MABTERA
Active material: Rituximab
When ATH: L01XC02
CCF: Anticancer drug. Monoklonalynыe antibodies
ICD-10 codes (testimony): C82, (C) 83.3, (C) 52.9, M05
When CSF: 05.02.01
Manufacturer: F.Hoffmann-La Roche Ltd. (Switzerland)
Pharmaceutical form, composition and packaging
Concentrate for solution for infusion clear or slightly opalescent, colorless or light yellow.
| 1 ml | 1 fl. | |
| rituximab | 10 mg | 100 mg |
Excipients: sodium citrate dihydrate, polysorbate 80, sodium chloride, hydrochloric acid or sodium hydroxide, water d / and.
10 ml – hydrolytic class glass vials 1 EPHESIANS (2) – packs cardboard.
Concentrate for solution for infusion clear or slightly opalescent, colorless or light yellow.
| 1 ml | 1 fl. | |
| rituximab | 10 mg | 500 mg |
Excipients: sodium citrate dihydrate, polysorbate 80, sodium chloride, hydrochloric acid or sodium hydroxide, water d / and.
50 ml – hydrolytic class glass vials 1 EPHESIANS (1) – packs cardboard.
Pharmacological action
Medical immuno-biological drug, is a chimerical mouse monoclonal antibody/person, which specifically binds to the CD20 Antigen transmembrane. This Antigen is pre-b lymphocytes mature b-lymphocytes and, but not on hematopoietic stem cells, Pro-in-cages, normal plasma cells, the cells of other tissues and is more, than 95% cases of non-Hodgkin lymphoma-cell. Jekspressirovannyj on the cell after binding to CD20 antibody is not internalizuetsja and no longer come with the cell membrane into the extracellular space. CD20 does not circulate in the plasma in the form of free Antigen and, therefore, does not compete for binding to antibodies.
Rituximab binds to the CD20 Antigen on lymphocytes and initiates the immunological reaction, mediating lysis of cells. Possible mechanisms of cell lysis include the complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity and induction of apoptosis. Rituximab sencibilisiruet human b-cell lymphoma to the zitotoksicsky action of some chemotherapeutic drugs in vitro.
The number of cells in the peripheral blood after the first injection of the drug decreases below normal, and begins to recover in patients with hematological malignant diseases through 6 Months, reaching normal values through 9-12 months after completion of therapy. In patients with rheumatoid arthritis to reduce duration of b-cell ranges, most patients follow-up therapy is prescribed before full restoration of their number.
Antihimernye antibodies have been detected in 1.1% (4 from 356) the examined patients with non-Hodgkin's lymphoma and 10% – with rheumatoid arthritis.
Pharmacokinetics
Nehodzhkinskaya lymphoma
C patients relapsed b-cell lymphoma concentration of rituximab in serum and its T1/2 increases with increasing doses. After 1 St in/in infusion dose 375 mg / m2 T1/2 rituximab is 76.3 no, After 4th infusion – 205.8 no. Cmax After the 1-St infusion 205.6 ug / ml, After the 4-th-infusion 464.7 ug / ml, plasma clearance – 0.0382 l / h 0.0092 l / hr, respectively. Individual differences in serum concentrations of the drug enough expressed. When effective treatment serum concentrations of rituximab higher. The concentration of the drug is negatively correlated with tumor load. Traces of rituximab can be detected in the body for 3-6 months after the last infusion.
In patients with diffuse Lymphoma anaplastic serum concentrations comparable with those of rituximab in patients with non-Hodgkin's lymphoma low zlokacestvennosti or Follicular, receiving the same dose.
Rheumatoid arthritis
After two infusions of 1000 mg with 2-week break Cmax rituximab – 369 ug / ml, Average T1/2 – 19.2-20.8 d, the average systemic clearance- 0.23 l/d and Vd in equilibrium- 4.6 l.
Pharmacokinetics in special clinical situations
Vd and clearance of rituximab, adjusted for body surface area in men slightly more, than in women; rituximab dose adjustment is not required.
Data on pharmacokinetics in patients with renal and hepatic insufficiency are absent.
