Instruction for use: Mabthera

Dosage form: Concentrate for solution for infusion; for subcutaneous administration

Active substance: Rituximabum

ATX

L01XC02 Rituximab

Pharmacological groups:

Medical immunobiological preparations and antibodies monoclonal [Immunodepressants]

Medical immunobiological preparations and antibodies monoclonal [Antitumor agents - monoclonal antibodies]

The nosological classification (ICD-10)

C82 Follicular [nodular] non-Hodgkin's lymphoma: Brill-Simmers disease; Malignant lymphoma; Hepatic Lymphoma; Recurrent non-Hodgkin's lymphoma; Follicular B-cell non-Hodgkin's lymphoma; Follicular lymphoma; Lymphoma of the liver

C83 Diffuse non-Hodgkin's lymphoma: Diffuse B-large-cell non-Hodgkin's lymphoma; Malignant lymphoma; Malignant lymphoma, especially of the histiocytic type; Lymphoblastic non-Hodgkin's lymphoma; Lymphoma non-Hodgkin's diffuse; Hepatic Lymphoma; Recurrence of lymphoma; Recurrent non-Hodgkin's lymphoma; Lymphoma of the liver

C85.1 B-cell lymphoma, unspecified: Chemically resistant B-cell non-Hodgkin's lymphoma; B-cell non-Hodgkin's lymphoma; Follicular B-cell lymphoma; Diffuse B-Large-Cell Non-Hodgkin's Lymphoma

M06.9 Rheumatoid arthritis, unspecified: Rheumatoid arthritis; Pain syndrome in rheumatic diseases; Pain in rheumatoid arthritis; Inflammation in rheumatoid arthritis; Degenerative forms of rheumatoid arthritis; Children's rheumatoid arthritis; Exacerbation of rheumatoid arthritis; Acute articular rheumatism; Rheumatic arthritis; Rheumatic polyarthritis; Rheumatoid arthritis; Rheumatic polyarthritis; Rheumatoid arthritis; Rheumatoid arthritis; Rheumatoid arthritis of active course; Rheumatoid periarthritis; Rheumatoid polyarthritis; Acute rheumatoid arthritis; Acute rheumatism

Composition and release form

Concentrate for solution for infusion 1 ml

Rituximab 10 mg

Auxiliary substances: sodium citrate dihydrate; Polysorbate 80; sodium chloride; Hydrochloric acid or sodium hydroxide; water for injections

In vials of 10 (100 mg) or 50 (500 mg) ml; In a pack of cardboard 2 (100 mg) or 1 (50 mg) vial.

Description of dosage form

Transparent or slightly opalescent, colorless or pale yellow liquid.

Pharmachologic effect

Mode of action - Antitumor, immunosuppressive.

Pharmacodynamics

Rituximab is 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. After binding to the antibody, CD20 is not internalized and ceases to flow from the cell membrane into the extracellular space. CD20 does not circulate in plasma as a free antigen and therefore does not compete for binding to antibodies.

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 sensitizes lines of human B-cell lymphoma 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 9-12 months after completion of therapy. In patients with rheumatoid arthritis, the duration of the reduction in the number of B cells varies, most patients are prescribed subsequent therapy until their number is completely restored.

Antichymeric antibodies were detected in 1.1% (4 of 356) of the examined patients with non-Hodgkin's lymphoma and 10% with rheumatoid arthritis.

Pharmacokinetics

Non-Hodgkin's Lymphoma

In patients with recurrent B-cell lymphoma, the concentration of rituximab in serum and its T1 / 2 increases with increasing dose. After the first intravenous infusion of 375 mg / m2 of T1 / 2 rituximab - 76.3 hours, after the fourth infusion - 205.8 hours, Cmax after the first infusion - 205.6 μg / ml, after the fourth infusion - 464.7 μg / Ml, plasma clearance - 0.0382 l / h and 0.0092 l / h, respectively. Individual differences in serum drug concentration are quite pronounced. With effective treatment, serum concentrations of rituximab are significantly higher. The concentration of the drug negatively correlates with the magnitude of the tumor load. Traces of rituximab can be detected in the body for 3-6 months after the last infusion.

