treatment with Levemir® FlexPen® provides less weight gain compared to the use of isophane insulin and insulin glargine.

The lower risk of nocturnal hypoglycemia compared to isophane insulin allows for more intense dose titration to achieve blood glucose targets in baseline bolus therapy.

In comparison with other insulins, particularly isophan insulin, the lower risk of episodes of mild nocturnal hypoglycemia allows for more intense dose titration to achieve blood glucose targets with Levemir treatment

sup>® FlexPen® in combination with oral hypoglycemic agents.

Leveremir® FlexPen® provides better glycemic control (based on fasting plasma glucose concentration measurements) compared to isophane insulin use.

People should consult with their physician before traveling for extended periods of time because changing time zones means they may have to eat and inject insulin at different times.

Inadequate dosing or discontinuation of therapy, especially in type 1 diabetes, can lead to hyperglycemia or diabetic ketoacidosis. Typically, the first symptoms of hyperglycemia appear gradually over a period of hours or days. These symptoms include thirst, frequent 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 the development of diabetic ketoacidosis and can lead to death.

Hypoglycemia can develop if the insulin dose is too high relative to insulin requirements, if meals are skipped, or if unplanned vigorous exercise occurs. After compensation of carbohydrate metabolism, such as with intensified insulin therapy, patients may have changes in their typical hypoglycemic precursor symptoms, and patients should be informed.

The usual precursor symptoms may disappear with the long-term course of diabetes.

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

The drug dose may also need to be adjusted if the patient has comorbid kidney, liver, or adrenal, pituitary, or thyroid dysfunction.

The patient’s transfer from other insulin medications. Transfer of a patient to a new type or a different manufacturer’s insulin medication must be done under strict medical supervision. Dose adjustments may be necessary if there is a change in concentration, manufacturer, type, type (human, human analogue insulin), and/or method of manufacture. Patients switching to Levemir® FlexPen® from another type of insulin may need dose adjustments compared to doses of previously used insulin products.

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

Injection site reactions. As with other insulin medications, injection site reactions may develop as manifested by pain, redness, urticaria, inflammation, bruising, swelling, and itching. Regularly changing the injection site in the same anatomical area may reduce symptoms or prevent a reaction from developing. Reactions usually disappear within a few days to a few weeks. In rare cases, reactions at the injection site require discontinuation of treatment.

The concomitant use of thiazolidinedione and insulin drugs has been reported in cases of chronic heart failure when treating patients with thiazolidinedione in combination with insulin drugs, especially if these patients have risk factors for chronic heart failure. This fact should be taken into account when prescribing combined therapy with thiazolidinediones and insulin drugs. When prescribing such combination therapy, medical examination of patients should be carried out to detect signs and symptoms of chronic heart failure, weight gain and edema. If patients have worsening symptoms of heart failure, treatment with thiazolidinedione should be discontinued.

Impact on ability to drive vehicles and operate mechanisms.Patients’ ability to concentrate and reaction speed may be impaired due to hypoglycemia, which may be dangerous in situations where these abilities are particularly necessary (such as driving or operating machines and mechanisms). Patients should be recommended to take measures to prevent hypoglycemia when driving vehicles and working with mechanisms. This is especially important for patients with the absence or reduced severity of precursor symptoms of developing hypoglycemia or who suffer from frequent episodes of hypoglycemia. In these cases, consideration should be given to the appropriateness of driving a vehicle or performing such work.

Contraindications

Individual hypersensitivity to insulin detemir or any of the drug components; we do not recommend using Levemir® FlexPen® in children under 2 years of age, since no clinical studies have been conducted in children under 2 years of age.

Side effects

Immune system disorders: allergic reactions, potentially allergic reactions, urticaria, skin rash, skin rash; anaphylactic reactions;

Metabolism and nutrition disorders: hypoglycemia;

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

Visual organ: refractive disorders; diabetic retinopathy;

Skin and subcutaneous tissue: Lipodystrophy;

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

Overdose

There is no specific dose that causes insulin overdose, but hypoglycemia can develop gradually if too high a dose has been administered for a particular patient.

Treatment: Mild hypoglycemia can be managed by the patient by ingesting glucose, sugar, or carbohydrate-rich foods. Therefore, it is recommended that diabetics carry sugar, candy, cookies, or sweet fruit juice with them at all times.

In case of severe hypoglycemia, when the patient is unconscious, 0.5 to 1 mg of glucagon should be administered either by injection or by injection (can be administered by a trained person) or by an IV solution of dextrose (glucose) (can only be administered by a medical professional). Dextrose should also be administered intravenously if the patient does not regain consciousness 10-15 minutes after glucagon administration. After recovery of consciousness, the patient is advised to take a meal rich in carbohydrates to prevent recurrence of hypoglycemia.

Pregnancy use

When using Levemir® FlexPen® during pregnancy, the extent to which its benefits outweigh the possible risks should be considered.

One randomized controlled clinical trial involving pregnant women with type 1 diabetes that examined the efficacy and safety of combination therapy with Levemir® FlexPen®/sup> with insulin aspart (152 pregnant women) compared with therapy with isofan-insulin combined with insulin aspart (158 pregnant women), showed no difference in overall safety profile during pregnancy, in pregnancy outcomes, or in effects on fetal and neonatal health (see “Pharmacodynamics, Pharmacokinetics).

Additional data on the efficacy and safety of treatment with Levemir®FlexPen®obtained from approximately 300 pregnant women during post-marketing use, indicate no adverse side effects of insulin detemir resulting in congenital malformations and malformative or feto/neonatal toxicity.

Reproductive studies in animals have shown no toxic effects of the drug on the reproductive system (see “Pharmacodynamics”, “Pharmacokinetics”).

In general, careful monitoring of pregnant women with diabetes mellitus throughout pregnancy, as well as during pregnancy planning, is necessary. The need for insulin usually decreases in the first trimester of pregnancy, then increases in the second and third trimesters. Shortly after delivery, insulin requirements quickly return to pre-pregnancy levels.

It is not known whether insulin detemir is excreted with breast milk. Insulin detemir is not expected to affect metabolic responses in newborns/infants during breastfeeding because it belongs to the peptide group, which is easily broken down in the digestive tract into amino acids and is absorbed by the body.

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