Нулоджикс

General characteristics. Structure:

Active ingredient: 275 mg of a belatatsept.

Excipients: sucrose, dihydrophosphate sodium monohydrate, sodium chloride, Acidum hydrochloricum, sodium hydroxide.

* Packing, is made taking into account a rebookmark in 10% that is necessary for a guarantee of full extraction of the declared dosage. At the same time the taken quantity of a belatatsept from one bottle – 250 mg.

Pharmacological properties:

Pharmacodynamics. Белатацепт represents the soluble protein consisting of the modified extracellular domain of antigen-4 of cytotoxic T lymphocytes (CTLA-4) in which replacement of two amino acids was made (a leucine in 104 positions on glutaminic acid, alanine in 29 positions – on tyrosine), Fc of a fragment of Gl (IgGl) immunoglobulin of the person connected with a part. Белатацепт is the rekombinatny protein received with use of methods of genetic engineering on the marked-out culture of cells of mammals. Белатацепт selectively modulates key to - the stimulating signal necessary for full activation of T lymphocytes. The activated T lymphocytes are the main mediators of the immunological answer of rejection of a transplanted organ. Full activation of T lymphocytes requires 2 signals from antigenprezentiruyushchy cells: the first – through recognition of a specific antigen receptors of T-cells (a signal 1); the second (nonspecific) to - the stimulating signal due to binding of the molecules CD80 and CD86, expressed on a superficial membrane with CD28 receptors, expressed on a membrane of T lymphocytes. Белатацепт specifically blocks interaction of CD 28 with CD80 and CD86, selectively inhibiting key to - the stimulating signal necessary for activation of T lymphocytes. As a result of modification of a fragment of CTLA-4 белатацепт the initial CTLA4-IgGl form contacts the molecules CD80 and CD86 more actively, than. It allows to achieve the level of immunosuppression necessary for suppression of reaction of graft rejection and the prevention of its dysfunction.

In the researches in vitro белатацепт inhibited proliferation of T lymphocytes and reduced products of cytokines (interleykina-2, интерферона-γ, interleykina-4 and the FNO-alpha). The inhibition of the answer of T lymphocytes to allogenic antigen is the most important factor of prevention of graft rejection. In preclinical trials on renal transplantation at primacies белатацепт in the form of monotherapy or in a combination with standard therapy considerably increased transplant life time in comparison with placebo, reducing development of antibodies against antigens of a donor organ.

Pharmacokinetics. Values of pharmacokinetic parameters are given in table 1.

Table 1. Pharmacokinetic parameters (average values and confidence intervals).

* - For patients with the replaced kidney the area under curve AUC was determined after repeated introductions with intervals - 4 weeks.

** The dose 10mg/kg was entered in day 1 - day of operation, before performing transplantation; day 5, day 14, day 28 after transplantation.

*** The dose of 5 mg of kg was entered 1 time in 4 weeks (plus or minus 3 days), since the end of the 16th week after transplantation.

The pharmacokinetics of a belatatsept at healthy volunteers and at patients was comparable to the replaced kidney. At single intravenous infusion to healthy volunteers proportional increase in Cmax and AUC values (the area under a curve "concentration time") in the range of doses from 1 mg/kg to 20 mg/kg was observed. Concentration in blood serum reaches an equilibrium state on the 8th week at appointment in the early post-transplant period and remains stable at continuous therapy within 6 months. When determining in 1, 4 and 6 months after transplantation average values of the minimum concentration made 22.7 (11.1 - 45.2) mkg/ml, 7.6 (2.1 - 18.0) mkg/ml and 4.0 (1.5 - 6.6) mkg/ml respectively.

The pharmacokinetics of a belatatsept did not change at its use during 1 year after transplantation of a kidney. The minimum concentration of a belatatsept were maintained within 5 years after transplantation against the background of the recommended therapy mode belatatsepty.

