MabThera

General characteristics. Structure:

Active ingredient: 10 mg of a rituksimab in 1 ml of solution.

Excipients: citrate sodium a dihydrate, polysorbate 80, sodium chloride, Acidum hydrochloricum or sodium hydroxide (to рН 6.5), water for injections.

The medicamentous drug intended for treatment of a lymphoma and other hematologic diseases.

Pharmacological properties:

Pharmacodynamics. Rituksimab - a himerny monoclone 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. CD20, expressed on a cell, after linkng with an antibody does not internalizutsya 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 in certain cases duration of the period of recovery of quantity of V-cells can be more.

At patients with a pseudorheumatism duration of decrease in quantity of V-cells varies, to most of patients the subsequent therapy is appointed to a complete recovery of their quantity. At a small number of patients long decrease in quantity of V-cells is observed (within two and more years after the last dose of drug).

At patients to a polyangiitis and a microscopic polyangiitis decrease in number CD19 - positive B-cells to level less than 10 cells / мкл happen to a granulomatosis after the two first infusions of a rituksimab, and at most of patients remains at this level within 6 months.

Anti-chimeric antibodies are revealed at 1.1% of the inspected patients with a nekhodzhkinsky lymphoma and at 10% - with a pseudorheumatism. 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 administration of the drug Mabtera® in the form of monotherapy or in a combination with chemotherapy according to the scheme CHOP (cyclophosphamide, doxorubicine, Vincristinum, Prednisolonum) the nonspecific clearance (CL1), specific clearance (CL2) (possibly, connected with V-cells or tumoral loading) and distribution volume in plasma (Vl) 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 a rituksimab of 375 mg/sq.m intravenously (in/in) once a week, within 4 weeks. The indicator of CL2 is higher at patients with higher CD19 level - 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 the CD19 level - positive cells. Rather little changes of an indicator of Vl 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 the listed factors significantly does not influence pharmacokinetic variability.

Average maximum concentration (Cmax) increases after each infusion: after the first infusion makes 243 mkg/ml, after the fourth infusion - 486 mkg/ml, and after the eighth - 550 mkg/ml. The minimum and maximum concentration of drug in inverse proportion correlate with initial number CD19 - positive V-cells and the 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 – International Working Formulation), than with a subtype A. Traces of a rituksimab can be found in an organism within 3-6 months after the last infusion.

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.

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

Pseudorheumatism. After two in/in infusions on 1000 mg with a two-week break average Cmax of a rituksimab – 369 mkg/ml, average T1/2 – 19.2-20.8 days, average system clearance – 0.23 l/days and the volume of distribution in an equilibrium state – 4.6 l. After performing the second infusion average Cmax is 16-19% higher in comparison with the first infusion. When carrying out a repeated course of treatment pharmacokinetic parameters of a rituksimab are comparable to the first course of treatment.

Granulomatosis with a polyangiitis (Wegener's granulomatosis) and a microscopic polyangiitis. According to the population pharmacokinetic analysis after four infusions of a rituksimab in a dose of 375 mg/sq.m once a week a median of T1/2 – 23 days, average clearance – 0.313 l/days and the volume of distribution – 4.5 l. Pharmacokinetic parameters of a rituksimab at a granulomatosis with a polyangiitis and a microscopic polyangiitis were practically same, as at a pseudorheumatism.

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 - a positive nekhodzhkinsky lymphoma of low degree of a zlokachestvennost or follicular.

Follicular lymphoma of the III-IV stage in a combination with chemotherapy at earlier not treated patients.

Follicular lymphoma as a maintenance therapy after the response to induction therapy.

CD20 - a 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.

Recurrent or himioustoychivy chronic lymphoid leukosis in a combination with chemotherapy.

Pseudorheumatism. A medium-weight and heavy pseudorheumatism (an active form) at adults in a combination with a methotrexate at intolerance or the inadequate answer to the current modes of therapy including one or more inhibitors of a factor of a necrosis of tumors (FNO-a), including for braking radiological the proved destruction of joints.

Granulomatosis with a polyangiitis (Wegener's granulomatosis) and a microscopic polyangiitis. Severe forms of an active granulomatosis with a polyangiitis (Wegener's granulomatosis) and a microscopic polyangiitis in a combination with glucocorticosteroids.

Route of administration and doses:

Rules of preparation and storage of solution. The necessary amount of drug 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 infusions or 5% dextrose solution (solutions have to be sterile and depyrogenized). For hashing accurately overturn a bottle (package) in order to avoid foaming. 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 Mabtera® does not contain preservatives, the prepared solution needs to be used immediately.