In patients with diffuse large B-cell lymphoma, serum concentrations of rituximab are comparable to those in patients with low-grade non-Hodgkin's lymphoma or follicular lymphoma receiving the same dose of the drug.

Rheumatoid arthritis

After two intravenous infusions of 1000 mg with a 2-week break, Cmax of rituximab is 369 μg / ml, the average of T1 / 2 is 19.2-20.8 days, the average system clearance is 0.23 l / day, and the volume of distribution in The equilibrium state is 4.6 liters.

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 not presented.

Indications of the preparation Mabthera

Non-Hodgkin's lymphoma:

Relapsing or chemically resistant B cell, CD20-positive non-Hodgkin's low-grade lymphoma or follicular;

Follicular lymphoma III-IV stage in combination with CVP chemotherapy in previously untreated patients;

Follicular lymphoma (as a supportive therapy after responding to induction therapy);

CD20-positive diffuse B-large-cell non-Hodgkin's lymphoma, in combination with CHOP chemotherapy.

Rheumatoid arthritis: (active form) in adults in combination with methotrexate with intolerance or inadequate response to current regimens that include one or more tumor necrosis factor (TNF-alpha) inhibitors.

Safety and efficacy in children are not established.

Contraindications

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

Acute infectious diseases;

Severe primary or secondary immunodeficiency.

Carefully:

With respiratory failure in history or tumor lung infiltration;

Number of circulating malignant cells> 25 thousand / mm3 or high tumor load (chronic lymphocytic leukemia or lymphoma from cells of the mantle zone);

Neutropenia (less than 1,5 thousand cells / μl), thrombocytopenia (less than 75 thousand / μl);

Chronic infections.

Application in pregnancy and breastfeeding

The action of rituximab in pregnant women has not been studied. The damaging effect of MabThera on the fetus and its effect on fertility is unknown.

The level of B-cells in newborns in the appointment of MabTheraŽ to women during pregnancy has not been studied.

Rituximab can cause depletion of the B-cell pool in newborn animals in the postnatal period.

MabThera should not be given to pregnant women, unless the potential benefits of therapy do not exceed the potential risk.

During the treatment period and within 12 months after the end of MabTheraŽ treatment, women of childbearing age should use effective methods of contraception.

It is not known whether rituximab is excreted in breast milk. Given that IgG immunoglobulins circulating in the mother's blood are excreted in breast milk, MabThera should not be used during lactation.

Side effects

Infusion reactions: chills, weakness, dyspnea, dyspepsia, nausea, rash, hot flushes, arterial hypotension, arterial hypertension, fever, itching, urticaria, pharyngeal irritation, rhinitis, tachycardia, vomiting, pain, signs of tumor lysis syndrome. In some cases, R-CHOP is a myocardial infarction, atrial fibrillation, and pulmonary edema during the procedure.

Infections: respiratory tract infections, most often - nasopharyngitis, sinusitis; Bronchitis, pneumonia, superinfection of the lungs, urinary tract infections, sepsis, herpes zoster, septic shock, infection of implants, staphylococcal septicemia; Severe viral infections (newly emerged or reactive) with possible fatal outcome caused by CMV, Varicella zoster, Herpes simplex, polyoma JC (progressive multifocal leukoencephalopathy (PML), hepatitis C virus, very rarely reactivation of viral hepatitis B.

On the part of the blood and lymphatic system: leukopenia, neutropenia (4 weeks or more after the last administration of rituximab), thrombocytopenia, anemia, febrile neutropenia; In less than 1% of patients - lymphadenopathy, a violation of blood clotting. Very rarely - pancytopenia, a transient increase in IgM levels in patients with Waldenstrom's macroglobulinemia, followed by a return to its baseline after 4 months; Transient partial aplastic anemia, hemolytic anemia.

On the part of the respiratory system: rhinitis, mucous discharge from the nose, bronchospasm, coughing or coughing, respiratory disease, dyspnea, acute respiratory failure, pulmonary infiltrates. In less than 1% of patients - hypoxia, impaired lung function, bronchiolitis obliterans, asthma.

