Composition, structure and packing
Concentrate for solution for infusion is transparent or slightly opalescent, colorless or pale yellow. 1 ml 1 vial. rituximab 10 mg 100 mg. Excipients: sodium citrate dihydrate, polysorbate 80, sodium chloride, water, d / and hydrochloric acid or sodium hydroxide.
Concentrate for solution for infusion is transparent or slightly opalescent, colorless or pale yellow. 1 ml 1 vial. rituximab 10 mg 500 mg. Excipients: sodium citrate dihydrate, polysorbate 80, sodium chloride, water, d / and hydrochloric acid or sodium hydroxide.
Clinico-pharmacological group: The antitumor drug. Monoclonal antibodies.
Pharmacological action
Medical immuno-biological product, is a chimeric monoclonal antibody mouse / human, which specifically binds to the transmembrane antigen, CD20. This antigen is located on the pre-B lymphocytes and mature B-lymphocytes, but not on hematopoietic stem 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 CD20 antibody is not internalized and no longer deal with the cell membrane into the extracellular space. CD20 does not circulate in plasma in the form of free antigen and therefore does not compete for binding to antibodies. Rituximab binds to CD20 antigen on B-lymphocytes and initiates immunological reactions that mediate lysis of B-cells.
Possible mechanisms of cell lysis include complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity and induction of apoptosis. Rituximab sensitizes the line of B-cell lymphoma rights to the cytotoxic action of some chemotherapeutic drugs in vitro. The number of B cells in peripheral blood after the first injection of the drug is reduced below normal, and begins to recover in patients with hematological malignant diseases after 6 months, reaching normal values by 9-12 months after completion of therapy.
In patients with rheumatoid arthritis duration of reducing the number of B-cells varies, most patients follow prescribed treatment until full recovery of their number. Antihimernye antibodies were detected in 1.1% (4 out of 356) examined patients with non-Hodgkin's lymphoma and in 10% - with rheumatoid arthritis. Pharmacokinetics Non-Hodgkin's lymphoma in patients with recurrent c B-cell lymphoma, rituximab concentration in the serum and its T1 / 2 increases with increasing dose. After a 1-y / v infusion at a dose of 375 mg/m2 T1 / 2 of rituximab was 76.3 h after the 4 th infusion - 205.8 hours after Cmax 1-y infusion of 205.6 mg / ml after the 4 th infusion - 464.7 ug / ml, plasma clearance - 0.0382 L / h and 0.0092 L / h, respectively.
Individual differences in serum concentrations of the drug rather pronounced. With effective treatment, serum concentration of rituximab was significantly higher. The concentration of the drug negatively correlates with tumor burden. Traces of rituximab can be found in the body for 3-6 months after the last infusion.
In patients with diffuse large cell lymphoma rituximab serum concentrations comparable to those in patients with non-Hodgkin's lymphoma low-grade or follicular, receiving the same dose. Rheumatoid arthritis after two / v infusion of 1000 mg at 2-week break Cmax rituximab - 369 ug / ml, mean T1 / 2 - 19.2-20.8 days, mean systemic clearance - 0.23 l / d and Vd in the equilibrium state - 4.6 l .
Pharmacokinetics in special clinical situations
Vd and clearance of rituximab, adjusted for body surface area in men is somewhat higher than in women; correct dose of rituximab is not required. The data on pharmacokinetics in patients with renal and hepatic insufficiency are absent.
Statement
Non-Hodgkin's lymphoma:
recurrent or resistant to chemotherapy-cell, CD20-positive non-Hodgkin's lymphoma low-grade or follicular;
follicular lymphoma, stage III-IV in combination with chemotherapy scheme CVP in previously untreated patients;
follicular lymphoma, as maintenance therapy after response to induction therapy;
CD20-positive diffuse large non-Hodgkin's lymphoma, in combination with chemotherapy CHOP scheme.
Rheumatoid arthritis (active form) in adults in combination with methotrexate in case of intolerance or inadequate response to current modes of therapy involving one or more inhibitors of tumor necrosis factor (TNF-α).
Dosage regimen
The standard dosing regime Enter in / by infusion (slow), via a separate catheter, a dose of 375 mg/m2, 1 times a week. You can not enter in / bolus or as a / v injection. Recommended initial velocity of the first infusion of 50 mg / h, in the future it may be increased to 50 mg / h every 30 minutes, bringing up to a maximum speed - 400 mg / h. Subsequent infusions can be started from 100 mg / h and increase it to 100 mg / h every 30 min to a maximum speed of 400 mg / h. Before each infusion of MabThera should hold premedication (analgesic / antipyretic such as paracetamol, antihistamine, such as diphenhydramine).
If Mabtera not used in combination with CHOP or CVP chemotherapy in the sedation also include corticosteroids. Correction dose during treatment reduces the dose of rituximab is not recommended. When MabThera is introduced in combination with chemotherapy scheme CHOP or CVP, reducing 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 in adults - 375 mg/m2 1 times per week for 4 weeks.
In combination with CVP (cyclophosphamide, vincristine, prednisolone): 375 mg/m2, on the first day of the cycle of chemotherapy after i / v administration of corticosteroids as part of a scheme CVP; 8 cycles (cycle - 21 days). Re-use in case of recurrence: patients who responded to the first course of therapy - 375 mg/m2 1 times per week for 4 weeks. Maintenance therapy: After the response to induction therapy administered in a dose of 375 mg/m2 1 time in 3 months, not exceeding 2 years or until disease progression.
Diffuse large non-Hodgkin's lymphoma.
In combination with chemotherapy scheme CHOP: 375 mg/m2, on the first day of each cycle of chemotherapy, 8 cycles, after i / v administration of corticosteroids. Other components of the circuit CHOP (cyclophosphamide, doxorubicin, and with vincristine) are introduced after the appointment of MabThera.
Rheumatoid arthritis
Initial therapy: prescribe a dose of 1000 mg / to drip slowly for 30 minutes to / in the introduction of methylprednisolone 100 mg, 1 every 2 weeks, a course of treatment - 2 infusion. Re-application is possible within 6 -12 months after the first course of therapy: 1000 mg 1 every 2 weeks, treatment - 2 infusion.
Patients older than 65 years of dose correction is required.
Terms of cooking and storage solution
Needed drug type in aseptic conditions and are bred to the calculated concentration (1-4 mg / ml) in infusion bottles (package) with a 0.9% solution of sodium chloride injection or 5% dextrose (solutions must be sterile and apyrogenic). To mix gently invert the vial (package) to avoid foaming. Before the introduction of the solution must be inspected for absence of impurities or discoloration. Since Mabtera not contain preservatives, the prepared solution should be used immediately.
The prepared infusion solution
MabThera is stable for 12 h at room temperature or for up to 24 hours at a temperature of 2 ° to 8 ° C. The physician responsible for the preparation conditions and storage time of the prepared solution before use.