The prepared infusion solution of the drug Mabtera® 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 drug Mabtera® is administered only in/in kapelno, through a separate catheter! To administer the drug in/in struyno or it is bolyusno impossible!

Dose adjustment during therapy. It is not recommended to reduce a dose of a rituksimab. If MabThera ® is entered into combinations with chemotherapy, the dose decline of chemotherapeutic 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 Mabtera® it is necessary to carry out premedication (analgetic/antipyretic, for example, paracetamol; antihistaminic drug, for example, дифенгидрамин). If Mabtera® is applied not in a combination with the chemotherapy containing glucocorticosteroids, then glucocorticosteroids also are a part of premedication.

Initial therapy:
- monotherapy of 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 later in/in introductions 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, Prednisolonum + 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 not treated 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 of the drug Mabtera® 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 Mabtera® should be stopped. 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.

Diffusion V-macrocellular nekhodzhkinsky lymphoma. Before each infusion of the drug Mabtera® it is necessary to carry out premedication (analgetic/antipyretic, for example, paracetamol; antihistaminic drug, for example, дифенгидрамин). If Mabtera® is applied not 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 SNOR: 375 mg/sq.m in the first day of each cycle of chemotherapy later in/in introductions of a glucocorticosteroid, 8 cycles. Other components of the scheme SNOR (cyclophosphamide, doxorubicine and Vincristinum) enter after purpose of the drug Mabtera®.

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.

Chronic lymphoid leukosis. Before each infusion of the drug Mabtera® it is necessary to carry out premedication (analgetic/antipyretic, for example, paracetamol; antihistaminic drug, for example, дифенгидрамин). If Mabtera® is applied not 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 Mabtera®.

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 the maintenance of lymphocytes> 25 thousand / мкл are recommended in/in administration of Prednisonum/Prednisolonum in a dose of 100 mg in 1 hour prior to infusion of the drug Mabtera® for decrease in frequency and weight of acute infusional reactions and/or a syndrome of release of cytokines.

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.

Pseudorheumatism. Before each infusion of the drug Mabtera® it is necessary to carry out premedication (analgetic/antipyretic, for example, paracetamol; antihistaminic drug, for example, дифенгидрамин). Besides, it is necessary to carry out premedication by glucocorticosteroids for reduction of frequency and weight of infusional reactions. Patients have to receive 100 mg of Methylprednisolonum in/in in 30 min. prior to each infusion of the drug Mabtera®.
Initial therapy: 1000 mg in/in kapelno, slowly, 1 time in 2 weeks, a course - 2 infusions.

Repeated use: need for repeated courses of therapy is recommended to be estimated in 24 weeks after the previous course. Repeated use is carried out in case of existence of residual activity of a disease or at increase in activity of a disease more than 2.6 on DAS28-SOE (an index of activity of a disease on 28 joints and a blood sedimentation rate). Repeated courses can be appointed not earlier than 16 weeks after the previous course.

The recommended dosing mode at repeated use: 1000 mg of 1 times in 2 weeks, a course – 2 infusions.

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. Time of performing infusion – to 4 h is 15 min.

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. Time of performing infusion – to 3 h is 30 min.

The alternative scheme of increase in speed of the subsequent infusions at patients with a pseudorheumatism. If at the patient development of serious infusional reactions at administration of the drug Mabtera® was not observed earlier, alternative time of performing the subsequent infusions of the drug Mabtera® divorced to concentration of 4 mg/ml (250 ml of solution) makes 120 min.:
·  within the first 30 min. the drug is administered with a speed of 250 mg/h, by the next 90 min. – with a speed of 600 mg/h.

In case of good tolerance it is also possible to recommend performing infusions lasting 120 min. at the subsequent infusions and courses.

It is not necessary to apply the alternative scheme of increase in speed of the subsequent infusions at patients with clinically significant cardiovascular diseases, including arrhythmias, and also in the presence in the anamnesis of serious infusional reactions to administration of biological drugs, including a rituksimaba.

Granulomatosis with a polyangiitis (Wegener's granulomatosis) and a microscopic polyangiitis. Before each infusion of the drug Mabtera® it is necessary to carry out premedication (analgetic/antipyretic, for example, paracetamol; antihistaminic drug, for example, дифенгидрамин).

The recommended dosing mode. Therapy by glucocorticosteroids is recommended to be begun within 2 weeks before the first infusion of the drug Mabtera® or directly in day of the first infusion of the drug Mabtera®: Methylprednisolonum (in/in) in a dose of 1000 mg/day lasting from 1 up to 3 days, then peroral Prednisolonum in a dose of 1 mg/kg/day (but no more than 80 mg/day) with a gradual dose decline of the last before full cancellation (rates of a dose decline are defined by a specific clinical situation).

