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Pharmacological properties

insulin glargine is designed as an analogue of human insulin, which has low solubility in a neutral environment. in the preparation, it is completely soluble due to the acidic medium of the solution for injection (pH 4). after introduction into the subcutaneous tissue, the acidic solution is neutralized, which leads to the appearance of microprecipitate, from which a small amount of insulin glargine is constantly released. this ensures a smooth (without peaks) and predicted auc profile, as well as a longer duration of the drug.

Insulin glargine is metabolized to two active metabolites - M1 and M2 (see Pharmacokinetics).

Binding to the insulin receptor: in vitro studies indicate that the affinity of insulin glargine and its metabolites M1 and M2 for the human insulin receptor is similar to that of human insulin.

Binding to the insulin-like growth factor (IGF) -1 receptor: the affinity of insulin glargine for the IGF-1 receptor is approximately 5–8 times higher than the affinity of human insulin (but approximately 70–80 times lower than the affinity of IGF-1 for this receptor), while the metabolites M1 and M2 bind to the IGF-1 receptor with an affinity that is slightly lower than the affinity of human insulin.

The total therapeutic concentration of insulin (insulin glargine and its metabolites), determined in patients with type I diabetes mellitus, was significantly lower than that which would be necessary for half-maximum binding to the IGF-1 receptor and for subsequent activation of the mitogenic proliferative mechanism that is triggered by the receptor IGF-1. Endogenous IGF-1 in physiological concentrations can activate the mitogen-proliferative mechanism; however, the therapeutic insulin concentrations used in insulin therapy, including insulin glargine therapy, are significantly lower than the pharmacological concentrations required to activate the IGF-1-mediated mechanism.

The most important action of insulin, including insulin glargine, is the regulation of glucose metabolism. Insulin and its analogues reduce blood glucose by stimulating its consumption by peripheral tissues, in particular skeletal muscle and adipose tissue, as well as inhibiting the formation of glucose in the liver. Insulin inhibits adipocyte lipolysis and proteolysis, while enhancing protein synthesis.

The equivalence of the same doses of insulin glargine and human insulin after iv administration of these drugs is proved. As with any insulin, the nature of the action of insulin glargine over time can be affected by physical activity and other factors.

Studies using the method of fixing the euglycemic state, conducted with the participation of healthy volunteers and patients with type I diabetes, demonstrated that, in contrast to the neutral protamine Hagedorn (NPH) - human insulin, the onset of action of insulin glargine after the administration of sc / s occurs later, the drug acts smoothly without causing Cmax glucose in the blood, and its duration is prolonged.

The long duration of the effect of the administered sc / insulin glargine is directly associated with a slower absorption, which allows the drug to be used once a day. The temporal nature of insulin and its analogues, such as insulin glargine, can have significant individual variability.

After iv administration of insulin glargine and human insulin, the symptoms of hypoglycemia or counterregulation of the hormonal response were similar in healthy volunteers and patients with type I diabetes.

Pharmacokinetics Comparison of the plasma insulin concentration in healthy volunteers and in patients with diabetes mellitus indicated a slower and longer absorption, and also showed the absence of a peak in activity after injection of sc / insulin glargine compared with NPH - human insulin. Thus, the obtained concentrations of insulin glargine fully corresponded to the profile of the pharmacodynamic activity of the drug over time.

With the introduction of insulin glargine once a day, the equilibrium concentration is reached already 2–4 days after the first injection.

With the on / in the introduction of T½ human insulin glargine and human insulin were comparable.

After sc injection in patients with diabetes mellitus, insulin glargine is rapidly metabolized at the carboxyl end of the beta chain to form two active metabolites - M1 (21A-glycine-insulin) and M2 (21A-glycine-des-30B-threonine-insulin). In the blood plasma, the main circulating compound is the metabolite M1. M1 exposure increases in proportion to the administered dose of insulin glargine. Pharmacokinetic and pharmacodynamic data indicate that the effect of injecting insulin glargine sc is associated mainly with exposure to M1.

Most of the research participants did not determine insulin glargine and metabolite M2, and when their content could be determined, their concentrations did not depend on the administered dose of insulin glargine.

In clinical studies, when analyzing subgroups formed by age and gender, there was no difference in safety and efficacy between patients using insulin glargine and the study population as a whole.

Children and teens. In children receiving insulin glargine, the minimum plasma levels of insulin glargine and its main metabolites (M1 and M2) in the blood plasma were determined, the results of which showed that the patterns of changes in plasma concentrations were similar to those in adults, and no evidence was found in favor cumulation of insulin glargine or its metabolites with prolonged use of the drug.