System cumulation of a belatatsept in an organism was minimum at long repeated administration of drug in a dose of 5-10 bucketed mg/kg in 1 month.

Pharmacokinetics at special categories of patients. It was revealed that higher clearance of a belatatsept is observed at patients with the increased body weight.

Age, sex, race, function of kidneys (assessment on value of glomerular filtering), function of a liver (assessment on concentration of albumine), a diabetes mellitus and holding sessions of dialysis do not influence clearance of a belatatsept.

Indications to use:

Белатацепт in a combination with glucocorticosteroids and the mikofenolata mofetily is applied to prevention of graft rejection of a kidney at adults. Before this therapy appointment of the antagonist of receptors interleykina-2 is recommended (IL-2) (базиликсимаб).

Route of administration and doses:

Белатацепт enter in the form of intravenous infusion within 30 minutes. The mode of dosing is given in the table (taking into account the body weight of the patient) and should not change during therapy if fluctuations of body weight of the patient do not exceed 10%:

At treatment belatatsepty premedication is not required. Mofetit Mikofenolat accept in the mode ordered by the doctor, having divided a daily dose (usually 2 g) into two receptions according to time of day and meals. On the basis of results of the analysis the daily dose of drug can be corrected.

Use of glucocorticosteroids should be begun in day of transplantation: Methylprednisolonum enter in a dose 500 mg intravenously before operation (in the operational hall); next day enter 250 mg intravenously; for the 3rd day - 100 mg inside; from the 4th to the 14th day - Prednisonum or Prednisolonum inside in a dose of 20-30 mg; then – gradually to lower a dose to 2,5 mg a day.

Baziliksimab enter only intravenously in the form of infusion, into peripheral or central veins. The recovered solution of a baziliksimab (20 mg / 5 ml) is dissolved up to the volume of 50 ml of 0,9% with solution of sodium of chloride or 5% solution of a dextrose and entered in the form of intravenous infusion lasting 20-30 minutes. The first dose of 20 mg is entered in day of transplantation; the 2nd dose of 20 mg - for the 4th day after operation. The second dose of a baziliksimab is not appointed if the patient accepted or will accept anti-lymphocytic medicines.

Instructions for preparation and administration of drug. Solution of a belatatsept should not be used using the equipment containing silicone.

After removal of a protective plastic cover the stopper is wiped with the sterile cotton wool moistened in alcohol. Contents of one bottle are dissolved in 10,5 ml of water for injections or 0,9% of solution of sodium of chloride for injections, or by 5% of solution of a dextrose for injections, using the one-time bessilikonovy syringe (the size of a needle 18-21) and without opening a bottle. For foaming reduction solvent is added slowly, holding the syringe piston with fingers. The stream of solvent is directed strictly to a bottle wall (but not to lyophilisate). Carefully mix contents, rotating a bottle roundabouts. NOT to STIR UP. After dissolution of lyophilisate from a bottle it is necessary to let out the air through a needle to remove all bubbles which could be formed. The received concentrate has to be colourless or pale yellow. It is impossible to use muddy solution, solution of other color or containing foreign debris.

For calculation of a dose use the following calculations:

•    The mass of the patient (in kg) x a dose of a belatatsept (in mg/kg) (5 or 10 mg/kg) = the general dose of a belatatsept (in mg);

•    The volume of a concentrate (ml) = a dose of a belatatsept (in mg) / 25.

The received concentrate (25 mg/ml) is diluted with solvent according to the scheme given below for receiving injection solution with concentration of 2 - 10 mg/ml.

From a vessel with suitable infusion solution (50 - 250 ml) select the volume equal to volume of the added concentrate. Then in the remained solution, using the same bessilikonovy syringe, as for lyophilisate recovery, slowly add a concentrate, then it is careful, roundabouts mix solution.