Therapy by a peroral glucocorticosteroid can be continued in time and after completion of use of the drug Mabtera®;
Мабтера® - 375 mg/sq.m once a week, within 4 weeks. 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.

In time and after completion of therapy the drug Mabtera® at patients with a granulomatosis with a polyangiitis (Wegener's granulomatosis) and a microscopic polyangiitis recommends performing prevention of the pneumocystic pneumonia (caused by Pneumocystis jiroveci).

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

Features of use:

Immunoglobulins G (IgG) are capable to get through a placental barrier.

Level of V-cells at newborns at purpose of the drug Mabtera® 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. In this regard pregnant women should not appoint the drug Mabtera® if only possible advantages of therapy do not exceed potential risk.

During treatment and within 12 months after the end of treatment by the drug Mabtera® of the woman of childbearing age have to use effective methods of contraception.

It is unknown whether it is allocated ритуксимаб with breast milk. Considering that the class IgG immunoglobulins circulating in mother's blood are emitted with breast milk, the drug Mabtera® should not be used during breastfeeding.

It is necessary to specify the trade name of drug (Мабтера®) in medical documentation of the patient. Replacement of drug by any other biological medicine demands approval of the attending physician. Information provided in this instruction belongs only to the drug Mabtera®.

The drug Mabtera® is administered under careful observation of the oncologist, hematologist or rheumatologist 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 fatal infusional reactions described during post-registration use of drug. Most of patients within 30 min. – 2 h after the beginning of the first infusion of the drug Mabtera® has a fever with a fever or a shiver. 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 administration of the drug Mabtera® and medicamentous therapy (intravenous administration of 0.9% of solution of sodium of chloride, a difengidramin and acetaminophen, 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 intersticial infiltrates in lungs or a fluid lungs, is often shown in the first 1-2 h after the beginning of the first infusion. 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. Мабтера® 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 infusion of the drug Mabtera® at patients with a large number of the circulating malignant lymphocytes. The syndrome of a lysis of a tumor includes a hyperuricemia, a hyperpotassemia, a hypocalcemia, a hyperphosphatemia, an acute renal failure, increase in activity of LDG. Patients from risk group (patients with high tumoral loading or a large number of the circulating malignant cells (> 25 thousand / мкл), 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 by the drug Mabtera® 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 thousand / мкл) 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 Mabtera® 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 thousand / мкл.

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 hypotension not less than for 12 h before infusion of the drug Mabtera® it is necessary to cancel anti-hypertensive medicines.

Control of uniform elements of blood. Though monotherapy by the drug Mabtera® has no myelosuppressive effect, it is necessary to approach with care purpose of drug at a neutropenia less than 1.5 thousand / мкл and/or thrombocytopenia less than 75 thousand / мкл as experience of its clinical use at such patients is limited. Мабтера® it 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 Mabtera® with a heavy acute infection.

Hepatitis B. At purpose of a combination of the drug Mabtera® with chemotherapy reactivation of a virus of hepatitis B or fulminantny hepatitis were noted (including with a fatal outcome). The contributing factors included both a stage of a basic disease, and cytotoxic chemotherapy.

Before purpose of the drug Mabtera® 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 Mabtera® should not be used at patients with active hepatitis B. Patients with positive serological markers of hepatitis B should consult with the hepatologist before drug Mabtera® use; 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 the drug Mabtera® for patients with a nekhodzhkinsky lymphoma and a chronic lymphoid leukosis PML cases were observed. Most of patients received the drug Mabtera® 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 Mabtera® should be cancelled.

Immunization. Safety and efficiency of immunization by the drug Mabtera® 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 nekhodzhkinsky 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 the drug Mabtera® (16% against 81% and 4% against 76% was observed (evaluation criterion – more than 2 – multiple 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 by the drug Mabtera® (when comparing with an antiserum capacity before treatment).

Pseudorheumatism, granulomatosis with a polyangiitis (Wegener's granulomatosis) and a microscopic polyangiitis. Concerning other autoimmune diseases efficiency and safety of use of the drug Mabtera® are not established.
Infusional reactions. Development of infusional reactions can be caused by release of cytokines and/or other mediators. Before each infusion of the drug Mabtera® it is necessary to carry out premedication by analgetic/antipyretic and antihistaminic drug. Besides, before each infusion of the drug Mabtera® patients with a pseudorheumatism have to receive premedication glucocorticosteroids for reduction of frequency and weight of infusional reactions.