Testimony
Nehodzhkinskaya lymphoma:
is recurrent or resistant to chemotherapy in cell, CD20-positive Lymphoma Lymphoma low zlokacestvennosti, or Follicular;
-III-IV follicular Lymphoma in combination with chemotherapy on the CVP scheme previously untreated patients;
-Follicular Lymphoma, as a maintenance therapy after response to induction therapy;
-CD20-positive diffuse large cell non-Hodgkin's lymphoma-, in combination with chemotherapy on the scheme, were CARRIED OUT.
Rheumatoid arthritis (active form) in adults in combination with methotrexate in rejecting or inadequate response to the current modes of therapy, include one or more tumor necrosis factor inhibitors (ФНО-a).
Dosage regimen
The standard dosing regimen
Introducing/in infusions (slowly), through a single catheter, dose 375 mg / m2, 1 once a week. You cannot enter in/in bolusno or as in/in the injection.
The recommended initial speed the first infusion is 50 mg / h, in the future it can be increased by 50 mg/h every 30 m, leading up to the maximum speed – 400 mg / h. Subsequent infusions You can start with speed 100 mg/h and increase it on the 100 mg/h every 30 min and max speed 400 mg / h.
Before each infusion Mabtery® needed premedikatia (analgesic/antipyretic, eg, paracetamol; an antihistamine, eg, difengidramin). If Mabthera® not to be used in combination with CHOP or CVP chemotherapy, the composition then also include corticosteroids.
Dose adjustment during therapy
Lower dose of rituximab is not recommended. If Mabteru® administered in combination with chemotherapy on the scheme, were CARRIED OUT or CVP, lower doses of chemotherapy drugs is carried out in accordance with standard recommendations.
Non-Hodgkin's lymphoma low zlokacestvennosti or Follicular
Initial therapy: When alone at Adult – 375 mg / m2 1 once a week, during 4 weeks.
In combination with CVP (cyclophosphamide, vynkrystyn, prednisolone): 375 mg / m2, on the first day of the cycle of chemotherapy after the on/in the corticosteroid as CVP schema component; 8 cycles (cycle – 21 day).
Re-use in case of recidivism: patients, responding to the first course of therapy – 375 mg / m2 1 once a week, during 4 weeks.
Maintenance therapy: After response to induction therapy is prescribed at a dose of 375 mg / m2 1 once every 3 of the month, no more 2 years or until disease progression.
Diffuse large cell non-Hodgkin's lymphoma-
In combination with chemotherapy on the scheme, were CARRIED OUT: 375 mg / m2, on the first day of each cycle of chemotherapy, 8 cycles, After the on/in the introduction of corticosteroid. Other schema components, were CARRIED OUT (cyclophosphamide, doxorubicin and vincristine) Enter after the appointment of Mabtery®.
Rheumatoid arthritis
Initial therapy: naznachajut dose 1000 mg / drip, slowly, through 30 minutes after the on/in the introduction of methylprednisolone 100 mg, 1 once every 2 of the week, a course of treatment – 2 infusion.
Reapply perhaps through 6 -12 months or more after the first course of therapy: 1000 mg 1 once every 2 of the week, a course of treatment – 2 infusion.
In older patients 65 years dose adjustment is required.
Rules of preparation and storage solution
The required quantity of the drug gaining in aseptic conditions and bred to the calculated concentration (1-4 mg / ml) in infuzionnom vial (package) from 0.9% solution of sodium chloride injection or 5% dextrose (solutions must be sterile and apirogennymi). For stirring gently invert the vial (package) to avoid foaming. Before the introduction of the solution should be inspected for extraneous matter or discoloration.
Unnecessarily. Mabthera® It contains no preservatives, cooked solution should be used immediately. Cooked recovery solution Mabtery® stable for 12 h at room temperature or for a period of not more than 24 hours at a temperature of from 2 ° to 8 ° C.. The physician is responsible for cooking, storage conditions and time prepared mortar before using it.
Effectiveness of treatment
Non-Hodgkin's lymphoma low zlokacestvennosti or Follicular
Monotherapy
Initial therapy, 4 of the week. In patients with recurrent or resistant to chemotherapy for non-Hodgkin's b-cell lymphoma low zlokacestvennosti or Follicular, receiving Mabteru® dose 375 mg / m2 as 4 in/infusions 1 Once a week the total frequency of remission was 48%, complete remission is 6%, partial remission- 42%. The median time to disease progression – 13 Months.
