Ацеллбия®

General characteristics. Structure:

Active ingredient: 10 mg of a rituksimab.

Pharmacological properties:

Pharmacodynamics. Component the drug Atsellbiya® is active ритуксимаб - himerny to a monoklonalyyua an antibody of the mouse/person which specifically contacts transmembrane CD20 antigen. This antigen is located on пре - In - lymphocytes and mature V-lymphocytes, but is absent on stem hemopoietic cells, about - In - cells, normal plasmocytes, cells of other fabrics and expresses more than in 95% of cases at V-cellular nekhodzhkinsky lymphoma. Expressirovaniy on CD20 cell after linkng with an antibody does not ipgernalizutsya and ceases to come from a cellular membrane to extracellular space. CD20 does not circulate in plasma in the form of free antigen and therefore does not compete for linkng with an antibody.

Rituksimab contacts CD20 antigen on V-lymphocytes and initiates the immunological reactions mediating a lysis of V-cells. Possible mechanisms of a cellular lysis include a complement - dependent cytotoxicity, an antibody - dependent cellular cytotoxicity and induction of apoptosis. Rituksimab increases sensitivity of lines of the V-cellular lymphoma of the person to cytotoxic effect of some chemotherapeutic drugs in vitro.

The number of V-cells in peripheral blood after the first administration of drug decreases below norm and begins to be recovered at patients with hematologic malignant diseases in 6 months, reaching normal values in 12 months after completion of therapy, however duration of the period of recovery of quantity of V-cells can be more.

Anti-chimeric antibodies are revealed at 1,1% of the inspected patients with a nekhodzhkinsky lymphoma. Anti-mouse antibodies at the inspected patients are not revealed.

Pharmacokinetics. Nekhodzhkinsky lymphoma. According to the population pharmacokinetic analysis at patients with a nekhodzhkinsky lymphoma at single or repeated introduction of a rituksimab in the form of monotherapy or in a combination with chemotherapy according to the scheme DISPUTE (cyclophosphamide, doxorubicine, Vincristinum, преднизолоп) nonspecific clearance (CL1), specific clearance (CL2)
(possibly, connected with V-cells or tumoral loading) and distribution volume in plasma (V1) make 0,14 l/day, 0,59 l/day and 2,7 l, respectively. The median of a terminal elimination half-life (T1/2) makes 22 days. The initial CD19 level - positive cells and the size of the tumoral center influences CL2 of the rituksimab entered intravenously in a dose of 375 mg/sq.m once a week within 4 weeks. The indicator of CL2 is higher at patients with higher level of CD19-positive cells or the big size of the tumoral center. Individual variability of CL2 remains also after correction of the size of the tumoral center and level of CD19-positive cells. Rather little changes of an indicator of V1 depend on the body surface area size (1,53-2,32 sq.m) and on chemotherapy according to the scheme CHOP and make 27,1% and 19,0%, respectively. Age, sex, race, the general state on a scale of WHO (World Health Organization) do not influence pharmacokinetics of a rituksimab. Thus, dose adjustment of a rituksimab depending on above-mentioned factors significantly does not influence pharmacokinetic variability.

Average maximum concentration (Cmax) increases after everyone infusions: after the first infusions makes 243 mkg/ml, after the fourth infusions - 486 mkg/ml, and after the eighth - 550 mkg/ml. The minimum and maximum concentration of drug in inverse proportion correlate with initial number of CD19-positive V-cells and size of tumoral loading. At effective treatment the median of equilibrium concentration of drug is higher. The median of equilibrium concentration of drug is higher at patients with histologic subtypes of a tumor In, C and D (IWF classification), than with a subtype A. Traces of a rituksimab can be found in an organism within 3-6 months after the last infusions.

The pharmacokinetic profile of a rituksimab (6 infusions on 375 mg/sq.m) in a combination with 6 cycles of chemotherapy of CHOP was practically same, as well as at monotherapy.

According to own comparative study of pharmacokinetics of a rituksimab at patients with a nekhodzhkinsky lymphoma of low degree of a zlokachestvennost, the area indicator under a curve "concentration time" in group of the drug Atsellbiya® made 16170,57 (mkg/ml) ×ч, when using drug Mabtera® - 17608,42 (mkg/ml) ×ч, clearance of a rituksimab - 43,87 ml / (ч×кг) and 43,17 ml / (ч×кг) respectively. The maximum concentration of Cmax of the drug Atsellbiya® equaled 172,19 mkg/ml, and time of its achievement of Tmax - 31,17 h, in group of the drug Mabtera® similar indicators made 190,68 mkg/ml and 37,47 hours respectively. The elimination half-life (T1/2) made in group of the drug Ацеллбия® 49,60 of the h, in group of the drug Мабтера® 48,95 of h. The relation of average geometrical AUC0-168 of the drug Atsellbiya® and the drug Mabtera® made 80,13 - 118,18%, the relation of average geometrical Cmax of the drug Atsellbiya® and the drug Mabtera® - 81,82 - 115,82% that testifies to equivalence of pharmacokinetic properties of the drugs Atsellbiya® and Мабтера® at intravenous administration to patients.