In most cases patients with a pseudorheumatism, had easy infusional reactions or moderate severity. During the post-marketing period heavy infusional reactions with a fatal outcome were registered. It is necessary to observe carefully patients with earlier revealed diseases of cardiovascular system, and also that at whom undesirable reactions were noted from heart and lungs earlier. The following infusional reactions were most often observed: a headache, an itch, feeling of irritation in a throat, inflows, rash, urticaria, increase in arterial pressure and fever. Infusional reactions were more often observed after the first infusion of any course of treatment, than after the second infusion. The subsequent infusions of the drug Mabtera® were transferred easier, than the first. Serious infusional reactions were observed less than at 1% of patients, is the most frequent - during the first infusion of the first cycle. Infusional reactions disappear after delay or interruption of administration of the drug Mabtera® and medicamentous therapy (antipyretic, antihistamines and sometimes oxygen, intravenous administration of 0.9% of solution of sodium of chloride, bronchodilators and in need of glucocorticosteroids). At development of infusional reactions, depending on their weight and necessary treatment, administration of the drug Mabtera® should be suspended or cancelled temporarily.

In most cases after total disappearance of symptomatology infusion can be resumed with a speed making 50% from preceding (for example, 50 mg/h instead of 100 mg/h).

The infusional reactions observed at a granulomatosis with a polyangiitis and a microscopic polyangiitis corresponded already described at a pseudorheumatism. Lower frequency and weight of infusional reactions at a granulomatosis with a polyangiitis and a microscopic polyangiitis could be connected using high doses of glucocorticosteroids.

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

Side effect from cardiovascular system. Because of a possibility of development of hypotension not less than for 12 h before infusion of the drug Mabtera® it is necessary to cancel anti-hypertensive medicines.

Careful observation of patients with cardiovascular diseases in the anamnesis in connection with a possibility of development of stenocardia or arrhythmia (trembling and fibrillation of auricles), heart failure or a myocardial infarction is required.

Infections. Due to the possible increase in risk of infectious complications patients should not appoint the drug Mabtera® with an acute infection or the expressed immunodeficiency (a hypogammaglobulinemia or the low CD4, CD8 level). It is necessary to be careful at purpose of the drug Mabtera® at patients with persistent infection or in the presence of the conditions contributing for development of serious infections. At emergence of an infectious complication it is necessary to appoint the corresponding therapy.

Hepatitis B. At use of the drug Mabtera® for patients with a pseudorheumatism, a granulomatosis with a polyangiitis and a microscopic polyangiitis cases of reactivation of a virus of hepatitis B were observed (including with a fatal outcome). Before purpose of the drug Mabtera® 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 Mabtera® should not be used at patients with active hepatitis B. Patients with positive serological markers of hepatitis B should consult with the hepatologist before drug Mabtera® use; 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). During post-registration use of the drug Mabtera® by patients with autoimmune diseases, including with a pseudorheumatism, fatal cases of PML were observed. Some patients had multiple factors of risk of PML: associated diseases, long reception of immunosuppressive therapy or chemotherapy. Cases of PML are registered also at patients with the autoimmune diseases which are not receiving the drug Mabtera®. 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 Mabtera® should be cancelled.

Immunization. Safety and efficiency of immunization by live virus vaccines, after treatment by the drug Mabtera® was not studied. Vaccination by live virus vaccines is not recommended. Vaccination by the inactivated vaccines is possible, however the frequency of the answer can decrease.

Before use of the drug Mabtera® for patients with a pseudorheumatism it is necessary to study the vaccinal status of the patient and to work according to the corresponding recommendations. It is necessary to complete vaccination not less than in 4 weeks prior to purpose of a rituksimab.

In 6 months of therapy the drug Mabtera® and a methotrexate observed decrease in frequency of the response to introduction of a polisakharidny pneumococcal vaccine (43% against 82%, at least 2 serotypes of antibodies to a pneumococcus), KHL-neoantigena (KHL - hemocyanin of a mollusk of a fissureliya) (34% against 80%) in comparison with monotherapy by a methotrexate. After therapy by the drug Mabtera® and a methotrexate the frequency of the response to administration of tetanic anatoxin was similar to that after monotherapy a methotrexate (39% against 42%).

In case of need vaccination by the inactivated vaccines has to be complete not less than in 4 weeks prior to a repeated course of therapy.