On the part of the body as a whole, reactions at the injection site: irritation of the pharynx, angioedema, back pain, pain in the chest, neck pain, pain in the tumor, flu-like syndrome, peripheral edema, mucositis, fainting, weight loss, multi-organ Insufficiency, a syndrome of rapid tumor lysis, very rarely - serum sickness. In less than 1% of patients - an increase in the abdomen, pain at the injection site, anaphylactic reactions.

On the part of the gastrointestinal tract: dyspepsia, nausea, vomiting, diarrhea, lack of appetite, dysphagia, stomatitis, constipation, abdominal pain, perforation of the stomach and / or intestines (possibly fatal).

From the side of the cardiovascular system: arterial hypotension, arterial hypertension, orthostatic hypotension, tachycardia, bradycardia, arrhythmia (including ventricular and supraventricular tachycardia, atrial fibrillation), unstable angina, vasodilation, venous thrombosis, incl. Deep vein thrombosis of the extremities, heart failure, reduction of ejection fraction, pulmonary edema, myocardial infarction; Very rarely - vasculitis, mainly skin (leukocytoclastic), ischemic impairment of cerebral circulation.

From the side of the nervous system: dizziness, headache, paresthesia, hypoesthesia, migraine, very rarely neuropathy of the cranial nerves, combined with or without peripheral neuropathy (marked reduction in visual acuity, hearing loss, damage to other sensory organs, paralysis of the facial nerve) At different periods of therapy - up to several months after the completion of the MabTheraŽ treatment course.

From the psychic sphere: confusion of consciousness; At less than 1% - nervousness, depression, feelings of anxiety, perversion of taste.

From the musculoskeletal system: myalgia, arthralgia, muscle hypertonus, muscle spasms, osteoarthritis.

On the part of the endocrine system: hyperglycemia, decompensation of diabetes mellitus.

From the skin and its appendages: itching, rashes, hives, increased sweating at night, sweating, alopecia; Very rarely - severe bullous reactions, toxic epidermal necrosis with fatal outcome.

On the part of the sense organs: disturbances of lacrimation, conjunctivitis, pain and noise in the ears.

On the part of laboratory indicators: increased LDH activity, hypocalcemia, hypercholesterolemia, hyperglycemia, bacteremia.

Monotherapy MabTheraŽ

Infusion reactions. Most often develop with the first infusions. The incidence of infusion reactions decreases from 77% (of which 7% - 3 and 4 degrees of severity) with the 1st infusion up to 30% (2% - 3 and 4 degrees of severity) at the 4th and 14% (no reactions 3 and 4 4 degrees of severity) with the 8th infusion.

Infections. MabTheraŽ causes depletion of the B-cell pool in 70-80% of patients and a decrease in serum Ig concentration in a small number of patients. Infectious complications (all, regardless of the cause) develop in 30.3% of patients: 18.8% have bacterial infections, 10.4% have viral infections, 1.4% have fungal infections, 5.9% have infections Without refined etiology (one patient could have different infections). Severe infections (3rd and 4th degree of severity), including sepsis, were noted in 3.9% of patients: during therapy (1.4%) and in patients without observation (2.5%).

On the part of the blood system: severe thrombocytopenia (grade 3 and 4) was noted in 1.7% of patients, severe neutropenia in 4.2% of patients and severe anemia (grade 3 and 4) in 1.1% of patients. A single case of transient aplastic anemia and two cases of hemolytic anemia have also been reported.

From the side of the cardiovascular system: side effects were noted in 18.8%. The most common are arterial hypo- and hypertension.

MabThera in combination with CVP chemotherapy (R-CVP)

Infusion reactions of 3 and 4 degrees of severity (9%): chills, weakness, dyspnea, dyspepsia, nausea, rash, hot flashes.

Infections (33% during treatment and 28 days after the end of therapy, compared with 32% of patients receiving only CVP): upper respiratory tract infection (12.4%), most often nasopharyngitis, serious infections (4.3% ), Life-threatening infections are not registered.