Total frequency of remission in patients with histological subtypes of tumors in, (C) and (D) (classification of IWF) It was higher, than with a subtype but (58% and 12%, respectively); in patients with the greatest diameter of the tumor lesion of less than 5 cm – higher, than with the diameter of the hearth more 7 cm (53% and 38% respectively) and in patients with recurrent himiochuvstvitel'nym-above, than himioustojchivym, duration of remission for less 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. Frequency response to therapy Mabteroj® not correlate with age, sex, the degree of malignancy, massive defeat, localization of lesions and level of LDH. Obtained statistically significant correlation between frequency response and lesions of bone marrow: 40% patients with damage to the bone marrow to respond to therapy, compared with 59% patients without bone marrow involvement (r = 0.0186).
Initial therapy, 8 weeks. In patients with recurrent or himioustojchivoj b-cell non-Hodgkin's lymphoma low zlokacestvennosti or follicular general answer is 57%, the median time to progression of the disease in response to therapy is 19.4 Months (range 5.3-38.9 Months).
Initial therapy for the disease with a massive lesion, 4 of the week. In patients with recurrent or himioustojchivoj b-cell non-Hodgkin's lymphoma low zlokacestvennosti or follicular with a massive lesion (tumor diameter hearth ≥ 10 cm) the general answer is 36% and the median time to progression of the disease in response to therapy- 9.6 Months (range of 4.5-16.7 months).
Repeated therapy, 4 of the week. Frequency of remission have repeatedly treated patients was comparable with that of the first course of therapy. In patients with recurrent or himioustojchivoj b-cell non-Hodgkin's lymphoma low zlokacestvennosti or follicular objective response to previous treatment Mabteroj® When her reappointment general response to treatment has reached 38%, the median time to progression of the disease in responding- 17.8 Months.
Combination with CVP (R-CVP)
With combination therapy (R)-CVP (Mabthera® 375 mg / m2 on the first day of each cycle, cyclophosphamide 750 mg / m2, vynkrystyn 1.4 mg / m2 to 2 mg/day in the first day of the cycle and prednisone 40 mg / m2/d, 1-5 day; every 3 of the week, Total 8 cycles) the main criterion of effectiveness – reducing the risk of treatment failure on 67% and increase the time until the therapeutic effect with 6.7 Months before 25.9 Months (p<0.0001). Frequency response (full answer, unconfirmed complete response, partial response) in Group R-CVP was: 80.9% compared with 57.2 % (p<0.0001). Through 18 months after the start of therapy, the median duration of response to treatment has not been achieved in Group R-CVP and amounted to 9.8 months in the Group CVP (p<0.0001). Risk of recurrence of the disease decreased by 70% in the appointment of R-CVP (p<0.0001). Frequency of event free survival through 12 months of therapy was 69% in Group R-CVP, compared with 32% in the Group of the CVP.
Mabthera® increases the time before the appointment of a new therapy or death, time to progression of the disease 14.5 to 27 Months (p<0.0001). Through 12 months from 81% patients, receiving Mabteru®, There had been no recurrence of the disease, compared with 58% patients, receiving only CVP.
The advantages of the combination Mabtery® with the CVP was observed in all patients, irrespective of age, number of extranodal lesions, bone marrow involvement, raising the level of LDH, b2-microglobulin, availability-symptoms, the massive defeat, the number of affected nodes, hemoglobin levels, values of International Prognostic Index (IPI) and FLIPI index in patients with follicular Lymphoma.
Maintenance therapy
In patients with recurrent or resistant to therapy of follicular non-Hodgkin's lymphoma after induction therapy R-CHOP, or CHOP supportive therapy Mabteroj® significant and statistically significantly increases survival without progression of disease prior to 42.2 month compared to 14.3 months in patients, not receiving supportive therapy, reduces the risk of disease progression or death at 61%. The expected level of survival without progression through 12 months in a group of supportive therapy amounted 78% compared with 57% in the control group, not receiving supportive therapy Mabteroj®. Supportive therapy Mabteroj® reduces the risk of death on 56%, increases the time before the appointment of the new schema therapy (38.8 month compared to 20.1 Months) and reduces the risk of new destination schema therapy- 50%.
In patients with full or unconfirmed complete response assignment Mabtery® as a maintenance therapy significantly increases survival rate without signs of disease 16.5 Months before 53.7 month and reduces the risk of recurrence in the 67%.