The number of patients with a pseudorheumatism and a positive antiserum capacity to Streptococcus pneumonia, influenza A, parotitis, a rubella, chicken pox and a tetanin to and in 1 year after the beginning of therapy by the drug Mabtera® did not change.

Anti-chimeric antibodies. Emergence of anti-chimeric antibodies in most of patients with a pseudorheumatism was not followed by clinical manifestations or increase in risk of reactions during the subsequent infusions, but seldom their existence can be associated with heavier allergic or infusional reactions at repeated infusions during the following courses and insufficient effect concerning decrease in a pool of V-cells when carrying out the subsequent courses of therapy.

The patients with a pseudorheumatism who were earlier not receiving a methotrexate. Мабтера® it is not recommended for treatment of the patients who were earlier not receiving a methotrexate since the favorable ratio advantage/risk for this category of patients is not confirmed.

Use for children. Safety and efficiency of drug at children are not established. At use of the drug Mabtera® for children the hypogammaglobulinemia, in some cases in the severe form which demanded long replacement therapy by immunoglobulins was observed. Effects of exhaustion of a pool of V-cells at children are unknown.

Utilization of the drug Mabtera® should be carried out according to local requirements.

Influence on ability to driving of transport and work with cars and mechanisms. Whether influences ритуксимаб 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 undesirable reactions the following criteria are used: very often ≥10%, often ≥1% - <10%, infrequently ≥0.l % - <1%.

Experience of use of drug at oncohematological diseases. Мабтера® at therapy of a nekhodzhkinsky lymphoma of low degree of a zlokachestvennost or follicular - monotherapy / a maintenance therapy. Messages on undesirable reactions arrived within 12 months after monotherapy and up to 1 month after a maintenance therapy the drug Mabtera®.

Infectious and parasitic diseases: very often – bacterial and viral infections; often – respiratory infections *, pneumonia *, the sepsis surrounding herpes *, the infections which are followed by fervescence *, 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, a bronchospasm, 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 – hypersensitivity reactions.

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 digestive tract: 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 *, a myocardial infarction *, 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 vazodilatation; 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 concentration of immunoglobulins G (IgG).

* frequency is specified only for side reactions ≥3 severity according to criteria of toxicity of National institute of cancer (NCI-CTC).
Мабтера® 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 * (reactivation of a virus of hepatitis B 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 of a recurrent / himioustoychivy 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 not treated patients or at patients with a recurrent / himioustoychivy chronic lymphoid leukosis.

The undesirable phenomena meeting at therapy by the drug Mabtera® 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, fervescence, deterioration in overall health, falling, multiorgan insufficiency, bacteremia, a diabetes mellitus decompensation.

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

Infusional reactions. Monotherapy by the drug Mabtera® (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, 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.

Мабтера® 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. Infusional reactions 3 and 4 severity during infusion or during 24 h after infusion of the drug Mabtera® 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 reached less than 1%. Infusional reactions in addition to stated above (at monotherapy by the drug Mabtera®) 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 by the drug Mabtera® (within 4 weeks). Мабтера® causes exhaustion of a pool of V-cells in 70-80% of patients and decrease in concentration of immunoglobulins in serum at a small number of patients. Bacterial, viral, fungal infections and infections without the specified etiology (everything, 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 the drug Mabtera® observed increase in the general frequency of infections, including infections 3-4 severity. 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.

Мабтера® 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 therapy the drug Mabtera® according to the scheme R-CVP did not observe increase 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% the Total frequency of infections 2-4 severity in the R-CHOP group made 45.5%. Frequency of fungal infections 2-4 severity in the R-CHOP group was higher, than in the SNOR 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 in comparison with the SNOR group and made 4.5%.

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

From system of blood. Monotherapy by the drug Mabtera® (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, a neutropenia (3 and 4 severity) - at 10% of the patients receiving the drug Mabtera®. Frequency of developing of thrombocytopenia (3-4 severity) at therapy by the drug Mabtera® 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 by the drug Mabtera® were required 12 and more months for recovery of number of V-cells to normal level.

Мабтера® 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. Heavy neutropenia and leukopenia (3 and 4 severity): at the patients receiving the drug Mabtera® 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 the drug Mabtera® 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 neutropenia was characterized by a long current or 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 himioustoychivy 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. Monotherapy by the drug Mabtera® (within 4 weeks). Side effects from cardiovascular system are noted at 18.8%. Most often decrease and increase in arterial pressure meet. 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 the drug Mabtera® 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 the drug Mabtera® 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%).

