Актрапид® NANOMETER of Penfill®

General characteristics. Structure:

Active agent: 100 ME (3,5 mg) insulin soluble (human genetically engineered). 1 ME there correspond 0,035 mg of anhydrous human insulin.

Excipients: zinc chloride about 7 mkg, glycerin (глицерол) 16 mg, metacresol of 3,0 mg, sodium hydroxide about 2,6 mg and/or Acidum hydrochloricum about 1,7 mg (for adjustment рН), water for injections to 1,0 ml.

Medicine гипогликемическиго appointments.

Pharmacological properties:

Pharmacodynamics. Актрапид® NANOMETER - the drug of insulin of short action produced by method of biotechnology of recombinant DNA with use of a strain of Saccharomyces cerevisiae. Decrease in level of glucose in blood happens due to increase in its intracellular transport after linkng of insulin with insulin receptors of muscular and fatty tissues and simultaneous reduction of speed of products of glucose liver.

Normalization of concentration of glucose in plasma (to 4,4-6,1 mmol/l) by means of intravenous administration of the drug Aktrapid® NANOMETER at the patients of intensive care unit who transferred serious surgical interventions (204 patients with a diabetes mellitus and 1344 patients without diabetes mellitus), having a hyperglycemia (concentration of glucose in plasma> 10 mmol/l), allowed to reduce mortality by 42% (4,6% instead of 8%).

 Effect of the drug Aktrapid® NANOMETER begins within half an hour after introduction, and the maximum effect is shown within 1,5-3,5 hours, at the same time the general duration of action makes about 7-8 hours.

Pharmacokinetics. The insulin elimination half-life from a blood-groove is equal to only several minutes. Duration of effect of drugs of insulin is generally caused by the absorption speed which depends on several factors (for example, from a dose of insulin, a way and an injection site, thickness of a hypodermic fatty layer and type of a diabetes mellitus). Therefore pharmacokinetic parameters of insulin are subject considerable inter-and intra-to individual fluctuations.

Absorption. The maximum concentration (Cmax) of insulin in plasma is reached within 1,5-2,5 hours after hypodermic introduction.

Distribution. The expressed linkng with proteins of plasma is not noted, except for antibodies to insulin (in case of their existence).

Metabolism. Human insulin is split under the influence of an insulinase or insulin - the splitting enzymes, and also, perhaps, under the influence of protein-disulfide-isomerase.

It is supposed what in a molecule of human insulin is available several sites of splitting (hydrolysis); however any of the metabolites which are formed owing to splitting is not active.

Removal. The period of semi-absorption (Т½) is determined by absorption speed from hypodermic fabrics. Thus, T½ is an absorption measure rather, but not actually a measure of removal of insulin from plasma (Т½, insulin from a blood-groove it is equal to only several minutes). Researches showed what Т½ makes about 2-5 hours.

Children and teenagers. The pharmacokinetic profile of the drug Aktrapid® NANOMETER was studied on few group of children with a diabetes mellitus (18 people) at the age of 6-12 years, and also teenagers (at the age of 13-17 years). Though the obtained data are considered limited, but all of them showed that the pharmacokinetic profile of the drug Aktrapid® NANOMETER at children and teenagers is similar to that at adults. At the same time, distinctions between different age groups on such indicator as Cmax were revealed that once again emphasizes need of individual selection of a dose.

Preclinical data on safety. During the preclinical trials including pharmacological researches of safety, a toxicity research at repeated introduction of a dose, a research of genotoxicity, cancerogenic potential and toxic impact on the reproductive sphere, specific risk for the person it was not revealed.

Indications to use:

Diabetes mellitus.

Route of administration and doses:

Drug is intended for hypodermic and intravenous administration. The dose of drug is selected individually, taking into account needs of the patient.

Usually the need for insulin makes from 0,3 to 1 МЕ/кг/сутки. The daily need for insulin can be higher at patients with insulin resistance (for example, during puberty, and also at patients with obesity), and below - at patients with residual endogenous products of insulin.

The drug is administered in 30 minutes prior to meal or the light meal containing carbohydrates. Актрапид® the NANOMETER is insulin of short action and can be used in a combination with insulin of the prolonged action.