Benefits of supportive therapy Mabteroj® obtained for all subgroups of patients regardless of the type of induction therapy (Or R-CHOP CHOP), response to induction therapy (complete or partial response), and regardless of age, gender, stage of the disease, IPI values, FLIPI, -Symptoms, bone marrow involvement, the number of the affected lymph node extranodal and hearths, number of previous modes of therapy, better response to therapy, level of LDH, hemoglobin and β2-microglobulin, except for the subgroup of patients with a massive lesion.
Diffuse large cell non-Hodgkin's lymphoma-
R-schema application, were CARRIED OUT (Mabthera® 375 mg / m2 on the first day of the cycle in combination with CHOP: cyclophosphamide 750 mg / m2, doxorubicin 50 mg / m2, vynkrystyn 1.4 mg / m2 up to a maximum of 1 mg on the first day of the cycle and prednisone 40 mg / m2/day of days 1-5, every 3 of the week, Total 8 cycles) among untreated patients of elderly and senile age (from 60 to 80 years) statistically reliable results in increased “patient” survival rates with 13 to 35 Months, compared to using a schema only, were CARRIED OUT (p = 0.0001) (to “events” include death, relapse or progression of lymphomas, as well as the appointment of a new schema therapy). R-schema application, were CARRIED OUT reduces the risk of these events on 41%. The median duration of observation was 31 month. Overall survival in the R-Group, were CARRIED OUT reliably increased to 68.2% compared with 57.4% in the group, were CARRIED OUT, the risk of death dropped by 33% (p = 0.0094). R-schema therapy, were CARRIED OUT also exceeded the scheme, were CARRIED OUT on the frequency of complete remission at the end of treatment (76.2% and 62.4%, respectively; p = 0.0028). The risk of disease progression in a group R-CHOP declined 46%, and the risk of relapse is on 51%.
R-scheme benefits, were CARRIED OUT were not dependent on sex, age, IPI values adjusted for age, ECOG, b2-microglobulin, LDH, Albumin, In-symptoms, the massive defeat, involvement of bone marrow and jekstranodal'nogo lesions.
Rheumatoid arthritis
Rituximab in combination with methotrexate reduces disease activity. Clinical effect of not less 20% According to the criteria of the American College of Rheumatology (AKR20), compared to methotrexate alone marked in most patients, regardless of the rheumatoid factor titer, age, gender, body surface area, race, prior therapy and disease activity. Clinically and statistically significant improvement in the treatment of Mabteroj® noted with regard to all criteria of ACRE: the number of swollen and painful joints, the pain index, C-reactive protein, rheumatoid factor, along with the improvement of the overall assessment of the effectiveness of treatment, in the opinion of the doctor and the patient, evaluation of pain intensity according to the patient, the index of the degree of disability.
Rituximab reduces disease activity index DAS28. Good and moderate response criteria have been reached EULAR significantly greater number of patients in the appointment Mabtery® with methotrexate, compared to methotrexate alone.
Patients, receiving therapy drug Mabthera®, noted a significant improvement in disability index (on the health assessment questionnaire-HAQ-DI), weakness (DOES-F) and improving physical, and mental indicators on the SF-36 questionnaire.
When you assign a significant degradation of rituximab rheumatoid factor concentration (range 45-64%). Concentration of immunoglobulins, the number of lymphocytes, leukocytes remained within normal range, except for transient decrease in the number of cells within the first 4 weeks from the beginning of therapy. As with monotherapies Mabteroj®, or in combination with methotrexate noted a significant reduction in inflammatory markers (IL-6, CDH, serum amyloid a protein, the protein S100 isotypes A8 and A9).
Frequency response to therapy Mabteroj® again have treated patients was comparable with that of the first course of therapy.
Side effect
Reaction, associated with infusion: chills, weakness, breathlessness, dyspepsia, nausea, rash, tides, hypotension, arterial hypertension, fever, itch, hives, throat irritation, rhinitis, tachycardia, vomiting, pain, signs of tumor Lysis syndrome. In some cases, during the R-scheme, were CARRIED OUT: myocardial infarction, atrial fibrillation and pulmonary edema.