Chronic lymphoid leukosis. Average maximum concentration (Cmax) after the fifth infusion of a rituksimab in a dose of 500 mg/sq.m makes 408 mkg/ml.

Pharmacokinetics at separate groups of patients. Floor: the volume of distribution and clearance of a rituksimab adjusted for body surface area at men is slightly more, than at women, dose adjustment of a rituksimab is not required.

Patients with a renal and liver failure: pharmacokinetic data at patients with a renal and liver failure are absent.

Indications to use:

Nekhodzhkinsky lymphoma:

— recurrent or himioustoychivy V-cellular, CD20-positive nekhodzhkinsky lymphoma of low degree of a zlokachestvennost or follicular;

— a follicular lymphoma of III-Ivstadii in a combination with chemotherapy at earlier uncured patients;

— a follicular lymphoma as a maintenance therapy after the response to induction therapy;

— A CD20-positive diffusion V-macrocellular nekhodzhkinsky lymphoma in a combination with chemotherapy according to the scheme SNOR.

Chronic lymphoid leukosis:

— a chronic lymphoid leukosis in a combination with chemotherapy at the patients who were earlier not receiving standard therapy;

— a recurrent or himioustoychivy chronic lymphoid leukosis in a combination with chemotherapy.

Route of administration and doses:

Rules of preparation and storage of solution. The necessary amount of the drug Atsellbiya® is gained in aseptic conditions and parted to settlement concentration (1-4 mg/ml) in an infusional bottle (package) from 0,9% with chloride sodium solution for infusion or 5% dextrose solution (solutions have to be sterile and depyrogenized). For hashing accurately overturn a bottle (package) in order to avoid pricing. Before introduction it is necessary to examine solution regarding lack of foreign impurity or change of coloring. The doctor is responsible for preparation, conditions and storage time of ready solution before its use.

As the drug Atsellbiya® does not contain preservatives, the prepared solution needs to be used immediately.

The prepared infusion solution physically is also chemically stable during 12 h at the room temperature or during no more than 24 h at a temperature from 2 ° to 8 °C.

The prepared solution of the drug Atsellbiya® is entered only intravenously, kapelno, through a separate catheter! To administer the drug intravenously struyno or it is bolyusno impossible!

The recommended initial speed of the first infusion of 50 mg/h, further it is possible to increase it by 50 mg/h each 30 min., bringing to the maximum speed of 400 mg/h. The subsequent infusions can be begun with the speed of 100 mg/h and to increase it by 100 mg/h each 30 min. to the maximum speed of 400 mg/h.

Dose adjustment during therapy. It is not recommended to reduce a drug Atsellbiya® dose. If the drug Atsellbiya® is administered in a combination with chemotherapy, the dose decline of himiotsrapevtichesky drugs is carried out according to standard recommendations.

Standard mode of dosing. Nekhodzhkinsky lymphoma of low degree of a zlokachestvennost or follicular. Before each infusion of the drug Atsellbiya® it is necessary to carry out premedication (analgetic/antipyretic, for example, paracetamol; antihistaminic drug, for example, дифенгидрамин). If Atsellbiya® is not applied in a combination with the chemotherapy containing glucocorticosteroids, then glucocorticosteroids also are a part of premedication.

Initial therapy:

- monotherapy at adult patients: 375 mg/sq.m once a week, within 4 weeks;

- in a combination with chemotherapy according to any scheme: 375 mg/sq.m in the first day of a cycle of chemotherapy after intravenous administration of a glucocorticosteroid as a therapy component, during:

• 8 cycles (cycle: 21 days) at the scheme R-CVP (ритуксимаб, cyclophosphamide. Vincristinum, Prednisolonum);

• 8 cycles (cycle: 28 days) at the scheme R-MCP (ритуксимаб, митоксантрон, hlorambutsit, Prednisolonum);

• 8 cycles (cycle: 21 days) at the scheme R-CHOP (ритуксимаб, cyclophosphamide, doxorubicine, Vincristinum, Prednisolonum); in case of achievement of full remission after 4 cycles it is possible to be limited to 6 cycles;

• 6 cycles (cycle: 21 days) at the scheme R-CHVP-Interferon (ритуксимаб, cyclophosphamide, doxorubicine, тенипозид, прсднизолон + interferon).

Repeated use in case of a recurrence (at the patients who answered the first course of therapy): 375 mg/sq.m once a week, within 4 weeks.

Maintenance therapy (after the response to induction therapy):

• At earlier uncured patients: 375 mg/sq.m of 1 times in 2 months, no more than 2 years (12 infusions). At emergence of signs of progressing of a disease therapy rituksimaby should be stopped;

• At a recurrent or himioustoychivy lymphoma: 375 mg/sq.m of 1 times in 3 months, no more than 2 years. At emergence of signs of progressing of a disease therapy of the drug Atsellbiya® should be stopped.

