Apidra® Solostar®

General characteristics. Structure:

Active ingredient: insulin глулизин - 100 PIECES (3,49 mg).
Auxiliary ingredients: metacresol (m cresol), трометамол (трометамин), sodium chloride, polysorbate 20, sodium hydroxide, Acidum hydrochloricum, water for injections.
Description: transparent, colourless or almost colourless liquid.

Pharmacological properties:

Pharmacodynamics. Insulin глулизин is a recombinant analog of human insulin which on force of action is equal to usual human insulin. Insulin глулизин begins to work quicker and has the smaller duration of action, than soluble human insulin.
The most important effect of insulin and analogs of insulin, including insulin глулизин, glucose exchange regulation is. Insulin reduces concentration of glucose in blood, stimulating glucose absorption with peripheral fabrics, especially skeletal muscles and fatty tissue, and also inhibiting formation of glucose in a liver. Insulin suppresses a lipolysis in adipocytes, suppresses proteolysis and increases protein synthesis. The researches conducted at healthy volunteers and patients with a diabetes mellitus showed that at hypodermic introduction insulin глулизин begins to work quicker and has the smaller duration of action, than soluble human insulin. At hypodermic introduction the effect of insulin of a glulizin lowering glucose level in blood begins in 10-20 minutes. At intravenous
 
introduction effects of decrease in level of glucose in blood of insulin of a glulizin and soluble human insulin are equal on force. One unit of insulin of a glulizin has the same glyukozoponizhayushchy activity, as one unit of soluble human insulin.
In a phase I research at patients with a diabetes mellitus of 1 type glyukozoponizhayushchy profiles of insulin of a glulizin and the soluble human insulin entered subcutaneously in a dose of 0,15 PIECES/kg at different times in relation to standard 15 to minute meal were estimated. Results of a research showed that insulin глулизин entered in 2 minutes prior to meal provided the same glycemic control after food, as the soluble human insulin entered in 30 minutes prior to meal. At introduction in 2 minutes prior to meal insulin глулизин provided the best glycemic control after food, than the soluble human insulin entered in 2 minutes prior to meal. Insulin глулизин, entered in 15 minutes after the beginning of meal gave the same glycemic control after food, as the soluble human insulin entered in 2 minutes prior to meal.
Obesity
The phase I research conducted with insulin gluliziny, insulin лизпро and soluble human insulin at group of patients with obesity showed that at these patients insulin глулизин keeps the characteristics of bystry action. In this research time of achievement of 20% of full AUC made 114 minutes for insulin of a glulizin, 121 minutes for insulin лизпро and 150 minutes for soluble human insulin, and AUC(0-2 of hour), reflecting also early glyukozoponizhayushchy activity, respectively, 427 mg/kg for insulin of a glulizin made, 354 mg/kg for insulin лизпро, and 197 mg/kg for soluble human insulin.
Clinical trials
Diabetes mellitus of 1 type.
In 26 week clinical trial of a phase III in which comparison of insulin of a glulizin with insulin лизпро was carried out entered subcutaneously shortly before food (in 0-15 minutes) to patients with the diabetes mellitus of 1 type using as basal insulin insulin гларгин insulin глулизин was comparable to insulin лизпро concerning glycemic control which was estimated on change of concentration of glikozilirovanny hemoglobin (HbA1c) at the time of a final point of a research in comparison with an outcome. The comparable values of glucose of blood defined by self-checking were observed. At administration of insulin of a glulizin unlike treatment by insulin лизпро increase in a dose of basal insulin was not required.
12-tinedelny clinical trial of the III phase conducted at patients with a diabetes mellitus of 1 type receiving as basal therapy insulin гларгин showed that efficiency of administration of insulin of a glulizin directly after food was comparable to that at administration of insulin of a glulizin just before meal (in 0-15 minutes) or soluble human insulin (in 30-45 minutes prior to food).
In population of the patients who fulfilled the protocol of a research in group of the patients receiving before food insulin глулизин authentically bigger decrease in NA1S in comparison with group of the patients receiving soluble human insulin was observed.
Diabetes mellitus 2 types
26 week clinical trial of a phase III with the week continuation which followed it 26 in the form of a research on safety were conducted for comparison of insulin of a glulizin (in 0-15 minutes prior to meal) with soluble human insulin (in 30-45 minutes of meal) which were entered subcutaneously at patients with a diabetes mellitus 2 types besides using insulin isophanes as basal insulin. The average index of body weight of patients made 34,55 kg/sq.m. Insulin глулизин proved to be comparable to soluble human insulin concerning changes of concentration of NA1S in 6 months of treatment in comparison with an outcome (-0,46% for insulin of a glulizin and-0,30% for soluble human insulin, p=0,0029) and in 12 months of treatment in comparison with an outcome (-0,23% for insulin of a glulizin and-0.13% for soluble human insulin, distinction is not reliable). In this research most of patients (79%) mixed the insulin of short action with insulin isofan just before an injection. 58 patients at the time of randomization used peroral hypoglycemic drugs and received instructions for continuation of their reception in the same (not changed) dose.
Racial origin and floor
In controlled clinical trials at adults distinctions in safety and efficiency of insulin of a glulizin in the analysis of the subgroups allocated on race to a floor were not shown.