Treatment effectiveness
Non-Hodgkin's lymphoma of low-grade or follicular
Monotherapy
Initial therapy, 4 weeks. In patients with relapsed or resistant to chemotherapy of B-cell non-Hodgkin's lymphoma, low-grade or follicular, MabThera received a dose 375 mg/m2 as a 4 / 1 by infusion once a week, the total frequency of remission was 48% complete remission - 6% , partial remission - 42%. The median time to disease progression - 13 months. Total frequency of remission in patients with histological subtypes of tumors, C and D (classification IWF) was higher than with subtype A (58% and 12%, respectively) in patients with the largest tumor focus diameter of less than 5 cm higher than the diameter the focus of more than 7 cm (53% and 38%) and in patients with relapsed himiochuvstvitelnym - higher than himioustoychivym (duration of remission less than 3 months) 53% and 36%, respectively. Total frequency of remission in patients after autologous bone marrow transplantation 78% compared with 43% in patients without bone marrow transplantation. The frequency of therapy response MabThera does not correlate with age, sex, degree of malignancy, a massive defeat, the localization of lesions and the level of LDH. But obtained a statistically significant correlation between the frequency response and bone marrow: 40% of patients with bone marrow involvement responded to therapy compared with 59% of patients without bone marrow involvement (p = 0.0186). Initial therapy for 8 weeks.
Patients with relapsed or himioustoychivoy-cell non-Hodgkin's lymphoma low-grade or follicular common answer is 57%, median times to disease progression in response to therapy is 19.4 months (range 5.3-38.9 months). Initial treatment for the disease with bulky disease, 4 weeks.
In patients with relapsed or himioustoychivoy B-cell non-Hodgkin's lymphoma low-grade or follicular with a massive defeat (the diameter of the tumor core ≥ 10 cm) overall response was 36% and median time to disease progression in response to therapy - 9.6 months (range 4.5-26.8 months). Re-treatment, 4 weeks. The frequency of remission in re-treated patients is comparable to that in the first course of therapy.
In patients with relapsed or himioustoychivoy B-cell non-Hodgkin's lymphoma of low-grade or follicular with an objective response to previous treatment with MabThera her reappointment overall response to treatment reached 38%, median time to disease progression among respondents - 17.8 months.
The combination with CVP (R-CVP) Combined therapy R-CVP (Mabtera 375 mg/m2 on the first day of each cycle, cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2 to 2 mg / day for the first day of the cycle, and prednisolone 40 mg / m2/sut, 1-5 day, every 3 weeks, with 8 cycles), the main criteria of efficiency - reducing the risk of lack of therapeutic response to the 67% increase in time to the development of ineffective treatment from 6.7 months to 25.9 months (p <0.0001).
Frequency response (complete response, unconfirmed complete response, partial response) in group R-CVP was: 80.9% compared with 57.2% (p <0.0001). After 18 months after the start of therapy the median duration of treatment response was not achieved in the group R-CVP and was 9.8 months in the group CVP (p <0.0001). The risk of recurrence decreased by 70% in the appointment of R-CVP (p <0.0001). Frequency of survival without events after 12 months of therapy was 69% in group R-CVP, compared with 32% in the CVP. Mabtera increases the time before the appointment of a new therapy or death, time to disease progression from 14.5 to 27 months (p <0.0001). After 12 months in 81% of patients treated with MabThera not observed recurrent disease, compared with 58% of patients receiving only the CVP. The advantages of a combination of MabThera with CVP were observed in all patients, regardless of age, number of extranodal lesions involving bone marrow, increasing the level of LDH, β2-microglobulin, the presence of B symptoms, bulky disease, number of affected sites, the hemoglobin values of the international prognostic index (IPI ) and index FLIPI in patients with follicular lymphoma.
Maintenance therapy
In patients with relapsed or resistant follicular non-Hodgkin's lymphoma therapy after induction therapy, R-CHOP or CHOP MabThera maintenance therapy significantly and statistically significantly increases progression-free survival to 42.2 months compared with 14.3 months in patients not receiving maintenance therapy reduces the risk of progression disease or death by 61%. The expected level of progression-free survival after 12 months in the group of maintenance therapy was 78% compared with 57% in the control group has not received MabThera maintenance therapy. Maintenance therapy with MabThera reduces the risk of death by 56%, increases the time before the appointment of new therapies (38.8 months compared to 20.1 months), and reduces the risk of the appointment of new therapies - up to 50%.
Patients with complete or unconfirmed complete response to the appointment of MabThera as maintenance therapy significantly improves survival without evidence of disease from 16.5 months to 53.7 months and reduces the risk of relapse by 67%. Benefits received MabThera maintenance therapy for all subgroups of patients regardless of the type of induction therapy (CHOP or R-CHOP), response to induction therapy (complete or partial response), and regardless of age, sex, stage of disease, the values of IPI, FLIPI, in -symptoms, involvement of bone marrow, the number of lymph nodes and extranodal foci, the number of previous modes of therapy, a better response to therapy, LDH, hemoglobin and β2-microglobulin, except for a subgroup of patients with bulky disease. Diffuse large non-Hodgkin's lymphoma
Application circuit R-CHOP (Mabtera 375 mg/m2 on the first day of the cycle in combination with CHOP: cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 up to a maximum of 1 mg on the first day of the cycle, and prednisolone 40 mg / m2/sut on days 1-5, every 3 weeks, with 8 cycles) in untreated patients in elderly (60 to 80 years) leads to a statistically significant increase "uneventful" survival from 13 to 35 months, compared with only scheme CHOP (p = 0.0001) (the "Events" refers deaths, relapses or progression of lymphoma, as well as the appointment of a new scheme of therapy).
Application of R-CHOP scheme reduces the risk of these events by 41%. The median duration of observation was 31 months. Overall survival in the group of R-CHOP was significantly increased to 68.2% compared with 57.4% in the CHOP group, with the risk of death decreased by 33% (p = 0.0094). Therapy scheme R-CHOP CHOP scheme also outperforms the frequency of complete remission by the end of treatment (76.2% and 62.4%, respectively, p = 0.0028). The risk of disease progression in the group of R-CHOP decreased by 46% and the risk of relapse - at 51%. The advantages of the scheme R-CHOP is not dependent on sex, age, IPI values, adjusted for age, ECOG, β2-microglobulin, LDH, albumin, B-symptoms, bulky disease, involvement in the bone marrow and extranodal lesions.
Rheumatoid arthritis
Rituximab in combination with methotrexate significantly reduces the activity of the disease. The clinical effect for at least 20% according to the criteria of the American College of Rheumatology (AKR20), compared with methotrexate monotherapy was observed in most patients, regardless of the titer of rheumatoid factor, age, sex, body surface area, race, previous therapy and disease activity. Clinically and statistically significant improvement in the treatment of MabThera noted with regard to all criteria, the AKP: the number of swollen and painful joints, pain index, C-reactive protein, rheumatoid factor, along with improving the overall evaluation of the effectiveness of treatment in the opinion of the physician and patient assessment of pain intensity according to patient index, degree of disability. Rituximab significantly reduces disease activity index DAS28. Good and moderate response by EULAR criteria was achieved in significantly more patients in the appointment of MabThera with methotrexate compared with methotrexate monotherapy.
Patients who received drug therapy Mabtera, noted a significant improvement in the index of disability (by questionnaire and health assessment - HAQ-DI), weakness (FACIT-F) and improving both physical and mental health indicators questionnaire SF-36. In the appointment of rituximab showed a significant decrease in the concentration of rheumatoid factor (range 45-64%). The concentration of immunoglobulins, the number of lymphocytes, white blood cells remained within normal limits, except for a transient reduction in the number of leukocytes in the first 4 weeks of therapy.
As with MabThera monotherapy and in combination with methotrexate showed a significant reduction in inflammatory markers (IL-6, CRH, serum amyloid protein type A protein isotype S100 A8 and A9). The frequency of response to therapy with MabThera re-treated patients is comparable to that in the first course of therapy.