Diffusion V-macrocellular nekhodzhkinsky lymphoma. Before each infusion of the drug Atsellbiya® it is necessary to carry out premedication (analgetic/antipyretic, for example, paracetamol; antihistaminic drug, for example, дифенгидрамин). If Atsellbiya® is not applied in a combination with the chemotherapy containing glucocorticosteroids, then glucocorticosteroids also are a part of premedication.

In a combination with chemotherapy according to the scheme CHOP: 375 mg/sq.m in the first day of each cycle of chemotherapy after intravenous administration of a glucocorticosteroid, 8 cycles. Other components of the scheme CHOP (cyclophosphamide, doxorubicine and Vincristinum) enter after administration of the drug Atsellbiya®.

Chronic lymphoid leukosis. Before each infusion of the drug Atsellbiya® it is necessary to carry out premedication (analgetic/antipyretic, for example, paracetamol; antihistaminic drug, for example, дифенгидрамин). If ритуксимаб it is not applied in a combination with the chemotherapy containing glucocorticosteroids, then glucocorticosteroids also are a part of premedication.

In a combination with chemotherapy (at the patients who were earlier not receiving standard therapy and at recurrent / химиоустойчивом a lymphoid leukosis): 375 mg/sq.m in the first day of the first cycle, then 500 mg/sq.m in the first day of each subsequent cycle, 6 cycles. The chemotherapy is carried out after administration of the drug Atsellbiya®.

For decrease in risk of emergence of a syndrome of a lysis of a tumor preventive ensuring adequate hydration and introduction of urikostatik in 48 hours prior to therapy is recommended. At patients with a chronic lymphoid leukosis and level of lymphocytes> 25×109/л intravenous administration of Prednisonum/Prednisolonum in a dose of 100 mg in 1 hour prior to infusions of a rituksimab for decrease in frequency and weight of acute infuzionpy reactions and/or a syndrome of release of cytokines is recommended.

Dosing in special cases. Advanced age. At patients 65 years of dose adjustment are more senior it is not required.

Features of use:

Use at pregnancy and feeding by a breast. Immunoglobulins G (IgG) are capable to get through a placental barrier. Level of V-cells at newborns at purpose of the drug Atsellbiya® to women during pregnancy was not studied. At some newborns whose mothers received ритуксимаб during pregnancy temporary exhaustion of a pool of V-cells and a lymphocytopenia were observed. Efficiency and safety of drug at pregnant women is not proved.

During treatment and within 12 months after the end of treatment by the drug Atsellbiya® of the woman of childbearing age have to use effective methods of contraception. It is unknown whether the drug Atsellbiya® with breast milk is emitted. Considering that the class IgG immunoglobulins circulating in mother's blood are emitted with breast milk, the drug Atsellbiya® should not be used during feeding by a breast.

Use for children. It is contraindicated to children up to 18 years (efficiency and safety are not established).

Use for elderly patients. At patients 65 years of dose adjustment are more senior it is not required.

Special instructions. The drug Atsellbiya® is administered under careful observation of the oncologist or hematologist in the presence of necessary conditions for holding resuscitation actions.

Nekhodzhkinsky lymphoma and chronic lymphoid leukosis. Infusional reactions. Development of infusional reactions can be caused by release of cytokines and/or other mediators. It is difficult to distinguish heavy infusional reactions from reactions of hypersensitivity or a syndrome of release of cytokines. There are messages on the lethal infusional reactions described during post-registration use of drug. At most of patients within 30 min. - later began 2 h the first infusions of a rituksimab fever with a fever or a shiver develops. Heavy reactions include symptoms from lungs, lowering of arterial pressure, a small tortoiseshell, a Quincke's disease, nausea, vomiting, weakness, a headache, an itch, irritation of language or hypostasis of a throat (vascular hypostasis), rhinitis, inflows, pain in the centers of a disease and, in certain cases, signs of a syndrome of a bystry lysis of a tumor. Infusional reactions disappear after interruption of introduction of a rituksimab and medicamentous therapy (intravenous administration of 0,9% of solution of sodium of chloride, a difengidramin and atsetamipofen, bronchodilators, glucocorticosteroids, etc.). In most cases after total disappearance of symptomatology infusion can be resumed with a speed making 50% from previous (for example, 50 mg/h instead of 100 mg/h). At most of patients with infusional reactions, not life-threatening, the course of treatment rituksimaby managed to be completed completely. Continuation of therapy after total disappearance of symptoms seldom is followed by repeated development of heavy infusional reactions.

Due to potentiality of development of anaphylactic reactions and other reactions of hypersensitivity at intravenous administration of proteinaceous drugs it is necessary to have means for their stopping: adrenaline, antihistaminic and glucocorticosteroid drugs.

