MabThera® (Mabthera®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceRituximabRituximab
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    • Dosage form: & nbspSolution for subcutaneous administration.
    Composition:
    1 ml of the preparation contains:

    active substance: rituximab - 120 mg;

    Excipients: recombinant human hyaluronidase (rHuPH20) -2000 ED, L-histidine 0.53 mg, L-histidine hydrochloride monohydrate 3.46 mg, α, α-trehalose dihydrate 79.22 mg, L-methionine 1.49 mg, polysorbate 80 0.60 mg, water for injections up to 1 ml.

    1 bottle contains 1400 mg of rituximab.
    Description:Transparent or opalescent, colorless or yellowish liquid.
    Pharmacotherapeutic group:Antitumor and immunomodulating agent - antibodies monoclonal.
    ATX: & nbsp

    L.01.X.C   Monoclonal antibodies

    L.01.X.C.02   Rituximab

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

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

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

    Antimony antibodies in the examined patients were not identified.With subcutaneous (sc) administration of MabThera in the dosage form of a "subcutaneous injection solution", patients who did not have antibodies at the time of initiation of therapy showed an anti-chimeric antibody in 2% of cases. Antibodies to recombinant human hyaluronidase (rHuPH20) are found in 4% of cases and persist after completion of therapy. The relationship between the detection of anti-chimeric antibodies or antibodies to rHuPH20 and the development of adverse events was not observed. The clinical significance of the formation of anti-chimeric antibodies or antibodies to rHuPH20 is unknown.
    Pharmacokinetics:

    Non-Hodgkin's Lymphoma

    Suction

    In patients with follicular lymphoma who responded to induction therapy for prepa MabThera, in the form of an intravenous drug, during maintenance treatment, which included at least one MabThera treatment cycle in an IV preparation, a median of maximum concentration (CmOh) rituximab in the blood serum with the subsequent use of the drug MabThera in the dosage form for the SC administration at a fixed dose of 1400 mg every 2 months was 201 μg / ml, with the introduction every 3 months - 189 μg / ml.The median time to reach the maximum concentration (TmOh) - 3 days.

    In previously untreated patients with follicular lymphoma during the 7 cycle of induction therapy, which included one cycle of the MabThera preparation in the IV administration form with the further use of the MabThera preparation in a dosage form for administration at a fixed dose of 1400 mg every 3 weeks in combination with chemotherapy, the geometric mean CmOh - 236.82 μg / ml (coefficient of variation of 29.41%).

    According to population pharmacokinetic analysis, absolute bioavailability

    after sc injection of MabThera in the dosage form "solution for subcutaneous

    introduction "- 71%.

    Distribution

    In patients with follicular lymphoma who responded to induction therapy with MabThera in an IV formulation, during a 2-cycle maintenance treatment that included at least one MabThera treatment cycle in an IV preparation, the median geometric values ​​of the minimum concentration (Ctraboutugh) rituximab in the blood serum with further use of the drug MabThera in the dosage form for SC administration at a fixed dose of 1400 mg once every 2 months and 1 time every 3 months was 32.2 and 12.1 μg / ml,respectively. The average geometric values ​​of the area under the concentration-time curve within the dosing interval t (AUCτ) were 5430 and 5320 μg x day / ml. In previously untreated patients with follicular lymphoma using MabThera in a dosage form for administration at a fixed dose of 1400 mg every 3 weeks in combination with chemotherapy to the 8 cycle of induction therapy that included one MabThera cycle for IV administration, geometric mean Ctraboutugh was 134.6 μg / ml, AUCτ - 3778 μg x day / ml.

    The median of the final half-life (T1 / 2) is 29.7 days. With an increase in the surface area of ​​the body, the parameters characterizing the clearance and the volume of distribution increase. Antibodies to the drug have no clinically significant effect on clearance.

    Pharmacokinetics in selected patient groups

    Elderly age

    With age, the central volume of distribution rises and the rate of suction rate decreases (in patients older than 60 years), while age does not affect the exposure of rituximab.

    Patients with renal and hepatic insufficiency

    Pharmacokinetic data in patients with renal and hepatic insufficiency are absent.

    Indications:
    Non-Hodgkin's Lymphoma

    Recurrent or chemo-resistant B-cell, CD20-positive non-Hodgkin's lymphoma of low grade or follicular. Follicular lymphoma III-IV stage in combination with chemotherapy in previously untreated patients.

