2010/09/21

Apidra

Composition, structure and packing

Solution for Serial to introduce a transparent, colorless or nearly colorless. 1 ml insulin glulisine 3.49 mg, which corresponds to the content of human insulin 100 IU.

Excipients: m-cresol, trometamol, sodium chloride, polysorbate 20, sodium hydroxide, hydrochloric acid, concentrated, water d / and.

Clinico-pharmacological group: a short-acting human insulin.

Pharmacological action

Insulin glulisine is a recombinant analogue of human insulin, which is equal to the strength of the soluble human insulin, but begins to act faster and has a shorter duration of action. The most important action of insulin and insulin analogues, including insulin glulisine, is regulation of glucose metabolism.

Insulin lowers the concentration of glucose in the blood, stimulating the absorption of glucose by peripheral tissues, especially skeletal muscle and adipose tissue, as well as inhibiting the formation of glucose in the liver. Insulin inhibits lipolysis in the adipocyte, proteolysis and increases protein synthesis. Studies in healthy volunteers and patients with diabetes showed that the s / c insulin glulisine starts to act faster and has a shorter duration of action than soluble human insulin.

When s / c administration hypoglycemic effect develops in 10-20 min.

When i / in the introduction of hypoglycemic effects of insulin glulisine and soluble human insulin are equal in strength. One unit of insulin glulisine has the same hypoglycemic activity, as one unit of soluble human insulin. In a study of Phase I in patients with diabetes mellitus type 1 assessed hypoglycemic profiles of insulin glulisine and soluble human insulin injected sc at a dose of 0.15 IU / kg at different times in relation to the standard 15-minute meals.

The results showed that insulin glulisine introduced for 2 minutes before a meal, provided similar control of blood glucose after meals, and that soluble human insulin, introduced 30 minutes before meals.

With the introduction of up to 2 minutes before a meal insulin glulisine provided better control of glucose levels after meals than soluble human insulin, introduced for 2 minutes before a meal. Insulin glulisine, introduced 15 min after the start of a meal, gave the same control glucose levels after meals, and that soluble human insulin injected 2 minutes before eating.

Obesity

Study Phase I, which took place with insulin glulisine, insulin lispro and soluble human insulin in a group of patients with obesity, has shown that these patients insulin glulisine saves the time of impact. In this study, the time to reach 20% of the total AUC was 114 minutes for insulin glulisine, 121 minutes for insulin lispro and 150 min for soluble human insulin, and AUC0-2 h, also reflects the early hypoglycemic activity, was 427 mghkg-1 for insulin glulisine , 354 mghkg-1 for insulin lispro, and 197 mghkg-1 for soluble human insulin.

Clinical studies

Diabetes mellitus type 1 in the 26-week clinical trial phase III, which were compared insulin glulisine with insulin lispro, put n / a just before eating (for 0-15 min) in patients with type 1 diabetes using insulin as basal insulin glargine, insulin glulisine was comparable to insulin lispro with respect to control glucose levels, which is estimated to change the concentration of glycated hemoglobin (HbA1S) at the time of the study endpoint, compared with the outcome. There were comparable concentrations of glucose in the blood, determined by self-control.

With the introduction of insulin glulisine in contrast to treatment with insulin lispro did not need to increase the dose of basal insulin. 12-week Phase III clinical trial conducted in patients with diabetes mellitus type 1 treated as the basal insulin glargine therapy, showed that the efficacy of insulin glulisine immediately after the meal was comparable to that with the introduction of insulin glulisine immediately before meals (for 0 -15 min) or soluble human insulin (about 30-45 minutes before eating). Among patients who fulfilled the study protocol, in patients treated with insulin glulisine before meals, there was significantly greater decrease HbA1S compared with patients receiving soluble human insulin.

Diabetes mellitus type 2 26-week clinical trial phase III, the subsequent 26-week extension in the form of safety studies that compared insulin glulisine (for 0-15 minutes before eating) with soluble human insulin (30-45 min meal ), which were introduced sc in patients with diabetes mellitus type 2, except that use as basal insulin izofan.

The average body mass index of patients was 34.55 kg/m2. Insulin glulisine has proved comparable with soluble human insulin with respect to changes in the concentration HbA1S after 6 months of treatment compared with outcome (-0.46% for insulin glulisine and -0.30% for soluble human insulin, p = 0.0029) and after 12 months of treatment compared with outcome (-0.23% for insulin glulisine and -0.13% for soluble human insulin, the difference is not significantly). In this study, most patients (79%) mixed their short-acting insulin with izofan-insulin immediately before injection. 58 patients at the time of randomization, use of oral hypoglycemic agents and were instructed to continue their use in the same dose.