Side effect
Reactions associated with infusion: fever, weakness, shortness of breath, indigestion, nausea, rash, flushing, hypotension, hypertension, fever, itching, rash, irritation of the throat, rhinitis, tachycardia, vomiting, pain, symptoms of tumor lysis syndrome.
In some cases, during the scheme R-CHOP: myocardial infarction, atrial fibrillation and pulmonary edema. Infections: upper respiratory tract infection (most often - nasopharyngitis, sinusitis, bronchitis, pneumonia, superinfection of the lungs), urinary tract infections, sepsis, herpes zoster, septic shock, infection of implants, staphylococcal septicemia; very rarely - reactivation of hepatitis B.
On the part of the hemopoietic system: leukopenia, neutropenia, thrombocytopenia, anemia, febrile neutropenia and less than 1% - lymphadenopathy, blood clotting, and very rarely - pancytopenia (4 weeks or more after the last administration of rituximab), a transient increase in the level of IgM in patients with makroglobulinemiey Valdenstrema, with subsequent return to its initial value after 4 months; partial transient aplastic anemia, hemolytic anemia.
On the part of the respiratory system: rhinitis, nasal mucus, bronchospasm, cough or increased cough, respiratory infection, dyspnea, acute respiratory failure, pulmonary infiltrates, less than 1% - hypoxia, pulmonary dysfunction, bronchiolitis obliterans, asthma.
On the part of the whole body: throat irritation, back pain, chest pain, pain in the neck, pain in the foci of the tumor, flu-like syndrome, peripheral edema, Mucosit, syncope, weight loss, multiple organ dysfunction syndrome, rapid lysis of the tumor; very rare - serum sickness and less than 1% - an increase in abdominal, anaphylactic reactions, pain at the injection site.
On the part of the digestive system: dyspepsia, nausea, vomiting, diarrhea, anorexia, dysphagia, stomatitis, constipation, abdominal pain.
Since the cardiovascular system: hypotension, hypertension, orthostatic hypotension, tachycardia, bradycardia, arrhythmia (including ventricular and supraventricular tachycardia, atrial fibrillation), unstable angina pectoris, vasodilatation, venous thrombosis, including extremity deep vein thrombosis, cardiac insufficiency, low ejection fraction, pulmonary edema, myocardial infarction, very rare: vasculitis, predominantly cutaneous (leukocytoclastic), ischemic cerebral circulation.
From the side of the central nervous system and peripheral nervous system: dizziness, headache, paresthesia, hypoesthesia, headache, confusion, and very rarely - neuropathy of cranial nerves, in conjunction with peripheral neuropathy with or without (marked reduction of visual acuity, hearing, failure of other organs emotions, facial nerve palsy) in different periods of therapy - until several months after treatment MabThera, confusion, less than 1% - anxiety, depression, anxiety, taste perversion.
From the Musculoskeletal System: myalgia, arthralgia, muscular hypertonicity, muscle cramps, osteoarthritis.
On the part of the endocrine system: hyperglycemia, diabetes decompensation. Dermatological reactions: itching, rash, urticaria, increased sweating at night, sweating, alopecia, very rarely - heavy bullous reaction, toxic epidermal necrolysis with fatal consequences.
From the senses: Violations watery, conjunctivitis, pain and tinnitus.
From the laboratory parameters: increase in activity of lactate dehydrogenase, hypocalcemia, hypercholesterolemia, hyperglycemia, bacteremia.
Monotherapy Infusion reactions often occur during the first infusion. The frequency of infusion reactions decreased from 77% (including 7% - 3, and 4 degrees) for 1 second infusion of up to 30% (2% - 3, and 4 degrees) at 4 and 14% (absence of reactions 3 and 4 degrees) at 8-second infusion.
Infections: Mabtera cause depletion of the pool of B cells in 70-80% of cases and reduce the concentration of immunoglobulins in serum in a small number of patients. 30.3% - infectious complications (for whatever reason), including 18.8% - bacterial infections, 10.4% - viral infections, 1.4% - fungal infections, 5.9% - infection without refined etiology (one patient could be different infection). Severe infections (3 and 4 degrees), including sepsis, were noted in 3.9% of patients: during therapy (1.4%) and in patients during observation without treatment (2.5%).
On the part of the hemopoietic system: severe thrombocytopenia (3 and 4 severity) was observed in 1.7% of patients, severe neutropenia - at 4.2% of patients with severe anemia and the severity (3, 4) - in 1.1% of patients. Have been reported 1 case of transient aplastic anemia and 2 cases of hemolytic anemia.
Since the cardiovascular system: side-effects were observed in 18.8% of cases, most often - arterial hypo-and hypertension.
Mabtera in combination with chemotherapy scheme SVP (R-CVP) Infusion reactions 3 and 4 degrees (9%): fever, weakness, shortness of breath, indigestion, nausea, rash, flushing. Infections: infections (33% during treatment and 28 days after the end of treatment, compared with 32% of patients who received only CVP), including 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 grade 3 and 4 severity (24%), neutropenia 4 degrees (3.1%). The higher incidence of neutropenia in the group of R-CVP does not increase the frequency of infections. Anemia - from 0.6% of patients in group R-CVP and in 1.9% of patients treated with CVP, thrombocytopenia - at 1.2% in group R-CVP and absent in patients treated with CVP. The overall incidence of cardiovascular disorders was similar in patients treated with CVP (5%) and R-CVP (4%).
Mabtera in combination with chemotherapy scheme CHOP (R-CHOP) Infusion reactions 3 and 4 degrees during the infusion or within 24 h after infusion of MabThera were observed during the first cycle of R-CHOP 9% of patients. By the eighth cycle of R-CHOP frequency of infusion reactions decreased to less than 1%. Infection: Infection 2-4 severity and / or febrile neutropenia in the group of R-CHOP - 55.4% in the CHOP group - 51.5%, febrile neutropenia without concomitant documented infection in patients receiving R-CHOP - 20.8% in patients receiving CHOP - 15.3%. The overall frequency of infections 2-4 degrees in the group R-CHOP was 45.5% in the CHOP group - 42.3%, with no marked difference in incidence of systemic bacterial and fungal infections.
The frequency of fungal infections 2-4 degrees in the group of R-CHOP was higher than in the CHOP group (4.5% and 2.6%, respectively), this difference was due to a higher rate of local candidiasis during therapy. The frequency of HSV infection 2-4 degrees, including with damage to the eye, was higher in group R-CHOP (4.5%) than in the CHOP group (1.5%), 7 of 9 cases recorded in group R-CHOP, the disease emerged during therapy.
On the part of the hemopoietic system: after each cycle, leukopenia (88% compared to 79%) and neutropenia (97% compared to 88%) 3 and 4 severity were observed more frequently in the R-CHOP group than in CHOP group, respectively.
Differences in the incidence of anemia 3 and 4 severity in the two groups was observed (19% in the CHOP group and 14% in the R-CHOP), there was no difference in the frequency of thrombocytopenia (15% in the CHOP group and 16% in the R-CHOP ). Time to resolution of all hematological disorders in two therapeutic groups were comparable.
Since the cardiovascular system: the frequency of cardiac arrhythmias 3 and 4 degrees, mostly supraventricular arrhythmias (tachycardia, atrial flutter and atrial fibrillation), a group of R-CHOP was higher (6.9%) than in the CHOP group (1.5%) .