Infection: respiratory tract infections (the most often-nasopharyngitis, sinusitis; bronchitis, pneumonia, pulmonary superinfection), urinary tract infection, sepsis, herpes zoster, septic shock, infection of implants, Staphylococcus septicaemia, severe viral infections (the newly arisen or reactivation) which can be fatal, caused by cytomegalovirus, Varicella zoster, Herpes simplex, JC poliomavirusom (progressive multifocal lejkojencefalopatija), hepatitis C virus; rarely – hepatitis b reactivation.
From the hematopoietic system: leukopenia, neutropenia (through 4 weeks after the last injection of rituximab), thrombocytopenia, anemia, febrile neutropenia; less 1% – lymphadenopathy, coagulation failure; rarely – pancytopenia, transient increase in the level of IgM in patients with waldenström Macroglobulinemia and returns to its original value through 4 of the month; collective transient aplastic anemia, gemoliticheskaya anemia.
The respiratory system: rhinitis, mucous discharge from the nose, bronchospasm, cough or increased cough, respiratory disease, breathlessness, acute respiratory failure, pulmonary infiltrates; less 1% – gipoksiya, lung function, obliterating bronchiolitis, asthma.
From the body as a whole: throat irritation, back pain, chest pain, Pain in the neck, pain in hotbeds of tumors, flu-like symptoms, peripheral edema, mukozit, fainting, weight loss, multiple organ failure, rapid tumor Lysis syndrome; rarely – serum sickness; less 1% – an increase in stomach, anaphylactic reactions, pain at the injection site.
From the digestive system: dyspepsia, nausea, vomiting, diarrhea, anorexia, dysphagia, stomatitis, constipation, stomach ache, perforation of the stomach and/or intestines (possibly fatal).
Cardio-vascular system: hypotension, arterial hypertension, orthostatic hypotension, tachycardia, bradycardia, arrhythmia (including ventricular tachycardia and najeludochkovuyu and, auricular fibrillation), unstable angina, vasodilation, venoznыy thrombosis, incl. deep vein thrombosis limb, heart failure, reduced ejection fraction, pulmonary edema, myocardial infarction; rarely – vasculitis, predominantly cutaneous (lejkocitoklasticheskij), Ischemic cerebrovascular accident.
From the central and peripheral nervous system: dizziness, headache, paresthesia, gipesteziya, migraine, confusion; rarely – cranial nerve neuropathy, in combination with peripheral neuropathy or without it (expressed by reduced Visual acuity, hearing, the defeat of the other senses, Bell's paralysis) in different periods of therapy-until several months after the course of treatment Mabteroj®, confusion; less 1% – nervousness, depression, anxiety, dysgeusia.
On the part of the musculoskeletal system: myalgia, arthralgia, Muscle hypertonicity, muscle spasms, osteoarthritis.
On the part of the endocrine system: giperglikemiâ, decompensation diabetes.
Dermatological reactions: itch, rash, hives, excessive sweating at night, Sweating, alopecia; rarely – severe Bullous reaction, Toxic Epidermal Necrolysis fatal.
From the senses: violations of slezootdelenija, conjunctivitis, pain and tinnitus.
From the laboratory parameters: LDH increase, hypocalcemia, hypercholesterolemia, giperglikemiâ, bacteraemia.
Monotherapy
Infusion Reactions often occur when first infuziah. The frequency of infusion reactions decreases with 77% (of them 7% – 3 and 4 severity) When 1 St before infusion 30% (2% – 3 and 4 severity) When the 4-th and up 14% (no reaction 3 and 4 severity) When the 8th infusion.
Infection: Mabthera® causes the depletion of b cells in the pool 70-80% cases and reduced concentrations of immunoglobulins in serum by a small number of patients. 30.3% – infectious complications (Regardless of the cause), incl. 18.8% – bacterial infection, 10.4% – viral infections, 1.4% – fungal infections, 5.9% – infection without refined etiology (one patient may have different infection). Severe infections (3 and 4 severity), including sepsis, were noted in 3.9% patients: during therapy (1.4%) and in patients during observation without treatment (2.5%).
From the hematopoietic system: tyazhelaya thrombocytopenia (3 and 4 severity) marked in 1.7% patients, severe neutropenia- 4.2% patients and anemia severe gravity (3 and 4) – in 1.1% patients. Reported on 1 case of transient aplastic anemia and 2 cases of hemolytic anemia.