    Follicular lymphoma as maintenance therapy after responding to induction therapy.

    C020-positive diffuse large B-cell non-Hodgkin's lymphoma in combination with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone).
    Contraindications:
    Hypersensitivity to rituximab, any auxiliary drug substance or to mouse proteins in anamnesis.

    Acute infectious diseases, pronounced primary or secondary immunodeficiency.

    Children under 18 years of age (efficacy and safety not established).

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

    Pregnancy and lactation:
    Immunoglobulins G (IgG) are able to penetrate the placental barrier. The level of B-cells in newborns during the appointment of MabThera® to women was not studied during pregnancy.

    Some newborns whose mothers received rituximab during pregnancy, there was a temporary depletion of the B-cell pool and lymphocytopenia. Concerning

    the drug MabThera in the dosage form "solution for subcutaneous administration" should not be given to pregnant women. Since the MabThera preparation in the dosage form of the "subcutaneous injection solution" contains recombinant human hyaluronidase, women who become pregnant during the treatment should stop the drug therapy.

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

    Before using MabThera, you should carefully read the instructions and make sure that the dosage form is appropriate for the patient ("concentrate for solution for infusion" or "solution for subcutaneous administration").

    The drug MabThera in the dosage form "solution for subcutaneous administration" is not intended for intravenous administration!

    The first dose of MabThera® (375 mg / m2) patients should receive in the form of IV infusion drug in the dosage form "concentrate for the preparation of solution for infusion."

    First intravenous infusion

    For intravenous administration, use the MabThera preparation in the dosage form "concentrate for the preparation of a solution for infusions" (see the relevant instructions for medical use).

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

    Patients who failed to receive a full dose of MabThera's drug® in the form of a "concentrate for the preparation of a solution for infusions", in subsequent cycles should continue to receive the preparation MabThera in a dosage form intended for intravenous administration. For more information, see "Special instructions".

    Subsequent subcutaneous injections

    Patients who received a full dose of MabThera in a dosage form "concentrate for the preparation of a solution for infusions" in the following cycles can receive the MabThera preparation in a dosage form intended for administration. Subcutaneous injections of MabThera in the dosage form "subcutaneous injection solution" are carried out for approximately 5 minutes.

    MabThera preparation in the dosage form "solution for subcutaneous administration" should be administered SC only in the anterior abdominal wall. Data on the experience of drug administration in any other zones are absent. Do not enter the drug into the hematoma, places with seals, hypersensitivity, redness, birthmarks, scar tissue.

    MabThera preparation in the dosage form "solution for subcutaneous administration" and others

    preparations, also intended for administration, should, if possible, be introduced into

    different places. If the injection is interrupted, it can be resumed in the same place

    or, if necessary, change the injection site.

    Correction of dose during therapy

    It is not recommended to reduce the dose of rituximab.

    The rules for storing the solution for a dormant injection after fetching in a syringe

    After the solution is taken into the syringe, the MabThera preparation, a subcutaneous injection solution of 1400 mg / 11.7 ml, is physically and chemically stable for 48 hours at a temperature of 2 to 8 ° C or 8 hours at 30 ° C and daylight scattered light. For reasons of microbiological safety, the drug should be used immediately. If the preparation is not used immediately, the time and storage conditions of the preparation are the responsibility of the user and should not exceed 48 hours at a temperature of 2 to 8 ° C or 8 hours at 30 ° C and daylight scattered light - provided that the solution was prepared in controlled and validated aseptic conditions.

    Standard dosing regimen

    Non-Hodgkin's lymphoma of low grade or follicular

    The first dose of the drug MabThera® patients should be obtained with iv administration of the drug in the dosage form "concentrate for the preparation of a solution for infusions." The drug MabThera in the dosage form "solution for subcutaneous administration" should be used only in the second and / or subsequent cycles of therapy.

