Insulin glargine

When ATH: A10AE04

Pharmacological action

Pharmacological action – hypoglycemic.

Application – diabetes, requiring insulin treatment, adult, adolescents and children over 6 years.

Associated with specific insulin receptors (binding parameters similar to those of human insulin), mediates the biological effect, similar to endogenous insulin. Regulates the metabolism of glucose. Insulin and its analogs lower blood glucose, stimulating glucose uptake by peripheral tissues (especially skeletal muscle and adipose tissue), and inhibiting glucose production in the liver (gluconeogenesis). Insulin inhibits lipolysis in adipocytes and proteolysis, while increasing protein synthesis.

Pharmacokinetics

After the introduction of subcutaneous fat acidic solution is neutralized to form mikropretsipitatov, of which are constantly released small amounts of insulin glargine, providing a predictable, smooth (without peaks) the profile of the curve "concentration-time", and longer duration of action.

After p / to the introduction of the onset of action occurs, average, through 1 no. The average duration of 24 no, maximum - 29 no. At once during the day s / to a steady average concentration of insulin glargine in the blood is reached after 2-4 days after the first dose.

A comparative study of concentrations of insulin glargine and insulin-Isophane in the serum of healthy individuals and patients, diabetes, after s / c administration of drugs revealed delayed significantly longer absorption, and no peak concentrations in insulin glargine compared with insulin-izofanom.

The subcutaneous fat in a human insulin glargine partly cleaved with the carboxyl terminus of the B chain with formation of active metabolites: M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr-insulin). The plasma contains both unmodified insulin glargine, and its cleavage products.

Carcinogenicity, mutagenicity, the effect on fertility

Two-year carcinogenicity study insulin glargine were conducted in mice and rats at doses up to the application 0,455 mg / kg (about 5 and 10 times the human dose for n / to a). These data do not allow definitive conclusions, on female mice, due to high mortality in all groups, regardless of the dose. Histiocytoma at the injection site were observed in male rats (statistically significant) and male mice (statistically insignificant) by using an acidic solvent. These tumors are not detected in female animals using saline control or by dissolving insulin in other solvents. The significance of this observation in humans is unknown.

There were no mutagennocti insulin glargine in a number of tests (Ames test, test hypoxanthine guanine mammalian cells), in tests on chromosomal aberrations (cytogenetic in vitro on V79 cells, in vivo in Chinese Hamster).

In a study of fertility, as well as pre-- and postnatal studies in male and female rats at n / a dose of insulin, about 7 times greater than the recommended starting dose for the p / to the introduction in humans, revealed maternal toxicity, induced a dose-dependent hypoglycemia, including some fatal cases.

Contraindications

Hypersensitivity.

Restrictions apply

Children up to age 6 years (Safety and efficacy have not been determined).

Pregnancy and lactation

Teratogenic effects. Reproduction and teratogenicity studies conducted in rats and rabbits at the Himalayan p / to the introduction of insulin (insulin glargine and human regular insulin). Insulin was administered to female rats before mating, during mating and throughout gestation at doses up to 0,36 mg / kg / day (about 7 times higher than the recommended starting dose when s / to a person). The rabbits were administered insulin during organogenesis at dosages 0,072 mg / kg / day (about 2 times higher than the recommended starting dose when s / to a person). The effects of insulin glargine and regular insulin in these animals did not differ in overall. There were no disturbances in fertility or early embryonic development.

For patients with pre-existing or gestational diabetes mellitus, it is important to maintain adequate metabolic regulation throughout pregnancy.. Insulin requirements may decrease during the first trimester of pregnancy and increase during the second and third trimesters.. Immediately after birth, the need for insulin decreases rapidly (the risk of developing hypoglycemia increases). Under these conditions is essential careful monitoring of blood glucose.

Should be used with caution during pregnancy (There are no strictly controlled clinical studies in pregnant women.).

Category actions result in FDA - C.

Use with caution during breastfeeding (unknown, Is insulin glargine excreted in women's breast milk?). Breastfeeding women may require adjustments to their insulin dosing regimen and diet..

Side effect

Hypoglycemia is the most common adverse effect of insulin therapy, may occur, if the dose of insulin is too high compared to the need for it. Attacks of severe hypoglycemia, especially repetitive, can lead to shock the nervous system. Episodes long and expressed hypoglycemia may endanger patients' lives. Neuropsychiatric disorders against the background of hypoglycemia ("twilight" consciousness or its loss, convulsions) usually preceded by symptoms of adrenergic counterregulation (activation of the sympathetic-adrenal system in response to hypoglycemia): hunger, irritability, "cold sweat, tachycardia (the faster hypoglycemia develops and the more significant it is, the more pronounced the symptoms of adrenergic counterregulation).

