Оренсия®

General characteristics. Structure:

Active ingredient: 125,875 mg of an abatatsept (taking into account surplus of 0,875 mg) in 1 syringe.

Excipients: sucrose, a nolokeamer 188, sodium dihydrophosphate monohydrate, sodium hydrophosphate anhydrous, water for q.s injections.

- Packing is made taking into account a rebookmark in 0,7% (0,007 ml) that is necessary for a guarantee of full extraction of the declared dosage. At the same time the taken quantity of an abatatsept in one syringe of 125 mg.

Pharmacological properties:

Pharmacodynamics. Абатацепт represents the soluble protein consisting of the extracellular domain of antigen of 4 cytotoxic T lymphocytes (CTLA-4) connected with the fragment of immunoglobulin of the joint venture (IgGl) of the person modified by Fc. Абатацепт is recombinant protein with a molecular weight about 92 cd which is produced by method of genetic engineering on the marked-out cellular culture of mammals. Абатацепт selectively modulates key to - the stimulating signal necessary for full activation of the T lymphocytes expressing a cluster of a differentiation of 28 (CDs 28).

With the pseudorheumatism (P) T lymphocytes are found in patients in synovial fluid. The activated T lymphocytes play an important role in a pathogeny of a pseudorheumatism and other autoimmune diseases. Full activation of T lymphocytes requires 2 signals from antigenprezentiruyushchy cells: the first for recognition of a specific antigen receptors of T-cells (a signal 1); the second (nonspecific) to - the stimulating signal assumes binding of the molecules CD80 and CD86 on a surface of antigenprezentiruyushchy cells with CD28 receptor on a surface of T lymphocytes (a signal 2). Абатацепт specifically contacts CD80 and CD86, selectively inhibiting this way.

It is established what абатацепт more influences the answer of not activated (naive) T lymphocytes, than memory T lymphocytes.

In the researches in vitro and on models of animals it is shown what абатацепт reduces antibody formation, dependent on T lymphocytes, and an inflammation. In vitro абатацепт reduces activation of T lymphocytes what decrease in proliferation and production of cytokines in lymphocytes of the person testifies to (the FNO-alpha, interferon - at and interleykina-2). At rats with kollagenindutsirovapny arthritis абатацепт suppresses an inflammation, reduces formation of anti-collagenic antibodies and antigenspetsifichny products of interferon - at.

Pharmacokinetics. The pharmacokinetics of an abatatsept after hypodermic introduction submits to linear dependence. Average minimum and maximum equilibrium concentration were established in 85 days after an initiation of treatment and 32,5 mkg/ml (6,6-113,8 mkg/ml) and 48,1 mkg/ml (9,8-132,4 mkg/ml) respectively made. Bioavailability of an abatatsept at hypodermic introduction makes 78,6% of its bioavailability at intravenous administration. Average values of system clearance (0,28 ml/h/kg), distribution volume (0,11 for kg), a terminal elimination half-life (14,3 days) are comparable for hypodermic and intravenous administration.

It was revealed that higher clearance of an abatatsept is observed at patients with high body weight. The age and a sex of patients (at correction of a pas body weight) did not influence clearance of an abatatsept. Co-administration of a methotrexate, antiinflammatory drugs, glucocorticosteroids and blockers of a factor of a necrosis of a tumor did not influence clearance of an abatatsept of the Research for assessment of metabolism and elimination of an abatatsept at people were not carried out. Due to the space structure and hydrophily абатацепт it is not metabolized in a liver by enzymes of system of P450 cytochrome. Considering the big molecular mass of an abatatsept, it is supposed what абатацепт is not removed with urine.

Pharmacokinetics at special categories of patients. Researches on impact assessment of a renal failure and a liver on pharmacokinetics of an abatatsept were not conducted.

Indications to use:

Абатацепт it is shown for reduction of symptoms, strengthening of the clinical answer, suppression of progressing of structural damages and improvement of functional activity of adult patients with moderately expressed or heavy active pseudorheumatism. Абатацепт it can be applied in the form of monotherapy or in combination with basic antiinflammatory drugs.

Route of administration and doses:

The drug is administered once a week subcutaneously in a dose of 125 mg (1 filled syringe) irrespective of body weight, after introduction of a load dose of the drug Orensiya®, lyophilisate for preparation of solution for infusions or without preliminary load dose.