Cardio-vascular system: side effects were observed in 18.8% cases, common – arterïalnaya hypo- and hypertension.
Mabthera® in combination with chemotherapy on the scheme of SVP (R-CVP)
Infusion Reactions 3 and 4 severity (9%): chills, weakness, breathlessness, dyspepsia, nausea, rash, tides.
Infection: infection (33% during treatment and after 28 days after the end of therapy, compared with 32% patients, receiving only CVP), including upper respiratory tract infection (12.4%), the most often-nasopharyngitis, serious infection (4.3%), life-threatening infections not registered.
Blood system: neutropenia 3 and 4 severity (24%), neutropenia 4 severity (3.1%). Higher frequencies of neutropenia in the R-Group CVP does not increase the frequency of infections. Anemia – in 0.6% patients in Group R-CVP and 1.9% patients, receiving CVP, thrombocytopenia – in 1.2% in Group R-CVP and absent in patients, receiving CVP.
The overall incidence of cardio-vascular disorders was similar in patients receiving CVP (5%) and R-CVP (4%).
Mabthera® in combination with chemotherapy on the scheme, were CARRIED OUT (R-CHOP)
Infusion Reactions 3 and 4 severity during infusion or within 24 h after infusion Mabtery® occurred during the first cycle of the R-, were CARRIED OUT at 9% patients. The eighth cycle of R-infusion reactions declined in frequency, were CARRIED OUT to less 1%.
Infection: infection 2-4 the severity and/or neutropenia in the R-Group, were CARRIED OUT – 55.4%, in the group, were CARRIED OUT – 51.5%; neutropenia without accompanying documented infection in patients, R-fed, were CARRIED OUT – 20.8%, patients, received, were CARRIED OUT – 15.3%. Total frequency of infections 2-4 the severity of the R-Group, were CARRIED OUT was 45.5%, in the group, were CARRIED OUT – 42.3%, While no difference in the incidence of systemic bacterial and fungal infections. Frequency of fungal infections 2-4 the severity of the R-Group, were CARRIED OUT was higher, than in the group, were CARRIED OUT (4.5% and 2.6%, respectively); This difference was due to the higher frequency local candidiasis during therapy. The frequency of herpes infection 2-4 severity, incl. with the defeat of the eye, was higher in the R-Group, were CARRIED OUT (4.5%), than in the group, were CARRIED OUT (1.5%), in 7 from 9 cases, recorded in the R-Group, were CARRIED OUT, the disease occurred on stage therapy.
From the hematopoietic system: After each cycle of leukopenia (88% compared with 79%) and neutropenia (97% compared with 88%) 3 and 4 severity observed more frequently in the R-Group, were CARRIED OUT, than in the group, were CARRIED OUT accordingly. Differences in the frequency of anaemia 3 and 4 the severity in the two groups was not observed (19% in the group, were CARRIED OUT and 14% R-Group, were CARRIED OUT); There was no difference in the incidence of thrombocytopenia (15% in the group, were CARRIED OUT and 16% R-Group, were CARRIED OUT). Time to resolve all hematologic violations in two therapeutic groups was comparable.
Cardio-vascular system: the frequency of heart rhythm disorders 3 and 4 severity, mainly supraventricular arrhythmias (tachycardia, atrial flutter and atrial fibrillation), R-Group, were CARRIED OUT was higher (6.9%), than in the group, were CARRIED OUT (1.5%). All arrhythmia developed either in connection with infusion Mabtery®, or to be connected with such conducive conditions, fever, infection, acute myocardial infarction or concomitant diseases of the respiratory and cardiovascular systems. R-Group, were CARRIED OUT, were CARRIED OUT and did not differ among themselves in terms of frequency of other cardiac adverse events 3 and 4 severity, including heart failure, diseases of the myocardium and manifestation of ISCHEMIC HEART DISEASE.
From the central and peripheral nervous system: during the first cycle of therapy with 4 patients (2%) of the R-Group, were CARRIED OUT with cardiovascular risk factors of cerebral circulation developed due to embolism, Unlike 1.5% the patients in the Group CHOP in the observation period without treatment. The difference between groups in the incidence of other thromboembolic breaches absent.
Rheumatoid arthritis
The frequency of infections is 0.9 cases per year, the proportion of severe infections, some of them were fatal, do not exceed 0.05 cases per year.