Race and sex in controlled clinical studies in adults did not show differences in the safety and efficacy of insulin glulisine when analyzing the subgroups identified by race and sex.

Pharmacokinetics

In the insulin glulisine amino acid substitution of asparagine human insulin at position B3 by lysine and lysine in position B29 by glutamic acid contributes to more rapid absorption from its injection site.

Absorption and bioavailability

Pharmacokinetic concentration-time curves in healthy volunteers and patients with diabetes mellitus type 1 and 2 showed that absorption of insulin glulisine compared with soluble human insulin was approximately 2 times faster than with the achievement of approximately 2 times greater than the maximum concentration. In a study conducted in patients with diabetes mellitus type 1, after s / c insulin glulisine at a dose of 0.15 IU / kg, C max was reached in 55 minutes and was 82 ± 1.3 mikroME / ml compared to the Cmax of soluble human insulin, which was achieved through 82 min and was 46 ± 1.3 mikroME / ml.

The mean time spent in the systemic circulation in insulin glulisine was shorter (98 min) than soluble human insulin (161 min). In a study in patients with diabetes mellitus type 2 after sc insulin glulisine at a dose of 0.2 IU / kg, C max was 91 mikroME / ml (from 78 to 104 mikroME / ml). When s / c insulin glulisine in the anterior abdominal wall, thigh or shoulder (deltoid region), absorption was faster when introduced into the anterior abdominal wall in comparison with drug administration in the thigh.

The rate of removals from the deltoid region was intermediate. The absolute bioavailability of insulin glulisine (70%) in different sites of injection were similar and had a low variability between different patients (coefficient of variation - 11%).

Distribution and excretion

Distribution and excretion of insulin glulisine and soluble human insulin after i / v administration are similar; Vd is 13 liters and 22 liters, T1 / 2 - 13 and 18 min, respectively. After sc insulin glulisine displays faster than soluble human insulin: with T1 / 2 is 42 minutes compared with T1 / 2 of soluble human insulin 86 min. Under cross-analysis of studies of insulin glulisine as in healthy individuals and patients with diabetes mellitus type 1 and 2, T1 / 2 ranged from 37 to 75 minutes.

Pharmacokinetics in special clinical situations

In a clinical study in patients without diabetes with a wide range of renal function (spacecraft more than 80 ml / min, 30-50 mL / min, less than 30 ml / min), fast onset of effect of insulin glulisine has remained. However, the need for insulin in renal insufficiency can be reduced. Patients with hepatic impairment the pharmacokinetic parameters were not studied. There are very limited data on the pharmacokinetics of insulin glulisine in elderly patients with diabetes mellitus.

Pharmacokinetic and pharmacodynamic properties of insulin glulisine were investigated in children (7-11 years) and adolescents (12-16 years) with diabetes mellitus type 1. In both age groups, insulin glulisine is rapidly absorbed, with time to achieve and the value of C max are similar to those in adults. As in adults with the introduction directly to the test with a meal insulin glulisine provides better control of blood glucose after meals, than soluble human insulin. Increasing concentrations of glucose in the blood after a meal (AUC0-6 h) was 641 mg × h × dl-1 for insulin glulisine and 801 mg × h × dl-1 for soluble human insulin.

Statement
diabetes requiring insulin treatment (in adults).

Dosage regimen

The drug Apidra should be administered shortly (for 0-15 min) before or shortly after meals. The drug Apidra should be used in regimens, which include insulin, or the average duration or insulin or long-acting insulin analogue.

The drug can be used in combination with oral hypoglycemic means.

Dosage regimen of the drug Apidra selected individually.

The introduction of the drug or drug Apidra injected by sc injection or by continuous infusion into subcutaneous fat with the help of pump systems. P / K injections should be made in the abdomen, shoulder or thigh, and the introduction of the drug by continuous infusion in the subcutaneous fat produced in the stomach area. The injection and infusion in the aforementioned areas (abdomen, thigh or shoulder) should be alternated with each new administration. The rate of absorption and, respectively, at the beginning and duration of action may affect injection site, exercise and other changing conditions. N / a introduction to the abdominal wall ensures a faster absorption than the introduction to the other aforementioned areas of the body. It should take precautions to avoid getting the drug directly into the blood vessels.

After injection of the drug can produce massage the area of administration. Patients should be instructed in proper injection technique.

Mixing the insulin

The drug Apidra should not be confused with any other drugs except for human izofan-insulin.