Preclinical safety data. In the framework of standard studies on the pharmacological safety, toxicity with repeated use of the drug, genotoxicity, carcinogenic potential and toxicity for reproductive function, no particular danger to humans has been identified.

Indications

Treatment of diabetes in adults, adolescents and children from the age of 2 years.

Application

Dosage. Aylar contains insulin glargine - an analogue of long-acting insulin. the drug is administered 1 time per day at any time of the day, but every time at the same time. a syringe pen allows you to enter doses of insulin in increments of 1 unit.

The dosage regimen of the drug Aylar (dose and time of administration) should be selected individually. Patients with type II diabetes Aylar can also be used simultaneously with oral antidiabetic drugs. The potency of this drug is expressed in units. These units are used exclusively for the drug Aylar and differ from ME or units in which the strength of the action of other insulin analogs is expressed.

Children and teens. It is used in children from the age of 2 years.

Elderly patients (over 65 years old). In the elderly, age-related progressive deterioration in kidney function can cause a permanent decrease in insulin requirements.

Renal failure. In patients with renal failure, the need for insulin may be reduced due to a weakening of insulin metabolism.

Liver failure. In patients with hepatic insufficiency, the need for insulin may decrease due to a decrease in the ability to gluconeogenesis and a slowdown in insulin metabolism.

Switching from other insulin to Aylar. When switching from medium-duration insulin treatment regimens or prolonged effects on the Aylar treatment regimen, it may be necessary to change the dose of basal insulin, as well as to correct concomitant antidiabetic therapy (doses and time of administration of additional conventional (regular) short-acting insulins or analogues of insulin or doses of oral antidiabetic drugs).

Transfer from a two-time administration of NPH-insulin to the drug Aylar.In order to reduce the risk of hypoglycemia at night or in the early morning hours, patients who change the regimen of basal insulin from double administration of NPH-insulin to a single injection of Aylar need to reduce the dose of basal insulin by 20-30% during the first weeks of treatment.

During this period, the dose reduction should be at least partially offset by an increase in the dose of insulin, the introduction of which is associated with food intake. After this period, the dosage regimen should be adjusted individually.

As with other insulin analogues, in patients receiving high doses of insulin due to the presence of antibodies to human insulin, an improvement in the bodys response to insulin administration may be observed when switching to Aylar.

When switching to another drug and during the first weeks after this, it is recommended to carefully monitor metabolic parameters.

Improving metabolic control and the associated increase in sensitivity to insulin may require additional correction of the dosage regimen. Dose adjustment may also be required, for example, when changing the patient’s body weight or changing his lifestyle, changing the time of day, when insulin is administered, or when other factors arise that increase the tendency to develop hypo- or hyperglycemia (see SPECIAL INSTRUCTIONS :).

Route of administration. Aylar should be administered s / c.

Aylar cannot be entered in / in. The long-term effect of the drug Aylar is due to its introduction into the subcutaneous adipose tissue. In / in the introduction of the usual sc dose can lead to severe hypoglycemia.

There is no clinically significant difference in plasma insulin or glucose levels after administration of insulin glargine in the abdominal region, the deltoid region, or the thigh. For each subsequent injection, the injection site should be changed each time within the body area recommended for insulin administration.

Aylar should not be mixed with any other insulin or diluted. When mixing or diluting, the profile of the drug’s action may change over time. In addition, mixing with other insulins can lead to precipitation.

Syringe pen for insulin. The introduction of the drug Aylar in cartridges requires the use of an appropriate metering device - a syringe pen. It is recommended to use devices: VitalPen (Copernicus Sp. Z o. O., Poland), i-PEN (INSUPen) ("Biocon Limited", India) or similar.

Syringe pens should be used as recommended by the manufacturer of the injection device.

The manufacturers instructions for using the syringe pen should be followed carefully when refilling the cartridge, attaching the needle, and injecting insulin.

If the insulin syringe pen is damaged or does not work properly (due to mechanical defects), it should be disposed of and a new syringe pen used.

In the event of a malfunction of the syringe pen, the solution from the cartridge can be inserted into a syringe (suitable for insulin injection and designed for 100 units / ml) and injected.

Cartridge. Before you insert the cartridge into the syringe pen, it must be kept for 1–2 hours at room temperature. Check cartridge before use. It can be used only when the solution in it is transparent, colorless, without visible solid particles and has a water consistency. Since Aylar is a r-rom, it does not require resuspension before use.

Before injection, remove all air bubbles from the cartridge. It is not permitted to refill empty cartridges.