Side effect from lungs. Hypoxia, pulmonary infiltrates and acute respiratory insufficiency. Some of these phenomena were preceded by a heavy bronchospasm and an asthma. Increase of symptomatology or clinical deterioration after initial improvement is possible over time. Patients with pulmonary symptomatology or other heavy infusional reactions should be observed carefully to full permission of symptoms. Acute respiratory insufficiency can be followed by formation of interstitsialpy infiltrates in lungs or a fluid lungs, is often shown in the first 1-2 h later began the first infusions. At development of heavy reactions from lungs infusion of a rituksimab it is necessary to stop and appoint intensive symptomatic care immediately. As initial improvement of clinical symptomatology can be replaced by deterioration, patients should be observed carefully to permission of pulmonary symptomatology.

Syndrome of a bystry lysis of a tumor. Rituksimab mediates a bystry lysis of high-quality or malignant CD20-positive cells. The syndrome of a lysis of a tumor is possible after the first infusions of a rituksimab at patients with a large number of the circulating malignant lymphocytes. The syndrome of a lysis of a tumor includes: hyperuricemia, hyperpotassemia, hypocalcemia, hyperphosphatemia, acute renal failure, increase in the LDG level. Patients from risk group (patients with high tumoral loading or a large number of the circulating malignant cells (> 25 ×109/л), for example, with a chronic lymphoid leukosis or a lymphoma from cells of a mantle zone) need careful medical observation and carrying out regular laboratory inspection. At development of symptoms of a bystry lysis of a tumor carry out the corresponding therapy. After full stopping of symptoms in limited number of cases therapy rituksimaby was continued in combination with prevention of a syndrome of a bystry lysis of a tumor.

Patients with a large number of the circulating malignant cells (> 25×109/л) or high tumoral loading (for example, with a chronic lymphoid leukosis or a lymphoma from cells of a mantle zone) at which the risk of extremely heavy infusional reactions can be especially high, should appoint the drug Atsellbiya® with extreme care, under careful observation. The first infusion of drug by such patient should be entered with a smaller speed or to divide a drug dose for two days during the first cycle of therapy and in each subsequent cycles if the number of the circulating malignant cells remains> 25×10/l.

Side effect from cardiovascular system. In the course of infusion careful observation of patients with cardiovascular diseases in the anamnesis in connection with a possibility of development of stenocardia, arrhythmia (trembling and fibrillation of auricles), heart failure or a myocardial infarction is required. Because of a possibility of development of a gipoteiziya not less than for 12 h before infusion of a rituksimab it is necessary to cancel anti-hypertensive medicines.

Control of uniform elements of blood. Though monotherapy rituksimaby has no myelosuppressive effect, it is necessary to approach with care purpose of drug at a neutropenia less 1,5×109/л and/or thrombocytopenia less 75×109/л as experience of its clinical use at such patients is limited. Rituksimab was applied at patients after autologous bone marrow transplantation and in other risk groups with possible dysfunction of marrow, without causing the miyelotoksichnost phenomena. During treatment it is necessary to define regularly developed analysis of peripheral blood, including calculation of quantity of thrombocytes according to routine practice.

Infections. Patients should not appoint the drug Atsellbiya® with a heavy acute infection.

Hepatitis B. Before purpose of a rituksimab all patients should undergo screening on hepatitis B. The minimum set of tests has to include definition of HbsAg and HbcAb; according to local recommendations the list of tests can be added. The drug Atsellbiya® should not be used at patients with active hepatitis B. Patients with positive serological markers of hepatitis B should consult with the hepatologist before use of a rituksimab; concerning such patients it is necessary to carry out the corresponding monitoring and to take measures for prevention of reactivation of a virus of hepatitis B according to local standards.

The progressing multifocal leukoencephalopathy (PML). At use of a rituksimab for patients with a nekhodzhkinsky lymphoma and a chronic lymphoid leukosis PML cases were observed. Most of patients received ритуксимаб in combination with chemotherapy or in combination with transplantation of haematopoietic stem cells. At emergence of neurologic symptoms at such patients it is necessary to carry out differential diagnosis for an exception of PML and consultation of the neurologist.

Skin reactions. Cases of development of such heavy skin reactions as a toxic epidermal necrolysis and Stephens-Johnson's syndrome, in some cases with a fatal outcome are registered. At identification of these reactions the drug Atsellbiya® should be cancelled. The issue of resuming of use of a rituksimab has to be resolved individually taking into account a ratio of advantage and risk for each specific patient.

Immunization. Safety and efficiency of immunization rituksimaby was not studied by live virus vaccines after treatment. Vaccination by live virus vaccines is not recommended. Vaccination by the inactivated vaccines is possible, however the frequency of the answer can decrease. At patients with a recurrent nekhodzhknnsky lymphoma of low degree of a zlokachestvennost decrease in frequency of the response to administration of tetanic anatoxin and KHL-neoantigen (KHL-hemocyanin of a mollusk of a fissureliya) in comparison with the patients who were not receiving ритуксимаб (16% against 81% and 4% against 69% was observed (evaluation criterion - more than 2-fold increase in an antiserum capacity), respectively). However, the average size of an antiserum capacity to a set of antigens (Streptococcus pneumonia, Influenza A, parotitis, a rubella, chicken pox) did not change at least within 6 months after therapy rituksimaby (when comparing with an antiserum capacity before treatment).