On the part of the blood system: neutropenia of the 3rd and 4th degree of severity (24%), neutropenia of the 4th degree of severity (3.1%). A higher incidence of neutropenia in the R-CVP group does not result in an increased incidence of infections. Anemia - in 0.6% of patients in the R-CVP group and in 1.9% of patients receiving CVP, thrombocytopenia - in 1.2% of the R-CVP group and absent in patients receiving CVP.

The overall incidence of cardiovascular events was similar in patients receiving CVP (5%) and R-CVP (4%).

MabThera in combination with CHOP chemotherapy (R-CHOP)

Infusion reactions. Infusion reactions of 3rd and 4th degree of severity during infusion or within 24 hours after infusion MabThera were observed during the first cycle of R-CHOP in 9% of patients. By the 8th cycle of R-CHOP, the frequency of infusion reactions decreased to less than 1%.

Infections. The proportion of patients with infections of 2-4 degrees of severity and / or febrile neutropenia in the R-CHOP group was 55.4%, and in the CHOP group - 51.5%. Cases of febrile neutropenia without concomitant documented infection during therapy were noted in 20.8% of patients receiving R-CHOP and 15.3% of patients receiving CHOP. The total incidence of infections of grade 2-4 in the R-CHOP group was 45.5%, in the CHOP group - 42.3%, with no difference in the incidence of systemic bacterial and fungal infections. The incidence of fungal infections of grade 2-4 in the R-CHOP group was higher than in the CHOP group (4.5 and 2.6%, respectively); This difference was due to a higher incidence of local candidiasis during therapy. The frequency of herpetic infection 2-4-th degree of severity, incl. With eye damage, was higher in the R-CHOP group (4.5%) than in the CHOP group (1.5%), in 7 of the 9 cases observed in the R-CHOP group, the disease appeared during the therapy phase.

System of blood. After each cycle, leukopenia (88 vs. 79%) and neutropenia (97 vs 88%) of the 3rd and 4th degree of severity were more frequent in the R-CHOP group than in the CHOP group, respectively. There were no differences in the incidence of grade 3 and 4 anemia in the two groups (19% in the CHOP group and 14% in the R-CHOP group); There was no difference in the frequency of thrombocytopenia (15% in the CHOP group and 16% in the R-CHOP group). The time to resolution of all hematologic abnormalities in the two therapeutic groups was comparable.

The cardiovascular system. The frequency of cardiac rhythm disorders of the 3rd and 4th degree of severity, mainly supraventricular arrhythmias (tachycardia, flutter and atrial fibrillation) in the R-CHOP group was higher (6.9%) than in the CHOP group (1.5%) . All arrhythmias developed either in connection with MabThera infusion, or were associated with predisposing conditions such as fever, infection, acute myocardial infarction, or concomitant diseases of the respiratory and cardiovascular systems. R-CHOP and CHOP groups did not differ in the frequency of other cardiological adverse events of the 3rd and 4th degree of severity, including heart failure, myocardial diseases, and manifestations of coronary heart disease.

Nervous system. During the first cycle of therapy, 4 patients (2%) from the R-CHOP group with cardiovascular risk factors developed thromboembolic disorders of the cerebral circulation, in contrast to 1.5% in patients in the CHOP group during the observation period without treatment. The difference between groups in the frequency of other thromboembolism was absent.

MabThera in the treatment of rheumatoid arthritis

Infections. The probability of infections with MabTheraŽ therapy was 0.9 cases per year, the proportion of severe infections, some of which were fatal, did not exceed 0.05 cases per year.

Malignant diseases. The frequency of malignant diseases after the appointment of MabThera is 1.5 per 100 patients per year and does not exceed the rates in the population.

Cases of fatal progressive multifocal leukoencephalopathy (PML) have been observed with MabThera therapy in patients with systemic lupus erythematosus (SLE), which is not prescribed by the medical instruction. There was no causative relationship with MabTheraŽ, patients had risk factors for developing PML - concomitant diseases, long-term use of immunosuppressive therapy. In patients with rheumatoid arthritis, no PML cases were noted. If neurologic symptoms occur with MabTheraŽ therapy, you should consult a neurologist and exclude PML.

