Levemir^® (Solution) Instructions for Use

ATC Code

A10AE05 (Insulin detemir)

Active Substance

Insulin detemir (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Long-acting human insulin analogue

Pharmacotherapeutic Group

Hypoglycemic agent – long-acting insulin analog

Pharmacological Action

Long-acting insulin, a soluble analogue of human insulin. It is produced by recombinant DNA biotechnology using a strain of Saccharomyces cerevisiae.

The prolonged action is due to the pronounced self-association of insulin detemir molecules at the injection site and the binding of the drug molecules to albumin through a connection with the side chain. Insulin detemir reaches peripheral target tissues more slowly compared to isophane insulin. These combined mechanisms of delayed distribution provide a more reproducible absorption and action profile of insulin detemir compared to isophane insulin.

It interacts with a specific receptor on the outer cytoplasmic membrane of cells and forms an insulin-receptor complex that stimulates intracellular processes, including the synthesis of a number of key enzymes (hexokinase, pyruvate kinase, glycogen synthase).

The decrease in blood glucose levels is due to increased intracellular transport, enhanced tissue uptake, stimulation of lipogenesis, glycogenesis, and a decrease in the rate of glucose production by the liver.

At doses of 0.2-0.4 U/kg, 50% of the maximum effect occurs in the interval from 3-4 hours to 14 hours after administration. The duration of action is up to 24 hours depending on the dose.

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

The profile of nocturnal glucose control is flatter and smoother for insulin detemir compared to isophane insulin, which is reflected in a lower risk of nocturnal hypoglycemia.

Pharmacokinetics

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

Indications

Diabetes mellitus.

ICD codes

Dosage Regimen

Solution

It is administered subcutaneously into the thigh, anterior abdominal wall, or shoulder area. It is necessary to rotate injection sites within the same anatomical area to prevent the development of lipodystrophy. Insulin will act faster if injected into the anterior abdominal wall area.

It is administered once or twice daily based on the patient’s needs. Patients who require the drug twice daily for optimal glycemic control can administer the evening dose either during dinner, or before bedtime, or 12 hours after the morning dose.

In elderly patients, as well as in cases of impaired liver and kidney function, blood glucose levels should be monitored more carefully and the insulin dose should be adjusted.

Dose adjustment may also be required if the patient’s physical activity increases, their usual diet changes, or in case of a concomitant illness.

When switching from intermediate-acting and long-acting insulins to Insulin detemir, dose and timing adjustments may be necessary. Careful monitoring of blood glucose levels is recommended during the switch and in the first weeks of treatment with insulin detemir. Adjustment of concomitant hypoglycemic therapy may be required (dose and timing of short-acting insulin preparations or the dose of oral hypoglycemic drugs).

Adverse Reactions

Adverse reactions related to the effect on carbohydrate metabolism – Common: hypoglycemia, the symptoms of which usually develop suddenly and may include pale skin, cold sweat, increased fatigue, nervousness, tremor, feeling of anxiety, unusual tiredness or weakness, disorientation, impaired concentration, drowsiness, pronounced hunger, visual disturbances, headache, nausea, palpitations. Severe hypoglycemia can lead to loss of consciousness and/or convulsions, temporary or permanent impairment of brain function, up to and including death.

Adverse reactions at the injection sites – Common: local hypersensitivity reactions (redness, swelling and itching at the injection site), which are usually temporary, i.e., disappear with continued treatment; Rare: lipodystrophy (as a result of non-compliance with the rule of rotating the injection site within one area).

Allergic reactions – Rare: urticaria, skin rash, as well as generalized reactions – skin itching, increased sweating, gastrointestinal disorders, angioedema, difficulty breathing, tachycardia, decreased blood pressure.

From the organ of vision – Rare: refraction disorders (usually temporary and observed at the beginning of insulin treatment), diabetic retinopathy (long-term improvement in glycemic control reduces the risk of progression of diabetic retinopathy; however, intensification of insulin therapy with a sharp improvement in carbohydrate metabolism control can lead to a temporary worsening of diabetic retinopathy).

From the nervous system – In some cases: peripheral neuropathy, which is usually reversible.

Other – Rare: edema.

Contraindications

Hypersensitivity to insulin detemir.

Use in Pregnancy and Lactation

Currently, there are no data from the clinical use of insulin detemir during pregnancy and lactation.