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. Group R-CHOP and CHOP did not differ among themselves on the frequency of other cardiac adverse events 3 and 4 degrees of severity, including heart disease, myocardial disease and manifestation of coronary heart disease.
From the side of the central nervous system and peripheral nervous system: during the first cycle of therapy in 4 patients (2%) of group R-CHOP with cardiovascular risk factors developed ischemic attacks due to thromboembolism, in contrast to 1.5% of patients in the CHOP group during observation without treatment. The difference between the groups in the incidence of other thromboembolic disorders was absent.
Rheumatoid arthritis
The frequency of infection is 0.9 cases per year, the proportion of heavy infections, some of which were fatal, was less than 0.05 cases per year. The frequency of malignant diseases after the appointment of MabThera was 1.5 per 100 patients per year and higher than in the population.
Specific categories of patients
The high tumor burden (the diameter of single foci of more than 10 cm): increased incidence of adverse reactions of grade 3-4 severity.
Elderly patients (over 65): the frequency and severity of side effects and side effects 3 and 4 severity did not differ from that in younger patients. Repeated therapy: frequency and severity of side effects did not differ from those in the initial therapy.
Contraindications
acute infectious diseases, expressed primary or secondary immunodeficiency;
Hypersensitivity to rituximab, a drug or any component of the mouse proteins.
Precautions to apply for respiratory failure in history, or tumor infiltration of the lungs, when the number of circulating malignant cells> 25 000/mkl or high tumor load (chronic lymphocytic leukemia, or lymphoma, mantle cell zone), neutropenia (less than 1500/mkl), thrombocytopenia (less than 75 000/mkl) for chronic infections.
Pregnancy and lactation
Effects of rituximab during pregnancy has not been studied. The injurious effect of MabThera in the fetus and the effect of the drug on fertility is unknown.
Given that the immunoglobulin class IgG penetrate through the placental barrier rituximab can cause depletion of the pool of B cells in the fetus. MabThera should not be given during pregnancy except in cases where the expected benefit of therapy to the mother outweighs the potential risk to the fetus. During the period of treatment and within 12 months after the end of women of childbearing age should use effective methods of contraception. It is not known whether rituximab is allocated through breast milk.
Given that the immunoglobulin class IgG, circulating in maternal blood, are provided with breast milk MabThera should not be used during lactation. Cautions MabThera introduced under the close supervision of oncologist, hematologist or rheumatologist, if the necessary conditions for resuscitation. The development of infusion reactions may be due to the release of cytokines or other mediators.
The majority of patients within 30 min-2 h after the first infusion of MabThera appear fever with chills or shivering. Severe reactions include symptoms from the lung, hypotension, urticaria, angioedema, nausea, vomiting, weakness, headache, itching, irritation of tongue or throat swelling (vascular edema), rhinitis, flushing, pain in the foci of the disease and, in some cases , signs of tumor lysis syndrome fast. Severe infusion reactions is difficult to distinguish from hypersensitivity reactions or cytokine release syndrome. There have been reports of fatal infusion reactions, described in the post-registration period of the drug.
Infusion reactions disappear after a delay or interruption of MabThera and the introduction of supportive measures (including on / in the introduction of 0.9% sodium chloride, diphenhydramine and acetaminophen, bronchodilators, SCS).
In most cases, after the complete disappearance of symptoms of infusion can be resumed at a rate of 50% from the previous (eg, 50 mg / h instead of 100 mg / h). The majority of patients with infusion reactions, no life-threatening, rituximab treatment was completed.
Adverse reactions in the lungs: may increase symptoms over time or clinical deterioration after initial improvement. Patients with pulmonary symptoms or other severe infusion reactions should be carefully observed until complete resolution of symptoms. Continuation of therapy after the complete disappearance of symptoms is rarely accompanied by a re-development of severe infusion reactions. Acute respiratory failure may be accompanied by the formation of interstitial infiltrates in the lungs or pulmonary edema, often seen in the first 1-2 h after the first infusion.
With the development of adverse reactions in the lungs infusion of rituximab should be stopped immediately and appoint an intensive symptomatic therapy. As an initial improvement of clinical symptoms can change as deterioration, patients should be carefully observed until the resolution of pulmonary symptoms. Rapid tumor lysis syndrome is possible after the first infusion of MabThera in patients with large numbers of circulating malignant lymphocytes.
Tumor lysis syndrome include hyperuricemia, hyperkalemia, hypocalcemia, acute renal failure, increased LDH. Patients at risk require careful medical supervision and conduct regular laboratory examination. With the rapid development of symptoms of tumor lysis conduct appropriate therapy. After complete relief of symptoms in a limited number of cases therapy.
MabThera continued in conjunction with the prevention of tumor lysis syndrome fast. Patients with large numbers of circulating malignant cells (more than 25 000/mkl) or high tumor burden (eg, chronic lymphocytic leukemia, or lymphoma cells from the mantle zone), in which the risk is extremely severe infusion reactions may be particularly high, MabThera should be prescribed with extreme caution , under the close supervision and only for inefficiency of all other methods of treatment. The first infusion of the drug in such patients should be administered at a lower speed.
Due to the potential development of anaphylactoid reactions during in / in the introduction of protein drugs must have a means for coping: epinephrine (adrenaline), antihistamines and corticosteroids.
During infusion requires careful monitoring of patients with cardiovascular disease history. Because of the possibility of hypotension is not less than 12 hours before the infusion of MabThera should be abolished antihypertensive drugs.
Although monotherapy with MabThera has no mielosupressivnogo actions need to be careful to make a decision on the appointment of the drug with less neutropenia and thrombocytopenia 1500/mkl least 75 000/mkl because the experience of its clinical application in such patients is limited. The use of MabThera in patients after autologous bone marrow transplantation and other high-risk groups with possible dysfunction of the bone marrow was not accompanied by symptoms of myelotoxicity.
In the course of treatment should be regularly conduct detailed analysis of the peripheral blood, including counting the number of platelets in accordance with routine practice. Infections: very rarely using the combination of MabThera to chemotherapy were observed reactivation of hepatitis B and fulminant hepatitis, whose connection with the reception MabThera is not installed.
Such patients should be carefully monitored. Immunization: The safety and effectiveness of immunization of any vaccine, particularly live viral vaccines, after treatment MabThera not been studied. Vaccination should be completed no less than 4 weeks prior to the appointment of rituximab. Vaccination with live vaccines is not recommended for reducing the number of B-cells.
Effects on ability to drive vehicles and management mechanisms
Does rituximab's ability to manage and work with machines and mechanisms is unknown, although pharmacological activity and the adverse effects described do not suggest such an influence.
Overdose
Cases of overdose in humans have not been observed. Efficacy and safety of rituximab in single doses over 1 g were not studied.
Drug Interactions
Data on possible drug interactions are limited MabThera. In the appointment of other monoclonal antibodies for diagnostic or therapeutic purposes patients with antibodies against proteins of the mouse or antihimernye antibodies increases the risk of allergic reactions.
Tolerability of concurrent or sequential use of MabThera and drugs that can reduce the number of normal B-cells (in addition to the scheme CHOP or CVP), if not installed. Mabtera compatible with PVC and polyethylene infusion systems or packages.
Terms and Conditions of storage
The drug should be kept in the dark, away from children at a temperature of 2 ° to 8 ° C. Shelf life - 2.5 years.