Influence on ability to manage vehicles and mechanisms. Whether the drug Atsellbiya® influences ability to management and work with cars and mechanisms - it is unknown though pharmacological activity and the described undesirable phenomena do not give the grounds to assume such influence.

Side effects:

For assessment of frequency of side reactions the following criteria are used: very often ≥ 10%, are frequent ≥ 1% - <10%, infrequently ≥ 0.1%-<1%.

Rituksimab at therapy of a nekhodzhkinsky lymphoma of low degree of a zlokachestvennost or follicular - monotherapy / a maintenance therapy

Messages on side reactions arrived within 12 months after an ionotherapy and up to 1 month after a maintenance therapy rituksimaby.

Infectious and parasitic diseases: very often - bacterial and viral infections; often - respiratory infections *, pneumonia *, the sepsis surrounding herpes *, the infections which are followed by temperature increase *, fungal infections, infections of an unknown etiology.

Disturbances from blood and lymphatic system: very often - a leukopenia, a neutropenia; often - thrombocytopenia, anemia; infrequently - a limfoadenopatiya, disturbance of coagulability of blood, tranzitorny partial aplastic anemia, hemolitic anemia.

Disturbances from respiratory system, bodies of a thorax and a mediastinum: often - rhinitis, бропхоспазм, cough, respiratory diseases, short wind, thorax pains; infrequently - a hypoxia, dysfunction of lungs, an obliterating bronchiolitis, bronchial asthma.

Disturbances from immune system: very often - a Quincke's disease; often - reactions of a giperchuvstvitelyyusta.

Disturbances from a metabolism and food: often - a hyperglycemia, weight reduction, peripheral hypostases, face edemas, increase in activity of LDG, a hypocalcemia.

The general frustration and disturbances in an injection site: very often - a headache, fever, a fever, an adynamy; often - pains in the tumor centers, a grippopodobny syndrome, inflows, weakness; infrequently - pains in the place of an injection.

Disturbances from a GIT: very often - nausea; often - vomiting, diarrhea, dyspepsia, lack of appetite, a dysphagy, stomatitis, a lock, abdominal pains, irritation in a throat; infrequently - increase in a stomach.

Disturbances from cardiovascular system: often - lowering of arterial pressure, increase in arterial pressure, orthostatic hypotension, tachycardia, arrhythmia, atrial fibrillation *, cardial pathology *; infrequently - left ventricular heart failure *, ventricular and supraventricular tachycardia *, bradycardia, myocardium ischemia *, стенокардия*.

Disturbances from a nervous system: often - dizziness, paresthesias, hypesthesias, a sleep disorder, feeling of alarm, excitement, a vazodilataiiya; infrequently - a food faddism.

Disturbances of mentality: infrequently - nervousness, a depression.

Disturbances from skeletal and muscular and connecting fabric: often - a mialgiya, an arthralgia, a muscle hyper tone, dorsodynias, pains in a neck, pains.

Disturbances from skin and hypodermic fabrics: very often - an itch, rash; often - a small tortoiseshell, the increased sweating at night, perspiration, алопеция*.

Disturbances from an organ of sight: often - disturbances of a slezootdeleniye, conjunctivitis.

Disturbances from an acoustic organ and labyrinth disturbances: often - pain and a sonitus.

Laboratory and tool data: very often - decrease in level of immunoglobulins of a class G (IgG).

* - frequency is specified only for side reactions ≥3 severity according to criteria of toxicity of National institute of cancer (NCI-CTC).

Rituksimab in a combination with chemotherapy (R-CHOP, R-CVP, R-FC) at a nekhodzhkinsky lymphoma and a chronic lymphoid leukosis

Heavy side reactions in addition to those which were observed at monotherapy / a maintenance therapy and/or meeting with higher frequency are included below.

Infectious and parasitic diseases: very often - bronchitis; often - an acute bronchitis, sinusitis, hepatitis B * (an aggravation and primary infection).

Disturbances from blood and lymphatic system: very often - a neutropenia **, a febrile neutropenia, thrombocytopenia; often - a pancytopenia, a granulocytopenia.

Disturbances from skin and hypodermic fabrics: very often - an alopecia; often - skin diseases.

The general frustration and disturbances in an injection site: often - fatigue, a fever.

* - frequency is specified on the basis of observations at therapy recurrent / химиоустоичивого a chronic lymphoid leukosis according to the scheme R-FC.

** - the long and/or delayed neutropenia was observed after completion of therapy according to the scheme R-FC at earlier uncured patients or at patients with recurrent / химиоустойчивым a chronic lymphoid leukosis.

The undesirable phenomena meeting at therapy rituksimaby with identical frequency (or is more rare), in comparison with control group are included below: a gematotoksichnost, neytropenichesky infections, infections of urinary tract, septic shock, superinfections of lungs, an infection of implants, a staphylococcal septicaemia, mucous allocations from a nose, the fluid lungs, heart failure, sensitivity disturbances, venous thrombosis, including a deep vein thrombosis of extremities, mukozit, hypostasis of the lower extremities, decrease in fraction of emission of a left ventricle, temperature increase, deterioration in overall health, bacteremia, multiorgan insufficiency, a diabetes mellitus decompensation.