Frequency malignant diseases After the appointment of Mabtery® is 1.5 on 100 patients per year and not exceeding in population.
Cases of fatal progressive having lejkojencefalopatii (PML) experienced in the treatment of Mabteroj® in patients with SLE, that is not provided in the regulations for medical application. A causal relationship with the admission Mabtery® not installed, patients there were risk factors for PML: comorbidities, the long reception immunosupressivna therapy. In patients with rheumatoid arthritis cases of PML are not marked. When the occurrence of neurological symptoms while therapy Mabteroj® You should consult a neurologist and delete the PML.
Efficacy and safety of Mabtery® in patients with SLE is not installed
Special categories of patients
High tumour load (the diameter of the single centers more than 10 cm): increased frequency of adverse reactions 3-4 severity.
Elderly patients (senior 65 years): the frequency and severity of all side effects and side effects 3 and 4 severity is not different from that in younger patients.
Repeated therapy: the frequency and severity of all the side effects did not differ from those in the initial therapy.
Contraindications
- Acute infectious diseases;
is pronounced primary or secondary immunodeficiency;
- Hypersensitivity to the drug;
-hypersensitivity to mouse proteins.
FROM caution apply for respiratory failure in history or neoplastic infiltration of the lungs; When the number of circulating malignant cells >25 000/MCL or high tumor load (chronic Lymphoblastic Lymphoma cells or mantijnoj zone); neutropenia (less than 1500/MKL), thrombocytopenia (less 75 000/l); chronic infections.
Pregnancy and lactation
Effect of rituximab in pregnant women have not been studied. Deleterious effect of Mabtery® on the fruit and the influence of the drug on the ability to procreate is unknown. Level B-cells in newborns in the appointment Mabtery® when pregnancy has not been studied. Mabteru® There should be appointed during pregnancy except, when the expected benefit of therapy for the mother outweighs the potential risk to the fetus.
During the treatment and for 12 months after the end women of childbearing age must use effective methods of contraception.
Unknown, whether allocated rituximab with breast milk. Considering, that immunoglobulins IgG class, circulating in maternal blood, stand out with breast milk Mabteru® should not be used during lactation.
IN jeksperimentalnyh studies shows, What causes depletion of rituximab in pool cells in newborn animals in the postnatal period.
Cautions
Mabteru® misleading under the close supervision of an oncologist, hematologist or rheumatologist, If you have the necessary conditions for the holding of resuscitation.
Development infusion reactions may be due to the release of cytokines or other mediators. In most patients within 30 min-2 hours after the start of the first infusion Mabtery® appear fever with shivering or trembling. Severe reactions include symptoms from the light, hypotension, krapivnicu, angioedema, nausea, vomiting, weakness, Headache, itch, language irritation or swelling of the throat (Vascular edema), rhinitis, tides, pain in hotbeds of disease and, in some cases, signs of rapid tumor Lysis syndrome. Severe infusion reactions are hard to distinguish from the reactions of hypersensitivity or cytokine release syndrome. There have been reports of fatal infusion reactions, described in postregistracionnogo period of application. Infusion reactions disappear after slowing or interrupting the introduction Mabtery® and conducting support actions (incl. in / introduction 0.9% sodium chloride solution, Diphenhydramine and acetaminophen, bronchodilator, GCS). In most cases, after the complete disappearance of the symptoms of infusion can resume with speed, component 50% from previous (eg, 50 mg/h instead of 100 mg / h). In most patients with the infusion reactions, not life threatening, the course of treatment rituksimabom was able to complete.
Side effects from the light: may increase symptoms or clinical deterioration over time after the initial improvements. Patients with pulmonary symptoms or other severe infusion reactions should carefully watch until full resolution of symptoms. Continued therapy after the complete disappearance of symptoms is rarely accompanied by repeated heavy development of infusion reactions. Acute respiratory failure may be accompanied by the formation of interstitial infiltrates in the lung or pulmonary congestion, often manifests itself in the first 1-2 hours after the first infusion. With the development of severe reactions from the lungs infusion of rituximab should be immediately discontinued and the intensive symptomatic therapy. Since an initial improvement in clinical symptoms can change or deterioration, patients should be carefully observed before allowing lung symptoms.