The efficacy and safety of MabThera in patients with SLE is not established.

Special categories of patients

High tumor load (diameter of single foci - more than 10 cm). Increased frequency of adverse reactions of the 3rd and 4th degree of severity.

Elderly (over 65 years): the frequency and severity of all side effects and side effects of the 3rd and 4th degree of severity does not differ from that of younger patients.

Repeated therapy: the frequency and severity of all side effects does not differ from those in the initial therapy.

Interaction

Data on possible drug interactions of MabTheraŽ are limited. 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.

The tolerability of the simultaneous or sequential use of MabTheraŽ and drugs that can reduce the number of normal B cells (in addition to the CHOP or CVP scheme) has not been accurately established.

MabTheraŽ is compatible with polyvinyl chloride or polyethylene infusion systems or bags.

Dosing and Administration

Rules of preparation and storage of a solution

The required amount of the drug is taken under aseptic conditions and diluted to the calculated concentration (1-4 mg / ml) in an infusion bottle (package) with 0.9% sodium chloride solution for injection 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 check the solution for any foreign matter or discoloration.

Since MabThera does not contain preservatives, the prepared solution must be used immediately. The prepared MabTheraŽ infusion solution is stable for 12 hours at room temperature or for a maximum of 24 hours at a temperature of 2 to 8 ° C. The doctor is responsible for the preparation, conditions and time of storage of the finished solution before its use.

Standard dosing regimen

IV, infusion (slowly), through a separate catheter, at a dose of 375 mg / m2, once a week. Do not administer IV bolus or IV injection.

The recommended initial speed of the first infusion is 50 mg / h, in the future it can be increased by 50 mg / h every 30 minutes, leading to a maximum speed of 400 mg / h. Subsequent infusions can be started at a rate of 100 mg / h and increased by 100 mg / h every 30 minutes to a maximum rate of 400 mg / h.

Before each infusion of MabTheraŽ, premedication should be performed (analgesic / antipyretic, eg paracetamol; antihistamine, eg diphenhydramine). If MabThera is not used in combination with CHOP or CVP chemotherapy, premedication also includes corticosteroids.

Correction of dose during therapy

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

Non-Hodgkin's lymphoma of low grade or follicular

Initial therapy

Monotherapy of adult patients: 375 mg / m2, once a week, for 4 weeks.

In combination with CVP (cyclophosphamide, vincristine, prednisolone): 375 mg / m2 - on the first day of the chemotherapy cycle after intravenous corticosteroid injection as a component of the CVP scheme; 8 cycles, (cycle - 21 days).

Repeated use in case of relapse (in patients who responded to the first course of therapy): 375 mg / m2, once a week, for 4 weeks.

Supportive therapy: after responding to induction therapy 375 mg / m2, 1 time per 3 months, no more than 2 years or until the disease progresses.

Diffuse B-Large-Cell Non-Hodgkin's Lymphoma

In combination with CHOP chemotherapy: 375 mg / m2 - on the first day of each chemotherapy cycle, 8 cycles, after intravenous corticosteroid administration. Other components of the CHOP regimen (cyclophosphamide, doxorubicin and vincristine) are administered after the administration of MabThera.

Rheumatoid arthritis

Initial therapy. 1000 mg IV drip slowly, 30 minutes after iv introduction of methylprednisolone at a dose of 100 mg, 1 time in 2 weeks, course - 2 infusions.

Repeated use. Perhaps 6-12 months after the first course of therapy. 1000 mg once every 2 weeks, course - 2 infusions.

Dosing in special cases

Elderly age

In patients older than 65 years, dose adjustment is not required.

Overdose

Cases of overdose in humans were not observed. Single doses of rituximab above 1000 mg have not been studied. A maximum dose of 5000 mg was given to patients with lymphatic leukemia, no additional safety data was obtained. In connection with the increased risk of infectious complications with the depletion of the B-lymphocyte pool, it is necessary to cancel or reduce the infusion rate, to consider the need for a detailed general blood test.

