MabThera - instructions for use, dose, side effects, contraindications

auxiliary substances: sodium citrate dihydrate - 7.35 mg, polysorbate 80 - 0.70 mg, sodium chloride - 9.00 mg, hydrochloric acid or sodium hydroxide (up to pH 6.5), water for injections up to 1 ml.

Description:Transparent or slightly opalescent, colorless or pale yellow liquid.

Pharmacotherapeutic group:Antitumor and immunomodulating agent - antibodies monoclonal.

ATX: & nbsp

L.01.X.C Monoclonal antibodies

L.01.X.C.02 Rituximab

Pharmacodynamics:Rituximab a chimeric mouse / human monoclonal antibody that specifically binds to the transmembrane CD20 antigen. This antigen is located on pre-B lymphocytes and mature B lymphocytes, but is absent on stem hemopoietic cells, pro-B cells, normal plasma cells, cells of other tissues and is expressed in more than 95% of cases with B-cell non-Hodgkin's lymphomas.Expression on the CD20 cell after binding to the antibody is not internalized and ceases to flow from the cell membrane to the extracellular space. CD20 does not circulate in the plasma as a free antigen, and therefore does not compete for binding to the antibody.

Rituximab binds to CD20 antigen on B lymphocytes and initiates immunological reactions mediating lysis of B cells. Possible mechanisms of cell lysis include complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and induction of apoptosis. Rituximab increases the sensitivity of human B-cell lymphoma lines to the cytotoxic effect of certain chemotherapeutic drugs in vitro.

The number of B cells in the peripheral blood after the first administration of the drug is lower than normal and begins to recover in patients with hematologic malignancies after 6 months, reaching normal values 12 months after the completion of therapy, however, in some cases, the duration of the recovery period of the number of B cells can be more.

In patients with rheumatoid arthritis, the duration of the decrease in the number of B-cells varies,Most patients receive subsequent therapy until they are fully restored. In a small number of patients, there is a long-term decrease in the number of B cells (for two or more years after the last dose of the drug).

In patients with granulomatosis with polyangiitis and microscopic polyangiitis, a decrease in the number of C019-positive B cells to a level of less than 10 cells / μl occurs after the first two infusions of rituximab, and most patients remain at this level for 6 months.

Antichymeric antibodies were detected in 1.1% of the examined patients with non-Hodgkin's lymphoma and 10% with rheumatoid arthritis. Antimony antibodies in the examined patients were not identified.

Pharmacokinetics:

Non-Hodgkin's Lymphoma

According to population pharmacokinetic analysis in patients with non-Hodgkin's lymphoma with a single or multiple injection of MabThera in the form of monotherapy or in combination with chemotherapy according to the scheme CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) nonspecific ground clearance (CLi), specific ground clearance (CL₂) (probably associated with B cells or tumor load) and the volume of distribution in plasma (V_I) make 0.14 l / day, 0.59 l / day and 2.7 l, respectively. The median of the terminal half-life (T1 / 2) is 22 days. Baseline Cd 19-positive cells and the size of the tumor focuses on CL₂ rituximab 375 mg / m intravenously (iv) once a week for 4 weeks. Index C1y> is higher in patients with a higher level Cd 19-positive cells or a large tumor tumor size. Individual variability CL₂ remains after the correction of the size of the tumor focus and level Cd 19-positive cells. Relatively small changes in the indicator V_I depend on the surface area of the body (1.53-2.32 m²) and from chemotherapy according to the scheme CHOP and account for 27.1% and 19.0%, respectively. Age, sex, race, general condition on the WHO scale (World Health Organization) do not affect the pharmacokinetics of rituximab. Thus, dose adjustment of rituximab, depending on the factors listed above, does not significantly affect pharmacokinetic variability.

The mean maximum concentration (C_ma_x) increases after each infusion: after the first infusion is 243 μg / ml, after the fourth infusion - 486 μg / ml, and after the eighth - 550 μg / ml.The minimum and maximum concentrations of the drug are inversely correlated with the original number Cd 19-positive B cells and the magnitude of the tumor burden. With effective treatment, the median equilibrium concentration of the drug is higher. The median of the equilibrium concentration of the drug is higher in patients with histological subtypes of tumor B, C and D (classification IWF - International Working Formulation), than with subtype A. Traces of rituximab can be detected in the body within 3-6 months after the last infusion.

The pharmacokinetic profile of rituximab (6 infusions of 375 mg / m²) in combination with 6 cycles of chemotherapy CHOP was almost the same as with monotherapy. Chronic lymphatic leukemia

The average Stach after the fifth infusion of rituximab at a dose of 500 mg / m ~ is 408 μg / ml. Rheumatoid arthritis

After two intravenous infusions of 1000 mg with a two-week break, the average C_m_Oh rituximab 369 μg / ml, mean T1 / 2 19.2-20.8 days, average systemic clearance 0.23 l / day and volume of distribution in the equilibrium state 4.6 l. After the second infusion, the average C_m_Oh on 16-19% above in comparison with the first infusion. When carrying out a repeated course of treatment, the pharmacokinetic parameters of rituximab are comparable with the first course of treatment.

Granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic popihaitis

According to population pharmacokinetic analysis after four infusions of rituximab in a dose of 375 mg / m² Once a week, the median T1 / 2 is 23 days, the average ground clearance is 0.313 liters / day and the volume of distribution is 4.5 liters. The pharmacokinetic parameters of rituximab in granulomatosis with polyangiitis and microscopic polyangiitis were almost the same as in rheumatoid arthritis.

Pharmacokinetics in selected patient groups

Floor: the volume of distribution and clearance of rituximab, adjusted for the body surface area in men is slightly larger than that of women, dose adjustment of rituximab is not required.

Patients with renal and hepatic insufficiency: pharmacokinetic data in patients with renal and hepatic insufficiency are absent.

Indications:

Non-Hodgkin's Lymphoma

Recurrent or chemically resistant B-cell, C020-positive non-Hodgkin's lymphoma of low grade or follicular. Follicular lymphoma III-IV stages in combination with chemotherapy in previously untreated patients.

Follicular lymphoma as maintenance therapy after responding to induction therapy.

C020-positive diffuse B-large-cell non-Hodgkin's lymphoma in combination with chemotherapy according to the scheme CHOP.

Chronic lymphatic leukemia

Chronic lymphocytic leukemia in combination with chemotherapy in patients who have not previously received standard therapy.

Recurrent or chemostatic chronic lymphocytic leukemia in combination with chemotherapy.

Rheumatoid arthritis

Severe and severe rheumatoid arthritis (active form) in adults in combination with methotrexate with intolerance or inadequate response to current regimens of therapy, including one or more tumor necrosis factor (TNF-α) inhibitors, including for inhibition of radiological evidence of joint destruction.

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

Contraindications:

Hypersensitivity to rituximab, to any component of the drug or to mouse proteins.

Acute infectious diseases, pronounced primary or secondary immunodeficiency.

Children under 18 years of age (efficacy and safety not established). Pregnancy and the period of breastfeeding.

Severe heart failure (Class IV according to the classification of the New York Heart Association (NYHA)) with rheumatoid arthritis.

Carefully:Respiratory failure in history or tumor pulmonary infiltration; number of circulating malignant cells> 25 thousand / μL or high tumor burden; neutropenia (less than 1.5 thousand / μL), thrombocytopenia (less than 75 thousand / μL); chronic infections.