Актрапид® NANOMETERS usually enter subcutaneously, into the area of a front abdominal wall. If it is convenient, then injections can be done also to the area of a hip, in a rump or to the area of a deltoid muscle of a shoulder. At administration of drug to the area of a front abdominal wall more bystry absorption is reached, than at introduction to other areas. If the injection is made in the delayed skin fold, the risk of accidental intramuscular administration of drug is minimized. The needle has to remain under skin not less than 6 seconds that guarantees full introduction of a dose. It is necessary to change constantly places of injections within anatomic area to reduce risk of development of lipodystrophies. Актрапид® it is also possible to NANOMETER to enter intravenously and only the health worker can make such procedures.

Intravenous administration of the drug Aktrapid® NANOMETER Penfill® from a cartridge is allowed only by way of exception in the absence of bottles. In this case it is necessary to gather drug in the insulin syringe without a set of air or to carry out infusion by means of system for infusions. This procedure has to be carried out only by the doctor.

Актрапид® the NANOMETER of Penfill® is developed for use with injection systems for administration of insulin of the company Is new Nordisk and needles of Novofayn® or Novotvist®. It is necessary to observe detailed recommendations about use and administration of drug (see. "Instructions for use of Aktrapid® of NANOMETER of Penfill® which need to be given to the patient").

Dose adjustment. Associated diseases, especially infectious and followed by fever, usually increase the need of an organism for insulin. Dose adjustment of drug can be also required in the presence at the patient of associated diseases of kidneys, a liver, dysfunction of adrenal glands, a hypophysis or thyroid gland.

Need for dose adjustment can also arise at change of an exercise stress or usual diet of the patient. Dose adjustment can be required at transfer of the patient from one type of insulin on another.

Features of use:

The insufficient dose of drug or the termination of treatment, especially at a diabetes mellitus of 1 type, can lead to development of a hyperglycemia.

As a rule, the first symptoms of a hyperglycemia appear gradually, within several hours or days. Symptoms of a hyperglycemia are the feeling of thirst, the speeded-up urination, nausea, vomiting, drowsiness, reddening and a xeroderma, dryness in a mouth, appetite loss, and also emergence of a smell of acetone in expired air. Without the corresponding treatment the hyperglycemia at patients with a diabetes mellitus of 1 type can lead to diabetic ketoacidosis - a state which is potentially lethal.

Hypoglycemia. The hypoglycemia can develop if too high dose of insulin in relation to need of the patient is entered.

The admission of meal or unplanned intensive exercise stress can lead to a hypoglycemia.

After compensation of carbohydrate metabolism, for example, at the intensified insulin therapy, at patients hypoglycemia symptoms harbingers, typical for them, can change what patients have to be informed on. Usual symptoms harbingers can disappear at a long current of a diabetes mellitus.

Transfer of patients into other type of insulin or into insulin of other company manufacturer has to be carried out only under medical control. At change of concentration, the producer of type, look (human insulin, an analog of human insulin) and/or a method of production change of a dose of insulin can be required. Change of a dose or increase in frequency of injections in comparison with earlier used insulin drugs can be required by the patients passing to treatment with the drug Aktrapid® NANOMETER. If at transfer of patients into treatment by the drug Aktrapid® NANOMETER dose adjustment is necessary, it can be made already at introduction of the first dose or to the first weeks or months of therapy.

As well as at treatment by other drugs of insulin, reactions in an injection site can develop that is shown by pain, reddening, a small tortoiseshell, an inflammation, bruises, puffiness and an itch. Regular change of the place of an injection in the same anatomic area will help to reduce symptoms or to prevent development of these reactions. Reactions usually disappear during from several days to several weeks. In rare instances cancellation of Aktrapid® of NANOMETER because of reactions in injection sites can be required.

Before the trip connected with change of time zones, the patient has to consult with the attending physician as change of the time zone means that the patient has to eat food and enter insulin into other time.

At addition of the drug Aktrapid® NANOMETER in solutions for infusions, the amount of the insulin absorbed by infusional system is unpredictable therefore use of Aktrapid® of NANOMETER in PPII is not allowed.

Simultaneous use of drugs of group of a tiazolidindion and drugs of insulin. It was reported about cases of development of congestive heart failure at treatment of patients of a tiazolidindionama in a combination with insulin drugs, especially in the presence such patients of risk factors have development of congestive heart failure. It is necessary to consider this fact at appointment to patients of a combination therapy of a tiazolidindionama and insulin drugs. At purpose of such combination therapy it is necessary to conduct medical examinations of patients regarding identification at them of signs and symptoms of congestive heart failure, increase in body weight and existence of hypostases. In case of deterioration at patients of symptomatology of heart failure, treatment of a tiazolidindionama needs to be stopped.