Concentrate for solution for infusion is transparent or slightly opalescent, colorless or pale yellow. 1 ml 1 vial. rituximab 10 mg 100 mg. Excipients: sodium citrate dihydrate, polysorbate 80, sodium chloride, water, d / and hydrochloric acid or sodium hydroxide.
Concentrate for solution for infusion is transparent or slightly opalescent, colorless or pale yellow. 1 ml 1 vial. rituximab 10 mg 500 mg. Excipients: sodium citrate dihydrate, polysorbate 80, sodium chloride, water, d / and hydrochloric acid or sodium hydroxide.
Clinico-pharmacological group: The antitumor drug. Monoclonal antibodies.
Pharmacological action
Medical immuno-biological product, is a chimeric monoclonal antibody mouse / human, which specifically binds to the transmembrane antigen, CD20. This antigen is located on the pre-B lymphocytes and mature B-lymphocytes, but not on hematopoietic stem 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 CD20 antibody is not internalized and no longer deal with the cell membrane into the extracellular space. CD20 does not circulate in plasma in the form of free antigen and therefore does not compete for binding to antibodies. Rituximab binds to CD20 antigen on B-lymphocytes and initiates immunological reactions that mediate lysis of B-cells.
Possible mechanisms of cell lysis include complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity and induction of apoptosis. Rituximab sensitizes the line of B-cell lymphoma rights to the cytotoxic action of some chemotherapeutic drugs in vitro. The number of B cells in peripheral blood after the first injection of the drug is reduced below normal, and begins to recover in patients with hematological malignant diseases after 6 months, reaching normal values by 9-12 months after completion of therapy.
In patients with rheumatoid arthritis duration of reducing the number of B-cells varies, most patients follow prescribed treatment until full recovery of their number. Antihimernye antibodies were detected in 1.1% (4 out of 356) examined patients with non-Hodgkin's lymphoma and in 10% - with rheumatoid arthritis. Pharmacokinetics Non-Hodgkin's lymphoma in patients with recurrent c B-cell lymphoma, rituximab concentration in the serum and its T1 / 2 increases with increasing dose. After a 1-y / v infusion at a dose of 375 mg/m2 T1 / 2 of rituximab was 76.3 h after the 4 th infusion - 205.8 hours after Cmax 1-y infusion of 205.6 mg / ml after the 4 th infusion - 464.7 ug / ml, plasma clearance - 0.0382 L / h and 0.0092 L / h, respectively.
Individual differences in serum concentrations of the drug rather pronounced. With effective treatment, serum concentration of rituximab was significantly higher. The concentration of the drug negatively correlates with tumor burden. Traces of rituximab can be found in the body for 3-6 months after the last infusion.
In patients with diffuse large cell lymphoma rituximab serum concentrations comparable to those in patients with non-Hodgkin's lymphoma low-grade or follicular, receiving the same dose. Rheumatoid arthritis after two / v infusion of 1000 mg at 2-week break Cmax rituximab - 369 ug / ml, mean T1 / 2 - 19.2-20.8 days, mean systemic clearance - 0.23 l / d and Vd in the equilibrium state - 4.6 l .
Pharmacokinetics in special clinical situations
Vd and clearance of rituximab, adjusted for body surface area in men is somewhat higher than in women; correct dose of rituximab is not required. The data on pharmacokinetics in patients with renal and hepatic insufficiency are absent.
Statement
Non-Hodgkin's lymphoma:
recurrent or resistant to chemotherapy-cell, CD20-positive non-Hodgkin's lymphoma low-grade or follicular;
follicular lymphoma, stage III-IV in combination with chemotherapy scheme CVP in previously untreated patients;
follicular lymphoma, as maintenance therapy after response to induction therapy;
CD20-positive diffuse large non-Hodgkin's lymphoma, in combination with chemotherapy CHOP scheme.
Rheumatoid arthritis (active form) in adults in combination with methotrexate in case of intolerance or inadequate response to current modes of therapy involving one or more inhibitors of tumor necrosis factor (TNF-α).
Dosage regimen
The standard dosing regime Enter in / by infusion (slow), via a separate catheter, a dose of 375 mg/m2, 1 times a week. You can not enter in / bolus or as a / v injection. Recommended initial velocity of the first infusion of 50 mg / h, in the future it may be increased to 50 mg / h every 30 minutes, bringing up to a maximum speed - 400 mg / h. Subsequent infusions can be started from 100 mg / h and increase it to 100 mg / h every 30 min to a maximum speed of 400 mg / h. Before each infusion of MabThera should hold premedication (analgesic / antipyretic such as paracetamol, antihistamine, such as diphenhydramine).
If Mabtera not used in combination with CHOP or CVP chemotherapy in the sedation also include corticosteroids. Correction dose during treatment reduces the dose of rituximab is not recommended. When MabThera is introduced in combination with chemotherapy scheme CHOP or CVP, reducing 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 in adults - 375 mg/m2 1 times per week for 4 weeks.
In combination with CVP (cyclophosphamide, vincristine, prednisolone): 375 mg/m2, on the first day of the cycle of chemotherapy after i / v administration of corticosteroids as part of a scheme CVP; 8 cycles (cycle - 21 days). Re-use in case of recurrence: patients who responded to the first course of therapy - 375 mg/m2 1 times per week for 4 weeks. Maintenance therapy: After the response to induction therapy administered in a dose of 375 mg/m2 1 time in 3 months, not exceeding 2 years or until disease progression.
Diffuse large non-Hodgkin's lymphoma.
In combination with chemotherapy scheme CHOP: 375 mg/m2, on the first day of each cycle of chemotherapy, 8 cycles, after i / v administration of corticosteroids. Other components of the circuit CHOP (cyclophosphamide, doxorubicin, and with vincristine) are introduced after the appointment of MabThera.
Rheumatoid arthritis
Initial therapy: prescribe a dose of 1000 mg / to drip slowly for 30 minutes to / in the introduction of methylprednisolone 100 mg, 1 every 2 weeks, a course of treatment - 2 infusion. Re-application is possible within 6 -12 months after the first course of therapy: 1000 mg 1 every 2 weeks, treatment - 2 infusion.
Patients older than 65 years of dose correction is required.
Terms of cooking and storage solution
Needed drug type in aseptic conditions and are bred to the calculated concentration (1-4 mg / ml) in infusion bottles (package) with a 0.9% solution of sodium chloride injection or 5% dextrose (solutions must be sterile and apyrogenic). To mix gently invert the vial (package) to avoid foaming. Before the introduction of the solution must be inspected for absence of impurities or discoloration. Since Mabtera not contain preservatives, the prepared solution should be used immediately.
The prepared infusion solution
MabThera is stable for 12 h at room temperature or for up to 24 hours at a temperature of 2 ° to 8 ° C. The physician responsible for the preparation conditions and storage time of the prepared solution before use.