The profile of safety of a rituksimab in a combination with chemotherapy according to schemes MCP, CHVP-IFN does not differ from drug, that at a combination, with CVP, SNOR or FC in the corresponding populations.

Infusional reactions. Monotherapy rituksimaby (within 4 weeks). More than at 50% of patients the phenomena reminding infusional reactions were observed, it is the most frequent - at the first infusions. Infusional reactions include a fever, a shiver, weakness, short wind, nausea, rash, inflows, a lowering of arterial pressure, fever, an itch, urticaria, feeling of irritation of language or hypostasis of a throat (Quincke's disease), rhinitis, vomiting, pains in the tumor centers, a headache, a bronchospasm. It was reported about development of signs of a syndrome of a lysis of a tumor.

Rituksimab in a combination with chemotherapy according to the following schemes: K-CVP at a nekhodzhkinsky lymphoma; R-CHOP at a diffusion V-macrocellular nekhodzhkinsky lnmfoma: R-FC at a chronic lymphoid leukosis

Infusional reactions 3 and 4 severity during infusion or during 24 h after infusion of a rituksimab were noted during the first cycle of chemotherapy at 12% of patients.

Frequency of infusional reactions decreased with each subsequent cycle and to the 8th cycle of chemotherapy the frequency of infusional reactions decreased to less than 1%. Infusional reactions in addition to stated above (at monotherapy rituksimaby) included: dyspepsia, rash, increase in arterial pressure, tachycardia, signs of a syndrome of a lysis of a tumor, in some cases - a myocardial infarction, fibrillation of auricles, a fluid lungs and acute reversible thrombocytopenia.

Infections. Monotherapy rituksimaby (within 4 weeks). Rituksimab causes exhaustion of a pool of V-cells in 70-80% of patients and decrease concentration of immunoglobulins in serum at a small number of patients. Bacterial, viral, fungal infections and infections without the specified etiology (weight, irrespective of the reason) develop at 30,3% of patients. Heavy infections (3 and 4 severity), including sepsis, are noted at 3,9% of patients.

Maintenance therapy (nekhodzhkinsky lymphoma) up to 2 years. At therapy rituksimaby increase in the general frequency of infections, including infections 3-4 severity was observed. Increase in cases of infectious complications at a maintenance therapy lasting 2 years was not observed.

Cases of the progressing multifocal leukoencephalopathy (PML) with a fatal outcome at patients with a nekhodzhkinsky lymphoma after progressing of a disease and repeated treatment are registered.

Rituksimab in a combination with chemotherapy according to the following schemes: R-Cvppri to a nekhodzhknnsky lnmfoma; R-CHOP at a diffusion V-macrocellular nekhodzhkinsky lymphoma; R-FC at a chronic lymphoid leukosis

At therapy rituksimaby according to the scheme R-CVPNE it was observed increases in frequency of infections or invasions. Upper respiratory tract infections (12,3% in the R-CVP group) were the most frequent. Serious infections were observed at 4,3% of the patients receiving chemotherapy according to the scheme R-CVP; life-threatening infections are not registered. The share of patients with infections 2-4 severity and/or a febrile neutropenia in the R-CHOP group made 55.4%. Total frequency of infections 2-4 severity in the R-CHOP group made 45,5%. Frequency fungal 2-4 severity in the R-Snorbyla group is higher than an infection, than in the CHOP group, at the expense of higher frequency of local candidiases and made 4,5%. Frequency of a herpes infection 2-4 severity was higher in the R-CHOP group, than in the CHOP group and made 4,5%.

At patients with a chronic lymphoid leukosis the hepatitis B frequency (an aggravation and primary infection) 3-4 severity in the R-FC group made 2%.

From system of blood. Monotherapy rituksimaby (within 4 weeks). Heavy thrombocytopenia (the 3 and 4 severity) is noted at 1,7% of patients, a heavy neutropenia - at 4,2% of patients and anemia of heavy severity (the 3 and 4 severity) - at 1,1% of patients.

Maintenance therapy (nekhodzhkinsky lymphoma) up to 2 years. The leukopenia (3 and 4 severity) was observed at 5% of patients, and a neutropenia (3 and 4 severity) - at 10% of the patients receiving ритуксимаб. Frequency of developing of thrombocytopenia (3-4 severity) was low and made <1%.

About 50% of patients concerning whom there were numbers of V-cells given on recovery after completion of induction therapy rituksimaby were required 12 and more months for recovery of number of V-cells to normal level.