Pregnancy and lactation:

Immunoglobulins G (IgG) are able to penetrate the placental barrier. The level of B cells in newborns with the appointment of MabThera8 to women during pregnancy has not been studied.

Some newborns whose mothers received rituximab during pregnancy, there was a temporary depletion of the B-cell pool and lymphocytopenia. Therefore, MabThera should not be given to pregnant women unless the potential benefits of therapy exceed the potential risk.

During the treatment period and within 12 months after the end of MabThera treatment, women of childbearing age should use effective methods of contraception. It is not known whether rituximab with breast milk.Given that IgG immunoglobulins circulating in the mother's blood are excreted in breast milk, MabThera should not be used during breastfeeding.

Dosing and Administration:

Rules for the preparation and storage of a solution

The necessary amount of the drug is taken under aseptic conditions and diluted to the estimated concentration (1-4 mg / ml) in the infusion bottle (package) with 0.9% sodium chloride solution for infusions or 5% dextrose solution (solutions must be sterile and pyrogen-free). For mixing, gently invert the vial (packet) to avoid foaming. Before administration, it is necessary to inspect the solution for any foreign matter or discoloration. The doctor is responsible for the preparation, conditions and time of storage of the prepared solution prior to its use.

Since the drug MabThera® does not contain preservatives, the prepared solution must be used immediately.

A prepared infusion solution of MabThera's preparation® physically and chemically stable for 12 hours at room temperature or for not more than 24 hours at a temperature of 2 to 8 ° C.

MabThera's drug® enter only in / in the drip, through a separate catheter! Enter the drug in / in a stream or bolusno it is impossible!

Correction of dose during therapy

It is not recommended to reduce the dose of rituximab. If MabThera® is administered in combination with chemotherapy, a reduction in the dose of chemotherapeutic drugs is carried out in accordance with standard recommendations.

Standard dosing regimen

Non-Hodgkin's lymphoma of low grade or follicular Before each infusion of the MabThera drug, it is necessary to perform a premedication (analgesic / antipyretic, for example, paracetamol; antihistamine, for example, diphenhydramine). If MabThera is not used in combination with chemotherapy containing glucocorticosteroids, premedication also includes glucocorticosteroids.

Initial therapy:

- monotherapy of adult patients: 375 mg / m² Once a week, for 4 weeks;

- in combination with chemotherapy according to any scheme: 375 mg / m² on the first day of the chemotherapy cycle after intravenous administration of glucocorticosteroid as a component of therapy, during:

- 8 cycles (cycle: 21 days) under the scheme R-CVP (rituximab, cyclophosphamide, vincristine, prednisolone);

- 8 cycles (cycle: 28 days) under the scheme R-MCP (rituximab, mitoxantrone, chlorambucil, prednisolone);

8 cycles (cycle: 21 days) under the scheme R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone); If complete remission is achieved after 4 cycles, it is possible to limit to 6 cycles;

- 6 cycles (cycle: 21 days) under the scheme R-CHVP-Interferon (rituximab, cyclophosphamide, doxorubicin, teniposide, andrednisolone + interferon).

Repeated use in case of relapse (in patients who responded to the first course of therapy): 375 mg / m "once a week, for 4 weeks.

Supportive therapy (after answering induction therapy):

- in previously untreated patients: 375 mg / m 1 every 2 months, no more than 2 years (12 infusions). If signs of disease progression appear, MabThera should be discontinued;

- with relapsing or chemo-resistant lymphoma: 375 mg / m 1 every 3 months, no more than 2 years. If signs of disease progression appear, MabThera should be discontinued.

Recommended initial speed first infusion 50 mg / h, in the future it can be increased by 50 mg / h every 30 minutes, bringing to a maximum speed of 400 mg / h. Subsequent infusions you can start with a speed of 100 mg / h and increase it by 100 mg / h every 30 minutes to a maximum speed of 400 mg / h.

Diffuse B-Large Non-Hodgkin Lymphoma

Before each infusion of the MabThera drug, it is necessary to perform a premedication (analgesic / antipyretic, for example, paracetamol; antihistamine, for example, diphenhydramine). If MabThera is not used in combination with chemotherapy containing glucocorticosteroids, premedication also includes glucocorticosteroids.

In combination with chemotherapy according to the scheme CHOP: 375 mg / m² on the first day of each cycle of chemotherapy after intravenous administration of a glucocorticosteroid, 8 cycles. Other components of the circuit CHOP (cyclophosphamide, doxorubicin and vincristine) is administered after the administration of MabThera®.

Chronic lymphatic leukemia

Before each infusion of the MabThera drug, it is necessary to perform a premedication (analgesic / antipyretic, for example, paracetamol; antihistamine, for example, diphenhydramine).If MabThera is not used in combination with chemotherapy, the content of glucocorticosteroids, then glucocorticosteroids also form part of the premedication.

In combination with chemotherapy (in patients who have not previously received standard therapy and priresidiviruemu / chemo-resistant lymphocytic leukemia): 375 mg / m on the first day of the first cycle, then 500 mg / m² on the first day of each subsequent cycle, 6 cycles. Chemotherapy is performed after the administration of MabThera®.

To reduce the risk of developing tumor lysis syndrome, preventive maintenance of adequate hydration and the introduction of uricostatics 48 hours before the start of therapy are recommended. In patients with chronic lymphocytic leukemia and lymphocyte count> 25 thousand / μL, the administration of prednisone / prednisolone at a dose of 100 mg per hour before the infusion of MabThera is recommended® to reduce the incidence and severity of acute infusion reactions and / or cytokine release syndrome.

Rheumatoid arthritis

Before each infusion of MabThera's drug® it is necessary to carry out premedication (analgesic / antipyretic, for example, paracetamol; antihistamine, for example, diphenhydramine). In addition, glucocorticosteroids should be premedicated

to reduce the frequency and severity of infusion reactions. Patients should receive

100 mg of methylprednisolone IV 30 minutes before each infusion of MabThera's drug®. Initial therapy: 1000 mg iv drip, slowly, once every 2 weeks, course - 2 infusions.

Repeated use: The need for repeated courses of therapy is recommended to be evaluated 24 weeks after the previous course. Repeated use is performed in the case of residual disease activity or when the disease activity is more than 2.6 DAS28-C03 (index of disease activity for 28 joints and erythrocyte sedimentation rate). Repeated courses can be scheduled no earlier than 16 weeks after the previous course.

Recommended dosage regimen for repeated use: 1000 mg once every 2 weeks, course - 2 infusions.

Recommended initial speed first infusion 50 mg / h, in the future it can be increased by 50 mg / h every 30 minutes, bringing to a maximum speed of 400 mg / h. Time of infusion - 4 h 15 min.

Subsequent infusions you can start with a speed of 100 mg / h and increase it by 100 mg / h every 30 minutes to a maximum speed of 400 mg / h. The time of the infusion is 3 hours 30 minutes.

An alternative scheme for increasing the rate of subsequent infusion in patients with rheumatoid arthritis

If the patient has not previously seen the development of serious infusion reactions with the introduction of MabThera, an alternative time for subsequent infusions

MabThera preparation diluted to a concentration of 4 mg / ml (250 ml solution) is 120 min:

- for the first 30 minutes the drug is administered at a rate of 250 mg / h, the next 90 minutes at a rate of 600 mg / h.