Pharmacokinetics. In insulin the glulizena amino acid substitution asparagine of human insulin in a B3 position on a lysine and a lysine in a B29 position on glutaminic acid promotes more bystry absorption.
Absorption and bioavailability
Pharmacokinetic curves concentration time at healthy volunteers and patients with a diabetes mellitus 1 and 2 types showed that absorption of insulin of a glulizin in comparison with soluble human insulin was approximately twice quicker, and the reached maximum plasma concentration (Stakh) was approximately twice more.
In the research conducted at patients with a diabetes mellitus of 1 type after hypodermic administration of insulin of a glulizin in a dose of 0,15 PIECES/kg, Ttakh (time of approach of the maximum plasma concentration) made 55 minutes, and Stakh made 82 ± 1,3 ¼¬àä/ml in comparison with Tmax, components are 82 minutes old, and Cmax, a component 46 ± 1,3 ¼¬àä/ml, for soluble human insulin the Average time of stay in a system blood-groove at insulin of a glulizin was shorter (98 minutes), than at soluble human insulin (161 minutes).
In a research at patients with a diabetes mellitus Stakh made 2 types after hypodermic administration of insulin of a glulizin in a dose of 0,2 PIECES/kg 91 ¼¬àä/ml with mezhkvartilny width from 78 to 104 ¼¬àä/ml.
At hypodermic administration of insulin of a glulizin to the area of a front abdominal wall, a hip or shoulder (to the area of a deltoid muscle) absorption was more bystry at introduction to area of a front abdominal wall in comparison with administration of drug to the area of a hip. Absorption speed from area of a deltoid muscle was intermediate. Absolute bioavailability of insulin of a glulizin after hypodermic introduction made about 70% (73% of area of a front abdominal wall, 71 of area of a deltoid muscle and 68% from area of a hip) and had low variability at different patients.
Distribution and removal
Distribution and removal of insulin of a glulizin and soluble human insulin after intravenous administration are similar, with distribution volumes, components 13 liters and 22 liters, and elimination half-lives, components of 13 and 18 minutes, respectively.
After hypodermic introduction insulin глулизин is removed quicker, than soluble human insulin, having the seeming elimination half-life making 42 minutes in comparison with the seeming elimination half-life of soluble human insulin, components are 86 minutes old. In the cross analysis of researches of insulin of a glulizin, both at healthy faces, and at persons with a diabetes mellitus 1 and 2 types, the seeming elimination half-life was in range from 37 to 75 minutes.
Special groups of patients
- Patients with a renal failure
In the clinical trial conducted at persons without diabetes mellitus with a broad range of a functional condition of kidneys (the clearance of creatinine (CC)> of 80 ml/min., 30-50 ml/min. <30 ml/min.), in general speed of approach of effect of insulin of a glulizin remained. However the need for insulin in the presence of a renal failure can be reduced.
- Patients with a liver failure
At patients with abnormal liver functions pharmacokinetic indicators were not studied.
- Elderly people
Patients of advanced age have very limited data on pharmacokinetics of insulin of a glulizin with a diabetes mellitus.
- Children and teenagers
Pharmacokinetic and pharmakodinamichesky properties of insulin of a glulizin were investigated at children (7-11 years) and teenagers (12-16 years) with a diabetes mellitus of 1 type. In both age groups insulin глулизин is quickly absorbed with Ttakh and Sshchakh similar that at adults. As well as at adults at introduction just before the test with meal insulin глулизин provides the best control of glucose of blood after food, than soluble human insulin. Increase in concentration of glucose in blood after food
(AUC is 0-6 hours old - the area under a curve concentration of glucose in blood - time from 0 to 6 hours) made 641 mg / (ч*дл) for insulin of a glulizin and 801 mg / (ч*дл) for soluble human insulin.