During the period of possible conception and throughout the entire term of pregnancy, it is necessary to carefully monitor the condition of patients with diabetes mellitus and control plasma glucose levels. The need for insulin usually decreases in the first trimester and gradually increases in the second and third trimesters of pregnancy. Soon after delivery, the need for insulin quickly returns to the level that was before pregnancy.

During breastfeeding, it may be necessary to adjust the dose of the drug and diet.

In experimental studies in animals, no differences were found between the embryotoxic and teratogenic effects of insulin detemir and human insulin.

Use in Hepatic Impairment

In cases of impaired liver function, blood glucose levels should be monitored more carefully and the insulin dose should be adjusted.

Use in Renal Impairment

In cases of impaired kidney function, blood glucose levels should be monitored more carefully and the insulin dose should be adjusted.

Pediatric Use

It is not recommended to use Insulin detemir in children under 6 years of age.

Geriatric Use

In elderly patients, blood glucose levels should be monitored more carefully and the insulin dose should be adjusted.

Special Precautions

It is not recommended to use Insulin detemir in children under 6 years of age.

It is believed that intensive therapy with insulin detemir does not lead to an increase in body weight.

The lower risk of nocturnal hypoglycemia compared to other insulins allows for more intensive dose titration to achieve target blood glucose levels.

Insulin detemir provides better glycemic control (based on fasting plasma glucose measurement) compared to the use of isophane insulin. Insufficient dose of the drug or discontinuation of treatment, especially in type 1 diabetes mellitus, 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, frequent urination, nausea, vomiting, drowsiness, flushed and dry skin, dry mouth, loss of appetite, and the smell of acetone on the breath. In type 1 diabetes mellitus, without appropriate treatment, hyperglycemia leads to the development of diabetic ketoacidosis and can be fatal.

Hypoglycemia can develop if the insulin dose is too high relative to the insulin requirement.

Skipping a meal or unplanned intense physical activity can lead to hypoglycemia.

After compensation of carbohydrate metabolism, for example, during intensified insulin therapy, the typical warning symptoms of hypoglycemia for patients may change, and patients should be informed about this. Usual warning symptoms may disappear with long-term diabetes.

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

Switching a patient to a new type or brand of insulin from a different manufacturer should occur under strict medical supervision. When changing the concentration, manufacturer, type, species (animal, human, human insulin analogue) and/or method of production (genetically engineered or animal insulin), dose adjustment may be required.

Insulin detemir should not be administered intravenously, as this can lead to severe hypoglycemia.

Mixing insulin detemir with a rapid-acting insulin analogue, such as insulin aspart, results in an action profile with a reduced and delayed maximum effect compared to their separate administration.

Effect on ability to drive vehicles and operate machinery

Patients’ ability to concentrate and reaction speed may be impaired during hypoglycemia and hyperglycemia, which may be dangerous in situations where these abilities are especially necessary (for example, when driving a car or working with machines and mechanisms). Patients should be advised to take measures to prevent the development of hypoglycemia and hyperglycemia when driving and operating machinery. This is especially important for patients with absent or reduced severity of warning symptoms of developing hypoglycemia or those suffering from frequent episodes of hypoglycemia. In these cases, the advisability of performing such work should be considered.

Drug Interactions

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, preparations containing ethanol. The hypoglycemic effect of insulin is weakened by oral contraceptives, glucocorticosteroids, thyroid hormones, thiazide diuretics, heparin, tricyclic antidepressants, sympathomimetics, danazol, clonidine, slow calcium channel blockers, diazoxide, morphine, phenytoin, nicotine.

Under the influence of reserpine and salicylates, both weakening and enhancement of the action of insulin detemir are possible.

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

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

Ethanol can enhance and prolong the hypoglycemic effect of insulin.

When using insulin preparations in combination with drugs of the thiazolidinedione group in patients with type 2 diabetes mellitus, fluid retention in the body may occur, resulting in an increased risk of development and progression of chronic heart failure, especially in patients with cardiovascular diseases and the presence of risk factors for chronic heart failure. Patients receiving such therapy should be regularly examined to identify signs of heart failure. If heart failure occurs, therapy should be carried out in accordance with current treatment standards.

Pharmaceutical interactions

Some medicinal products, for example, those containing thiol or sulfite, when added to insulin detemir, can cause degradation of insulin detemir.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.