Ready solution is used for intravenous administration to the patient in aseptic conditions. Infusion is carried out immediately or during 24 h after lyophilisate dissolution. Ready solution has to be stored in the refrigerator at a temperature from 2 °C to 8 °C protected from light (at storage the general time spent of solution at the room temperature and on light should not exceed 4 h).

Just before administration of drug it should be examined to be convinced that color of solution did not change and in it there are no foreign particles. If before introduction in solution foreign particles or discoloration are observed, solution needs to be poured out.

The prepared infusion solution is entered within 30 minutes through infusional system with sterile depyrogenized - the filter with low ability to connect proteins (the size of a time from 0,2 to 1,2 microns). Белатацепт it is impossible to enter along with other drugs through one infusional system.

Features of use:

Use at pregnancy and a lactation. There are no sufficient data on use of a belatatsept for pregnant women. Drug of Nulodzhiks can be used at pregnancy, only if the potential advantage of use for mother exceeds potential risk for a fruit. Also there are no data on whether gets белатацепт into breast milk. In this regard it is not necessary to nurse at drug use.

Post-transplant limfoproliferativny frustration. At purpose of a belatatsept the risk of development of a post-transplant limfoproliferativny disease increases (first of all with involvement of TsNS). It is necessary to pay special attention to patients with for the first time the revealed symptoms of neurologic and cognitive frustration and changes of behavior, and also at deterioration in already being available similar symptomatology.

In clinical trials use of drug for patients seronegative on Epstein-Barre's virus led to much higher frequency of developing of a post-transplant limfoproliferativny disease in comparison with seropositive patients. So before purpose of drug it is necessary to determine the serological status of the patient by this virus. Use of drug for patients with seronegative or unspecified serological the status is contraindicated.

Other risk factors of development of a post-transplant limfoproliferativny disease are the Cytomegaloviral infection and use of anti-lymphocytic medicines in case of development of reaction of acute graft rejection. It is necessary to be careful at use of these drugs. It is recommended to carry out prevention of a Cytomegaloviral infection at least within 3 months after operation of transplantation of a kidney.

Infections. Use of immunodepressants, including белатацепт, can increase sensitivity to bacterial, viral, fungal and protozoan infections, including opportunistic, tuberculosis, herpes which can lead to serious, including fatal effects. Prevention of a Cytomegaloviral infection is recommended to be carried out within not less than 3 months after transplantation, especially patients have risk groups. Prevention of pneumocystic pneumonia is recommended to be carried out within not less than 6 months after transplantation. Before purpose of a belatatsept it is necessary to carry out skin tuberkulinovy test for identification of existence of a tuberculosis infection. In the presence of positive reaction, before purpose of drug it is necessary to carry out standard antitubercular therapy.

The progressing multifocal leukoencephalopathy. The Progressing Multifocal Leukoencephalopathy (PML) - the rare, opportunistic infection of TsNS caused by JC poliomavirusy. PML is usually diagnosed by means of scanning of a brain by methods of a magnetic and resonant or computer tomography, and also researches of medullispinal liquid on availability of JC DNA of a poliomavirus by method of polymerase chain reaction. In case of suspicion on PML and at impossibility of confirmation of the diagnosis the brain biopsy can be applied by standard methods. It is necessary to pay special attention to patients with for the first time the revealed symptoms of neurologic and cognitive frustration, and also to patients with changes of behavior and cognitive frustration. At identification of PML at the patient it is necessary to consider the possibility of reduction of a dose of immunosuppressor therapy or its cancellation, considering risk of rejection of the replaced kidney.

The nephropathy caused by a polioma virus. In view of the increased risk of development of the nephropathy caused poliomavirusy monitoring is necessary for identification of risk of development of this disease in the patients receiving immunosuppressive therapy. At identification of signs of a virus nephropathy it is necessary to consider the possibility of reduction of immunosuppressor therapy according to recommendations about use of a mikofenolat of a mofetil. It is undesirable to change the mode of a drug dosing of Nulodzhiks as reduction of its doses and change of the mode of dosing in clinical trials is not studied.