In case of good tolerability, infusions of 120 minutes with subsequent infusions and courses can also be recommended.

Do not use an alternative scheme to increase the rate of subsequent infusions in patients with clinically significant cardiovascular diseases, including arrhythmias, as well as in the presence of serious infusion reactions to the introduction of biological agents, including rituximab.

Granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis Before each infusion of the MabThera drug, it is necessary to perform a premedication (analgesic / antipyretic, for example, paracetamol; antihistamine, for example, diphenhydramine).

Recommended dosing regimen:

- Glucocorticosteroid therapy is recommended to begin within 2 weeks before the first infusion of MabThera® or directly on the day of the first infusion of MabThera®: methylprednisolone (IV) at a dose of 1000 mg / day for 1 to 3 days, then oral prednisolone at a dose of 1 mg / kg / day (but not more than 80 mg / day) with a gradual reduction in the dose of the latter until complete reversal (the rate of dose reduction is determined by the specific clinical situation). Oral glucocorticosteroid therapy can be continued during and after the completion of MabThera®;

- MabThera® 375 mg / m² Once a week, for 4 weeks.

During and after the completion of MabThera therapy in patients with granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis, it is recommended that pneumocystis pneumonia Pneumocystis jiroveci).

Dosing in special cases

Elderly age

In patients older than 65 years, no dose adjustment is required.

Side effects:

The following criteria are used to estimate the frequency of undesired reactions: very

often >10%, often >1% - <10%, infrequently >0.1% - <1%.

Experience in the use of the drug in oncohematological diseases

MabThera® when treating non-Hodgkin's lymphoma with a low degree of malignancy or follicular - monotherapy / maintenance therapy

Reports of adverse reactions have been reported for 12 months after monotherapy and up to 1 month after maintenance therapy with MabThera.

Infectious and parasitic diseases: very often - bacterial and viral infections; often - respiratory infections *, pneumonia *, sepsis, herpes zoster *, infections accompanied by fever *, fungal infections, infections of unknown etiology.

Violations from the blood and lymphatic system: very often - leukopenia, neutropenia; often - thrombocytopenia, anemia; infrequently - lymphadenopathy, bleeding disorders, transient partial aplastic anemia, hemolytic anemia.

Disturbances from the respiratory system, chest and mediastinal organs: often - rhinitis, bronchospasm, cough, respiratory diseases, dyspnea, chest pain; infrequently - hypoxia, impaired lung function, bronchiolitis obliterans, bronchial asthma.

Immune system disorders: very often - angioedema; often - hypersensitivity reactions.

Disorders from the metabolism and nutrition: often - hyperglycemia, weight loss, peripheral edema, facial swelling, increased LDH activity, hypocalcemia. General disorders and disorders at the site of administration: very often - headache, fever, chills, asthenia; often - pain in the foci of the tumor, flu-like syndrome, hot flashes, weakness; infrequently - pain at the injection site.

Disorders from the gastrointestinal tract: very often - nausea; often - vomiting, diarrhea, dyspepsia, lack of appetite, dysphagia, stomatitis, constipation, abdominal pain, choking in the throat; infrequently - an increase in the abdomen.

Disorders from the cardiovascular system: often - lowering blood pressure, increasing blood pressure, orthostatic hypotension, tachycardia, arrhythmia, atrial fibrillation *, myocardial infarction *, cardiac pathology *; infrequently - left ventricular heart failure *, ventricular and supraventricular tachycardia *, bradycardia, myocardial ischemia *, angina *.

Impaired nervous system: often - dizziness, paresthesia, hypodesis, sleep disturbance, anxiety, agitation, vasodilation; infrequently - a perversion of taste.

Disorders of the psyche: infrequently - nervousness, depression.

Disturbances from the musculoskeletal and connective tissue: often - myalgia, arthralgia, muscle hypertonia, back pain, neck pain, pain.

Disturbances from the skin and subcutaneous tissues: very often - itching, rash; often - hives, increased sweating at night, sweating, alopecia *.

Disorders from the side of the organ of vision: often - tearing disorders, conjunctivitis. Hearing disorders and labyrinthine disturbances: often - pain and noise in the ears.

Laboratory and instrumental data: very often - a decrease in the concentration of immunoglobulins G (IgG).

* The frequency is indicated only for adverse reactions> 3 degrees of severity according to the toxicity criteria of the National Cancer Institute (NCI-CTC).

Mabtersg in combination with chemotherapy (R-CHOP, R-CVP, R-FC) with non-Hodgkin's lymphoma and chronic lymphocytic leukemia

The following are severe adverse reactions in addition to those observed with monotherapy / maintenance therapy and / or occurring with a higher frequency-

Infectious and parasitic diseases: very often bronchitis; often acute bronchitis, sinusitis, hepatitis B * (reactivation of the hepatitis B virus and primary infection).

Violations from the blood and lymphatic system: very often - neutropenia **, febrile neutropenia, thrombocytopenia; often - pancytopenia, granulocytopenia. Disturbances from the skin and subcutaneous tissues: very often - alopecia; often - skin diseases.

General disorders and disorders at the site of administration: often - fatigue, chills.

* frequency is indicated on the basis of observations in the therapy of recurrent / chemo-resistant chronic lymphocytic leukemia according to the scheme R-FC.

** prolonged and / or delayed neutropenia was observed after completion of therapy according to the scheme R-FC in previously untreated patients or in patients with recurrent / chemostable chronic lymphocytic leukemia.

Below are the undesirable events observed with MabThera with the same frequency (or less frequently) than the control group: hematoxicity, neutropenic infections, urinary tract infections, septic shock, superinfections of the lungs, infection of implants, staphylococcal septicemia, mucosal discharge from nose, pulmonary edema, heart failure, sensitivity disorders, venous thrombosis, incl. deep vein thrombosis of the extremities, mucosis, edema of the lower limbs, reduction of the left ventricular ejection fraction, increase in body temperature, deterioration in overall health, falling, multiple organ failure, bacteremia, decompensation of diabetes mellitus.

The safety profile of MabThera preparation in combination with chemotherapy according to MCP regimens, CHVP-IFN does not differ from that in combination with the drug with CVP, CHOP or FC in the corresponding populations.

Infusion reactions

Monoterie with MabThera® (within 4 weeks)

More than 50% of the patients had symptoms resembling infusion reactions, most often with the first infusions. Infusion reactions include chills, shivering, weakness, dyspnoea, nausea, rash, hot flashes, low blood pressure, fever, itching, hives, irritation of the tongue or laryngeal edema (angioedema), rhinitis, vomiting, pain in the foci of the tumor, headache, bronchospasm. It was reported on the development of signs of tumor lysis syndrome.

MabThera® in combination with chemotherapy according to the following schemes: R-CVP with non-Hodgkin's lymphoma: R-CHOP with diffuse B-large-cell non-Hodgkin's lymphoma; R- FC with chronic lymphocytic leukemia

Infusion reactions of 3 and 4 degrees of severity during infusion or within 24 hours after infusion of MabThera were noted during the first cycle of chemotherapy in 12% of patients. The frequency of infusion reactions decreased with each subsequent cycle and the frequency of infusion reactions reached less than 1% by the 8th cycle of chemotherapy. Infusion reactions in addition to the above (with monotherapy with MabThera) included: dyspepsia, rash, increased blood pressure, tachycardia, signs of tumor lysis syndrome, in some cases - myocardial infarction, fibrillation in the pre

serdias, pulmonary edema and acute reversible thrombocytopenia.