Rapid tumor Lysis syndrome possible after the first infusion Mabtery® in patients with a large number of circulating malignant lymphocytes. Tumor Lysis syndrome includes giperurikemiju, hyperkalemia, gipocalziemia, acute kidney failure, LDH increase. At-risk patients need careful medical supervision and carrying out regular laboratory tests. When developing symptoms of rapid lysis of tumor carry out appropriate therapy. After full cupping symptoms in a limited number of cases, therapy Mabteroj® continued in conjunction with rapid tumor Lysis syndrome prevention.
Patients with a large number of circulating malignant cells (more 25 000/l) or high tumor load (eg, with chronic lymphocytic leukemia or lymphoma cells mantijnoj zone), which risk severe infusion reactions may be particularly high, Mabteru® It should be administered with extreme caution, under close supervision, and only with the ineffectiveness of all other treatments. The first infusion of the drug should be so sick with lower speed.
The potential of anaphylactoidnykh reactions when in/with the introduction of protein drugs must have means of cupping: epinephrine (adrenaline), antihistamines and corticosteroid drugs.
Infusion process requires careful observation of patients with cardiovascular diseases in history. Due to the possibility of hypotension is not less than 12 hours before infusion Mabtery® should abolish the antihypertensive medicines.
Although monotherapy Mabteroj® has no mielosupressivnogo action, be careful to take the decision to appoint drug in neutropenia less 1500/MKL and thrombocytopenia less 75 000/l, because of his experience of clinical application of such patients is limited. Use Mabtery® in patients after autologous bone marrow transplantation and other groups at risk with the possible breach of the bone marrow was not accompanied by symptoms of mielotoksicnosti. During treatment, it is necessary to regularly conduct a detailed analysis of the peripheral blood, including platelet count in accordance with the usual practice,.
Infection: possible increased risk of infectious complications. Mabteru® should not be prescribed to patients with acute infection or pronounced immune deficiency (hypogammaglobulinemia or low CD4, CD8). Caution must be exercised in the appointment Mabtery® in patients with chronic infection or in the presence of conditions predisposing to the development of serious infections. When an infectious complications should appoint appropriate therapy.
Very rarely, when appointing a combination Mabtery® with chemotherapy in patients with non-Hodgkin Lymphoma marked reactivation of hepatitis b or hepatitis ful'minantnyj, whose relationship with the admission Mabtery® not installed. Such patients should be carefully observed.
Immunization: the safety and efficacy of any immunization vaccine, particularly live viral vaccines, After treatment Mabteroj® We have not been studied. Vaccination should be completed no less than 4 weeks before the appointment of rituximab. Vaccination living vaccines are not recommended for reducing the number of b-cells.
Antihimernye antibody. The emergence of antihimernyh antibody in most patients with rheumatoid arthritis have not been accompanied by clinical symptoms or increased risk of reactions during subsequent infusions, but rarely their existence may be associated with more severe allergic or infusion reactions in repeated infuziah during the following courses and the lack of effect in reducing the pool of cells with follow-up courses of therapy.
Use in Pediatrics
The safety and effectiveness of drugs in children are not installed.
Effects on ability to drive vehicles and management mechanisms
Does rituximab on the ability to manage and work with machines and mechanisms is unknown, Although pharmacological activity and described adverse events do not give grounds to believe such an effect.
Overdose
Cases of overdose in humans have not been observed. One-time dose of rituximab more 1000 mg have not been studied. Maximum dose 5000 mg prescribed for patients with Lymphocytic Leukemia, additional safety data is not received. Due to increased risk of infectious complications in depletion of the pool of lymphocytes should abolish or reduce speed infusion, It is recommended that deployed General blood analysis.
Drug Interactions
Information about any possible medication with Mabtery® limited. When the appointment of other monoclonal antibodies with diagnostic or therapeutic purpose sick, having antibodies against mouse proteins or antibodies antihimernye, increases the risk of allergic reactions.
Portability of simultaneous or sequential application Mabtery® and preparations, that can reduce the number of normal cells (In addition to the scheme, were CARRIED OUT or CVP), not exactly installed.
Mabthera® compatible with polyvinylchloride or polyethylene infusion systems or packages.
Conditions of supply of pharmacies
The drug is released under the prescription.
Conditions and terms
The drug should be stored out of reach of children, dark place at a temperature of 2 ° to 8 ° C. Shelf life – 2.5 year.