Before each injection, the insulin label should be checked to avoid erroneous administration of other insulin instead of insulin glargine (see SPECIAL INSTRUCTIONS).

Bottle. Check vial before use.It can be used only when the solution in it is transparent, colorless, without visible solid particles and has a water consistency.

Since Aylar is a r-rom, it does not require resuspension before use.

Children. The drug should be used in children over the age of 2 years only under close medical supervision.

Contraindications

Hypersensitivity to the active substance or to any of the excipients that make up the drug.

Side effects

Hypoglycemia, as a rule, is the most common adverse reaction observed during insulin therapy. it occurs when the dose of insulin administered far exceeds the need for it.

Adverse reactions associated with the use of the drug are given below for the classes of organs and systems according to MedDRA:

from the immune system: allergic reactions;

metabolic and nutritional disorders: hypoglycemia;

from the nervous system: dysgeusia;

on the part of the organ of vision: visual impairment, retinopathy;

on the part of the skin and subcutaneous tissues: lipohypertrophy, lipoatrophy;

from the musculoskeletal system and connective tissue: myalgia;

disturbances in the general condition and reactions at the injection site: reactions at the injection site of the drug, edema.

Metabolic and nutritional disorders. Severe episodes of hypoglycemia, especially if they occur repeatedly, can cause damage to the nervous system. Prolonged or severe hypoglycemia can pose a threat to the patients life.

In many patients, the onset of symptoms suggesting an insufficient supply of glucose to brain tissue (neuroglycopenia) is preceded by signs of adrenergic counter-regulation. As a rule, the more and faster the level of glucose in the blood decreases, the more pronounced is the adrenergic counter-regulation and the characteristic symptoms intensify.

Immune System Disorders. Immediate-type hypersensitivity reactions to insulin are rare. The manifestations of such reactions to insulin (including insulin glargine) or excipients can be: generalized skin reactions, angioedema, bronchospasm, hypotension and shock, which can pose a threat to the patients life.

The introduction of insulin preparations can cause the formation of antibodies to it. During clinical studies in groups of patients treated with NPH-insulin and insulin glargine, the formation of antibodies that cross-reacted with human insulin was observed with the same frequency. In isolated cases, due to the presence of antibodies to insulin, there may be a need for dose adjustment to prevent the occurrence of hypo- or hyperglycemia.

Disorders of the organ of vision. A significant change in blood glucose can cause temporary visual impairment due to a temporary change in turgor and a violation of the lens refraction.

The risk of progression of diabetic retinopathy is reduced when long-term normalization of blood glucose levels is achieved. However, the intensification of insulin therapy with a sudden improvement in glycemic control may be accompanied by a temporary deterioration in the course of diabetic retinopathy. In patients with proliferative retinopathy, especially those who have not had photocoagulation, episodes of severe hypoglycemia can lead to temporary loss of vision.

Disorders of the skin and subcutaneous tissue. As with any other insulin preparation, lipodystrophy can occur at the injection site, resulting in a decrease in the rate of absorption of insulin at the injection site. Constant change of injection site within a single injection site can reduce the severity of these phenomena or prevent their occurrence.

Violations of the general condition and reaction at the injection site. Reactions that occur at the injection site include redness of the skin, pain, itching, hives, swelling, or inflammation. Most mild insulin reactions that occur at the injection site usually go away from a few days to a few weeks.

Occasionally, insulin can lead to a delay in the bodys sodium and the appearance of edema, especially in cases where, thanks to an increase in the intensity of insulin therapy, it is possible to improve glycemic control, which until then was not adequate.

Children and teens. In general, the safety profile of the drug in children (aged ≤18 years) does not differ from its safety profile in adult patients.

More frequent reactions were reported at the injection site (pain at the injection site, reaction at the injection site), as well as skin reactions (rash, urticaria) in children and adolescents aged ≤18 years) compared with adults.

Research data on the safety of the drug in children under 2 years of age are not yet available.

special instructions

Aylar is not the drug of choice for the treatment of diabetic ketoacidosis. instead, in such cases, it is recommended to / in the introduction of the usual (regular) insulin.

If as a result of treatment it is not possible to achieve sufficient control of glucose level or there is a tendency to increase the number of episodes of hypo- or hyperglycemia before changing the dosage of the drug, you should check whether the patient follows the recommendations regarding the treatment regimen, place of drug administration, proper injection technique, and also evaluate other important factors affecting treatment effectiveness.

Transfer of the patient to another type or brand of insulin must be carried out under close medical supervision. In the event of a change in the strength of action, brand (manufacturer), type (regular, NPH, tape, long-acting, etc.), origin (animal, human, analogue of human insulin) and / or production method, it may be necessary to change the dose of insulin.