Infections

Monotherapy with MabThera® (within 4 weeks)

MabThera® causes depletion of the B-cell pool in 70-80% of patients and a decrease in serum immunoglobulin concentrations in a small number of patients. Bacterial, viral, fungal infections and infections without a specified etiology (all, regardless of the cause) develop in 30.3% of patients. Severe infections (grade 3 and 4), including sepsis, were noted in 3.9% of patients.

Supportive therapy (non-Hodgkin's lymphoma) up to 2 years

With MabThera therapy⁸ there was an increase in the overall incidence of infections, including infections of 3-4 degrees of severity. There was no increase in the incidence of infectious complications with maintenance therapy lasting 2 years. Cases of progressive multifocal leukoencephalopathy (PML) with a fatal outcome in patients with non-Hodgkin's lymphoma after the progression of the disease and re-treatment.

MabThera^Mr. in combination with chemotherapy according to the following schemes: R-CVP with non-Hodgkin's lymphoma; R-CHOP with diffuse B-Kuopi-cell non-Hodgkin's lymphoma; R-

FC with chronic lymphocytic leukemia

With MabThera therapy® according to the scheme R-CVP there was no increase in the incidence of infections or invasions. The most frequent were upper respiratory tract infections (12.3% in the group R-CVP). Serious infections were observed in 4.3% of patients who received chemotherapy according to the scheme R-CVP; life-threatening infections are not registered. The proportion of patients with infections of 2-4 degrees of severity and / or febrile neutropenia in the group R-CHOP was 55.4% The incidence of infections of 2-4 degrees of severity in the group R-CHOP was 45.5%. The incidence of fungal infections is 2-4 degrees of severity in the group R-CHOP was higher than in the group CHOP, due to a higher incidence of local candidiasis and accounted for 4.5%. The frequency of herpetic infection 2-4 degrees of severity was higher in the group R-CHOP compared to the group CHOP and amounted to 4.5%. In patients with chronic lymphocytic leukemia, the frequency of hepatitis B (reactivation of the hepatitis B virus and primary infection) is 3-4 degrees of severity in the group R-FC was 2%.

On the part of the blood system

Monotherapy with MabThera® (within 4 weeks)

Severe thrombocytopenia (grade 3 and 4) was noted in 1.7% of patients, severe neutropenia in 4.2% of patients and severe severity of anemia (grade 3 and 4) and 1.1% of patients.

Supportive therapy (non-Hodgkin's lymphoma) up to 2 years

Leukopenia (grade 3 and 4) was observed in 5% of patients, neutropenia (grade 3 and 4) in 10% of patients receiving MabThera. The incidence of thrombocytopenia (3-4 degrees of severity) with MabThera was low and was <1%.

Approximately 50% of patients for whom B cell recovery data were available, after MabThera induction therapy was completed, it took 12 months or more to restore the number of B cells to the normal level.

MabThera® at combinations with chemotherapy according to the following schemes: R-CVP with non-Hodgkin's lymphoma; R-CHOP with diffuse B-large-cell non-Hodgkin's lymphoma; R- FC with chronic lymphocytic leukemia

Severe neutropenia and leukopenia (grade 3 and 4): in patients who received the MabThera drug in combination with chemotherapy, leukopenia of grade 3 and 4 were more frequent compared to patients receiving chemotherapy alone. The incidence of severe leukopenia was 88% in patients who received R-CHOP, and 23% in patients who received R-FC. The frequency of severe neutropenia was 24% in gr. R-CVP, 97% of the group R-CHOP and 30% in the group R-FC with previously untreated chronic lymphocytic leukemia. The higher incidence of neutropenia in patients receiving MabThera and chemotherapy was not associated with an increased incidence of infections and invasions compared to patients receiving chemotherapy alone. In patients with relapsing or chemically resistant chronic lymphocytic leukemia after therapy according to the scheme R-FC in some cases, neutropenia was characterized by a prolonged course or later timing of the manifestation.

Severe anemia and thrombocytopenia (grade 3 and 4): there was no significant difference in the incidence of grade 3 and 4 anemia in the groups. In a group R-FC At the first line of therapy for chronic lymphocytic leukemia, grade 3 and 4 anemia occurred in 4% of patients, thrombocytopenia of 3 and 4 severity in 7% of patients. In a group R-FC with recurrent or chemostable chronic lymphocytic leukemia, grade 3 and 4 anemia occurred in 12% of patients, thrombocytopenia 3 and 4 severity in 11% of patients.

From the side of the cardiovascular system

Monotherapy with MabThera® (within 4 weeks)

Side effects from the cardiovascular system were noted in 18.8%. The most common decrease and increase in blood pressure. In single

There was a violation of cardiac rhythm of 3 and 4 degrees of severity (including, ventricular and supraventricular tachycardia) and angina.

Supportive therapy (non-Hodgkin's lymphoma) up to 2 years

The incidence of cardiovascular disorders of 3 and 4 severity was similar in patients receiving MabThera and not receiving it. Serious cardiovascular disorders occurred in less than 1% of patients who did not receive MabThera, and 3% of patients who received the drug (atrial fibrillation in 1%, myocardial infarction in 1%, left ventricular failure <1%, myocardial ischemia in < 1%).

MabThera® in combination with chemotherapy according to the following schemes: R-CVP at non-Hodgkin's lymphoma; R-CHOP with diffuse B-large-cell non-Hodgkin's lymphoma; R- FC with chronic lymphocytic leukemia

The frequency of heart rhythm disorders of 3 and 4 degrees of severity, mainly supraventricular arrhythmias (tachycardia, flutter and atrial fibrillation), in the group R-CHOP was higher than in the group CHOP and amounted to 6.9%. All arrhythmias developed either in connection with the infusion of MabThera, or were associated with predisposing conditions such as fever, infection, acute myocardial infarction, or concomitant diseases of the respiratory and cardiovascular systems. Groups R-CHOP and CHOP did not differ in the frequency of other cardiological adverse events of grade 3 and 4, including heart failure, myocardial disease, and manifestation of coronary heart disease.

The overall incidence of cardiovascular disorders of grade 3 and 4 was low, as in the first line of therapy for chronic lymphocytic leukemia (4% in the group R-FC), and in the treatment of recurrent / chemo-resistant chronic lymphocytic leukemia (4% in the group R-FC).

Nervous system

MabThera® in combination with chemotherapy according to the following schemes: R-CVP with non-Hodgkin's lymphoma; R-CHOP with diffuse B-large-cell non-Hodgkin's lymphoma; R- FC with chronic lymphocytic leukemia

In patients (2%) of the group R-CHOP with cardiovascular risk factors, thromboembolic disorders of cerebral circulation developed during the first cycle of therapy, in contrast to patients in the group CHOP, whose cerebral circulation disorders developed during the period of observation without treatment. The difference between groups in the frequency of other thromboembolism was absent.