Adverse eye effects. Significant changes in the regulation of blood glucose can cause temporary visual impairment due to changes in tissue turgor and the refractive index of the eye lens. The long-term normalization of blood glucose reduces the risk of progression of diabetic retinopathy. Insulin therapy, accompanied by sharp fluctuations in blood glucose levels, may lead to temporary worsening of diabetic retinopathy. Patients with proliferative retinopathy, especially untreated photocoagulation, episodes of severe hypoglycemia can lead to the development of transient loss of vision.

Lipodystrophy. As with treatment with any other insulin preparations, lipodystrophy and local delay in insulin absorption/absorption may develop at the injection site. During clinical studies during insulin therapy using insulin glargine, lipodystrophy was observed in 1–2% of patients, whereas lipoatrophy was generally uncharacteristic. Constant change of the injection site within the body regions, recommended for s / c insulin, It can reduce the severity of this reaction or prevent its development.

Local reactions in the injection area and allergic reactions. In clinical studies of insulin therapy using insulin glargine, reactions at the injection site were observed in 3–4% of patients. These reactions included redness, pain, itch, hives, swelling or inflammation. Most minor insulin injection site reactions usually resolve within a few days to a few weeks.. Allergic reactions of immediate hypersensitivity to insulin are rare.. Similar reactions to insulin (including insulin glargine) or excipients may be manifested by the development of generalized skin reactions, angioedema, bronchospasm, hypotension or shock and may, thus, pose a threat to the patient's life.

Other reactions. The use of insulin can induce the formation of antibodies thereto. During clinical studies in groups of patients, treated with insulin isophane and insulin glargine, antibody formation, cross-react with human insulin, observed with the same frequency. In rare cases, the presence of such antibodies to insulin may necessitate dosage adjustments in order to eliminate the tendency to develop hypothyroidism.- or hyperglycemia. Rarely, insulin may cause sodium retention and edema., especially if intensified insulin therapy leads to improvement of previously insufficient regulation of metabolic processes.

Drug Interactions

Pharmaceutical incompatible with solutions of other drugs. Insulin glargine should not be mixed with other insulin preparations or diluted (when mixed or diluted, its action profile over time may change, Besides, A mixture with other insulin can cause precipitation). A number of drugs affect glucose metabolism, which may require dose adjustment of insulin glargine. PM, which can enhance the hypoglycemic effect of insulin and increase susceptibility to the development of hypoglycemia, include oral hypoglycemic agents, ACE inhibitors, disopyramide, fibrates, fluoxetine, MAO inhibitors, pentoxifylline, propoksyfen, salicylates and sulfonamide antimicrobial agents. PM, which may weaken the hypoglycemic effect of insulin, include glucocorticoids, danazol, diazoksid, Diuretic, glucagon, Isoniazid, Estrogens, progestins, somatotropin, such sympathomimetics, kak epinephrine, salbutamol, terbutaline and thyroid hormones, protease inhibitors, phenothiazines, olanzapine, klozapyn.

Beta-blockers, klonidin, lithium salt, alcohol - can intensify, and weaken the hypoglycemic action of insulin. Pentamidine may cause hypoglycemia, which is sometimes replaced by hyperglycemia. Under the influence of such drugs with sympatholytic action, like beta-adrenoblokatora, klonidin, guanfacine and reserpine signs of adrenergic counterregulation may be reduced or absent.

Overdose

Symptoms: sometimes heavy and prolonged hypoglycemia, threatening the life of the patient.

Treatment: episodes of moderate hypoglycemia are usually managed by ingestion of easily digestible carbohydrates. It may be necessary to change the dosing of the drug, diet and physical activity. Episodes of severe hypoglycemia, accompanied by coma, convulsions or neurological disorders, demand / m or s / c injection of glucagon, as well as intravenous administration of a concentrated dextrose solution. You may need long-term use of carbohydrates and surveillance specialist, tk. hypoglycemia may recur after visible clinical improvement.

Dosing and Administration

P /, into the subcutaneous fat of the abdomen, shoulder or hip, always at the same time 1 once a day. Injection sites should be alternated with each new injection within the recommended areas for subcutaneous administration of the drug. The dose and time of day for administration are selected individually. In patients with diabetes mellitus type 2 can be used as monotherapy, and in combination with other hypoglycemic drugs.

In / in a normal dose, designed to s / c administration, It can cause the development of severe hypoglycemia.