Treatment effectiveness
Non-Hodgkin's lymphoma of low-grade or follicular
Monotherapy
Initial therapy, 4 weeks. In patients with relapsed or resistant to chemotherapy of B-cell non-Hodgkin's lymphoma, low-grade or follicular, MabThera received a dose 375 mg/m2 as a 4 / 1 by infusion once a week, the total frequency of remission was 48% complete remission - 6% , partial remission - 42%. The median time to disease progression - 13 months. Total frequency of remission in patients with histological subtypes of tumors, C and D (classification IWF) was higher than with subtype A (58% and 12%, respectively) in patients with the largest tumor focus diameter of less than 5 cm higher than the diameter the focus of more than 7 cm (53% and 38%) and in patients with relapsed himiochuvstvitelnym - higher than himioustoychivym (duration of remission less than 3 months) 53% and 36%, respectively. Total frequency of remission in patients after autologous bone marrow transplantation 78% compared with 43% in patients without bone marrow transplantation. The frequency of therapy response MabThera does not correlate with age, sex, degree of malignancy, a massive defeat, the localization of lesions and the level of LDH. But obtained a statistically significant correlation between the frequency response and bone marrow: 40% of patients with bone marrow involvement responded to therapy compared with 59% of patients without bone marrow involvement (p = 0.0186). Initial therapy for 8 weeks.
Patients with relapsed or himioustoychivoy-cell non-Hodgkin's lymphoma low-grade or follicular common answer is 57%, median times to disease progression in response to therapy is 19.4 months (range 5.3-38.9 months). Initial treatment for the disease with bulky disease, 4 weeks.
In patients with relapsed or himioustoychivoy B-cell non-Hodgkin's lymphoma low-grade or follicular with a massive defeat (the diameter of the tumor core ≥ 10 cm) overall response was 36% and median time to disease progression in response to therapy - 9.6 months (range 4.5-26.8 months). Re-treatment, 4 weeks. The frequency of remission in re-treated patients is comparable to that in the first course of therapy.
In patients with relapsed or himioustoychivoy B-cell non-Hodgkin's lymphoma of low-grade or follicular with an objective response to previous treatment with MabThera her reappointment overall response to treatment reached 38%, median time to disease progression among respondents - 17.8 months.
The combination with CVP (R-CVP) Combined therapy R-CVP (Mabtera 375 mg/m2 on the first day of each cycle, cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2 to 2 mg / day for the first day of the cycle, and prednisolone 40 mg / m2/sut, 1-5 day, every 3 weeks, with 8 cycles), the main criteria of efficiency - reducing the risk of lack of therapeutic response to the 67% increase in time to the development of ineffective treatment from 6.7 months to 25.9 months (p <0.0001).
Frequency response (complete response, unconfirmed complete response, partial response) in group R-CVP was: 80.9% compared with 57.2% (p <0.0001). After 18 months after the start of therapy the median duration of treatment response was not achieved in the group R-CVP and was 9.8 months in the group CVP (p <0.0001). The risk of recurrence decreased by 70% in the appointment of R-CVP (p <0.0001). Frequency of survival without events after 12 months of therapy was 69% in group R-CVP, compared with 32% in the CVP. Mabtera increases the time before the appointment of a new therapy or death, time to disease progression from 14.5 to 27 months (p <0.0001). After 12 months in 81% of patients treated with MabThera not observed recurrent disease, compared with 58% of patients receiving only the CVP. The advantages of a combination of MabThera with CVP were observed in all patients, regardless of age, number of extranodal lesions involving bone marrow, increasing the level of LDH, β2-microglobulin, the presence of B symptoms, bulky disease, number of affected sites, the hemoglobin values of the international prognostic index (IPI ) and index FLIPI in patients with follicular lymphoma.
Maintenance therapy
In patients with relapsed or resistant follicular non-Hodgkin's lymphoma therapy after induction therapy, R-CHOP or CHOP MabThera maintenance therapy significantly and statistically significantly increases progression-free survival to 42.2 months compared with 14.3 months in patients not receiving maintenance therapy reduces the risk of progression disease or death by 61%. The expected level of progression-free survival after 12 months in the group of maintenance therapy was 78% compared with 57% in the control group has not received MabThera maintenance therapy. Maintenance therapy with MabThera reduces the risk of death by 56%, increases the time before the appointment of new therapies (38.8 months compared to 20.1 months), and reduces the risk of the appointment of new therapies - up to 50%.
Patients with complete or unconfirmed complete response to the appointment of MabThera as maintenance therapy significantly improves survival without evidence of disease from 16.5 months to 53.7 months and reduces the risk of relapse by 67%. Benefits received MabThera maintenance therapy for all subgroups of patients regardless of the type of induction therapy (CHOP or R-CHOP), response to induction therapy (complete or partial response), and regardless of age, sex, stage of disease, the values of IPI, FLIPI, in -symptoms, involvement of bone marrow, the number of lymph nodes and extranodal foci, the number of previous modes of therapy, a better response to therapy, LDH, hemoglobin and β2-microglobulin, except for a subgroup of patients with bulky disease. Diffuse large non-Hodgkin's lymphoma
Application circuit R-CHOP (Mabtera 375 mg/m2 on the first day of the cycle in combination with CHOP: cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 up to a maximum of 1 mg on the first day of the cycle, and prednisolone 40 mg / m2/sut on days 1-5, every 3 weeks, with 8 cycles) in untreated patients in elderly (60 to 80 years) leads to a statistically significant increase "uneventful" survival from 13 to 35 months, compared with only scheme CHOP (p = 0.0001) (the "Events" refers deaths, relapses or progression of lymphoma, as well as the appointment of a new scheme of therapy).
Application of R-CHOP scheme reduces the risk of these events by 41%. The median duration of observation was 31 months. Overall survival in the group of R-CHOP was significantly increased to 68.2% compared with 57.4% in the CHOP group, with the risk of death decreased by 33% (p = 0.0094). Therapy scheme R-CHOP CHOP scheme also outperforms the frequency of complete remission by the end of treatment (76.2% and 62.4%, respectively, p = 0.0028). The risk of disease progression in the group of R-CHOP decreased by 46% and the risk of relapse - at 51%. The advantages of the scheme R-CHOP is not dependent on sex, age, IPI values, adjusted for age, ECOG, β2-microglobulin, LDH, albumin, B-symptoms, bulky disease, involvement in the bone marrow and extranodal lesions.
Rheumatoid arthritis
Rituximab in combination with methotrexate significantly reduces the activity of the disease. The clinical effect for at least 20% according to the criteria of the American College of Rheumatology (AKR20), compared with methotrexate monotherapy was observed in most patients, regardless of the titer of rheumatoid factor, age, sex, body surface area, race, previous therapy and disease activity. Clinically and statistically significant improvement in the treatment of MabThera noted with regard to all criteria, the AKP: the number of swollen and painful joints, pain index, C-reactive protein, rheumatoid factor, along with improving the overall evaluation of the effectiveness of treatment in the opinion of the physician and patient assessment of pain intensity according to patient index, degree of disability. Rituximab significantly reduces disease activity index DAS28. Good and moderate response by EULAR criteria was achieved in significantly more patients in the appointment of MabThera with methotrexate compared with methotrexate monotherapy.
Patients who received drug therapy Mabtera, noted a significant improvement in the index of disability (by questionnaire and health assessment - HAQ-DI), weakness (FACIT-F) and improving both physical and mental health indicators questionnaire SF-36. In the appointment of rituximab showed a significant decrease in the concentration of rheumatoid factor (range 45-64%). The concentration of immunoglobulins, the number of lymphocytes, white blood cells remained within normal limits, except for a transient reduction in the number of leukocytes in the first 4 weeks of therapy.
As with MabThera monotherapy and in combination with methotrexate showed a significant reduction in inflammatory markers (IL-6, CRH, serum amyloid protein type A protein isotype S100 A8 and A9). The frequency of response to therapy with MabThera re-treated patients is comparable to that in the first course of therapy.