The introduction of insulin preparations can cause the formation of antibodies to it. In isolated cases, due to the presence of antibodies to insulin, there may be a need for dose adjustment to prevent hypo- or hyperglycemia (see ADVERSE EFFECTS).

Hypoglycemia. The time interval through which hypoglycemia develops depends on the action profile of the used insulin, therefore, it can change with a change in the treatment regimen. Due to the more stable intake of basal insulin in the body when using the drug Aylar, the likelihood of hypoglycemia at night is lower, whereas in the early morning hours hypoglycemia is more likely.

Special care and tight control of blood glucose levels is necessary for patients in whom hypoglycemia attacks can be especially dangerous from a clinical point of view, in particular for patients with severe stenosis of the coronary arteries or blood vessels supplying the brain with blood (risk of cardiac or cerebral complications of hypoglycemia) as well as patients with proliferative retinopathy who have not had photocoagulation (risk of transient posthypoglycemic blindness).

Patients should be aware that under certain circumstances, the first symptoms of hypoglycemia may be subtle. Symptoms that indicate the development of hypoglycemia may change, become less pronounced or even absent in patients belonging to certain risk groups. Among them are patients:

  • which have a significant improvement in glycemic control;
  • in which hypoglycemia develops gradually;
  • advanced age;
  • switched from insulin of animal origin to human insulin;
  • with autonomic (vegetative) neuropathy;
  • suffering from diabetes for a long period;
  • with mental disorders;
  • simultaneously receiving therapy with certain other drugs (see Interaction with other drugs and other types of interactions).

In such situations, severe hypoglycemia (possibly with loss of consciousness) may occur even before the patient realizes that he has lowered blood glucose.

Since insulin glargine with the introduction of s / c acts for a long period of time, this can lead to the fact that it will take longer to normalize the glycemic state.

If the patient has a normal or low level of glycosylated hemoglobin, this may indicate the occurrence of periodic undiagnosed (especially nightly) episodes of hypoglycemia.

To reduce the risk of hypoglycemia, it is very important for the patient to observe the dose of the drug, diet, proper insulin administration, as well as patient awareness of the symptoms of hypoglycemia. There are a number of factors that increase the tendency to hypoglycemia and require careful monitoring of the patients condition, and sometimes dose adjustment. These include:

  • change in the place of administration of insulin;
  • increased sensitivity to insulin (for example, when eliminating stress factors);
  • unusual, excessive or prolonged physical activity;
  • concomitant illness (e.g. vomiting, diarrhea);
  • poor nutrition;
  • skipping meals;
  • alcohol consumption;
  • some violations of the endocrine system (dysfunction of the thyroid gland, insufficiency of the adenohypophysis or adrenal cortex) in the stage of decompensation;
  • the simultaneous use of certain other drugs.

Accompanying illnesses. The presence of a concomitant disease requires increased control over metabolic parameters. In many cases, a urinalysis for the presence of ketone bodies is indicated and often there is a need for dose adjustment of insulin. The need for insulin can often grow. Patients with type I diabetes need to continue to regularly consume at least a small amount of carbohydrates, even if they are able to take only a small amount of food or cannot take food at all or they experience vomiting. They should never stop using insulin completely.

Antibodies to insulin. The introduction of insulin preparations can cause the formation of antibodies to it. In rare cases, due to the presence of antibodies to insulin, a dosage adjustment may be necessary to prevent the occurrence of hypo- or hyperglycemia (see PHARMACOLOGICAL PROPERTIES).

Using a syringe pen. Before using the syringe pen, you must carefully read the instructions for its use. Aylar should be used in accordance with the instructions.

Erroneous administration of another drug. Erroneous administration of drugs was reported when instead of insulin glargine, other insulins were accidentally administered, in particular short-acting insulins. Before each injection, the insulin label should be checked to avoid erroneous administration of other insulins instead of insulin.

The combination of the drug Aylar with pioglitazone. Cases of heart failure have been reported with pioglitazone in combination with insulin, especially in patients at risk of developing heart failure. This should be considered when considering the possibility of treatment with a combination of pioglitazone and the drug Aylar. When using this combination, patients should be monitored due to the possibility of symptoms of heart failure, weight gain and edema.For any worsening cardiological symptoms, the use of pioglitazone must be discontinued.

This medicine contains 1 mmol / dose of sodium (23 mg), i.e. it is practically free of sodium.