Indications to use:

The diabetes mellitus demanding treatment by insulin at adults, teenagers and children is more senior than 6 years.

Route of administration and doses:

Apidr's drug should be administered shortly (in 0-15 minutes) to or soon after meal.
Apidr's drug has to be used in the schemes of treatment including or insulin of average duration of action or is long the operating insulin or an analog of insulin of long action, and also Apidr's drug can be used in combination with peroral hypoglycemic means.
The mode of a drug dosing of Apidr is selected individually.
Administration of drug
Apidr's drug is administered either by a subcutaneous injection or by continuous infusion in a hypodermic fatty tissue by means of pompovy system.
Subcutaneous injections of drug of Apidr should be made to the area of a stomach, shoulder or hip, and administration of drug by continuous infusion in a hypodermic fatty tissue is made to the area of a stomach. Places of injections and the place of infusions in above-mentioned areas (a stomach, a hip or a shoulder) have to alternate at  each new administration of drug. And, respectively, for the beginning and duration of action can influence the speed of absorption: an injection site, an exercise stress and other changing conditions. Hypodermic introduction to an abdominal wall provides a little more bystry absorption, than introduction to other above-stated body parts.
It is necessary to observe precautionary measures for a drug hit exception directly in blood vessels. After administration of drug it is impossible to make massage of area of introduction. Patients have to be taught the correct technique of carrying out injections.
Mixing with insulin
Apidr's drug should not mix up with any other drug, except human insulin isophanes.
The Pompovy device for performing continuous hypodermic infusion
When using drug of Apidr with pompovy system for infusion of insulin it cannot be mixed with other medicines.
For more information according to the treatment of drug (watch the section "Instructions for Use and Address").
It is necessary to carry out precisely instructions on the proper handling with previously filled syringes (watch the section "Instructions for Use and Address").
Special groups of patients
Renal failure
The need for insulin at a renal failure can decrease. Abnormal liver function
At patients with an abnormal liver function the need for insulin can decrease because of reduced ability to a gluconeogenesis and delay of metabolism of insulin.
Patients of advanced age
The available data on pharmacokinetics at the patients of advanced age suffering from a diabetes mellitus are insufficient.
The renal failure at advanced age can lead to decrease in need for insulin.
Children and teenagers
Apidr's drug can be used at children 6 years and teenagers are more senior.
Clinical information on use of drug for children is younger than 6 years is limited.