The overall incidence of grade 3 and 4 neurologic disorders was low, as in the first line of therapy for chronic lymphocytic leukemia (4% in the group R-FC), and in therapy

recurrent / chemo-resistant chronic lymphocytic leukemia (3% in the group R-FC). Concentration IgG

Supportive therapy (non-Hodgkin's lymphoma) up to 2 years

After induction therapy, concentration IgG was below the lower limit of the norm (<7 g / l) in the group receiving the MabThera preparation, and in the group not receiving the drug. In the group not receiving MabThera medication, the median concentration IgG consistently increased and exceeded the lower limit of the norm, while the median concentration IgG has not changed in the group receiving the MabThera drug. In 60% of patients who received the MabThera preparation for 2 years, the concentration IgG remained below the lower limit. In the group without MabThera treatment in 2 years, the concentration IgG remained below the lower limit in 36% of patients.

Special categories of patients

Monotherapy with MabThera® (within 4 weeks)

Elderly age (>65 years): the frequency and severity of all unwanted reactions and adverse reactions of 3 and 4 degrees of severity does not differ from that in younger patients.

Combination Therapy

Elderly age (>65 years): with the first line of therapy, as well as with therapyrecurrent / chemo-resistant chronic lymphocytic leukemia, the incidence of adverse events of grade 3 and 4 severity on the part of the blood system and lymphatic system was higher compared with younger patients.

High tumor load (diameter of single foci more than 10 cm): the frequency of undesired reactions of 3 and 4 severity was increased.

Repeated therapy: the frequency and severity of adverse reactions does not differ from

such during the initial therapy.

Experience with rheumatoid arthritis

Below are the undesirable events encountered with MabThera with a frequency of at least 2% and at least a 2% difference compared to the control group.

Immune system disorders, general disorders and disorders at the site of administration: very often - infusion reactions * (often - increasing and lowering blood pressure, hot flashes, rash, urticaria, pruritus, chills, fever, nausea, rhinitis, a feeling of sore throat, tachycardia, weakness, pain in the mouth and throat, peripheral edema, erythema ).

* The following clinically significant infusion reactions were also infrequently observed:

generalized edema, bronchospasm, wheezing, laryngeal edema, angioedema, generalized itching, anaphylaxis, anaphylactoid reaction. Infectious and parasitic diseases: very often - urinary tract infections, upper respiratory tract infections; often - bronchitis, sinusitis, gastroenteritis, dermatophytia stop.

Disorders from the gastrointestinal tract: often - dyspepsia, diarrhea, gastroesophageal reflux disease, ulceration of the mucous membranes of the mouth, pain in the right upper quadrant of the abdomen.

Impaired nervous system: very often - headache; often - migraine, paresthesia, dizziness, sciatica.

Disorders of the psyche: often - depression, anxiety.

Disturbances from the musculoskeletal and connective tissues: often - arthralgia, musculoskeletal pain, osteoarthritis, bursitis.

Disturbances from the skin and subcutaneous tissues: often - alopecia.

Laboratory and instrumental data: often - hypercholesterolemia.

Repeated therapy. The profile of unwanted reactions during repeated use does not differ from that in the initial therapy.The safety profile improved with each subsequent course of therapy and was characterized by a decrease in the incidence of infusion reactions, infections and exacerbations of the disease that were most frequent in the first 6 months of therapy.

Infusion reactions. Infusion reactions were the most common undesirable reaction when MabThera was used®. At 35% of patients, at least one infusion reaction was observed, while severe infusion reactions were observed in less than 1% of patients, regardless of dose. In most cases, the infusion reactions were 1 and 2 degrees of severity. The proportion of infusion reactions of the 3rd degree of severity and infusion reactions leading to discontinuation of therapy decreased with each subsequent course of treatment, and, starting from the 3rd course, such reactions were rarely observed. There were no infusion reactions of the 4th degree of severity or deaths due to their development.

In 23% of patients after the first administration of MabThera's preparation® the following symptoms of infusion reactions occurred: nausea, pruritus, fever, urticaria / rash, chills, tremors, sneezing, angioedema, irritation of the pharynx, cough and bronchospasm with or without an increase or decrease in blood pressure.Premedication with intravenous glucocorticosteroids significantly reduces the frequency and severity of such events.

When MabThera was administered for 120 minutes to patients with moderate to severe severe rheumatoid arthritis (active form) who had no serious infusion reactions during or within 24 hours after the first infusion of the drug, and there were no serious infusion reactions to the introduction of biological drugs for the treatment of rheumatoid arthritis in history, the frequency, type and severity of the infusion reactions corresponded to those described previously. Development of serious infusion reactions was not observed.

Infections. With MabThera, the overall incidence of infections, which were predominantly of mild to moderate severity (most often upper respiratory tract infections and urinary tract infections), was 97 per 100 patient-years. The incidence of severe infections, some of which were fatal, was 4 per 100 patient-years. Among clinically significant serious adverse events, pneumonia (1.9%) was also observed.

Malignant diseases. The frequency of malignant diseases after the administration of the MabThera preparation does not exceed the parameters in the population corresponding to age and sex, and is 0.8 per 100 patient-years.

From the laboratory indicators. Hypogammaglobulinemia (decrease in the concentration of immunoglobulins IgG and IgM below the lower limit of the norm), not accompanied by an increase in the overall incidence of infections or the incidence of serious infections. During the first course of therapy with MabThera, including several months after completion of therapy, cases of development of neutropenia, predominantly transient and mild or moderate, were reported. The frequency of severe neutropenia (grade 3 and 4) was 0.94% compared with 0.27% in the group who did not receive the drug.

Considering that after the first course of treatment with MabThera, the frequency of severe neutropenia was 1.06 per 100 patient-years, compared with 0.53 per 100 patient-years in the absence of such therapy, and after repeated application, the frequency of severe neutropenia was 0.97 per 100 patients -let compared with 0.88 per 100 patient-years in the absence of such therapy, severe neutropenia can be considered as an undesirable reaction only for the first course of therapy with MabThera.The time of neutropenia manifestation was different. Neutropenia was not associated with an increase in the incidence of serious infections, and in most cases after episodes of neutropenia patients received repeated courses of MabThera.

The experience of using the drug for granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis

The following are undesirable phenomena that were observed with MabThera preparation at a frequency of >10% (very often) in comparison with the incidence of adverse events with cyclophosphamide (cross-substitution or substitution for another therapy based on a weighted clinical decision was allowed).

Infectious and parasitic diseases: infection, including the most common infections of the upper respiratory tract, urinary tract infections, herpes zoster - 61.6% (in the comparison group - 46.9%).

Disorders from the gastrointestinal tract: nausea - 18.2% (in the comparison group - 20.4%), diarrhea - 17.2% (in the comparison group - 12.2%).

Impaired nervous system: headache - 17.2% (in the comparison group - 19.4%).

Disturbances from the musculoskeletal and connective tissue: muscle spasms - 17.2% (in the comparison group -15.3%), arthralgia - 13.1% (in the comparison group - 9.2%). Violations from the blood and lymphatic system: anemia - 16.2% (in the comparison group - 20.4%), leukopenia - 10.1% (in the comparison group - 26.5%).

General disorders and disorders at the site of administration: peripheral edema - 16.2% (in the comparison group - 6.1%), weakness - 13.1% (in the comparison group - 21.4%). H

the immune system: infusion reactions, including the most common, cytokine release syndrome, redness, throat irritation, tremor - 12.1% (in the comparison group - 11.2%).

Disorders of the psyche: insomnia - 14.1% (in the comparison group - 12.2%).