Side effect
Reactions associated with infusion: fever, weakness, shortness of breath, indigestion, nausea, rash, flushing, hypotension, hypertension, fever, itching, rash, irritation of the throat, rhinitis, tachycardia, vomiting, pain, symptoms of tumor lysis syndrome.
In some cases, during the scheme R-CHOP: myocardial infarction, atrial fibrillation and pulmonary edema. Infections: upper respiratory tract infection (most often - nasopharyngitis, sinusitis, bronchitis, pneumonia, superinfection of the lungs), urinary tract infections, sepsis, herpes zoster, septic shock, infection of implants, staphylococcal septicemia; very rarely - reactivation of hepatitis B.
On the part of the hemopoietic system: leukopenia, neutropenia, thrombocytopenia, anemia, febrile neutropenia and less than 1% - lymphadenopathy, blood clotting, and very rarely - pancytopenia (4 weeks or more after the last administration of rituximab), a transient increase in the level of IgM in patients with makroglobulinemiey Valdenstrema, with subsequent return to its initial value after 4 months; partial transient aplastic anemia, hemolytic anemia.
On the part of the respiratory system: rhinitis, nasal mucus, bronchospasm, cough or increased cough, respiratory infection, dyspnea, acute respiratory failure, pulmonary infiltrates, less than 1% - hypoxia, pulmonary dysfunction, bronchiolitis obliterans, asthma.
On the part of the whole body: throat irritation, back pain, chest pain, pain in the neck, pain in the foci of the tumor, flu-like syndrome, peripheral edema, Mucosit, syncope, weight loss, multiple organ dysfunction syndrome, rapid lysis of the tumor; very rare - serum sickness and less than 1% - an increase in abdominal, anaphylactic reactions, pain at the injection site.
On the part of the digestive system: dyspepsia, nausea, vomiting, diarrhea, anorexia, dysphagia, stomatitis, constipation, abdominal pain.
Since the cardiovascular system: hypotension, hypertension, orthostatic hypotension, tachycardia, bradycardia, arrhythmia (including ventricular and supraventricular tachycardia, atrial fibrillation), unstable angina pectoris, vasodilatation, venous thrombosis, including extremity deep vein thrombosis, cardiac insufficiency, low ejection fraction, pulmonary edema, myocardial infarction, very rare: vasculitis, predominantly cutaneous (leukocytoclastic), ischemic cerebral circulation.
From the side of the central nervous system and peripheral nervous system: dizziness, headache, paresthesia, hypoesthesia, headache, confusion, and very rarely - neuropathy of cranial nerves, in conjunction with peripheral neuropathy with or without (marked reduction of visual acuity, hearing, failure of other organs emotions, facial nerve palsy) in different periods of therapy - until several months after treatment MabThera, confusion, less than 1% - anxiety, depression, anxiety, taste perversion.
From the Musculoskeletal System: myalgia, arthralgia, muscular hypertonicity, muscle cramps, osteoarthritis.
On the part of the endocrine system: hyperglycemia, diabetes decompensation. Dermatological reactions: itching, rash, urticaria, increased sweating at night, sweating, alopecia, very rarely - heavy bullous reaction, toxic epidermal necrolysis with fatal consequences.
From the senses: Violations watery, conjunctivitis, pain and tinnitus.
From the laboratory parameters: increase in activity of lactate dehydrogenase, hypocalcemia, hypercholesterolemia, hyperglycemia, bacteremia.
Monotherapy Infusion reactions often occur during the first infusion. The frequency of infusion reactions decreased from 77% (including 7% - 3, and 4 degrees) for 1 second infusion of up to 30% (2% - 3, and 4 degrees) at 4 and 14% (absence of reactions 3 and 4 degrees) at 8-second infusion.
Infections: Mabtera cause depletion of the pool of B cells in 70-80% of cases and reduce the concentration of immunoglobulins in serum in a small number of patients. 30.3% - infectious complications (for whatever reason), including 18.8% - bacterial infections, 10.4% - viral infections, 1.4% - fungal infections, 5.9% - infection without refined etiology (one patient could be different infection). Severe infections (3 and 4 degrees), including sepsis, were noted in 3.9% of patients: during therapy (1.4%) and in patients during observation without treatment (2.5%).
On the part of the hemopoietic system: severe thrombocytopenia (3 and 4 severity) was observed in 1.7% of patients, severe neutropenia - at 4.2% of patients with severe anemia and the severity (3, 4) - in 1.1% of patients. Have been reported 1 case of transient aplastic anemia and 2 cases of hemolytic anemia.
Since the cardiovascular system: side-effects were observed in 18.8% of cases, most often - arterial hypo-and hypertension.
Mabtera in combination with chemotherapy scheme SVP (R-CVP) Infusion reactions 3 and 4 degrees (9%): fever, weakness, shortness of breath, indigestion, nausea, rash, flushing. Infections: infections (33% during treatment and 28 days after the end of treatment, compared with 32% of patients who received only CVP), including 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 grade 3 and 4 severity (24%), neutropenia 4 degrees (3.1%). The higher incidence of neutropenia in the group of R-CVP does not increase the frequency of infections. Anemia - from 0.6% of patients in group R-CVP and in 1.9% of patients treated with CVP, thrombocytopenia - at 1.2% in group R-CVP and absent in patients treated with CVP. The overall incidence of cardiovascular disorders was similar in patients treated with CVP (5%) and R-CVP (4%).
Mabtera in combination with chemotherapy scheme CHOP (R-CHOP) Infusion reactions 3 and 4 degrees during the infusion or within 24 h after infusion of MabThera were observed during the first cycle of R-CHOP 9% of patients. By the eighth cycle of R-CHOP frequency of infusion reactions decreased to less than 1%. Infection: Infection 2-4 severity and / or febrile neutropenia in the group of R-CHOP - 55.4% in the CHOP group - 51.5%, febrile neutropenia without concomitant documented infection in patients receiving R-CHOP - 20.8% in patients receiving CHOP - 15.3%. The overall frequency of infections 2-4 degrees in the group R-CHOP was 45.5% in the CHOP group - 42.3%, with no marked difference in incidence of systemic bacterial and fungal infections.
The frequency of fungal infections 2-4 degrees in the group of R-CHOP was higher than in the CHOP group (4.5% and 2.6%, respectively), this difference was due to a higher rate of local candidiasis during therapy. The frequency of HSV infection 2-4 degrees, including with damage to the eye, was higher in group R-CHOP (4.5%) than in the CHOP group (1.5%), 7 of 9 cases recorded in group R-CHOP, the disease emerged during therapy.
On the part of the hemopoietic system: after each cycle, leukopenia (88% compared to 79%) and neutropenia (97% compared to 88%) 3 and 4 severity were observed more frequently in the R-CHOP group than in CHOP group, respectively.
Differences in the incidence of anemia 3 and 4 severity in the two groups was observed (19% in the CHOP group and 14% in the R-CHOP), there was no difference in the frequency of thrombocytopenia (15% in the CHOP group and 16% in the R-CHOP ). Time to resolution of all hematological disorders in two therapeutic groups were comparable.
Since the cardiovascular system: the frequency of cardiac arrhythmias 3 and 4 degrees, mostly supraventricular arrhythmias (tachycardia, atrial flutter and atrial fibrillation), a group of R-CHOP was higher (6.9%) than in the CHOP group (1.5%) .