Influence on ability to driving and work with mechanisms. Ability of patients to concentration of attention and speed of response can be broken during a hypoglycemia that can constitute danger in those situations when these abilities are especially necessary (for example, during the driving or work with cars and mechanisms). Patients need to recommend to undertake measures for the prevention of development of a hypoglycemia when driving the car. It is especially important for patients with absence or decrease in expressiveness of symptoms harbingers of the developing hypoglycemia or suffering from frequent episodes of a hypoglycemia. In these cases it is necessary to consider expediency of driving and performance of similar works.

Precautionary measures when using. The infusional systems containing the drug Aktrapid® NANOMETER of 100 ME/ml in concentration from 0,05 ME/ml to 1 ME/ml of human insulin in infusion solutions, such as 0,9% solution of sodium chloride, 5% and 10% the dextrose solutions including potassium chloride in concentration of 40 mmol/l are applied to intravenous administration; in system for intravenous administration the infusional bags made of polypropylene are used; these solutions keep stability within 24 hours at the room temperature.

Though these solutions keep stability during certain time, at the initial stage absorption of a quantity of insulin by material of which the infusional bag is made is noted. During performing infusion it is necessary to exercise control of level of glucose in blood.

Cartridges should be used in a combination only to compatible products that also efficiency of their use ensures safety.

The drug Aktrapid® NANOMETER Penfill® and needles are intended only for individual use. The cartridge refill is not allowed.

It is impossible to use insulin drugs if they were frozen.

It is impossible to use insulin if it stopped being transparent and colourless.

Актрапид® the NANOMETER cannot be used in insulin pumps for long hypodermic infusion of insulin.

Inform the patient on need to throw out a needle after each injection.

In case of emergency (hospitalization, malfunction of the device for administration of insulin) the patient can take Aktrapid® of NANOMETER for introduction from a cartridge by means of the insulin syringe U100.

Side effects:

The most often found undesirable phenomenon at use of insulin is the hypoglycemia. During clinical trials, and also during use of drug after its release on the consumer market it was established that the frequency of emergence of a hypoglycemia changes depending on population of patients, the mode of a drug dosing and level of control of a glycemia (see. "Description of separate side reactions").

At an initial stage of an insulin therapy there can be disturbances of a refraction, hypostases and reactions in drug injection sites (the including pain, reddening, a small tortoiseshell, an inflammation, bruises, a swelling and an itch in the place of an injection). These symptoms usually are temporary. Bystry improvement of control of a glycemia can lead to a condition of "acute painful neuropathy" which usually is reversible. The insulin therapy intensification with sharp improvement of control of carbohydrate metabolism can lead to a temporary aggravation of symptoms of a diabetic retinopathy, at the same time, long improvement of control of a glycemia reduces risk of progressing of a diabetic retinopathy.

The list of by-effects is presented in the table.

All side effects given below based on the data obtained during clinical tests are distributed on groups according to development frequency according to MedDRA and systems of bodies. Frequency of development of side effects is determined as: very often (≥ 1/10); often (≥ 1/100 to <1/10); infrequently (≥1/1,000 to <1/100); seldom (≥1/10,000 to <1/1,000), it is very rare (<1/10,000) and it is unknown (it is impossible to estimate on the basis of the available data).

Disturbances from immune system	Infrequently - urticaria, skin rash
Very seldom - anaphylactic reactions *
Disturbances from a metabolism and food	Very often - a hypoglycemia *
Disturbances from a nervous system	Infrequently - peripheral neuropathy ("acute painful neuropathy")
Disturbances from an organ of sight	Infrequently - disturbances of a refraction
Very seldom - a diabetic retinopathy
Disturbances from skin and hypodermic fabrics	Infrequently - a lipodystrophy *
The general frustration and disturbances in an injection site	Infrequently - reactions in injection sites
Infrequently - hypostases

* See. "Description of separate side reactions"

Description of separate side reactions:

Anaphylactic reactions. Very rare reactions of generalized hypersensitivity are noted (including generalized skin rash, an itch, perspiration, gastrointestinal frustration, a Quincke's disease, breath difficulties, tachycardia, a lowering of arterial pressure, and also a syncope / loss of consciousness which are potentially life-threatening).