Tumors. Due to the increase in risk of development of malignant new growths, including a carcinoma cutaneum, at use of immunodepressants patients should protect skin from influence of ultraviolet radiation.

Allergic reactions. Allergic reactions to administration of drug were observed at 5% of the patients receiving белатацепт within 3 years. At emergence of serious allergic reaction or an anaphylaxis use of drug has to be stopped.

Vaccination. During treatment belatatsepty and within 3 months after its cancellation vaccination should not be carried out by live vaccines. The drugs influencing immune system including белатацепт, can reduce efficiency of vaccination.

Influence on ability to manage motor transport and to work with mechanisms. Influence on ability to manage motor transport and to work with mechanisms it is not established. The patient has to be informed that at development of an indisposition and weakness during treatment it is necessary to abstain from driving of motor transport and occupations potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

The undesirable medicinal reactions (UMR) at use of a belatatsept in clinical trials are listed below. NLR are presented on bodies and systems and frequency: very frequent (≥10%); frequent (≥1% and <10%); infrequent (≥0.1% and <1%); rare (≥0.01% and, <1%).

1. Infections and invasions	Very frequent	Infections of urinary tract, upper respiratory tract infections, bronchitis, nasopharyngitis, Cytomegaloviral infection
	Frequent	Sepsis, gastroenteritis, the simple and surrounding herpes, candidiasis, including oral cavities, flu, lower respiratory tract infection, pneumonia. Rhinitis. Sinusitis, pyelonephritis. Wound fevers, poliomavirusny infections, an onychomycosis, a virus gastroenteritis, an inflammation of hypodermic cellulose, multi-colored deprive, the infection caused by Escherichia coli, the localized infections
	Infrequent	The nephropathy caused poliomavirusy, genital herpes, staphylococcal infections, Cytomegaloviral colitis, the progressing multifocal leukoencephalopathy, a fungal infection of the central nervous system (CNS)
2. Benign and malignant tumors (including cysts and polyps)	Frequent	Skin papillomas, planocellular carcinoma cutaneum, bazalnokletochny cancer, to the limfotsela
	Infrequent	The Limfoproliferativny disturbances caused by Epstein-Barre's virus
3. From bodies of a hemopoiesis	Very frequent	Anemia, leukopenia
	Frequent	Thrombocytopenia, neutropenia, leukocytosis, lymphopenia, polycytopenia
	Infrequent	Monocytopenia
4. Disturbances from immune system	Frequent	Decrease in concentration of immunoglobulin G, decrease in concentration of immunoglobulin M
5. Metabolic disturbances	Very frequent	Hypophosphatemia, hypopotassemia, hyperpotassemia, dislipidemiya, hyperglycemia, hypocalcemia, hypercholesterolemia
	Frequent	Hypomagnesiemia, hyperuricemia, increase or decrease in body weight, acidosis, diabetes mellitus, dehydration
6. Mental disorders	Very frequent	Sleeplessness, uneasiness
7. Neurologic frustration	Very frequent	Headache
	Frequent	Tremor, paresthesia
	Infrequent	Encephalitis, Syndrome to Giyena-Barra
8. From serdechnoyososudisty system	Very frequent	Arterial hypertension, arterial hypotension
	Frequent	Venous thrombosis, tachycardia, bradycardia, hematomas, fibrillation of auricles
9. From a respiratory organs	Very frequent	Cough, диспноэ
	Frequent	Hoarseness, pains in an oral cavity and a throat, lung hypostasis
10. From digestive tract	Very frequent	Lock, diarrhea, nausea, vomiting, abdominal pains
	Frequent	Stomatitis, including aphthous, dyspepsia, gastritis
	Infrequent	Gastrointestinal frustration
11. From a liver and biliary tract	Frequent	Increase in activity of "hepatic" enzymes, cytolytic hepatitis
12. From skin and hypodermic cellulose	Frequent	Acne, itch, alopecia, rash, hyperhidrosis, the increased night sweating, injuries of skin
13. From a musculoskeletal system and connecting fabric	Very frequent	Arthralgia, dorsodynias, extremity pains
	Frequent	Mialgiya, musculoskeletal pain
14. From kidneys and urinary tract	Very frequent	Increase in concentration of creatinine, proteinuria, dysuria, kidney transplant dysfunction
	Frequent	Necrosis of renal tubules, chronic nephropathy of a transplant of a kidney, fibrinferments of a renal vein, hamaturia, proteinuria, hydronephrosis, renal failure, urine incontience
	Infrequent	Thrombosis of a renal artery
15. The general symptoms and reactions in an injection site	Very frequent	Pain at introduction, pain in an injection site, peripheral hypostases, fever
	Frequent	Fatigue, feeling sick, stethalgias, discrepancy of edges of a wound, fibrinferments of an arteriovenous fistula