Laboratory and instrumental data: an increase in activity of alanine aminotransferase - 13.1% (in the comparison group - 15.3%).

Disturbances from the respiratory system, chest and mediastinal organs: cough - 13.1% (in the comparison group - 11.2%), nosebleeds 11.1% (in the comparison group - 6.1%), dyspnoea - 10.1% (in the comparison group - 11.2%).

Disorders from the cardiovascular system: increase in blood pressure - 12.1% (in the comparison group - 5.1%).

Disturbances from the skin and subcutaneous tissues: Rash - 10.1% (in the comparison group - 17.3%).

Infusion reactions. All infusion reactions observed during the infusion of the MabThera preparation or within 24 hours after it were 1 and 2 degrees of severity.The most frequently observed syndrome of cytokine release, redness, throat irritation and tremor. The use of MabThera in combination with intravenous glucocorticosteroids could reduce the incidence and severity of the described adverse events.

Infections. The overall incidence of infections with MabThera was 210 per 100 patient-years. Infections were predominantly mild or moderate, and most often included upper respiratory tract infections, urinary tract infections and herpes zoster. The incidence of serious infections with MabThera was 25 per 100 patient-years. Among the serious infections with MabThera, the most frequently reported pneumonia (4%). Malignant diseases. The incidence of new cases of malignant diseases with MabThera is consistent with the population and is 2.05 per 100 patient-years.

From the laboratory indicators. Hypogammaglobulinemia (decrease in the concentration of immunoglobulins below the lower limit of normal) IgA, IgG and IgM for 6 months of therapy

In the MabThera group, 27%, 58% and 51%, respectively, compared with 25%, 50% and 46% in the comparison group. In patients with low concentrations IgA, IgG and IgM there was no increase in the overall incidence of infections or the incidence of serious infections.

Neutropenia of 3 and 4 severity was observed in 24% of patients in the drug group

MabThera and 23% of the patients in the comparison group.In patients receiving rituximab, there was no increase in the incidence of serious infections associated with neutropenia.The effect of rituximab on the development of neuropyenia with repeated use was not investigated.

Post-marketing application of MabThera® with non-Hodgkin's lymphoma and chronic lymphocytic leukemia

From the cardiovascular system: severe cardiovascular events associated with infusion reactions, such as heart failure and myocardial infarction, mainly in patients with a history of cardiovascular disease and / or receiving cytotoxic chemotherapy; very rarely - vasculitis, mainly skin (leukocytoclastic).

On the part of the respiratory system: respiratory insufficiency and pulmonary infiltrates caused by infusion reactions; In addition to undesirable phenomena from the lungs caused by infusion reactions, interstitial lung disease was observed, in some cases with a fatal outcome.

From the blood and lymphatic system: reversible acute thrombocytopenia associated with infusion reactions.

From the skin and its appendages: rarely - severe bullous reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome, in some cases with fatalities

outcome.

From the nervous system: rarely - neuropathy of the cranial nerves in combination with or without peripheral neuropathy (marked decrease in visual acuity, hearing loss, other sensory organs, facial nerve paresis) at various periods of therapy up to several months after the completion of the MabThera treatment course. In patients who received the drug MabThera, there were cases of the development of the syndrome of reversible encephalopathy with damage to the posterior parts of the brain (RNE8) / reversible leukoencephalopathy syndrome with a lesion of the posterior parts of the brain (PRLS). Symptoms included visual impairment, headache, convulsions and mental disorders, accompanied by an increase in blood pressure. Confirm diagnosis PRES/PRLS it is possible with the help of methods of visualization of the brain. In the described cases, patients had risk factors for development PRES/PRLS, such as underlying disease, high blood pressure, immunosuppressive therapy, and / or chemotherapy.

On the part of the body as a whole, the reactions at the injection site: rarely - serum sickness. Infections: reactivation of the hepatitis B virus (in most cases with the combination of MabThera and cytotoxic chemotherapy); as well as other severe viral infections (primary infection, reactivation of the virus or exacerbation), some of which were fatal due to cytomegalovirus, Varicella Zoster, Herpes simplex, polyomavirus JC (PML), hepatitis C virus.

When MabThera was prescribed for indications not prescribed by the medical instruction, patients with previously diagnosed Kaposi's sarcoma had progression of the sarcoma (most of the patients were HIV positive).

From the gastrointestinal tract: perforation of the stomach and / or intestines (possibly with a fatal outcome) with a combination of MabThera and chemotherapy with non-Hodgkin's lymphoma.

On the part of the blood system and lymphatic system: rarely - neutropenia, occurring 4 weeks after the last administration of rituximab; transient increase in concentration IgM in patients with Waldenstrom's macroglobulinemia followed by a return to baseline after 4 months.

Post-marketing application of MabThera® with rheumatoid arthritis, granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis

Below are the undesirable effects that have been observed in patients with rheumatoid arthritis in the post-marketing use of MabThera, and are also expected or observed in patients with granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis.

Infections: PML, reactivation of hepatitis B virus.

On the part of the body as a whole, reactions at the injection site: reactions that resemble serum sickness; severe infusion reactions, in some cases with fatal outcome.

From the skin and its appendages: very rarely - toxic epidermal iscoliosis and Stevens-Johnson syndrome, in some cases with fatal outcome.

On the part of the blood system and lymphatic system: rarely - neutropenia (including severe cases with late manifestation and cases of prolonged neutropenia), some of which have been associated with infections leading to a fatal outcome.

From the nervous system: patients who received the drug MabThera, there were cases of development PRES/PRLS. Symptoms included visual impairment, headache, convulsions and mental disorders, accompanied by an increase in blood pressure. Confirm diagnosis PRES/PRLS it is possible with the help of methods of visualization of the brain. In the described cases, patients had risk factors for development PRES/PRLS, such as high blood pressure, immunosuppressive therapy and / or other concomitant therapy.

Overdose:No cases of overdose were observed in humans. Single doses of rituximab above 1000 mg have not been studied. A maximum dose of 5000 mg was given to patients with chronic lymphocytic leukemia, no additional safety data was obtained. In connection with an increased risk of infectious complications when the B-lymphocyte pool is depleted, it is necessary to abolish the MabThera® infusion, monitor the patient's condition and prescribe a detailed general blood test.

Interaction:Data on drug interactions of MabThera® are limited. In patients with chronic lymphocytic leukemia with the simultaneous use of MabThera, fludarabine and cyclophosphamide, pharmacokinetic parameters do not change.Concurrent administration of methotrexate does not affect the pharmacokinetics of rituximab in patients with rheumatoid arthritis.

When administered with other monoclonal antibodies for diagnostic or therapeutic purposes, patients with antibodies against mouse proteins or anti-chimera antibodies increase the risk of allergic reactions.

In patients with rheumatoid arthritis, the incidence of serious infections during therapy with MabThera® (before the therapy with other biological basic anti-inflammatory drugs (DMAP)) is 6.1 per 100 patient-years, while during subsequent therapy with other DMAPs, 4.9 per 100 patient- years. When MabThera is administered, polyvinyl chloride or polyethylene infusion systems or bags can be used due to the compatibility of the material with the preparation.