The main indicators of the effectiveness of the drug at various nosologies and treatment regimens

Non-Hodgkin's lymphoma of low grade or follicular

Monotherapy

Initial therapy - 4 weeks

In patients with recurrent or chemically resistant B-cell non-Hodgkin's lymphoma of low grade or follicular, who received MabThera at a dose of 375 mg / m2 in the form of 4 IV infusions 1 time a week, the total remission rate was 48%, complete remission - 6% Partial remission - 42%. The median time to disease progression is 13 months.

The total remission rate in patients with histological subtypes of tumors B, C and D (IWF classification) was higher than with subtype A (58 and 12%, respectively); In patients with a diameter of the largest tumor site less than 5 cm - higher than with a focal diameter of more than 7 cm (53 and 38%) and in patients with chemosensitive relapse - higher than with chemo-resistant (duration of remission - less than 3 months) - 53 and 36 % Respectively. The total remission rate in patients after autologous bone marrow transplant is 78% (compared with 43% in patients without bone marrow transplantation). The frequency of response to MabTheraŽ therapy does not correlate with age, gender, malignancy, massive lesion, lesion localization and LDH level. But a statistically significant correlation was found between the response rate and bone marrow damage: 40% of patients with bone marrow disease responded to therapy compared with 59% of patients without bone marrow involvement (p = 0.0186).

Initial therapy - 8 weeks

In patients with recurrent or chemically resistant B-cell non-Hodgkin's lymphoma of low grade or follicular, the overall response is 57%, the median time to progression of the disease responds to therapy at 19.4 months (range 5.3-38.9 months).

Initial therapy for a disease with massive lesion - 4 weeks

In patients with recurrent or chemically resistant B-cell non-Hodgkin's low-grade lymphoma or follicular with massive lesion (tumor site diameter ≥10 cm), the overall response is 36% and the median time to progression of the disease in the responding patients is 9.6 months (range 4 , 5-26.8 months).

Repeat therapy - 4 weeks

The frequency of remission in re-treated patients is comparable to that of the first course of therapy. In patients with recurrent or chemically resistant low-grade B-cell non-Hodgkin's lymphoma or follicular with an objective response to previous treatment with MabThera, when it was re-administered, the overall response to treatment was 38%, the median time to progression of the disease in the responders was 17.8 months.

Combination with CVP (R-CVP)

In the administration of combination therapy, R-CVP (MabThera 375 mg / m2 on the 1st day of each cycle, cyclophosphamide 750 mg / m2, vincristine 1.4 mg / m2 to 2 mg / day on the first day of the cycle and prednisolone - 40 mg / m2 / day, on days 1 to 5, every 3 weeks, total - 8 cycles), the main criterion of effectiveness - the risk of failure of therapy decreased by 67% and the time to failure of therapy increased from 6.7 months Up to 25.9 months (p <0.0001). The response rate (complete response, unconfirmed complete response, partial response) in the R-CVP group was: 80.9% compared to 57.2% (p <0.0001). At 18 months after initiation of therapy, the median duration of response to treatment was not achieved in the R-CVP group and was 9.8 months in the CVP group (p <0.0001). The risk of relapse of the disease decreased by 70% with the appointment of R-CVP (p <0.0001). The incidence of survival without events after 12 months of therapy was 69% in the R-CVP group, compared to 32% in the CVP group.

MabThera increases the time to the appointment of new therapy or death, the time to progression of the disease from 14.5 to 27 months (p <0.0001). After 12 months, 81% of patients receiving MabThera had no relapse of disease, compared with 58% in patients receiving only CVP.

The benefits of combining MabTheraŽ with CVP were observed in all patients, regardless of age, the number of extranodal lesions, bone marrow involvement, increased LDH, β2-microglobulin, B-symptoms, massive lesions, number of nodes, hemoglobin, international prognostic index values (IPI ) And FLIPI index in patients with follicular lymphoma.