Features of use:

Transfer of the patient into new type of insulin or insulin of other producer has to be carried out under strict medical observation as change of a dosage owing to change of concentration of insulin, a trademark (producer), insulin type (soluble, insulin isophanes etc.), a type of insulin (animal origin) and/or a way of production can be required. Besides, correction of the accompanying peroral hypoglycemic therapy can be required. Use of inadequate doses of insulin or the termination of treatment, especially at patients with a diabetes mellitus of 1 type, can lead to development of a hyperglycemia and diabetic ketoacidosis - states which are potentially life-threatening.
Hypoglycemia
Time through which the hypoglycemia develops depends on the speed of approach of effect of the used insulin and, in this regard, can change at change of the scheme of treatment. Treat conditions which can change or make less expressed harbingers of development of a hypoglycemia: long existence of a diabetes mellitus, an insulin therapy intensification, existence of diabetic neuropathy, reception of some medicines, such as beta adrenoblockers, or transfer of the patient from insulin of animal origin on human insulin.
Correction of doses of insulin can be also required if patients increase physical activity or change the usual schedule of meal. The exercise stress executed directly after food can increase risk of development of a hypoglycemia. In comparison with soluble human insulin after an injection of quickly operating insulin analogs the hypoglycemia can develop earlier.
Noncompensated hypoglycemic or hyper glycemic reactions can lead to a loss of consciousness, development of a coma or death.
The need for insulin can change at diseases or emotional overloads.
Drug period of validity in one-time the syringe handle Apidra® Solostar® after the first use - 4 weeks. It is recommended to celebrate date of the first administration of drug on the label.
The syringe handle Apidra® Solostar® cannot be cooled before use (the injection of the cooled solution is more painful).
After the beginning of use one-time the syringe handle Apidra® Solostar® should be stored at a temperature not above 25 °C in the place, unavailable to children, to protect from light influence.

Side effects:

The hypoglycemia, the most frequent undesirable effect of an insulin therapy, can arise in case of use of too high doses of insulin exceeding the need for it.
The following adverse reactions observed in clinical trials connected with administration of drug are listed below on systems of bodies and as reduction of frequency of emergence (very often meeting> 1/10; often meeting:> 1/100, <1/10; infrequently meeting:> 1/1000, <1/100; rare:> 1/10000, <1/1000; very rare:
<1/10000).
Metabolic disturbances
Very often: hypoglycemia
Symptoms of development of a hypoglycemia usually arise suddenly. However usually psychoneurological disturbances against the background of a neuroglycopenia (feeling of fatigue, unusual fatigue or weakness, decline in the ability to concentration of attention, drowsiness, visual frustration, a headache, nausea, confusion of consciousness or its loss, a convulsive syndrome) are preceded by symptoms of adrenergic counterregulation (activation of sympathoadrenal system in response to a hypoglycemia): feeling of hunger, irritability, nervous excitement or a tremor, concern, pallor of integuments, "cold" sweat, tachycardia, the expressed heartbeat (the quicker the hypoglycemia develops and than it is heavier, symptoms of adrenergic counterregulation are stronger expressed to those).
The attacks of a heavy hypoglycemia which are especially repeating can lead to defeat of a nervous system. Episodes of the long and expressed hypoglycemia can threaten life of patients as at increase of a hypoglycemia even death is possible.
Disturbances from skin and hypodermic fabrics
Often meeting: reactions in the place of injections and local reactions of hypersensitivity. During treatment local reactions of hypersensitivity (a hyperemia, puffiness and an itch in the place of an injection) can arise insulin. These reactions usually are passing, and normal at treatment continuation they disappear.
Rare: lipodystrophy.
As a result of disturbance of alternation of injection sites of insulin in any of areas (administration of drug in one and too the place) in an injection site development of a lipodystrophy is possible.
General disturbances
Not often meeting: system reactions of hypersensitivity.
System reactions of hypersensitivity can be shown in the form of a small tortoiseshell, feeling of constraint in breasts, suffocation, allergic dermatitis and an itch. Hard cases of a generalized allergy, including anaphylactic reactions, can be life-threatening.