1. Appointment to the patients who were earlier not using the drug Orensiya®: - Without load dose. The drug is administered once a week subcutaneously in a dose of 125 mg (1 filled syringe) irrespective of body weight; With a load dose. If introduction of a load dose of drug is necessary, to the patient carry out intravenous administration of the drug Orensiya® according to the application instruction of the drug Orensiya®, lyophilisate for preparation of solution for infusions, then during the day carry out the first hypodermic administration of drug.

2. Transfer of the patient from an intravenous form of the drug Orensiya® on a hypodermic form: - At transfer of the patient from an intravenous pas hypodermic administration of the drug Orensiya® the first subcutaneous injection is carried out instead of the following planned drug Orensiya® infusion. Drug for hypodermic introduction is not intended for intravenous injections or infusions. Administration of drug is carried out by medical personnel. If the patient is capable to do injections independently, the medical personnel are obliged to be convinced that the patient is correctly trained in this procedure and accurately follow instructions on carrying out a subcutaneous injection of drug.

Drug before introduction is examined. Solution has to be transparent or slightly opalescent, from colourless till light yellow color; in the presence of particles or discoloration of solution the syringe with solution of nanosecond is subject to use. It is necessary to administer all volume of the drug in the syringe, changing the place of an injection at each introduction.

It is impossible to administer the drug in zones with the gentle or coarsened skin, in the presence of damage or erubescence. Detailed instructions on carrying out an injection are provided in "Operating instructions of the preliminary filled syringe / previously filled syringe with the cleaning-up needle".

Admission of a dose. If the patient missed date of the next injection of Orensii® hypodermic for a period of up to Zkh of days, he should carry out a drug injection immediately and further to hold to the initial weekly plan of administrations of drug. If at the admission of a dose there passed more than 3 days of the expected Date of Introduction, the patient needs to see a doctor for obtaining instructions on the further schedule of introductions which has to be specified depending on a condition of the patient and a stage of a disease. Change of a dose is not required from patients of advanced age.

Features of use:

Pregnancy and lactation. Due to the lack of clinical trials with participation of pregnant women, drug should not be used at pregnancy. It is unknown whether drug gets into breast milk therefore it is not necessary to nurse at drug use.

Reactions of hypersensitivity can be observed at treatment by any injection proteinaceous drug. Such reactions were observed at use of the drug Orensiya® during clinical a research.

After the first administration of drug there is a probability of development of an anaphylaxis or anaphylactoid reactions, including zhizneugrozhayushchy. During the post-market researches the anaphylaxis case with a lethal outcome after performing the first infusion of the drug Orensiya® was noted. In clinical trials cases of an anaphylaxis met seldom, hypersensitivity reactions - infrequently. In case of anaphylactic or other serious allergic reaction it is necessary to stop drug use (both an intravenous, and hypodermic form) without the subsequent resuming and to immediately begin the corresponding therapy of side reaction.

Infections. At use of drug cases of development of serious infections, including sepsis and pneumonia, including with a fatal outcome were noted, is more often at the patients applying the accompanying therapy by immunosuppressors. If in the course of treatment at the patient the new infectious disease is revealed, it is necessary to establish careful observation of the patient, and in case of development of a new serious infection - to cancel drug. Safety of drug at patients with latent tuberculosis is not studied. At purpose of drug it is necessary to carry out diagnosis regarding tuberculosis detection. Before purpose of an abatatsept patients with latent tuberculosis need to carry out standard antitubercular therapy.

At purpose of antirheumatic drugs reactivation of a virus of hepatitis B therefore before an initiation of treatment abatatsepty it is necessary to exclude a carriage of this activator can be observed. Use of drug for patients with a viral hepatitis was not studied.

Influence on development malignant new growth. The potential role of the drug Orensiya® in development of malignant new growths of nanosecond is established. At use of the drug Orensiya® for patients with a pseudorheumatism increase in frequency of development of malignant new growths was not noted.

Influence on immune system. The drugs influencing an immune response including the drug Orensiya®, can influence efficiency of the carried-out vaccination, ability of an organism to resist to infections and development of malignant tumors.

Because the drugs influencing immune system including абатацепт, can reduce efficiency of vaccination, it is not necessary to use live vaccines during treatment abatatsepty and within 3 months after its cancellation. There are no data on secondary infection of the patients who are on therapy by drug абатацепт from the patients receiving live vaccines. Use of the inactivated vaccines is possible during treatment by drug.

