Composition, form of production and packaging
Concentrate for the preparation of solution for infusions is transparent or slightly opalescent, colorless or light yellow in color.
1 ml of 1 fl.
rituximab 10 mg 100 mg
Excipients: sodium citrate dihydrate - 7.35 mg, polysorbate 80 - 0.7 mg, sodium chloride - 9 mg, hydrochloric acid or sodium hydroxide (up to pH 6.5), water d / u - up to 1 ml.
10 ml - bottles from glass of hydrolytic class 1 EF (2) - packs cardboard.
Concentrate for the preparation of solution for infusions is transparent or slightly opalescent, colorless or light yellow in color.
1 ml of 1 fl.
rituximab 10 mg 500 mg
Excipients: sodium citrate dihydrate - 7.35 mg, polysorbate 80 - 0.7 mg, sodium chloride - 9 mg, hydrochloric acid or sodium hydroxide (up to pH 6.5), water d / u - up to 1 ml.
50 ml - bottles from glass of hydrolytic class 1 EF (1) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
PHARMACHOLOGIC EFFECT
Antitumor and immunomodulating drug. 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. The CD20 expressed on the 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 the 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 a decrease in the number of B-cells varies, most patients are prescribed subsequent therapy until their number is completely restored. In a small number of patients, there is a long-term decrease in the number of B-cells (for 2 years or more after the last dose of the drug).
In patients with granulomatosis with polyangiitis and microscopic polyangiitis, a decrease in the number of CD19-positive B cells to less than 10 cells / Ојl occurs after the first two infusions of rituximab, and in most patients it remains 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 the population pharmacokinetic analysis in patients with non-Hodgkin's lymphoma, single or multiple administration of MabThera as monotherapy or in combination with CHOP chemotherapy (cyclosporine, doxorubicin, vincristine, prednisolone), non-specific clearance (CL 1 ), specific clearance (CL 2 ), (probably associated with B-cells or tumor load), and the volume of distribution in plasma (V 1 ) is 0.14 l / day, 0.59 l / day and 2.7 l, respectively. The median of the terminal T1/2 is 22 days. The baseline level of CD19 positive cells and the size of the tumor focuses on CL 2 rituximab 375 mg / m 2 IV once a week, for 4 weeks. The CL 2index is higher in patients with a higher level of CD19-positive cells or a larger size of the tumor focus. Individual variability of CL 2 persists after correction of the size of the tumor and the level of CD19-positive cells. Relatively small changes in the V 1 index depend on the surface area of ​​the body (1.53-2.32 m 2 ) and on CHOP chemotherapy and are 27.1% and 19%, respectively. Age, sex, race, general condition on the WHO scale do not affect the pharmacokinetics of rituximab. Thus, dose adjustment of rituximab, depending on the factors listed above, does not significantly affect the pharmacokinetic variability.
The average C max increases after each infusion: after the first infusion - 243 Ојg / ml, after the fourth infusion - 486 Ојg / ml, after the eighth - 550 Ојg / ml. C min and Cmax of the drug are inversely correlated with the initial number of CD19-positive B cells and the magnitude of the tumor burden. With an effective treatment, the median C ss of the drug is higher. Median C ss 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 / m 2 ) in combination with 6 cycles of chemotherapy for CHOP was almost the same as for monotherapy.
Chronic lymphatic leukemia
The average C max after the fifth infusion of rituximab at a dose of 500 mg / m 2 is 408 Ојg / ml.
Rheumatoid arthritis
After two intravenous infusions of 1000 mg with a 2-week break, the mean C max of rituximab is 369 Ојg / ml, the mean T 1/2 is 19.2-20.8 days, the average system clearance is 0.23 l / day, and V d in the equilibrium state - 4.6 liter. After the second infusion, the average C max is 16-19% higher than 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 polyangiitis
According to the population pharmacokinetic analysis, after four infusions of rituximab at a dose of 375 mg / m 2 once a week, the median T 1/2 is 23 days, the average clearance is 0.313 l / day and V d is 4.5 l. 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
V d and clearance of rituximab, corrected for the body surface area in men is slightly higher than in women, dose adjustment of rituximab is not required.