Мабтера® 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. 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, than in the SNOR group and made 6.9%. All arrhythmias developed or in connection with drug Mabtera® infusion, 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. Мабтера® 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 from the CHOP group at whom disturbances of cerebral circulation developed in the observation period without treatment. The difference between groups in the frequency of other thromboembolisms 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 the drug Mabtera® and in the group which was not receiving drug. In the group which was not receiving the drug Mabtera®, the median of concentration of IgG consistently increased and exceeded the lower bound of norm while the median of concentration of IgG did not change in the group receiving the drug Mabtera®. At 60% of the patients receiving the drug Mabtera® within 2 years, concentration of IgG remained below the lower bound. In group without therapy by the drug Mabtera® in 2 years concentration of IgG remained below the lower bound with 36% of patients.

Special categories of patients. Monotherapy by the drug Mabtera® (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 (≥65 years): at the first line of therapy, and also at therapy recurrent / химиоустойчивого the frequency of the undesirable phenomena 3 and 4 severity from system of blood and lymphatic system was higher than a chronic lymphoid leukosis 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.

Experience of use of drug at a pseudorheumatism. The undesirable phenomena meeting at therapy by the drug Mabtera® with frequency not less than 2% and, at least, from 2% a difference in comparison with control group are included below. 

Disturbances from immune system, the general frustration and disturbances in an injection site: very often – infusional reactions * (it is frequent – increase and lowering of arterial pressure, inflows, rash, urticaria, an itch, a fever, fever, nausea, rhinitis, feeling of irritation in a throat, tachycardia, weakness, mouth and drink pain, peripheral hypostases, an erythema).

* the following clinically significant infusional reactions were also infrequently observed: generalized hypostasis, bronchospasm, goose breathing, throat hypostasis, Quincke's disease, generalized itch, anaphylaxis, anaphylactoid reaction.

Infectious and parasitic diseases: very often – infections of urinary tract, upper respiratory tract infections; often – bronchitis, sinusitis, a gastroenteritis, a dermatofitiya of feet.

Disturbances from digestive tract: often – dyspepsia, diarrhea, a gastroesophageal reflux, an ulceration of a mucous membrane of an oral cavity, pain in the right upper quadrant of a stomach.

Disturbances from a nervous system: very often – a headache; often – migraine, paresthesias, dizziness, a sciatica.

Disturbances of mentality: often – a depression, alarm. Disturbances from skeletal and muscular and connecting fabric: often – an arthralgia, musculoskeletal pain, an osteoarthritis, a bursitis.

Disturbances from skin and hypodermic fabrics: often – an alopecia.

Laboratory and tool data: often – a hypercholesterolemia.

Repeated therapy. The profile of undesirable reactions at repeated use does not differ from that when performing initial therapy. The profile of safety improved with each subsequent course of therapy and was characterized by reduction of frequency of infusional reactions, infections and exacerbations of a disease most of which often met in the first 6 months of therapy.

Infusional reactions. Infusional reactions were the often being most found undesirable reaction at drug Mabtera® use. At 35% of patients at least one infusional reaction was observed, at the same time serious infusional reactions were observed less than at 1% of patients, irrespective of a dose. In most cases infusional reactions were 1 and 2 severity. The share of infusional reactions 3 severity and the infusional reactions leading to the therapy termination decreased with each subsequent course of treatment, and, since the 3rd course, such reactions were observed seldom. Infusional reactions 4 severity or death cases owing to their development are not revealed.

23% of patients after the first administration of the drug Mabtera® had following symptoms of infusional reactions: nausea, an itch, fever, urticaria/rash, a fever, a shiver, sneezing, a Quincke's disease, irritation of a throat, cough and a bronchospasm with or without increase or lowering of arterial pressure. Premedication by means of intravenous administration of glucocorticosteroids considerably reduces the frequency and weight of the similar phenomena.
At administration of the drug Mabtera® within 120 min. to patients with a medium-weight and heavy pseudorheumatism (an active form) at which serious infusional reactions in time or during 24 h after the first infusion of drug were not observed and also there were no serious infusional reactions to administration of biological drugs for treatment of a pseudorheumatism in the anamnesis, frequency, the type and weight of infusional reactions corresponded described earlier. Development of serious infusional reactions was not observed.

Infections. At therapy by the drug Mabtera® the general frequency of infections which preferential were easy and moderate severity (it is the most frequent – upper respiratory tract infections and infections of urinary tract), made 97 for 100 patsiyento-years. Frequency of heavy infections some of which were fatal made 4 for 100 patsiyento-years. Among clinically significant serious undesirable phenomena pneumonia (1.9%) was also observed.
Malignant diseases. Frequency of malignant diseases after purpose of the drug Mabtera® does not exceed indicators in the population corresponding on age and a floor and makes 0.8 for 100 patsiyento-years.