Switching from treatment with other hypoglycemic drugs to insulin glargine. When replacing a treatment regimen with intermediate-acting or long-acting insulins with a treatment regimen with insulin glargine, it may be necessary to adjust the daily dose of basal insulin, and there may also be a need to change concomitant antidiabetic therapy (doses and mode of administration of additionally used short-acting insulins or their analogues or doses of oral hypoglycemic drugs). When transferring patients from twice daily administration of isophane insulin to single administration of insulin glargine, in order to reduce the risk of hypoglycemia at night and early morning, the initial dose of basal insulin should be reduced by 20–30% in the first weeks of treatment.. During the dose reduction period, the dose of short-acting insulin can be increased, and then the dosage regimen should be adjusted individually. During the transition to insulin glargine and in the first weeks after it, careful monitoring of blood glucose levels is required.

In the case of improving the regulation of metabolism and the resulting increase in insulin sensitivity may be a need for further correction mode. Dose adjustment may also be required, eg, Change in body weight, his lifestyle, the time of day for administration of the drug or when other circumstances, contributing to increased susceptibility to the development of hypo-- or hyperglycemia.

The drug should not be administered in /, the duration of action is due to its introduction into the subcutaneous adipose tissue.

Precautions

Not a drug of choice for the treatment of diabetic ketoacidosis (in such cases, intravenous administration of short-acting insulin is recommended).

Application experience is limited, therefore, it was not possible to evaluate its effectiveness and safety in the treatment of patients with impaired liver function or with moderate to severe renal impairment. In patients with renal impairment, insulin requirements may be reduced due to the weakening of its elimination. In elderly patients, progressive deterioration of renal function may lead to a persistent decrease in insulin requirements. In patients with severe liver failure, insulin requirements may be reduced due to the reduced capacity for gluconeogenesis and biotransformation insulin. In the case of poor control of glucose levels in the blood, as well as a trend towards the development of hypo- or hyperglycemia, Before you begin to adjust the dosage regimen, you should check the accuracy of compliance with the prescribed treatment regimen., Places of administration and technology literate of s / c injection, taking into account all factors, relevant to the problem.

Gipoglikemiâ. The time it takes for hypoglycemia to develop depends on the action profile of the insulins used and may, thus, changed by changing the treatment regimen. Due to the increase in the time it takes long-acting insulin to enter the body, using Lantus reduces the likelihood of developing nocturnal hypoglycemia, whereas in the morning hours this probability may increase. Patients, who have hypoglycemia may be of particular clinical relevance, such as patients with severe stenosis of the coronary arteries or cerebral vessels (the risk of cardiac and cerebral complications of hypoglycaemia), as well as patients with proliferative retinopathy, especially if they do not receive treatment photocoagulation (risk of transient loss of vision due to hypoglycemia), should take special precautions, and it is also recommended to intensify blood glucose monitoring. Patients need to know the circumstances, in which symptoms that predict hypoglycemia may change, become less pronounced or absent in certain risk groups, incl. patients, which significantly improved the regulation of blood glucose; patients, who hypoglycaemia develops gradually; in elderly patients; in patients with neuropathy; in patients with long-term diabetes mellitus; patients, suffering from mental disorders; patients, receiving concomitant treatment with other drugs (cm. "Interaction"). Such situations can lead to the development of severe hypoglycemia (with possible loss of consciousness) before, the patient understands, he develops hypoglycemia.

When, if normal or reduced levels of glycosylated hemoglobin are observed, you must consider the possibility of repeating unrecognized hypoglycemia (especially at night).

Respect for patient dosing, diet and nutrition, Correct use of insulin and control of symptoms of hypoglycemia help to significantly reduce the risk of developing hypoglycemia. Factors, increasing susceptibility to hypoglycemia, require particularly careful monitoring, tk. may require insulin dosage adjustments. These factors include: changing insulin injection site; increased insulin sensitivity (for example, when eliminating stress factors); unusual, increased or prolonged physical activity; intercurrent illness, accompanied by vomiting, diarrhea; violation of diet and nutrition; missed meal; alcohol consumption; some uncompensated endocrine disorders (such as hypothyroidism, lack of anterior pituitary or the adrenal cortex); concomitant treatment with certain other drugs.

Intercurrent disease. Intercurrent illnesses require more intensive monitoring of blood glucose levels. In many cases, the analysis indicated the presence of ketone bodies in urine, often requires correction dosing regimen of insulin. Insulin requirements often increases. Diabetics type 1 should continue to regularly consume at least small amounts of carbohydrates, even if they are only able to consume small amounts of food or cannot eat at all, if they are vomiting, etc.. These patients should never completely stop insulin.