Rituksimab in a combination with chemotherapy according to the following schemes: R-CVP at a nekhodzhknnsky lymphoma; R-CHOP at a diffusion V-macrocellular nekhodzhkinsky lymphoma; R-FC at a chronic lymphoid leukosis

Heavy neutropenia and leukopenia: at the patients receiving ритуксимаб in a combination with chemotherapy a leukopenia 3 and 4 severity were noted more often in comparison with the patients receiving only chemotherapy. Frequency of a heavy leukopenia made 88% at the patients receiving R-CHOP, and the patients receiving R-FC have 23%. Frequency of a heavy neutropenia made 24% in the R-CVP group, 97% in the R-CHOP group and 30% in the R-FC group at earlier not treated chronic lymphoid leukosis. Higher frequency of a neutropenia at the patients receiving ритуксимаб and chemotherapy, was not associated with increase in frequency of infections and invasions in comparison with the patients receiving only chemotherapy. At patients with a recurrent or himioustoychivy chronic lymphoid leukosis after performing therapy according to the scheme R-FC in some cases the peytropeniya was characterized by a long current and later terms of manifestation.

Heavy anemia and thrombocytopenia (3 and 4 severity): the significant difference in anemia frequency 3 and 4 severity in groups was not. In the R-FC group at the first line of therapy chronic lymphoid leukosis anemia 3 and 4 of severity thrombocytopenia 3 and 4 severity - at 7% of patients occurred at 4% of patients. In the R-FC group at a recurrent or chronic lymphoid leukosis anemia 3 and 4 severity occurred at 12% of patients, thrombocytopenia 3 and 4 severity - at 11% of patients.

From cardiovascular system. Monoterapiya rituksimaby (within 4 weeks). Side effects from cardiovascular system are noted at 18,8%. Most often increase and lowering of arterial pressure meet arterial. In isolated cases disturbance of a cordial rhythm 3 and 4 severity (including, ventricular and supraventricular tachycardia) and stenocardia was observed.

Maintenance therapy (nekhodzhkinsky lymphoma) up to 2 years. 3 and 4 severity the patients who were receiving ритуксимаб, and not receiving it had a similar frequency of cardiovascular disturbances. Serious cardiovascular violations arose at less than 1% of the patients who were not receiving ритуксимаб and at 3% of the patients receiving drug (a ciliary arrhythmia at 1%, a myocardial infarction at 1%, a left ventricular failure at <1%, myocardium ischemia at <1%).

Rituksimab and combinations with chemotherapy according to the following schemes: R-CVP at a nekhodzhkinsky lymphoma; R-CHOP at a diffusion V-macrocellular nekhodzhkinsky lymphoma; R-FC at a chronic lymphoid leukosis

Frequency of disturbances of a cordial rhythm 3 and 4 severity, mainly supraventricular arrhythmias (tachycardia, trembling and atrial fibrillation), in the R-CHOP group was higher and made 6,9%. All arrhythmias developed or in connection with infusion of a rituksimab, or were connected with such contributing states as fever, an infection, an acute myocardial infarction or associated diseases of respiratory and cardiovascular systems. The R-CHOP and CHOP groups did not differ among themselves on the frequency of other cardiological undesirable phenomena 3 and 4 severity, including heart failure, diseases of a myocardium and manifestation of coronary heart disease.

The general frequency of cardiovascular disturbances 3 and 4 severity was low as at the first line of therapy of a chronic lymphoid leukosis (4% in the R-FC group), and at therapy recurrent / химиоустойчивого a chronic lymphoid leukosis (4% in the R-FC group).

Nervous system. Rituksimab in a combination with chemotherapy according to the following schemes: R-CVP at a nekhodzhkinsky lymphoma; R-CHOP at a diffusion V-macrocellular nekhodzhkinsky lymphoma; R-FC at a chronic lymphoid leukosis

At patients (2%) from the R-CHOP group with cardiovascular risk factors thromboembolic disturbances of cerebral circulation developed during the first cycle of therapy, unlike patients in the CHOP group at whom disturbances of cerebral circulation developed in the observation period without treatment. The difference between groups in the frequency of others of a thromboembolism was absent.

The general frequency of neurologic disturbances 3 and 4 severity was low as at the first line of therapy of a chronic lymphoid leukosis (4% in the R-FC group), and at therapy recurrent / химиоустойчивого a chronic lymphoid leukosis (3% in the R-FC group).

Concentration of IgG. A maintenance therapy (a nekhodzhkinsky lymphoma) up to 2 years. After induction therapy concentration of IgG was below the lower bound of norm (<7 g/l) in the group receiving ритуксимаб and in the group which was not receiving drug. In the group which was not receiving ритуксимаб the IgG level median consistently increased and exceeded the lower bound of norm while the median of the IgG level did not change in the group receiving ритуксимаб. At 60% of the patients receiving ритуксимаб within 2 years, the IgG level remained below the lower bound. In group without therapy rituksimaby in 2 years the IgG level remained below the lower bound with 36% of patients.

Special categories of patients. Monotherapy rituksimaby (within 4 weeks). Advanced age (≥65 years): frequency and severity of all undesirable reactions and undesirable reactions 3 and 4 severity does not differ from that at younger patients.

Combination therapy. Advanced age (of 65 years is also more senior): at the first line of therapy, and also at therapy of a retsidivirugoshchego/himioustoychivy chronic limfolsykoz the frequency of side effects 3 and 4 severity from system of blood and lymphatic system was higher in comparison with younger patients.