Pharmacokinetic data in patients with renal and hepatic insufficiency are absent.
INDICATIONS
Non-Hodgkin's Lymphoma:
- recurrent or chemically resistant B-cell, CD20-positive non-Hodgkin's lymphoma of low grade or follicular;
- follicular lymphoma of III-IV stage in combination with chemotherapy in previously untreated patients;
- follicular lymphoma as maintenance therapy after responding to induction therapy;
- CD20-positive diffuse B-large-cell non-Hodgkin's lymphoma in combination with CHOP chemotherapy.
Chronic lymphocytic leukemia:
- chronic lymphocytic leukemia in combination with chemotherapy in patients who had not previously received standard therapy;
- recurrent or chemo-resistant chronic lymphocytic leukemia in combination with chemotherapy.
Rheumatoid arthritis:
- moderate and severe rheumatoid arthritis (active form) in adults in combination with methotrexate with intolerance or an inadequate response to current regimens that include one or more TNF inhibitors, including for inhibition of radiologically proven destruction of the joints.
Granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis
- severe forms of active granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis in combination with GCS.
DOSING MODE
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.
Because MabThera В® contains no preservatives, the prepared solution should be used immediately.
The prepared infusion solution of MabThera В® is physically and chemically stable for 12 hours at room temperature or for not more than 24 hours at a temperature of 2 В° to 8 В° C.
The drug MabThera В® is administered only in / in the drip, through a separate catheter! Enter the drug in / in a stream or bolusno it is impossible!
The recommended initial speed of the first infusion is 50 mg / h, then it can be increased by 50 mg / h every 30 minutes, bringing 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.
Correction of dose during therapy
It is not recommended to reduce the dose of rituximab. If the MabThera drug 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 MabThera В® , premedication should be performed (analgesic / antipyretic, for example, paracetamol; antihistamine, eg diphenhydramine). If MabThera is not used in combination with chemotherapy containing glucocorticosteroids, then SCS is also part of the premedication.
Initial therapy
Monotherapy of adult patients: 375 mg / m 2 once a week, for 4 weeks.
In combination with chemotherapy under any scheme: 375 mg / m 2 on the first day of the chemotherapy cycle after intravenous administration of GCS as a component of therapy, during:
- 8 cycles (cycle: 21 days) with the R-CVP scheme (rituximab, cyclophosphamide, vincristine, prednisolone);
- 8 cycles (cycle: 28 days) with the R-MCP scheme (rituximab, mitoxantrone, chlorambucil, prednisolone);
- 8 cycles (cycle: 21 days) with the R-CHOP scheme (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) with the R-CHVP-Interferon scheme (rituximab, cyclophosphamide, doxorubicin, teniposide, prednisolone + interferon).
Repeated use in case of relapse (in patients who responded to the first course of therapy): 375 mg / m 2 once a week, for 4 weeks.
Supportive therapy (after responding to induction therapy):
- in previously untreated patients: 375 mg / m 2 once in 2 months, not 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 2 once in 3 months, not more than 2 years. If signs of disease progression appear, MabThera should be discontinued.
Diffuse B-Large-Cell Non-Hodgkin's Lymphoma
Before each infusion of MabThera В® , premedication should be performed (analgesic / antipyretic, for example, paracetamol; antihistamine, eg diphenhydramine). If MabThera is not used in combination with chemotherapy containing glucocorticosteroids, then SCS is also part of the premedication.
In combination with CHOP chemotherapy: 375 mg / m 2 on the first day of each chemotherapy cycle after intravenous administration of GCS, 8 cycles. Other components of the CHOP scheme (cyclophosphamide, doxorubicin and vincristine) are administered after the administration of MabTheraВ®.
Chronic lymphatic leukemia
Before each infusion of MabThera В® , premedication should be performed (analgesic / antipyretic, for example, paracetamol; antihistamine, eg diphenhydramine). If MabThera is not used in combination with chemotherapy containing glucocorticosteroids, then SCS is also part of the premedication.
In combination with chemotherapy (in patients who had not previously received standard therapy and with relapsing / chemo-resistant lymphocytic leukemia): 375 mg / m 2 on the first day of the first cycle, then 500 mg / m 2 on the first day of each subsequent cycle, 6 cycles. Chemotherapy is performed after the administration of MabTheraВ®.