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. Group R-CHOP and CHOP did not differ among themselves on the frequency of other cardiac adverse events 3 and 4 degrees of severity, including heart disease, myocardial disease and manifestation of coronary heart disease.
From the side of the central nervous system and peripheral nervous system: during the first cycle of therapy in 4 patients (2%) of group R-CHOP with cardiovascular risk factors developed ischemic attacks due to thromboembolism, in contrast to 1.5% of patients in the CHOP group during observation without treatment. The difference between the groups in the incidence of other thromboembolic disorders was absent.
Rheumatoid arthritis
The frequency of infection is 0.9 cases per year, the proportion of heavy infections, some of which were fatal, was less than 0.05 cases per year. The frequency of malignant diseases after the appointment of MabThera was 1.5 per 100 patients per year and higher than in the population.
Specific categories of patients
The high tumor burden (the diameter of single foci of more than 10 cm): increased incidence of adverse reactions of grade 3-4 severity.
Elderly patients (over 65): the frequency and severity of side effects and side effects 3 and 4 severity did not differ from that in younger patients. Repeated therapy: frequency and severity of side effects did not differ from those in the initial therapy.
Contraindications
acute infectious diseases, expressed primary or secondary immunodeficiency;
Hypersensitivity to rituximab, a drug or any component of the mouse proteins.
Precautions to apply for respiratory failure in history, or tumor infiltration of the lungs, when the number of circulating malignant cells> 25 000/mkl or high tumor load (chronic lymphocytic leukemia, or lymphoma, mantle cell zone), neutropenia (less than 1500/mkl), thrombocytopenia (less than 75 000/mkl) for chronic infections.
Pregnancy and lactation
Effects of rituximab during pregnancy has not been studied. The injurious effect of MabThera in the fetus and the effect of the drug on fertility is unknown.
Given that the immunoglobulin class IgG penetrate through the placental barrier rituximab can cause depletion of the pool of B cells in the fetus. MabThera should not be given during pregnancy except in cases where the expected benefit of therapy to the mother outweighs the potential risk to the fetus. During the period of treatment and within 12 months after the end of women of childbearing age should use effective methods of contraception. It is not known whether rituximab is allocated through breast milk.
Given that the immunoglobulin class IgG, circulating in maternal blood, are provided with breast milk MabThera should not be used during lactation. Cautions MabThera introduced under the close supervision of oncologist, hematologist or rheumatologist, if the necessary conditions for resuscitation. The development of infusion reactions may be due to the release of cytokines or other mediators.
The majority of patients within 30 min-2 h after the first infusion of MabThera appear fever with chills or shivering. Severe reactions include symptoms from the lung, hypotension, urticaria, angioedema, nausea, vomiting, weakness, headache, itching, irritation of tongue or throat swelling (vascular edema), rhinitis, flushing, pain in the foci of the disease and, in some cases , signs of tumor lysis syndrome fast. Severe infusion reactions is difficult to distinguish from hypersensitivity reactions or cytokine release syndrome. There have been reports of fatal infusion reactions, described in the post-registration period of the drug.
Infusion reactions disappear after a delay or interruption of MabThera and the introduction of supportive measures (including on / in the introduction of 0.9% sodium chloride, diphenhydramine and acetaminophen, bronchodilators, SCS).
In most cases, after the complete disappearance of symptoms of infusion can be resumed at a rate of 50% from the previous (eg, 50 mg / h instead of 100 mg / h). The majority of patients with infusion reactions, no life-threatening, rituximab treatment was completed.
Adverse reactions in the lungs: may increase symptoms over time or clinical deterioration after initial improvement. Patients with pulmonary symptoms or other severe infusion reactions should be carefully observed until complete resolution of symptoms. Continuation of therapy after the complete disappearance of symptoms is rarely accompanied by a re-development of severe infusion reactions. Acute respiratory failure may be accompanied by the formation of interstitial infiltrates in the lungs or pulmonary edema, often seen in the first 1-2 h after the first infusion.
With the development of adverse reactions in the lungs infusion of rituximab should be stopped immediately and appoint an intensive symptomatic therapy. As an initial improvement of clinical symptoms can change as deterioration, patients should be carefully observed until the resolution of pulmonary symptoms. Rapid tumor lysis syndrome is possible after the first infusion of MabThera in patients with large numbers of circulating malignant lymphocytes.
Tumor lysis syndrome include hyperuricemia, hyperkalemia, hypocalcemia, acute renal failure, increased LDH. Patients at risk require careful medical supervision and conduct regular laboratory examination. With the rapid development of symptoms of tumor lysis conduct appropriate therapy. After complete relief of symptoms in a limited number of cases therapy.
MabThera continued in conjunction with the prevention of tumor lysis syndrome fast. Patients with large numbers of circulating malignant cells (more than 25 000/mkl) or high tumor burden (eg, chronic lymphocytic leukemia, or lymphoma cells from the mantle zone), in which the risk is extremely severe infusion reactions may be particularly high, MabThera should be prescribed with extreme caution , under the close supervision and only for inefficiency of all other methods of treatment. The first infusion of the drug in such patients should be administered at a lower speed.
Due to the potential development of anaphylactoid reactions during in / in the introduction of protein drugs must have a means for coping: epinephrine (adrenaline), antihistamines and corticosteroids.
During infusion requires careful monitoring of patients with cardiovascular disease history. Because of the possibility of hypotension is not less than 12 hours before the infusion of MabThera should be abolished antihypertensive drugs.
Although monotherapy with MabThera has no mielosupressivnogo actions need to be careful to make a decision on the appointment of the drug with less neutropenia and thrombocytopenia 1500/mkl least 75 000/mkl because the experience of its clinical application in such patients is limited. The use of MabThera in patients after autologous bone marrow transplantation and other high-risk groups with possible dysfunction of the bone marrow was not accompanied by symptoms of myelotoxicity.
In the course of treatment should be regularly conduct detailed analysis of the peripheral blood, including counting the number of platelets in accordance with routine practice. Infections: very rarely using the combination of MabThera to chemotherapy were observed reactivation of hepatitis B and fulminant hepatitis, whose connection with the reception MabThera is not installed.
Such patients should be carefully monitored. Immunization: The safety and effectiveness of immunization of any vaccine, particularly live viral vaccines, after treatment MabThera not been studied. Vaccination should be completed no less than 4 weeks prior to the appointment of rituximab. Vaccination with live vaccines is not recommended for reducing the number of B-cells.
Effects on ability to drive vehicles and management mechanisms
Does rituximab's ability to manage and work with machines and mechanisms is unknown, although pharmacological activity and the adverse effects described do not suggest such an influence.
Overdose
Cases of overdose in humans have not been observed. Efficacy and safety of rituximab in single doses over 1 g were not studied.
Drug Interactions
Data on possible drug interactions are limited MabThera. In the appointment of other monoclonal antibodies for diagnostic or therapeutic purposes patients with antibodies against proteins of the mouse or antihimernye antibodies increases the risk of allergic reactions.
Tolerability of concurrent or sequential use of MabThera and drugs that can reduce the number of normal B-cells (in addition to the scheme CHOP or CVP), if not installed. Mabtera compatible with PVC and polyethylene infusion systems or packages.
Terms and Conditions of storage
The drug should be kept in the dark, away from children at a temperature of 2 ° to 8 ° C. Shelf life - 2.5 years.
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