From laboratory indicators. Gipogammaglobulinemiya (decrease in concentration of IgG and IgM immunoglobulins is lower than the lower bound of norm) who is not followed by increase in the general frequency of infections or frequencies of serious infections.

When carrying out the first course of therapy by the drug Mabtera®, including several months later after completion of therapy, it was reported about cases of development of a neutropenia, preferential passing and easy or moderate severity. At the same time the frequency of a heavy neutropenia (3 and 4 degrees) made 0.94% in comparison with 0.27% in group which were not receiving drug.

Considering what after carrying out the first course of therapy by the drug Mabtera® the frequency of a heavy neutropenia made 1.06 for 100 patsiyento-years in comparison with 0:53 for 100 patsiyento-years in the absence of such therapy, and after repeated use the frequency of a heavy neutropenia made 0.97 for 100 patsiyento-years in comparison with 0.88 for 100 patsiyento-years in the absence of such therapy, the heavy neutropenia can be considered as undesirable reaction only concerning the first course of therapy by the drug Mabtera®. Time of manifestation of a neutropenia was various. The neutropenia was not connected with increase in frequency of serious infections, and in most cases after neutropenia episodes patients received repeated rates of the drug Mabtera®.

Experience of use of drug at a granulomatosis with a polyangiitis (Wegener's granulomatosis) and a microscopic polyangiitis. Further the undesirable phenomena which were observed at use of the drug Mabtera® with a frequency of 10% (very often) in comparison with the frequency of the undesirable phenomena at cyclophosphamide use are given (cross replacement of drug or replacement by other therapy on the basis of the weighed clinical decision was allowed).

Infectious and parasitic diseases: infections, including the often being most found upper respiratory tract infections, infections of urinary tract, the surrounding herpes – 61.6% (in group of comparison – 46.9%).

Disturbances from digestive tract: nausea – 18.2% (in group of comparison – 20.4%), diarrhea – 17.2% (in group of comparison – 12.2%).

Disturbances from a nervous system: a headache – 17.2% (in group of comparison – 19.4%).

Disturbances from skeletal and muscular and connecting fabric: muscular spasms – 17.2% (in group of comparison of-15.3%), an arthralgia – 13.1% (in group of comparison – 9.2%).

Disturbances from blood and lymphatic system: anemia – 16.2% (in group of comparison – 20.4%), a leukopenia – 10.1% (in group of comparison – 26.5%).

The general frustration and disturbances in an injection site: peripheral hypostases – 16.2% (in group of comparison – 6.1%), weakness – 13.1% (in group of comparison – 21.4%).

Disturbances from immune system: infusional reactions, including the most often meeting, a syndrome of release of cytokines, reddening, irritation of a throat, a tremor – 12.1% (in group of comparison – 11.2%).

Disturbances of mentality: sleeplessness – 14.1% (in group of comparison – 12.2%).

Laboratory and tool data: increase in activity of alaninaminotranspherase – 13.1% (in group of comparison – 15.3%).

Disturbances from respiratory system, bodies of a thorax and a mediastinum: cough – 13.1% (in group of comparison – 11.2%), nasal bleeding of 11.1% (in group of comparison – 6.1%), диспноэ – 10.1% (in group of comparison – 11.2%).

Disturbances from cardiovascular system: increase in arterial pressure – 12.1% (in group of comparison – 5.1%).

Disturbances from skin and hypodermic fabrics: rash – 10.1% (in group of comparison – 17.3%).

Infusional reactions. All infusional reactions observed during infusion of the drug Mabtera® or during 24 h after it were 1 and 2 severity. The syndrome of release of cytokines, reddening, irritation of a throat and a tremor were most often observed. Use of the drug Mabtera® in a combination with intravenous glucocorticosteroids could reduce the frequency and weight of the described undesirable phenomena.

Infections. The general frequency of infections at use of the drug Mabtera® made 210 for 100 patsiyento-years. Infections were preferential easy or moderate severity and most often included upper respiratory tract infections, infections of urinary tract and the surrounding herpes. Frequency of serious infections at use of the drug Mabtera® made 25 for 100 patsiyento-years. Among serious infections at use of the drug Mabtera® it was most often reported about pneumonia (4%).

Malignant diseases. Frequency of new cases of malignant diseases at use of the drug Mabtera® corresponds to indicators in population and makes 2.05 for 100 patsiyento-years.