Pump-action device for the continuous sc infusion

When using the drug with Apidra Pumping system for infusion of insulin can not be mixed with other drugs.

Terms of use of the drug

Since drug Apidra is a solution of resuspenzirovaniya before its use is not required.

Mixing the insulin

When mixed with human izofan-insulin drug Apidra syringe first. The injection should take place immediately after mixing, because no data on the use of mixtures prepared long before the injection. Ink Cartridges should be used together with insulin injection pen, such as OptiPen Pro1, and in accordance with the recommendations in the instructions provided by the manufacturer. Manufacturer's instructions on the use of syringe handles OptiPen Pro1 on BitTorrent cartridge, joining the needle and inject insulin should be carefully implemented.

Before using the cartridge should be inspected and used only if the solution is clear, colorless, does not contain visible particulate matter. Before installing the cartridge into a syringe pen refillable cartridge should be pre-placed 1-2 h at room temperature. Before the injection of the cartridge to remove air bubbles (see instructions on the use of syringe-pen). Empty cartridges can not be filled again. If the syringe pen OptiPen Pro1 is damaged, it can not be used. If the injection pen is defective, the solution can be drawn from the cartridge into a plastic syringe, suitable for insulin concentrations of 100 IU / ml, and introduced to the patient.

To prevent infection with a syringe-pen refillable should be used only for one patient. Cartridge system OptiKlik cartridge system OptiKlik a glass cartridge containing 3 ml of insulin glulisine, which is fixed in a transparent plastic container with an attached piston mechanism. OptiKlik cartridge system should be used with a syringe-pen OptiKlik in accordance with the recommendations of the instructions provided by the manufacturer. Manufacturer's instructions for the use of syringe-pen OptiKlik (relative to loading cartridge system, connecting the needle and inject insulin) should be accurately performed. If the syringe pen OptiKlik damaged or not working properly (due to mechanical defect), it should be replaced regularly.

Before installing the cartridge system syringe pen OptiKlik should be 1-2 hours at room temperature. Inspect the cartridge before installing the system. It should be used only if the solution is clear, colorless, does not contain visible particulate matter. Before the injection of the cartridge system to remove air bubbles (see instructions on the use of syringe-pen). Empty cartridges can not be filled again. If the injection pen is not in working order, the solution can be collected from the cartridge system into a plastic syringe, suitable for insulin concentrations of 100 IU / ml, and introduced to the patient.

To prevent infection with a syringe-pen refillable should be used only for one patient.

Side effect

Hypoglycemia - the most common adverse effect of insulin, which may arise in the case of too high doses of insulin, excess demand for it. Observed in clinical studies of adverse reactions associated with the introduction of the drug are listed below by organ systems and in order of decreasing frequency of occurrence. When describing the frequency of occurrence of the following criteria: very often -> 10%; often -> 1% and <10%,> 0.1% and <1%,> 0.01% and <0.1%, very rare - <0.01 %. On the part of metabolism: very often - hypoglycemia.

Symptoms of hypoglycaemia usually occur suddenly. These include the emergence of a cold sweat, paleness of the skin, fatigue, nervous agitation or tremor, restlessness, weakness, confusion, difficulty concentrating, drowsiness, excessive hunger, visual disturbances, headache, nausea, and marked heart rate. Hypoglycemia can increase, which may lead to unconsciousness and / or the appearance of convulsions, as well as temporary or permanent deterioration of brain function or even death.

Local reactions: often - Local hypersensitivity reactions (hyperemia, swelling and itching at the injection site). These reactions are usually transient and disappear with continued treatment.

Rarely - lipodystrophy (a violation of alternating beds of insulin in any of the regions of the drug in the same place /).

Allergic reactions: sometimes - urticaria, feeling chest tightness, bronchospasm, allergic dermatitis, pruritus. Severe cases of generalized allergic reactions (including anaphylactic) can be life threatening.

Contraindications
hypoglycemia;
increased sensitivity to insulin glulisine or any of the components of the drug. Precautions should be used during pregnancy.

Pregnancy and lactation

In the appointment of the drug during pregnancy should be careful. Required careful monitoring of blood glucose. Clinical data on the use of insulin glulisine in pregnancy. Patients with diabetes (including gestational) should be throughout the pregnancy to maintain optimal metabolic control. In the I trimester of pregnancy the need for insulin may decrease, and in II and III trimester of it, as a rule, may increase.