Hypoglycemia. The hypoglycemia is the most frequent by-effect. It can develop if the dose of insulin is too high in relation to the need for insulin. The heavy hypoglycemia can lead to a loss of consciousness and/or spasms, temporary or irreversible dysfunction of a brain or even by a lethal outcome. Hypoglycemia symptoms, as a rule, develop suddenly. They can include "cold sweat", pallor of integuments, increased fatigue, nervousness or a tremor, feeling of alarm, unusual fatigue, or weakness, orientation disturbance, decrease in concentration of attention, drowsiness, the expressed feeling of hunger, a vision disorder, a headache, nausea and tachycardia.

Lipodystrophy. It was reported about infrequent cases of development of a lipodystrophy. The lipodystrophy can develop in a drug injection site.

Interaction with other medicines:

There is a number of medicines which influence the need for insulin. Hypoglycemic effect of insulin peroral hypoglycemic drugs, monoaminooxidase inhibitors, inhibitors of an angiotensin-converting enzyme, karboangidraza inhibitors, non-selective beta adrenoblockers, Bromocriptinum, sulfonamides, anabolic steroids, tetracyclines, Clofibratum, кетоконазол strengthen, Mebendazolum, a pyridoxine, theophylline, cyclophosphamide, фенфлурамин, lithium drugs, salicylates.

Hypoglycemic effect of insulin oral contraceptives, glkzhokortikosteroida, thyroid hormones, thiazide diuretics, heparin, tricyclic antidepressants, this stalemate of an imetika weaken, a growth hormone (соматропин), даназол, a clonidine, blockers of slow calcium channels, diazoxide, morphine, Phenytoinum, nicotine.

Beta adrenoblockers can mask symptoms of a hypoglycemia and complicate recovery after a hypoglycemia.

Oktreotid/lanreotid can both raise, and to reduce the need of an organism for insulin.

Alcohol can strengthen or reduce hypoglycemic effect of insulin.

Incompatibility. Актрапид® the NANOMETER can add only to those connections to which it, as we know, is compatible. Some drugs (for example, the drugs containing thiols or sulfites) at addition to solution of insulin can cause its degradation.

Contraindications:

Hypersensitivity to human insulin or to any component which is a part of this drug.

Pregnancy and lactation. Restrictions on use of insulin during pregnancy do not exist as insulin does not get through a placental barrier.

Both the hypoglycemia, and a hyperglycemia which can develop in cases of insufficiently precisely picked up therapy increase risk of developing of malformations of a fruit and pre-natal death of a fruit. Pregnant women with diabetes during all pregnancy have to be under observation, at them it is necessary to exercise the strengthened control of level of glucose in blood; the same recommendations concern also to women who plan pregnancy.

The need for insulin usually decreases in the first trimester of pregnancy and gradually increases in the second and third trimesters.

After the delivery the need for insulin, as a rule, quickly is returned to the level which was noted before pregnancy.

Also there are no restrictions for use of the drug Aktrapid® NANOMETER during breastfeeding. Performing insulin therapy to nursing mothers does not constitute danger to the child. However correction of the mode of a drug dosing of Aktrapid® of NANOMETER and/or a diet can be required by mother.

Overdose:

The certain dose necessary for insulin overdose, it is not established, however the hypoglycemia can gradually develop if too high doses of insulin in relation to need of the patient are entered.

• The patient can eliminate an easy hypoglycemia itself, having accepted inside glucose or sacchariferous food stuffs. Therefore, the sick diabetes mellitus recommends to carry constantly with itself sacchariferous products.

• In case of a heavy hypoglycemia when the patient is unconscious, it is necessary to enter from 0,5 mg to 1 mg of a glucagon intramusculary or subcutaneously (the trained person can enter), or intravenously glucose solution (only the health worker can enter). It is also necessary to enter intravenously glucose if in 10-15 min. after introduction of a glucagon the patient does not recover consciousness. After consciousness recovery the patient is recommended to eat carbohydrate-rich food for prevention of a recurrence of a hypoglycemia.

Storage conditions:

Period of validity of 30 months. Not to use after a period of validity. To store to temperature from 2 °C to 8 °C (in the refrigerator), but not near the freezer. Not to freeze. To store cartridges in a cardboard pack for protection against light. For the opened cartridges: not to store in the refrigerator. To store at a temperature not above 30 °C within 6 weeks. Актрапид® the NANOMETER of Penfill® should be protected from influence of excess heat and light. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Solution for injections of 100 ME/ml. On 3 ml of drug in the cartridges from glass of 1 hydrolytic class corked by rubber disks and pistons. On 5 cartridges together with the application instruction in a cardboard pack.