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> 25 000 / ОјL, the administration of prednisone / prednisolone 100 mg / hour prior to infusion of the MabThera preparation is recommended to reduce the incidence and severity of acute infusion reactions and / or cytokine release syndrome.
Rheumatoid arthritis
Before each infusion of MabThera В® , premedication should be performed (analgesic / antipyretic, for example, paracetamol; antihistamine, eg diphenhydramine). In addition, pre-medication of SCS should be performed to reduce the frequency and severity of infusion reactions. Patients should receive 100 mg of methylprednisolone IV 30 minutes before each infusion of MabTheraВ®.
Initial therapy: 1000 mg IV drip, slowly, 1 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. The repeated application is carried out in the case of residual activity of the disease or an increase in the activity of the disease more than 2.6 according to DAS28-COE (disease activity index 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.
Granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis
Before each infusion of MabThera В® , premedication should be performed (analgesic / antipyretic, for example, paracetamol; antihistamine, eg diphenhydramine).
Recommended dosing regimen:
- SCS therapy is recommended to begin within 2 weeks before the first infusion of MabTheraВ® 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 decrease in the dose of the latter until complete withdrawal (the rate of dose reduction is determined by the specific clinical situation). Oral GCS therapy can be continued during and after the completion of MabTheraВ®;
- MabThera preparation - 375 mg / m 2 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 (caused by Pneumocystis jiroveci) be prevented.
Dosing in special cases
In patients older than 65 years, dose adjustment is not required.
SIDE EFFECT
To assess the frequency of adverse reactions, the following criteria are used: very often (? 10%), often (? 1% - <10%), infrequently (? 0.1% - <1%).
Experience in the use of the drug in oncohematological diseases
MabThera В® in the treatment of low-grade non-Hodgkin's lymphoma or follicular - monotherapy / maintenance therapy
Reports of adverse reactions were 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.
On the part of the blood and lymphatic system: very often - leukopenia, neutropenia; often - thrombocytopenia, anemia; infrequently - lymphadenopathy, clotting of blood, transient partial aplastic anemia, hemolytic anemia.
On the part of 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.
From the immune system: very often - angioedema; often - hypersensitivity reactions.
On the part of metabolism and nutrition: often - hyperglycemia, weight loss, peripheral edema, facial swelling, increased LDH activity, hypocalcemia.
General disorders and disorders at the injection site: 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.
From the digestive 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.
Cardio-vascular system: often - a decrease in blood pressure, increased 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.
From the nervous system: often - dizziness, paresthesia, hypoesthesia, insomnia, anxiety, agitation, vasodilatation; infrequently - dysgeusia.
On the part of the psyche: rarely - nervousness, depression.
On the part of the musculoskeletal and connective tissue disorders: often - myalgia, arthralgia, muscle hypertonicity, back pain, neck pain, pain. Skin and subcutaneous tissue disorders:
very often - itching, rash; often - urticaria, sweating night, sweating, alopecia *.
From a sight organ: often - disorders lacrimation, conjunctivitis.
On the part of the ear and labyrinth disorders: often - pain and tinnitus.
Laboratory and instrumental data: very often - reduction in the concentration of immunoglobulin G (IgG).
* Rate is valid only for adverse reactions? 3 degrees of severity according to the criteria of the National Cancer Institute Common Toxicity (NCI-CTC).
Mabthera В® in combination with chemotherapy (R-CHOP, R-CVP , R-FC) with non-Hodgkin's lymphoma and chronic lymphocytic leukemia
Below are severe adverse reactions in addition to those that have been observed with monotherapy / maintenance therapy, and / or occurring at a higher frequency.
Infectious and parasitic diseases: very often - bronchitis; often - acute bronchitis, sinusitis, hepatitis B * (reactivation of hepatitis B virus and primary infection).
From the blood and lymphatic system: very often - neutropenia **, febrile neutropenia, thrombocytopenia; often - pancytopenia, granulocytopenia.
Skin and subcutaneous tissue disorders: very often - alopecia; often - skin diseases.