From laboratory indicators. Gipogammaglobulinemiya (decrease in concentration of immunoglobulins is lower than the lower bound of norm) IgA, IgG and IgM for the 6th month of therapy in group of the drug Mabtera® made 27%, 58% and 51%, respectively, in comparison with 25%, 50% and 46% in group of comparison. At patients with low concentration of IgA, IgG and IgM increase in the general frequency of infections or frequency of serious infections was not observed.

The neutropenia 3 and 4 severity was observed at 24% of patients in group of the drug Mabtera® and at 23% of patients in group of comparison. At the patients receiving ритуксимаб at the same time increase in frequency of the serious infections connected with a neutropenia was not observed. Influence of a rituksimab on development neurosinging at repeated use was not investigated.

Post-registration use of the drug Mabtera® 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, including a toxic epidermal necrolysis and Stephens-Johnson's syndrome, in some cases with a fatal 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 the drug Mabtera®.

At the patients receiving the drug Mabtera® cases of development of a syndrome 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, the increased 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 virus of hepatitis B (in most cases at a combination of the drug Mabtera® 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 fatal outcome, caused by a cytomegalovirus, Varicella Zoster, Herpes simplex, poliomavirusy JC (PML), a hepatitis C virus.

At purpose of the drug Mabtera® 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 fatal outcome) at a drug Mabtera® combination 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 concentration of IgM at patients with Valdenstrem's macroglobulinemia with the subsequent return to its reference value in 4 months.

Post-registration use of the drug Mabtera® at a pseudorheumatism, a granulomatosis with a polyangiitis (Wegener's granulomatosis) and a microscopic polyangiitis. The undesirable phenomena which were observed at patients with a pseudorheumatism at post-marketing use of the drug Mabtera® are included below, and also are expected, or were observed at patients with a granulomatosis with a polyangiitis (Wegener's granulomatosis) and a microscopic polyangiitis.

Infections: PML, reactivation of a virus of hepatitis B. From an organism in general, reactions in an injection site: the reactions reminding a serum disease; heavy infusional reactions, in some cases with a fatal outcome.

From skin and its appendages: very seldom – a toxic epidermal necrolysis and Stephens-Johnson's syndrome, in some cases with a fatal outcome.

From system of blood and lymphatic system: seldom – a neutropenia (including hard cases with late manifestation and cases of a long neutropenia) some of which were associated with the infections leading to a fatal outcome.

From a nervous system: at the patients receiving the drug Mabtera® PRES/PRLS development cases 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 the increased arterial pressure, immunosuppressive therapy and/or other accompanying therapy.

Interaction with other medicines:

Data on medicinal interactions of the drug Mabtera® are limited. At patients with a chronic lymphoid leukosis at simultaneous use of the drug Mabtera®, a fludarabin and cyclophosphamide pharmacokinetic indicators do not change.

The concomitant use of a methotrexate does not influence pharmacokinetics of a rituksimab at patients with a pseudorheumatism.

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 patients with a pseudorheumatism the frequency of serious infections during therapy by the drug Mabtera® (before therapy by other biological basic antiinflammatory drugs (BPVP)) makes 6.1 for 100 patsiyento-years while during the subsequent therapy by other BPVP – 4.9 for 100 patsiyento-years.

At administration of the drug Mabtera® 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 drug 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.

Heavy heart failure (the IV class on classification of the New York cardiological association (NYHA)) at a pseudorheumatism.

With care. Respiratory insufficiency in the anamnesis or tumoral infiltration of lungs; number of the circulating malignant cells> 25 thousand / мкл or high tumoral loading; neutropenia (less than 1.5 thousand / мкл), thrombocytopenia (less than 75 thousand / мкл); 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 on safety is not obtained. Due to the increase in risk of infectious complications at exhaustion of a pool of V-lymphocytes it is necessary to cancel drug Mabtera® infusion, to watch a condition of the patient and to appoint the developed general blood test.

Storage conditions:

Period of validity 2 years 6 months. Drug should not be used after the period of validity specified on packaging.

At a temperature of 2-8 °C in protected from light and the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Concentrate for preparation of solution for infusions of 100 mg / 10 ml and 500 mg / 50 млПо 100 mg / 10 ml or 500 mg / 50 drug ml in the glass bottle (glass of a hydrolytic class 1 EF) corked by the stopper from the butyl rubber laminated by a ftorpolimer which is pressed out by an aluminum cap and closed by a plastic cover.

Two bottles on 100 mg / 10 ml or one bottle from 500 mg / 50 place ml together with the application instruction in a cardboard pack.