Special instructions:

In patients with rheumatoid arthritis, the incidence of serious infections during MabThera therapy⁸ (before therapy with other biological basic anti-inflammatory drugs (DMAP)) is 6.1 per 100 patient-years, while during subsequent therapy with other BPVP, 4.9 per 100 patient-years. When MabThera is administered, polyvinyl chloride or polyethylene infusion systems or bags can be used due to the compatibility of the material with the preparation.

special instructions

In the patient's medical records, the trade name of the drug (MabThera®) should be indicated. Replacement of the drug with any other biological medicinal product requires agreement with the attending physician. The information provided in this manual applies only to the MabThera product.

The drug MabThera is administered under close supervision of an oncologist, hematologist or rheumatologist, provided there are necessary conditions for resuscitation.

Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Infusion reactions. The development of infusion reactions may be due to the release of cytokines and / or other mediators. Severe infusion reactions are difficult to distinguish from hypersensitivity reactions or cytokine release syndrome.There are reports of fatal infusion reactions described during the period of post-marketing use of the drug. In most patients within 30 minutes - 2 hours after the first infusion of the drug MabThera appears fever with chills or tremors. Severe reactions include symptoms from the lungs, lowering blood pressure, urticaria, angioedema, nausea, vomiting, weakness, headache, itching, tongue irritation, or swelling of the pharynx (vascular edema), rhinitis, hot flashes, pain in the foci of the disease and, in some cases, signs of fast tumor lysis syndrome. Infusion reactions disappear after the interruption of MabThera drug administration and drug therapy (intravenous administration of 0.9% sodium chloride solution, diphenhydramine and acetaminophen, bronchodilators, glucocorticosteroids, etc.). In most cases, after complete disappearance of the symptomatology, the infusion can be resumed at a rate of 50% of the preceding (eg 50 mg / h instead of 100 mg / h). In most patients with life-threatening infusion reactions, the course of treatment with rituximab was completely completed.Continuation of therapy after complete disappearance of symptoms is rarely accompanied by repeated development of severe infusion reactions.

In connection with the potential for the development of anaphylactic reactions and other hypersensitivity reactions with intravenous administration of protein preparations, it is necessary to have the means for their reduction: adrenaline, antihistamine and glucocorticosteroid preparations.

Side effect of the lungs. Hypoxia, pulmonary infiltrates and acute respiratory failure. Some of these phenomena were preceded by severe bronchospasm and shortness of breath. Perhaps the increase in symptoms over time or clinical deterioration after initial improvement. Patients with pulmonary symptoms or other severe infusion reactions should be carefully observed until the symptoms are completely resolved. Acute respiratory failure may be accompanied by the formation of interstitial infiltrates in the lungs or pulmonary edema, often manifested in the first 1-2 hours after the start of the first infusion. With the development of severe reactions from the lungs, infusion of rituximab should be stopped immediately and intensive symptomatic therapy should be prescribed.Since the initial improvement in clinical symptoms may be replaced by worsening, patients should be carefully monitored before resolution of pulmonary symptoms.

Syndrome of rapid lysis of the tumor. MabThera mediates the rapid lysis of benign or malignant SB20-positive cells. Tumor lysis syndrome is possible after the first infusion of MabThera in patients with a large number of circulating malignant lymphocytes. Tumor lysis syndrome includes hyperuricemia, hyperkalemia, hypocalcemia, hyperphosphatemia, acute renal failure, increased LDH activity. Patients at risk (patients with high tumor burden or a large number of circulating malignant cells (> 25 thousand / μL), for example, with chronic lymphocytic leukemia or lymphoma from cells of the mantle zone) need careful medical supervision and regular laboratory examination. With the development of symptoms of rapid lysis of the tumor, appropriate therapy is carried out. After complete relief of symptoms in a limited number of cases, MabThera therapy continued in combination with the prevention of rapid tumor lysis syndrome.

Patients with a large number of circulating malignant cells (> 25 thousand / μL) or high tumor load (eg, with chronic lymphocytic leukemia or lymphoma

from cells of the mantle zone), in which the risk of extremely severe infusion reactions can be particularly high, MabThera should be given with extreme caution, under close supervision. The first infusion of the drug in such patients should be administered at a lower rate or divided the dose of the drug for two days during the first cycle of therapy and every subsequent cycle if the number of circulating malignant cells remains> 25 thousand / μL.

Side effect of the cardiovascular system. During the infusion, careful monitoring of patients with a history of cardiovascular disease is required in connection with the possibility of developing angina pectoris, arrhythmia (flutter and atrial fibrillation), heart failure or myocardial infarction. Because of the possibility of developing hypotension at least 12 hours before the infusion of MabThera, antihypertensive drugs should be discontinued.

Control of blood elements. Although monotherapy with MabThera does not have a myelosuppressive effect, caution should be taken to prescribe the drug for neutropenia of less than 1.5 thousand / μL and / or thrombocytopenia less than 75

thousand / mkl, since the experience of its clinical use in such patients is limited. MabThera was used in patients after autologous bone marrow transplantation and in other risk groups with possible disruption of bone marrow function without causing the phenomena of myelotoxicity. During the treatment, it is necessary to regularly determine the detailed analysis of peripheral blood, including counting the number of platelets in accordance with routine practice.

Infections. MabThera should not be given to patients with severe acute infection.

Hepatitis B. When a combination of MabThera® and chemotherapy was prescribed, reactivation of the hepatitis B virus or fulminant hepatitis (including fatal outcome) was noted. Predisposing factors included both the stage of the underlying disease and cytotoxic chemotherapy.

Before prescribing MabThera, all patients should be screened for hepatitis B. A minimum set of tests should include a definition HBsAg and HBcAb, in accordance with local recommendations, a list of tests can be supplemented. MabThera should not be used in patients with active hepatitis B. Patients with positive serological markers of hepatitis B should consult a hepatologist before using MabThera; in respect of such patients, it is necessary to conduct appropriate monitoring and take measures to prevent the reactivation of the hepatitis B virus in accordance with local standards.

Progressive multifocal leukoencephalopathy (PML). When using the drug

MabThera in patients with non-Hodgkin's lymphoma and chronic lymphocytic leukemia were observed cases PML. Most patients received the MabThera preparation in combination with chemotherapy or in combination with hematopoietic stem cell transplantation. If neurologic symptoms occur in these patients, differential diagnosis should be made to exclude PML and a neurologist's consultation.

Skin reactions. The cases of development of such severe skin reactions as toxic epidermal necrolysis and Stevens-Johnson syndrome,in some cases with a fatal outcome. When these reactions are identified, MabThera should be discarded.

Immunization. The safety and effectiveness of immunization with live viral vaccines after treatment with MabThera has not been studied. Vaccination with live viral vaccines is not recommended. Vaccination with inactivated vaccines is possible, but the frequency of response may be reduced. In patients with recurrent non-Hodgkin's lymphoma of low grade, there was a decrease in the response rate to the administration of tetanus toxoid and KHL-neoantigen (KHL-hemocyanin mollusc fissurelia) compared with patients who did not receive MabThera® (16% vs. 81% and 4% vs 76% (evaluation criterion-more than 2-fold increase in antibody titer), respectively). However, the average value of antibody titre to a set of antigens (,Streptococcus pneumonia, influenza A, parotitis, rubella, chicken pox) did not change for at least 6 months after MabThera therapy (when compared with the antibody titre before treatment).

Rheumatoid arthritis, granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangi

In relation to other autoimmune diseases, the efficacy and safety of

MabThera is not established.