The significant influence of drug on efficiency of vaccinal prevention by means of a 23-valent pneumococcal vaccine was not revealed, at most of patients the adequate immune response (increase of an antiserum capacity) after this vaccination was observed. Also during treatment by the drug Orensiya® performing vaccination by a trivalent vaccine from a seasonal influenza virus is possible - the immune response at most of patients was expressed in at least 4-fold increase in an antiserum capacity.

Because the risk of development of serious infections and malignant new growths at patients is more senior than 65 years in general above, than at persons of younger age, it is necessary to be careful at purpose of an abatatsept to elderly patients.

Patients before an initiation of treatment the drug Orensiya® have to examine "the operating instructions of the preliminary filled syringe attached to drug / previously filled syringe automatically cleaning up needle".

Influence on ability to manage vehicles and mechanisms. It is necessary to refrain from control of vehicles and occupations other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions if drug causes dizziness, vision disorders and other side effects which can influence the specified abilities.

Side effects:

The undesirable medicinal reactions (UMR) revealed at use of an abatatsept in clinical and post-market researches of drug where drug or placebo were used together with other types of therapy of RA are listed below. The headache, nausea and upper respiratory tract infections were the most frequent undesirable phenomena at use of drug.

NLR are presented on bodies and systems and frequency: very frequent (> 1/10); frequent (> 1/100 and <1/10); infrequent (> I/1000 and <1/100); rare (> 1/10 000 and <1/1000) and very rare (<1/10 000).

1. Infections and invasions	Very frequent: upper respiratory tract infections (including tracheitises and nasopharyngites) Frequent: lower respiratory tract infections (including bronchitis), infections of urinary tract, herpes infections (including a herpes simplex, herpes of an oral cavity and shingles), rhinitis, pneumonia, flu. Infrequent: infections of teeth, onychomycosis, sepsis, muscular skeletal infections, skin abscesses, pyelonephritis, inflammation of bodies of a basin. Rare: Tuberculosis, infections of a GIT and bacteremia.
2. Benign and malignant tumors (including cysts and polyps)	Infrequent: bazalnokletochny carcinoma cutaneum, keratosic carcinoma cutaneum, skin papillomas Rare: lymphoma, malignant new growths of lungs,
3. From outside bodies hemopoiesis	Frequent: leukopenia Infrequent: thrombocytopenia
4. Immune frustration	Infrequent: Hypersensitivity reactions
5. Mental disorders	Infrequent: depression, alarm, sleep disorders (including sleeplessness)
6. Neurologic frustration	Frequent: headache, dizziness, paresthesias Infrequent: migraine
7. From sense bodys	Frequent: conjunctivitis Infrequent: xerophthalmus, decrease in visual acuity
8. From outside cardiovascular systems	Frequent: increase in arterial pressure, "inflows" Infrequent: tachycardia, bradycardia, heart consciousness, lowering of arterial pressure, feeling of heat, vasculitis
9. From a respiratory organs	Frequent: cough, HOBL aggravation Infrequent: bronchospasm, asthma, диспноэ Rare: a spasm in a throat
10. From outside gastro intestinal path	Frequent: abdominal pain, diarrhea, nausea, dyspepsia, ulcerations of a mucous membrane of an oral cavity, aphthous stomatitis Infrequent: gastritis
11. From skin and hypodermic Yozhirovy cellulose	Frequent: rash (including dermatitis), an alopecia, an itch Infrequent: tendency to formation of bruises, xeroderma, psoriasis, erythema, hyperhidrosis
12. From a musculoskeletal system and connecting fabric	Frequent: extremity pain Infrequent: arthralgia
13. From generative organs and mammary glands	Infrequent: amenorrhea, menorrhagia
14. General and local symptoms	Frequent: fatigue, an adynamy, reactions in an injection site Infrequent: grippopodobny syndrome, increase in body weight
15. Laboratory indicators	Frequent: deviations of laboratory indicators of function of a liver (including increase in activity of transaminases)

The most frequent serious infections (frequency of 0,1-0.4%) at treatment by the drug Orensiya® were: pneumonia, inflammation of hypodermic cellulose, local infections, infections of urinary tract, bronchitis, diverticulitis and acute pyelonephritis. In rare instances at the patients who were on treatment by the drug Orensiya® the following types of malignant new growths were observed: non-melanoma new growths of skin, solid tumors (lung cancer), hematologic new growths (lymphoma). At use of the drug Orensiya® for patients with a pseudorheumatism increase in frequency of development of malignant new growths was not noted.