Use during pregnancy or lactation. Pregnancy. There are no data from controlled clinical trials on the use of insulin glargine during pregnancy. Data on the use of this drug in pregnant women (data on more than 1000 cases of pregnancy) indicate that insulin glargine does not adversely affect the course of pregnancy, nor does it cause developmental defects in the fetus / newborn, or toxic effects on it. No evidence of reproductive toxicity in animals. The drug Aylar can be prescribed during pregnancy, if necessary.

It is very important for patients with diabetes mellitus that pre-pregnancy and patients with gestational diabetes throughout the pregnancy to maintain proper metabolic control. The need for insulin can decrease in the first trimester of pregnancy and, as a rule, grow in the second and third trimesters. Immediately after birth, the need for insulin quickly decreases (the risk of hypoglycemia increases). Therefore, careful monitoring of blood glucose levels is of great importance.

Lactation. It is not yet known whether insulin glargine is excreted in breast milk. No metabolic effects caused by the penetration of insulin glargine into the newborn / infant with breast milk are expected, since insulin glargine is a peptide that is split into amino acids in the human gastrointestinal tract. However, women during breastfeeding may need to adjust the dose of the drug and diet.

Reproductive function. There was no direct negative effect on reproductive function in animals.

The ability to influence the reaction rate when driving vehicles or other mechanisms. The patients ability to concentrate and the speed of his reaction may be impaired due to the occurrence of hypo- or hyperglycemia or, for example, due to visual disturbances. This can be dangerous in situations where these qualities are especially important (while driving or working with machinery).

Patients should be advised to take the necessary precautions to avoid hypoglycemia while driving. This is especially important for those patients in whom the first signs of hypoglycemia are weak or absent, as well as for those in whom hypoglycemia occurs quite often. You should carefully weigh whether it is worth sitting behind the wheel or working with mechanisms in this condition.

Interactions

There are a number of substances that affect glucose metabolism, and therefore, their use may require dose adjustment of insulin glargine.

Substances that can enhance the hypoglycemic effect of insulin and increase the tendency to hypoglycemia include oral antidiabetic drugs, ACE inhibitors, disopyramides, fibrates, fluoxetine, MAO inhibitors, pentoxifylline, propoxyphene, salicylates and sulfonamide antimicrobials.

Substances that can attenuate the hypoglycemic effect of insulin include corticosteroids, danazole, diazoxide, diuretics, glucagon, isoniazid, estrogens and progestins, phenothiazine derivatives, somatropin, sympathomimetics (epinephrine (adrenaline), salbutamide, gorbuta, terbutum, gorbutone, terbutum , atypical antipsychotic drugs (e.g. clozapine and olanzapine) and protease inhibitors.

Beta-blockers, clonidine, lithium salts or alcohol can both enhance and weaken the hypoglycemic effect of insulin. Pentamidine can cause hypoglycemia, after which hyperglycemia sometimes occurs.

In addition, under the influence of sympatholytic agents, such as beta-blockers, clonidine, guanethidine and reserpine, the signs of adrenergic counterregulation may weaken or completely disappear.

Overdose

Symptoms an overdose of insulin can lead to severe and sometimes prolonged hypoglycemia, which can be life threatening to the patient.

Treatment. Mild hypoglycemia can usually be corrected by the oral administration of carbohydrates. It may also be necessary to adjust the dose of the drug and make changes to the diet or physical activity.

More severe hypoglycemia, accompanied by coma, convulsions or neurological disorders, requires the introduction of glucagon in / m or s / c or the introduction of concentrated solution of glucose in / in. Since hypoglycemia can recur even after a clear improvement in the patient’s clinical condition, long-term carbohydrate intake and patient monitoring are necessary.

Storage conditions

Unopened cartridges. Store at 2–8 ° C (in the refrigerator). do not freeze! Avoid contact with the freezer compartment or cold stores. Store the cartridge in an outer carton to protect it from light.

Cartridges after first use. The shelf life of the drug in the cartridge after opening is 28 days, provided that it is stored at a temperature not exceeding 25 ° C. Protect from overheating and direct sunlight. The cartridges that are used should not be kept in the refrigerator.

Unopened vials. Store at 2-8 ° C (in the refrigerator). Do not freeze! Avoid contact with the freezer compartment or cold stores. Store the bottle in an outer carton to protect it from light.

Shelf life after the first opening of the bottle. The shelf life of the drug in the bottle after opening is 28 days, provided that it is stored at a temperature not exceeding 25 ° C. Protect from overheating and direct sunlight. Store the bottle in an outer carton to protect it from light. It is recommended to indicate the date the bottle was first opened on the label.

Tags: Insulin glargine