High tumoral loading (diameter of the single centers more than 10 cm): frequency of undesirable reactions 3 and 4 severity is increased.

Repeated therapy: frequency and severity of undesirable reactions does not differ from those when performing initial therapy.

Data on post-registration use of a rituksimab at a nekhodzhkinsky lymphoma and a chronic lymphoid leukosis. From cardiovascular system: the heavy cardiovascular phenomena associated with infusional reactions, such as heart failure and myocardial infarction generally at patients with cardiovascular diseases in the anamnesis and/or receiving cytotoxic chemotherapy; very seldom - a vasculitis, preferential skin (leykotsitoklasticheskiya).

From a respiratory organs: the respiratory insufficiency and pulmonary infiltrates caused by infusional reactions; in addition to the undesirable phenomena from the lungs caused by infusional reactions the intersticial pulmonary disease, in some cases with a fatal outcome was observed.

From circulatory and lymphatic system: the reversible acute thrombocytopenia associated with infusional reactions.

From skin and its appendages: seldom - heavy violent reactions, a toxic epidermal necrolysis and Stephens-Johnson's syndrome, in some cases with a lethal outcome.

From a nervous system: seldom - a neuropathy of cranial nerves in combination with a peripheral neuropathy or without it (the expressed decrease in visual acuity, hearing, defeat of other sense bodys, paresis of a facial nerve) during various periods of therapy up to several months after end of a course of treatment rituksimaby. At the patients who received treatment rituksimaby cases of reversible encephalopathy with defeat of back departments of a brain (PRES)/syndrome of a reversible leukoencephalopathy with defeat of back departments of a brain (PRLS) were observed. The symptomatology included a vision disorder, a headache, spasms and the mental disturbances accompanied or not increase in arterial pressure. It is possible to confirm the diagnosis of PRES/PRLS by means of methods of visualization of a brain. In the described cases patients had risk factors of development of PRES/PRLS, such as basic disease, increase in arterial pressure, immunosuppressive therapy and/or chemotherapy.

From an organism in general, reactions in an injection site: seldom - a serum disease.

Infections: reactivation of a viral hepatitis In (in most cases at a combination of a rituksimab and cytotoxic chemotherapy); and also other heavy viral infections (primary infection, reactivation of a virus or an aggravation) some of which were followed by a lethal outcome, caused by a cytomegalovirus, Varicella zoster, Herpes simplex, poliomavirusy JC(PML), a hepatitis C virus.

At purpose of a rituksimab according to the indications which are not provided by the instruction on a medical use at patients with earlier diagnosed Kaposha's sarcoma progressing of sarcoma was observed (most of patients were HIV-positive).

From digestive tract: perforation of a stomach and/or intestines (it is possible with a lethal outcome) at a combination of a rituksimab with chemotherapy at a nekhodzhkinsky lymphoma.

From system of blood and lymphatic system: seldom - the neutropenia arising in 4 weeks after the last introduction of a rituksimab; passing increase in the IgM level at patients with Valdenstrem's macroglobulinemia with the subsequent return to its reference value in 4 months.

Interaction with other medicines:

Data on medicinal interactions of a rituksimab are limited. Patients with a chronic lymphoid leukosis at simultaneous use have a rituksimaba, a fludarabin and cyclophosphamide фармакокинетическис indicators do not change. There are no data of clinical trials on existence of synergetic effect at use of the drug Atsellbiya® in a combination with chemotherapy.

At appointment with other monoclones with the diagnostic or medical purpose as the patient having antibodies against proteins of a mouse or anti-chimeric antibodies the risk of allergic reactions increases.

At administration of the drug Atsellbiya® polyvinyl chloride or polyethylene infusional systems or packages owing to compatibility of material with drug can be used.

Contraindications:

— hypersensitivity to a rituksimab, any component of the drug Atsellbiya® or to mouse proteins;

— acute infectious diseases, the expressed primary or secondary immunodeficience;

— children's age up to 18 years (efficiency and safety are not established);

— pregnancy and period of breastfeeding.

With care. Respiratory insufficiency in the anamnesis or tumoral infiltration of lungs; number of the circulating malignant cells> 25×109/л or high tumoral loading; neutropenia (less 1.5×109/л), thrombocytopenia (less 75×109/л); persistent infections.

Overdose:

Overdose cases at the person were not observed. Single doses of a rituksimab higher than 1000 mg were not studied. The maximum dose of 5000 mg was appointed to patients with a chronic lymphoid leukosis, additional data but safety are not received. Due to the increase in risk of infectious complications at exhaustion of a pool of V-lymphocytes it is necessary to cancel or reduce the speed of infusions, to consider need of performing the developed general blood test.

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. A period of validity - 2 years 6 months.

Issue conditions:

According to the recipe

Packaging:

10 ml - bottles (2) - packs cardboard.
30 ml - bottles (1) - packs cardboard.
50 ml - bottles (1) - packs cardboard.