General disorders and the site of injection: often - fatigue, chills.
* Contains frequency based on observations in the treatment of recurrent / chronic lymphocytic leukemia himioustoychivogo scheme R-FC.
** prolonged and / or delayed by neutropenia was observed after R-FC circuit completion of therapy in previously untreated patients or in patients with recurrent / chronic lymphocytic leukemia himioustoychivym.
Below are side reactions encountered during therapy with Mabthera В®with the same frequency (or less) as compared with the control group: hematotoxicity, neutropenic infection, urinary tract infection, septic shock, superinfection lung, implant infection, staphylococcal septicemia, mucous nasal, pulmonary edema, heart failure, sensory disturbances, venous thrombosis, including deep vein thrombosis limbs, mucositis, edema of lower extremities, decreased left ventricular ejection fraction, increased body temperature, general health deterioration, drop, multiple organ failure, bacteremia, decompensation of diabetes.
The safety profile of the drug Mabthera В® in combination with chemotherapy regimens MCP, CHVP-IFN is not different from that in the drug combination with CVP, CHOP or FC in relevant populations.
Infusion reactions
monotherapy Mabthera В® (for 4 weeks),
more than 50% of patients were observed phenomenon resembling infusion reactions, most often - at the first infusion. Infusion reactions include chills, shaking, weakness, shortness of breath, nausea, rash, flushing, low blood pressure, fever, itching, hives, feeling tongue irritation or swelling of the throat (angioneurotic edema), rhinitis, vomiting, pain in the foci of the tumor, headache, bronchospasm . It reported on the development of symptoms of tumor lysis syndrome.
Mabthera В® in combination with chemotherapy for the following schemes: R-CVP with non-Hodgkin's lymphoma; R-CHOP with diffuse large non-Hodgkin's lymphoma; R-FC in chronic lymphocytic leukemia
Infusion reactions 3 and 4 severity during infusion or within 24 hours after infusion of the drug Mabthera В® were noted during the first cycle of chemotherapy in 12% of patients. The frequency of infusion reactions decreased with each subsequent cycle and the 8th cycle frequency chemotherapy infusion reactions reached less than 1%. Infusion reaction further to the above (with monotherapy Mabthera В® ) included: dyspepsia, rash, increased blood pressure, tachycardia, signs of tumor lysis syndrome, in some cases - myocardial infarction, atrial fibrillation, pulmonary edema and acute reversible thrombocytopenia.
Infections
monotherapy Mabthera В® (within 4 weeks)
Mabthera В®pool causes depletion of B cells in 70-80% of patients and reducing the concentration of immunoglobulins in serum of a small number of patients. Bacterial, viral, fungal infections, and infection without the refined etiology (all, regardless of the cause) developed 30.3% of patients. Severe infection (grade 3 and 4 severe), including sepsis, marked in 3.9% of patients.
Supportive therapy (non-Hodgkin's lymphoma) to 2 years
When therapy with MabThera В®We observed an increase in the overall frequency of infections, including Grade 3-4 infections. No increase in the incidence of infectious complications in maintenance therapy lasting 2 years. Cases of progressive multifocal leukoencephalopathy (PML) with a fatal outcome in patients with non-Hodgkin's lymphoma after disease progression and retreatment.
Mabthera В® in combination with chemotherapy for the following schemes: R-CVP with non-Hodgkin's lymphoma; R-CHOP with diffuse large non-Hodgkin's lymphoma; R-FC in chronic lymphocytic leukemia
When therapy with Mabthera В®scheme R-CVP was no increase in the frequency of infections or infestations. The most common were upper respiratory infection (12.3% in the group R-CVP). Serious infections occurred in 4.3% of patients receiving chemotherapy scheme R-CVP; life-threatening infections are not logged in.
The proportion of patients with infections of 2-4 severity and / or febrile neutropenia in the R-CHOP group was 55.4%. The total rate of infection of 2-4 severity in R-CHOP group was 45.5%. The frequency of fungal infections severity 2-4 in R-CHOP group was higher than in the CHOP group, due to the higher frequencies of the local candidosis and amounted 4.5%. Frequency of HSV infection 2-4 severity was higher in the group R-CHOP versus CHOP and the group was 4.5%.