Immediately after birth the need for insulin rapidly decreases. In experimental studies of reproduction does not reveal any differences between the influence of insulin glulisine and human insulin during pregnancy, the developing embryo and fetus, childbirth and postnatal development. It is unknown whether insulin glulisine is allocated with breast milk, but not human insulin is excreted in breast milk and is not absorbed when administered. During the period of lactation (breastfeeding) may require adjustment of doses of insulin and diet.

Cautions

Transfer the patient to a new type of insulin or insulin with another vendor must be used under strict medical supervision, because may require correction of all the treatment.

The use of inadequate doses of insulin or termination of treatment, particularly in patients with diabetes mellitus type 1 may lead to the development of hyperglycemia and diabetic ketoacidosis - states that are potentially hazardous to human life. Time of the possible development of hypoglycemia depends on the speed of onset of effect of insulin used, and, therefore, may change when the treatment regimen. For conditions that may change or be made less pronounced harbingers of hypoglycemia include prolonged existence of diabetes, intensified insulin therapy, presence of diabetic neuropathy, taking some drugs (such as beta-blockers), or transfer of a patient with insulin of animal origin for human insulin. Correction doses of insulin may also need regime change, motor activity or meals. Physical activity, performed immediately after a meal may increase the risk of hypoglycemia.

Compared with soluble human insulin after injection of high-speed analog insulin hypoglycemia may develop earlier. Uncompensated hypoglycemic or hyperglycemic reaction can lead to loss of consciousness, the development of coma or death. The need for insulin may change with concomitant diseases or emotional overload.

Overdose

Symptoms: no specific data on overdose of insulin glulisine, hypoglycemia may develop varying degrees of severity.

Treatment: mild episodes of hypoglycemia can be cropped with admission glucose or products containing sugar. It is therefore recommended that patients with diabetes constantly were carrying pieces of sugar, sweets, biscuits or sweet fruit juice. Episodes of severe hypoglycemia, during which the patient loses consciousness, can be cropped in the / m or sc administration of 0.5-1 mg of glucagon, or in / to the introduction of dextrose (glucose) If the patient does not respond to the introduction of glucagon for 10-15 minutes, you must also enter dextrose in /. After recovery of consciousness should give their patients carbohydrates inside to prevent the recurrence of hypoglycemia. After the introduction of glucagon to determine the cause of this severe hypoglycemia and prevent the development of other similar episodes of patient should be observed in the hospital.

Drug Interactions

Studies on the Pharmacokinetic drug interactions of the drug was carried out. Based on the available empirical knowledge regarding other similar drugs occurrence of clinically significant pharmacokinetic interaction is unlikely. Certain substances can affect the metabolism of glucose, which may require adjustment of doses of insulin glulisine and particularly close monitoring of the therapy and the patient's condition.

When combined use of oral hypoglycemic means, ACE inhibitors, dizopiramid, fibrates, fluoxetine, MAO inhibitors, pentoxifylline, propoxyphene, salicylates and sulfanilamidnye antimicrobials may increase the hypoglycemic effect of insulin and increase susceptibility to hypoglycemia.

When the joint application of the SCS, danazol, diazoxide, diuretics, isoniazid, phenothiazine derivatives, somatropin, sympathomimetic (eg, epinephrine / adrenaline /, salbutamol, terbutaline), thyroid hormones, estrogens, progestins (eg, oral contraceptives), protease inhibitors and antipsychotic drugs (eg olanzapine and clozapine) may reduce the hypoglycemic action of insulin. Beta-blockers, clonidine, lithium salts or ethanol can either potentiate or weaken the hypoglycemic effect of insulin. Pentamidine may cause hypoglycemia followed by hyperglycemia c.

In the application of preparations with sympatholytic activity (beta-blockers, clonidine, and reserpine guanetidin) symptoms of reflex adrenergic activation during hypoglycemia may be less pronounced or absent.

Pharmaceutical interactions

In the absence of compatibility studies insulin glulisine should not be confused with any other drugs except for human izofan-insulin. When you enter through an infusion pump drug Apidra should not be mixed with other drugs.

Terms and Conditions of storage

Cartridges and cartridge system OptiKlik Keep out of reach of children, protected from light at 2 ° to 8 ° C, not frozen. Once you start using cartridges and cartridge system OptiKlik Keep out of reach of children, protected from light at a temperature not above 25 ° C.

To protect from exposure to light should be stored cartridges and cartridge system OptiKlik in its own carton.

Shelf life - 2 years. Shelf life of the drug in a cartridge, cartridge system OptiKlik after the first use - 4 weeks. It is recommended to observe on the label the date of the first intake of the drug.

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