Interaction with other medicines:

Researches on pharmacokinetic interactions were not conducted. On the basis of the available empirical knowledge concerning other similar medicines emergence of clinically significant pharmacokinetic interactions is improbable. Some substances can influence glucose metabolism that can demand correction of doses of insulin of a glulizin and especially careful control of treatment.
To the substances capable to increase hypoglycemic effect of insulin and to increase predisposition to a hypoglycemia, belong: peroral hypoglycemic means, inhibitors of an angiotensin-converting enzyme, Disopyramidum, fibrata, fluoxetine, monoamine oxidase inhibitors, пентоксифиллин, propoxyhair dryer, salicylates and sulfanamide antimicrobic means.
To the substances capable to reduce hypoglycemic effect of insulin, belong: glucocorticosteroids, даназол, diazoxide, diuretics, an isoniazid, derivatives of a fenotiazin, соматропин, sympathomimetics (for example, Epinephrinum [adrenaline], salbutamol, тербуталин), hormones of a thyroid gland, are oestrogenic, gestagena (for example, in hormonal contraceptives), inhibitors of protease and atypical neuroleptics (for example, olanzapine and clozapine).
Beta adrenoblockers, clonidine, salts of lithium or alcohol can or potentiate or weaken hypoglycemic effect of insulin. Pentamidine can cause a hypoglycemia with the subsequent hyperglycemia.
Besides, under the influence of drugs with sympatholytic activity, such as beta adrenoblockers, a clonidine, гуанетидин and Reserpinum, symptoms of reflex adrenergic activation can be less expressed or be absent.
Instructions on compatibility
Due to the lack of researches on compatibility, insulin глулизин should not be mixed with any other drugs except for human insulin isophane.
At introduction by means of an infusional pomp the drug Apidra® Solostar® should not mix up with other drugs.

Contraindications:

Hypersensitivity to insulin to a glulizin or to any of drug components.
Hypoglycemia.

With care
At pregnancy.
Pregnancy and feeding by a breast
There is no enough information on use of insulin of a glulizin at pregnant women.
Reproductive researches on animals did not reveal any distinctions between insulin gluliziny and human insulin concerning the course of pregnancy, embryonic/fetalis development, childbirth and post-natal development.
Purpose of the drug Apidra® Solostar® at pregnant women has to be carried out with care. Careful monitoring of level of glucose in blood is obligatory.
Patients with the being available before pregnancy or gestational diabetes mellitus need to support glycemic control during all pregnancy. During the first trimester of pregnancy the need for insulin can decrease, and during the second and third trimesters it, as a rule, can increase. At once after the delivery the need for insulin quickly decreases.
At women during feeding by a breast correction of the mode of dosing of insulin and a diet can be required.

Overdose:

At surplus of a dose of insulin in relation to the need for it which is defined by consumption of food and energy expenditure the hypoglycemia can develop.
There are no special data on overdose of insulin of a glulizin. However, at its overdose development of the hypoglycemia passing the stages provided below is possible.
Episodes of an easy hypoglycemia can be stopped by means of the reception of glucose or products containing sugar. Therefore it is recommended that patients with a diabetes mellitus constantly had at themselves pieces of sugar, candy, cookies or sweet fruit juice.
Episodes of a heavy hypoglycemia during which the patient faints can be stopped by intramuscular or hypodermic introduction of 0,5-1 mg of a glucagon or intravenous administration of a dextrose (glucose) by the health worker. If the patient does not react to introduction of a glucagon within 10-15 minutes, it is also necessary to enter a dextrose intravenously.
After recovery of consciousness it is recommended to give to the patient carbohydrates inside for prevention of repetition of a hypoglycemia.
After introduction of a glucagon for establishment of the reason of this heavy hypoglycemia and prevention of development of other similar episodes the patient has to be observed in a hospital.

Storage conditions:

At a temperature from 2 °C to 8 °C in the place protected from light. Not to freeze! To store in the place, unavailable to children! Period of validity 2 years. After a period of validity drug cannot be used.

Issue conditions:

According to the recipe

Packaging:

Solution for hypodermic introduction of 100 PIECES/ml.
On 3 ml of drug in a cartridge from transparent, colourless glass (type I). The cartridge is corked on the one hand by a stopper and pressed out by an aluminum cap, on the other hand - a plunger.
The cartridge is built in in one-time the syringe handle Solostar®. On the 5th syringe handles Solostar® together with the application instruction in the cardboard pack supplied with the cardboard fixer.