At some patients (on average 2,6%) in an injection site of drug the undesirable phenomena in the form of an itch, the hematomas, an erythema, weak or moderate degree of manifestation which are not demanding drug withdrawal were observed.

At use of drug for patients with the chronic obstructive pulmonary disease (COPD) the undesirable phenomena were observed more often than in group of placebo, including serious - an aggravation of HOBL and bronchitis. Respiratory frustration (including an asthma and an aggravation of HOBL) were observed at 5,9% of patients.

At 9,3% of patients antibody formation to an abatatsept which remained also after drug withdrawal was observed. However dependence of expressiveness of clinical effect and development of side effects on existence of antibodies to an abatatsept in a blood plasma is not revealed. Data concerning antibody formation to drug did not differ between group of the patients receiving абатацепт directly in the form of a subcutaneous injection and group of the patients transferred with intravenous to a hypodermic form.

During the two-year-old blind person for the researcher of the first direct comparison not of smaller efficiency biological a disease - the modifying antirheumatic drugs абатацепт subcutaneously (without load intravenous dose) and адалимумаб subcutaneously, clinical, functional and radiological data show their identical efficiency at the patients with moderately expressed or heavy active pseudorheumatism receiving therapy by a methotrexate and which did not answer on bore. In general in both groups the identical frequency of the undesirable phenomena was observed, however, on an abatatsepta was less cases of the early termination of therapy caused by the undesirable phenomena, the serious undesirable phenomena and serious infections less reactions in the place of an injection in number.

Data of post-market researches. During the post-market researches it was established that system reactions to infusional administration of drug were similar to the reactions revealed during clinical trials of the drug Orensiya® except for one case of an anaphylaxis with a lethal outcome. Undesirable medicinal reactions at hypodermic administration of the drug Orensiya® included an itch, feeling of constraint in a throat, an asthma.

Interaction with other medicines:

At use of an abatatsept together with blockers of a factor of a necrosis of a tumor the risk of developing of serious infections therefore use of this combination is not recommended increases. At transfer of the patient from treatment by a blocker of a factor of a necrosis of tumors on therapy abatatsepty it is necessary to control a condition of the patient in connection with possible development of an infection. In view of lack of enough data, combined use of an abatatsept with other biological drugs for treatment of a pseudorheumatism is not recommended (for example, anakinry).

Drug can be used together with basic antiinflammatory drugs: methotrexate, glucocorticosteroids, salicylates, NPVP. and also more rare the used antiinflammatory drugs chloroquine/hydroxychloroquine, Sulfasalazinum and лефлуномид. Change of clearance of an abatatsept at its combined use with a methotrexate, NPVP, glucocorticosteroids and FNO-a inhibitors was not observed.

Data on safety and efficiency of a combination of an abatatsept with Azathioprinum, drugs of gold and anakinry are not enough therefore combined use with these drugs is not recommended.

Абатацепт it was not studied in a combination with the drugs causing decrease in number of lymphocytes. At such combination potentiation of action of an abatatsept on immune system is possible.

Contraindications:

- Hypersensitivity to an abatatsept and/or any of auxiliary components of drug.

- Combined use with tumor necrosis factor blockers.

- Pregnancy and period of a lactation.

- Age up to 18 years (efficiency and safety are not studied).

- Heavy uncontrollable infections (sepsis, opportunistic infections), active infections (including tuberculosis) before establishment of control over them.

- Combined use with Azathioprinum, drugs of gold and anakinry.

With care. Абатацепт it is necessary to apply with care at patients with recurrent infections; the states contributing to infections (diabetes mellitus), hepatitises; at patients of advanced age. Introduction of an abatatsept should be stopped in case of development of a serious infectious disease.

Overdose:

Doses to 50 mg/kg (at intravenous administration) did not cause overt toxic effects. At overdose observation of the doctor and, if necessary, a symptomatic treatment is recommended.
Symptoms of overdose are not described.

Storage conditions:

At a temperature from 2 to 8 °C in the place protected from light. Not to freeze! To store in the place, unavailable to children. A period of validity - 2,5 years. Not to use drug but expiry date, the specified pas to packaging.

Issue conditions:

According to the recipe

Packaging:

Solution for hypodermic introduction of 125 mg/ml. Packaging: on 1,007 ml of solution in the syringe or the syringe with automatically cleaning up needle from colourless glass like I. On 1 syringe, or on 1 or 4 syringes with automatically cleaning up needle in the plastic pallet together with the application instruction and operating instructions of the syringe or syringe with automatically cleaning up needle place in a pack cardboard.