In clinical trials more than at 2% of patients by 3rd year of use of a belatatsept the following serious undesirable reactions were observed: infections of urinary tract, a Cytomegaloviral infection, fever, increase in concentration of creatinine in blood serum, pyelonephritis, diarrhea, a gastroenteritis, kidney transplant dysfunction, a leukopenia, pneumonia, anemia, bazalnokletochny cancer, dehydration.

The most frequent undesirable reactions (more than 20% of patients) by 3rd year of use of a belatatsept had a diarrhea, anemia, infections of urinary tract, peripheral hypostases, a lock, arterial hypertension, fever, nausea, transplant dysfunction, cough, vomiting, a leukopenia, a hypophosphatemia and a headache.

Undesirable reactions, such as the renal thromboembolism and Cytomegaloviral infections which developed on the 3rd year of treatment belatatsepty led to interruption of therapy or drug withdrawal more than at 1% of patients.

Interaction with other medicines:

Белатацепт represents recombinant protein which is not metabolized by means of fermental systems of P450 cytochrome and uridinediphosphate-glyukuroniltransferazy (UDF-GUT) in this connection existence of ability is not supposed to cause inhibition or induction of these enzymes in it.

Besides, at change of activity of isoenzymes of system of P450 or UDF-GUT cytochrome as a result of reception of the accompanying drugs, influence on metabolism and removal of a belatatsept is not expected.

At introduction of a dose of a mikofenolat of a mofetil life expectancy of mikofenolny acid (an active metabolite of a mikofenolat of a mofetil) is about 40% higher at joint appointment with belatatsepty, than at combined use with cyclosporine as белатацепт does not interfere with gepatoenteralny recirculation of mikofenolny acid.

The clinical importance of increase in life expectancy of mikofenolny acid is unknown.

Immunosuppressive therapy reduces effect of vaccination.

Contraindications:

- Hypersensitivity to a belatatsept and/or any of auxiliary components of drug.

- The seronegative or unspecified serological status concerning Epstein's virus - Barrel.

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

- Lactation period.

With care. Белатацепт it is necessary to apply with care at patients with persistent recurrent infections; the states contributing to infections (diabetes mellitus). Introduction of a belatatsept should be stopped in case of development of an infectious disease.

Overdose:

Белатацепт it is entered in the form of intravenous infusion under medical observation. Doses to 20 mg/kg did not cause overt toxic effects. At overdose observation of the doctor and, if necessary, a symptomatic treatment is recommended. Cases of overdose are not registered.

Storage conditions:

At a temperature from 2 to 8 °C in the place protected from light. To store in the place, unavailable to children. A period of validity - 2 years. Not to use drug after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Lyophilisate for preparation of solution for infusions of 250 mg. On 275 mg of active agent in the glass bottle (type I) corked by a butyl-rubber stopper and an aluminum cap with a protective plastic cover. 1 or 2 sets (a bottle with drug and the syringe bessilikonovy) place in a box cardboard.