In patients with chronic lymphocytic leukemia frequency hepatitis B (HBV reactivation and primary infection) Grade 3-4 in R-FC group was 2%.
From the hemopoietic system
monotherapy Mabthera В® (within 4 weeks)
1.7% - severe thrombocytopenia (3 and 4 severity); 4.2% - severe neutropenia; 1.1% - severe anemia severity (3 and 4 severity).
Supportive therapy (non-Hodgkin lymphoma) aged 2
Leukopenia (3 and 4 severity) was observed in 5% of patients, neutropenia (grade 3 and 4 severe) - 10% of patients receiving the drug Mabthera В® . The incidence of thrombocytopenia (Grade 3-4) during therapy with Mabthera В®It was low and was <1%.
Approximately 50% of patients for whom data were available for recovery of B cells after the induction therapy with Mabthera В® took 12 months or more for recovery of B cells to normal levels.
Mabthera В® in combination with chemotherapy for the following schemes: R-CVP with non-Hodgkin's lymphoma; R-CHOP with diffuse large non-Hodgkin's lymphoma; R-FC in chronic lymphocytic leukemia
Severe neutropenia and leukopenia (3 and 4 severity) in patients receiving the drug Mabthera В®in combination with chemotherapy, leukopenia 3 and 4 severity were observed more frequently than patients receiving chemotherapy alone. The frequency of severe leucopenia was 88% in patients treated with R-CHOP, and 23% in patients treated with R-FC. The frequency of severe neutropenia was 24% in the R-CVP, 97% in the R-CHOP and 30% in R-FC group with previously untreated chronic lymphocytic leukemia. The higher incidence of neutropenia in patients treated with the drug Mabthera В®and chemotherapy was not associated with an increased incidence of infections and infestations compared to patients receiving chemotherapy alone. Patients with recurrent or himioustoychivym chronic lymphocytic leukemia after therapy for R-FC scheme in some cases neutropenia was characterized by a long passage, or a later date demonstrations.
Severe anemia and thrombocytopenia (grade 3 and 4 severe):significant difference in the incidence of anemia 3 and 4 in the severity was groups. In the group R-FC when a first line treatment of chronic lymphocytic leukemia, anemia, 3 and 4 severity occurs in 4% of patients thrombocytopenia 3 and 4 severity - 7% of patients. In the group R-FC in recurrent or chronic lymphoblastic anemia himioustoychivom 3 and 4 severity met in 12% of patients with thrombocytopenia 3 and 4 severity - 11% of patients.
From the side of the cardiovascular system
Monotherapy drug Mabthera В® (within 4 weeks)
Adverse effects to the cardiovascular system noted in 18.8% of cases. The most frequently - the rise and fall of blood pressure; in rare cases - cardiac arrhythmias 3 and 4 severity (including ventricular and supraventricular tachycardia), angina pectoris.
Supportive therapy (non-Hodgkin lymphoma) aged 2
Frequency cardiovascular disorders 3 and 4 severity was similar in patients treated with the drug Mabthera В® and not receiving it. Severe cardiovascular disorders occur in less than 1% of patients not receiving the drug Mabthera В®And 3% of patients receiving the drug (atrial fibrillation - 1%, myocardial infarction - 1%, left ventricular failure - y <1%, myocardial ischemia - y <1%).
Mabthera В® in combination with chemotherapy for the following schemes: R-CVP with non-Hodgkin's lymphoma; R-CHOP with diffuse large non-Hodgkin's lymphoma; R-FC in chronic lymphocytic leukemia
incidence of cardiac arrhythmias 3 and 4 severity mainly supraventricular arrhythmia (tachycardia, atrial flutter and atrial fibrillation) was higher than in the CHOP group and was 6.9% in the R-CHOP group. All arrhythmias developed or in connection with the infusion of MabThera В®Or were associated with predisposing conditions such as fever, infection, acute myocardial infarction or accompanying diseases of the respiratory and cardiovascular systems. R-CHOP and CHOP group did not differ between a frequency other cardiac adverse events 3 and 4 severity, including heart failure, myocardial disease and coronary artery disease manifestation.