Supportive therapy

In patients with recurrent or resistant follicular non-Hodgkin's lymphoma after induction therapy with R-CHOP or CHOP, maintenance therapy with MabThera significantly and statistically significantly increases the progression-free survival to 42.2 months compared with 14.3 months in patients who did not receive supportive Therapy, reduces the risk of progression of the disease or death by 61%. The expected level of survival without progression at 12 months in the maintenance group was 78%, compared with 57% in the control group who did not receive maintenance therapy with MabThera. Supportive MabTheraŽ therapy reduces the risk of death by 56%, as well as the time to the appointment of a new therapy regimen (38.8 vs 20.1 months) and the risk of setting a new therapy regimen by 50%.

In patients with complete or unconfirmed complete response, the appointment of MabThera as a maintenance therapy significantly increases the disease-free survival from 16.5 to 53.7 months and reduces the risk of recurrence by 67%.

The benefits of supporting MabTheraŽ therapy are obtained for all subgroups of patients regardless of the type of induction therapy (CHOP or R-CHOP), the response to induction therapy (complete or partial response), and regardless of age, sex, stage of disease, IPI values) FLIPI, B-symptoms, bone marrow involvement, the number of affected lymph nodes and extranodal foci, the number of previous regimens, better response to therapy, LDH, hemoglobin and β2-microglobulin, except for a subgroup of patients with massive lesions.

Diffuse B-Large-Cell Non-Hodgkin's Lymphoma

The use of the R-CHOP scheme (MabTheraŽ 375 mg / m2 on the 1st day of the cycle in combination with CHOP: cyclophosphamide 750 mg / m2, doxorubicin 50 mg / m2, vincristine 1.4 mg / m2 maximal 1 Mg - on the 1st day of the cycle and prednisolone 40 mg / m2 / day on days 1 to 5, every 3 weeks, in total - 8 cycles) in untreated elderly and senile patients (from 60 to 80 years) leads To a statistically significant increase in "event-free" survival from 13 to 35 months, compared with the use of only the CHOP regimen (p = 0.0001) ("events" include deaths, recurrences or progression of lymphomas Om, as well as the appointment of a new therapy regimen). The use of the R-CHOP scheme reduces the risk of these events by 41%. The median follow-up was 31 months. Overall survival in the R-CHOP group significantly increased to 68.2% compared with 57.4% in the CHOP group, while the risk of death was reduced by 33% (p = 0.0094). R-CHOP therapy also outperformed the CHOP scheme for the frequency of complete remission at the end of the course of treatment (76.2 and 62.4%, respectively, p = 0.0028). The risk of progression of the disease in the R-CHOP group decreased by 46%, and the risk of recurrence was reduced by 51%.

The benefits of the R-CHOP scheme are independent of sex, age, the value of the international age-adjusted prognostic index, ECOG, β2-microglobulin, LDH, albumin, B-symptoms, massive lesions, bone marrow involvement and extranodal lesions.

Rheumatoid arthritis

Rituximab in combination with methotrexate significantly reduces the activity of the disease. Clinical effect - at least 20% according to the criteria of the American College of Rheumatology (AKP-20), in comparison with methotrexate monotherapy was noted in the majority of patients, irrespective of the titer of the rheumatoid factor, age, sex, body surface area, race, previous therapy and disease activity. Clinically and statistically significant improvement in MabTheraŽ treatment was noted for all criteria of AKP: the number of swollen and painful joints, pain index, C-reactive protein, rheumatoid factor, along with an improvement in the overall assessment of the effectiveness of treatment in the opinion of the doctor and patient, The patient's opinion, the index of disability.

Rituximab significantly reduces the DAS28 activity index. A good and moderate response to the EULAR criteria was achieved in a significantly larger number of patients with MabTheraŽ with methotrexate compared with methotrexate monotherapy.

Patients who received therapy with MabThera indicated a significant improvement in the index of disability (based on the HAQ-DI health assessment questionnaire), reduction of weakness (FACIT-F), and improvement in both physical and mental parameters in the SF-36 questionnaire.