Infusion reactions. The development of infusion reactions may be due to the release of cytokines and / or other mediators. Before each infusion of the drug MabThera should be premedication with analgesic / antipyretic and antihistamine. In addition, before each infusion of MabThera®, patients with rheumatoid arthritis should receive premedication with glucocorticosteroids to reduce the frequency and severity of infusion reactions.

In most cases, the infusion reactions in patients with rheumatoid arthritis were of mild or moderate severity. During the postmarketing period, there were registered Severe infusion reactions with a fatal outcome have been reported. It is necessary to carefully monitor patients with previously identified diseases of the cardiovascular system, as well as those who previously had undesirable reactions from the heart and lungs. The most frequently observed infusion reactions were: headache, itching, sensation of sore throat, hot flashes, rashes, hives,increased blood pressure and fever. Infusion reactions were more often observed after the first infusion of any course of treatment than after the second infusion. Subsequent infusions of the MabThera drug were tolerated more easily than the first. Serious infusion reactions were observed in less than 1% of patients, most often during the first infusion of the first cycle. Infusion reactions disappear after slowing or interrupting the administration of MabThera and medication (antipyretic, antihistamines and sometimes oxygen, intravenous injection of 0.9% sodium chloride solution, bronchodilators and, if necessary, glucocorticosteroids). With the development of infusion reactions, depending on their severity and the necessary treatment, the administration of MabThera should be temporarily suspended or canceled.

In most cases, after complete disappearance of the symptomatology, the infusion can be resumed at a rate of 50% of the preceding (eg 50 mg / h instead of 100 mg / h).

The infusion reactions observed with granulomatosis with polyangiitis and microscopic polyangiitis corresponded already described in rheumatoid arthritis.The lower frequency and severity of the infusion reactions with granulomatosis with polyangiitis and microscopic polyangiitis could be associated with the use of high doses of glucocorticosteroids.

In connection with the potential for the development of anaphylactic reactions and other immediate-type hypersensitivity reactions with intravenous administration of protein preparations, it is necessary to have the means for their reduction: adrenaline, antihistamine and glucocorticosteroid preparations.

Side effect from the side, cardiovascular system. Because of the possibility of developing hypotension at least 12 hours before the infusion of MabThera, antihypertensive drugs should be discontinued.

Careful observation of patients with a history of cardiovascular disease is required in connection with the possibility of developing angina or arrhythmia (flutter and atrial fibrillation), heart failure or myocardial infarction.

Infections. In connection with the possible increase in the risk of infectious complications, the MabThera preparation should not be administered to patients with an acute infection or a pronounced immune response deficiency (giogammaglobuliaemia or low level Cd4, Cd8). Caution should be exercised when prescribing MabThera in patients with chronic infection or in the presence of conditions predisposing to the development of serious infections. If an infection occurs, appropriate therapy should be prescribed. Hepatitis B. When MabThera was used in patients with rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis, there were cases of reactivation of hepatitis B virus (including fatal outcome). Before prescribing MabThera, all patients should be screened for hepatitis B. A minimum set of tests should include a definition HBsAg and HBcAb, in accordance with local recommendations, a list of tests can be supplemented. MabThera should not be used in patients with active hepatitis B. Patients with positive serological markers of hepatitis B should consult a hepatologist before using MabThera; in respect of such patients, it is necessary to conduct appropriate monitoring and take measures to prevent the reactivation of the hepatitis B virus in accordance with local standards.

Progressive multifocal leukoencephalopathy (PML). During the period of post-marketing application of MabThera®, patients with autoimmune diseases, including rheumatoid arthritis, had fatal cases PML. Some patients had multiple risk factors PML: concomitant diseases, long-term use of immunosuppressive therapy or chemotherapy. Cases PML registered in patients with autoimmune diseases not receiving the MabThera preparation. If neurologic symptoms occur in these patients, differential diagnosis should be made to exclude PML and a neurologist's consultation.

Skin reactions. The cases of development of such severe skin reactions as

toxic epidermal necrolysis and Stevens-Johnson syndrome, in some cases with

fatal outcome. When these reactions are identified, MabThera should be discarded.

Immunization. The safety and effectiveness of immunization with live viral vaccines, after treatment with MabThera, has not been studied. Vaccination with live viral vaccines is not recommended. Vaccination with inactivated vaccines is possible, but the frequency of response may be reduced.

Before using MabThera in patients with rheumatoid arthritis, the vaccine status of the patient should be studied and acted according to the appropriate reko ment. Vaccination should be completed at least 4 weeks before the appointment of rituximab.

After 6 months of therapy with MabThera and methotrexate, the response rate to polysaccharide pneumococcal vaccine was reduced (43% vs. 82%, at least 2 serotypes of antibodies to pneumococcus), KHL-neoantigen (KHL - Hemocyanin mollusc fissurelia) (34% vs. 80%) compared with methotrexate monotherapy. After therapy with MabThera and methotrexate, the response rate for tetanus toxoid was similar to that seen with monotherapy with methotrexate (39% versus 42%).

If necessary, vaccination with inactivated vaccines should be completed at least 4 weeks before the second course of therapy.

The number of patients with rheumatoid arthritis and a positive antibody titer Streptococcus pneumonia, influenza A, mumps, rubella, chickenpox and tetanus toxin before and 1 year after the initiation of MabThera treatment did not change. Anti-Chimeric Antibodies. The appearance of anti-chimeric antibodies in most patients with rheumatoid arthritis was not accompanied by clinical manifestations or increased risk of reactions during subsequent infusions, but rarely their presence could be associated with more severe allergic or infusion reactions with repeated infusions during the following courses and an insufficient effect on reducing the pool B cells during subsequent courses of therapy.

Patients with rheumatoid arthritis who had not previously received methotrexate. MabThera is not recommended for the treatment of patients who have not previously received methotrexate, t. favorable benefit / risk ratio for this category of patients is not confirmed.

Use in children. Safety and efficacy of the drug in children are not established. When MabThera was used in children, hypogammaglobulinemia was observed, in some cases in severe form, requiring prolonged replacement therapy with immunoglobulins. The consequences of depletion of the B-cell pool in children are unknown. Disposal of MabThera should be carried out in accordance with local requirements.

Effect on the ability to drive transp. cf. and fur:Does rituximab on the ability to manage and work with machines and mechanisms - is unknown, although the pharmacological activity and the described undesirable phenomena do not give grounds for assuming such an effect.

Form release / dosage:Concentrate for the preparation of a solution for infusions of 100 mg / 10 ml and 500 mg / 50 ml.

Packaging:100 mg / 10 ml or 500 mg / 50 ml of the drug in a glass vial (hydrolytic class 1 EF glass) sealed with a butyl rubber stopper, laminated with fluoropolymer, crimped with an aluminum cap and a closed plastic lid. Two vials of 100 mg / 10 ml or one bottle with 500 mg / 50 ml along with the instructions for use are placed in a cardboard box.

Storage conditions:At a temperature of 2-8 ° C in a place protected from light and inaccessible to children.

Shelf life:

2 years and 6 months.

The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N013127 / 01

Date of registration:09.07.2010

Date of cancellation:2016-04-08

The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland

Manufacturer: & nbsp

F.Hoffmann-La Roche, Ltd. Switzerland

Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland

Information update date: & nbsp04.05.2016

Illustrated instructions

Instructions

MabThera® (Mabthera®)