The overall incidence of cardiovascular events 3 and 4 severity was low as in the first-line therapy for chronic lymphocytic leukemia (4% in the R-FC), and in the treatment of recurrent / chronic lymphocytic leukemia himioustoychivogo (4% in R-FC group).
Nervous system
Mabthera В®in combination with chemotherapy for the following schemes: R-CVP with non-Hodgkin's lymphoma; R-CHOP with diffuse large non-Hodgkin's lymphoma; R-FC in chronic lymphocytic leukemia
patients (2%) from the group R-CHOP with cardiovascular risk factors developed thromboembolic disorders of cerebral circulation during the first cycle of therapy, in contrast to the patients in the CHOP, whose cerebrovascular evolved during observation without treatment. The difference between the groups in the incidence of other thromboembolic events was absent.
The overall incidence of neurological disorders 3 and 4 severity was low as in the first-line therapy for chronic lymphocytic leukemia (4% in R-FC group) and in the treatment of recurrent / chronic lymphocytic leukemia himioustoychivogo (3% in R-FC group).
The concentration of IgG
Supportive therapy (non-Hodgkin lymphoma) to 2 years
After induction therapy IgG concentration was below the lower limit of normal (<7 g / L) in the group receiving the drug Mabthera В® , and in the group not receiving the drug. In the group receiving no drug Mabthera В® , the median concentration of IgG sequentially increased and exceeded the lower limit of normal, while the median IgG concentration did not change in group receiving drug Mabthera В® . In 60% of patients receiving the drug Mabthera В® for 2 years, IgG concentration remained below the lower limit. The group without drug treatment Mabthera В® in 2 years IgG concentration remained below the lower limit at 36% of patients.
Specific categories of patients
Monotherapy MabThera В® (for 4 weeks)
Elderly patients (65 years and older) the frequency and severity of adverse reactions and side effects of grade 3 and 4 severity did not differ from that in younger patients.
Combination Therapy
In elderly patients (65 years and older) as first-line therapy and in the treatment of recurrent / chronic lymphocytic leukemia himioustoychivogo frequency side reactions 3 and 4 severity from blood and lymphatic system was higher in comparison with younger patients.
At high tumor load (diameter single foci of more than 10 cm) increased frequency of adverse reactions 3 and 4 degrees.
When re-treatment frequency and severity of adverse reactions did not differ from those during initial therapy.
Experience with the drug in rheumatoid arthritis
following are adverse reactions encountered in therapy drug Mabthera В® with a frequency of at least 2% and at least a 2% difference compared to the control group.
By the immune system, general disorders and at the injection site: very often - infusion reactions * (often - increase and decrease of blood pressure, flushing, rash, hives, itching, chills, fever, nausea, rhinitis, feeling a tickle in the throat, tachycardia, weakness, pain in the mouth and pharynx, peripheral edema, erythema).
* - also rarely observed following clinically significant infusion reactions: generalized edema, bronchospasm, wheezing, laryngeal edema, angioneurotic edema, generalized pruritus, anaphylaxis, anaphylactoid reactions.
Infectious and parasitic diseases: very often - urinary tract infection, upper respiratory tract infection; often - bronchitis, sinusitis, gastroenteritis, tinea pedis.
From the digestive system: often - dyspepsia, diarrhea, gastroesophageal reflux disease, ulceration of the oral mucosa, pain in the right upper quadrant of the abdomen.
From the nervous system: very often - headache; often - headache, paresthesia, dizziness, sciatica.
Mental disorders:often - depression, anxiety.
On the part of the musculoskeletal system and connective tissue disorders: often - arthralgia, musculoskeletal pain, osteoarthritis, bursitis.
Skin and subcutaneous tissue disorders: often - alopecia.
Laboratory and instrumental data: often - hypercholesterolemia.
Repeated therapy. Profile undesired reactions with repeated use is not different from that during initial therapy. Improved safety profile with each subsequent course of therapy and was characterized by a decrease in the frequency of infusion reactions, infections and exacerbations of the disease that are frequently encountered in the first 6 months of therapy.
Infusion reaction. Infusion reactions were most frequently occurring undesirable reaction with