When rituximab is prescribed, there is a significant decrease in the concentration of rheumatoid factor (range - 45-64%). The concentration of immunoglobulins, the number of lymphocytes, and leukocytes remained within the normal range, except for a transient decrease in the number of leukocytes during the first four weeks after the initiation of therapy. Both MabTheraŽ monotherapy and combination with methotrexate showed a significant decrease in inflammatory markers (IL-6, C-RB, serum type A amyloid protein, S100 protein isotypes A8 and A9).

The frequency of response to MabThera therapy in re-treated patients is comparable to that of the first course of therapy.

Special instructions

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

Infusion reactions. The development of infusion reactions may be due to the release of cytokines or other mediators. In most patients within 0.5 to 2 hours after the onset of the first infusion of MabThera, fever occurs with chills or tremors. Severe reactions include lung symptoms, arterial hypotension, hives, 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. Severe infusion reactions are difficult to distinguish from hypersensitivity reactions or cytokine release syndrome. There are reports of lethal infusion reactions described during the post-marketing use of the drug. Infusion reactions disappear after slowing or interrupting MabThera administration and supporting activities (intravenous infusions of 0.9% solution of sodium chloride, diphenhydramine and acetaminophen, bronchodilators, GCS, 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.

Side effect of the lungs. 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. Continuation of therapy after complete disappearance of symptoms is rarely accompanied by repeated development of severe infusion reactions. 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.

The rapid tumor lysis syndrome is possible after the first MabThera infusion in patients with a large number of circulating malignant lymphocytes. Tumor lysis syndrome includes: hyperuricemia, hyperkalemia, hypocalcemia, acute renal failure, increased LDH level. Patients at risk are in need of close medical supervision and regular laboratory testing. When developing symptoms of rapid lysis of the tumor, appropriate therapy is carried out. After complete relief of symptoms in a limited number of cases, MabTheraŽ therapy continued in conjunction with the prevention of rapid tumor lysis syndrome.

Patients with a large number of circulating malignant cells (> 25 thousand / mm3) or a high tumor burden (eg with chronic lymphocytic leukemia or mantle cell lymphoma) who are at risk of extremely severe infusion reactions may be particularly high, MabThera should be given with extreme Caution, under close supervision and only if all other methods of treatment are ineffective. The first infusion of the drug in such patients should be administered at a lower rate.

In connection with the potential for the development of anaphylactoid reactions with intravenous administration of protein preparations, it is necessary to have the means for their reduction: adrenaline, antihistamines and corticosteroids.

During the infusion, careful monitoring of patients with a history of cardiovascular disease is required. Because of the possibility of developing hypotension at least 12 hours before the infusion of MabTheraŽ, antihypertensives should be discontinued.

Although MabThera's monotherapy does not have a myelosuppressive effect, it is necessary to use caution in prescribing the drug for neutropenia (<1,500 / μl) and thrombocytopenia (<75,000 / μl), 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. Very rarely, when a combination of MabTheraŽ and chemotherapy was prescribed in patients with non-Hodgkin's lymphoma, reactivation of hepatitis B or fulminant hepatitis, which were not associated with MabTheraŽ, was noted. Such patients should be carefully observed.

Immunization. The safety and effectiveness of immunization with any vaccine, especially live viral vaccines, after treatment with MabTheraŽ has not been studied. Vaccination should be completed at least 4 weeks before the appointment of rituximab. Vaccination with live vaccines is not recommended with a decrease in the number of B cells.

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 infusion, 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.

Influence on ability to drive transport and work with machines and mechanisms

It is not known whether rituximab affects the ability to manage and work with machines and mechanisms, although pharmacological activity and the described undesirable phenomena do not give grounds for assuming such an effect.

Manufacturer

ŤF. Hoffmann-La Roche Ltd., Switzerland.

Storage conditions of the drug Mabthera

In the dark place at a temperature of 2-8 ° C.

Keep out of the reach of children.

Shelf life of the drug Mabthera

2,5 years.

Do not use after the expiry date printed on the package.