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

    Initial therapy:

    in combination with chemotherapy: 1 cycle MabThera preparation IV at a dose of 375 mg / m2, then the MabThera® preparation at a fixed dose of 1400 mg, regardless of body surface area, on the first day of the chemotherapy cycle after intravenous administration of glucocorticosteroid as a component of therapy, for:

    - 1 cycle preparation MabThera IV in / in combination with CVP (cyclophosphamide, vincristine, prednisolone) + 7 cycles MabThera preparation in combination with C VP (cycle: 21 days);

    - 1 cycle preparation MabThera IV in / in combination with MCP (mitoxantrone, chlorambucil, prednisolone) + 7 cycles MabThera preparation in combination with MCP (cycle: 28 days);

    - 1 cycle preparation MabThera IV in / in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) + 7 cycles MabThera preparation in combination with CHOP (cycle: 21 days); if complete remission is achieved after 4 cycles, it is possible to limit to 6 cycles (1 cycle MabThera IV, then 5 cycles MabThera preparation);

    - 1 cycle preparation MabThera IV in / in combination with CHVP-Interferon (cyclophosphamide,

    doxorubicin, teniposide, prednisolone + interferon) + 5 cycles MabThera preparation in combination with CHVP-Interferon (cycle: 21 days).

    Supportive therapy (after answering induction therapy):

    - in previously untreated patients: MabThera preparation at a fixed dose of 1400 mg regardless of body surface area once in 2 months, not more than 2 years (12 injections). If signs of disease progression appear, MabThera should be discontinued;

    with relapsing or chemically resistant lymphoma: MabThera preparation at a fixed dose of 1400 mg regardless of body surface area once in 3 months, not more than 2 years. If signs of disease progression appear, MabThera should be discontinued.

    Diffuse B-Large Cellular Non-Hodgkin Lymphoma

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

    The first dose of MabThera® should be given to all patients by IV administration of the drug in the dosage form "concentrate for solution for infusion". The drug MabThera in the dosage form "solution for subcutaneous administration" should be used only in the second and / or subsequent cycles of therapy.

    Initial therapy in combination with chemotherapy according to the scheme CHOP: 1 cycle preparation MabThera IV in the dose of 375 mg / m2 in combination with CHOP + 7 cycles MabThera preparation at a dose of 1400 mg, regardless of body surface area, in combination with CHOP; on the first day of each cycle of chemotherapy after intravenous administration of a glucocorticosteroid as a component of therapy.

    Dosing in special cases

    Elderly age

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

    Side effects:

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

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

    Experience in the use of the drug in oncohematological diseases

    The safety profile of the MabThera preparation in the dosage form is a "subcutaneous injection solution" comparable to the safety profile of MabThera in the dosage form "concentrate for the preparation of a solution for infusions." With n / k introduction, local skin reactions, including reactions at the injection site, were very frequent and included pain, swelling, tightness, bleeding, erythema, pruritus and rash. In most cases, the phenomena were mild or moderate in severity.

    Cases of anaphylaxis and severe hypersensitivity reactions, cytokine release syndrome, or tumor lysis syndrome with the use of MabThera in the dosage form "solution for subcutaneous administration" have not been observed in clinical studies.

    The reactions observed with intravenous administration of MabThera in the dosage form "concentrate for solution for infusion"

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

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

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

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

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

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

    Disorders from the metabolism and nutrition: often - hyperglycemia, weight loss, peripheral edema, facial swelling, increased lactate dehydrogenase (LDH) activity, hypocalcemia.

    General disorders and disorders at the site of administration: very often - headache, fever, chills, asthenia; often - pain in the foci of the tumor, flu-like syndrome, "hot flashes", weakness; infrequently - pain at the injection site.

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

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

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

    Disorders of the psyche: infrequently - nervousness, depression.

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

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

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

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

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

    MabThera® in combination with chemotherapy (CHOP, FROMVR, FC) with non-Hodgkin's lymphoma and chronic lymphocytic leukemia

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

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

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

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

    - frequency is indicated on the basis of observations in the therapy of recurrent / chemostable chronic lymphocytic leukemia according to the scheme R-FC (rituximab, fludarabine, cyclophosphamide).

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

    Below are the undesirable events observed with MabThera with the same frequency (or less frequently) than the control group: hematotoxicity, neutropenic infections, urinary tract infections, septic shock, superinfections of the lungs, implant infection, staphylococcal septicemia, nasal mucus, pulmonary edema, heart failure, sensitivity disorders, venous thrombosis, incl.deep vein thrombosis of the extremities, mucositis, edema of the lower extremities, reduction of the left ventricular ejection fraction, increase in body temperature, deterioration in overall well-being, falling, multiple organ failure, bacteremia, decompensation of diabetes mellitus.

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

    Reactions associated with the administration of the drug

    Monotherapy with MabThera® (within 4 weeks)

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

    MabThera® in combination with chemotherapy according to the following schemes: R-CVP (rituximab, diclofosfamide, vincristine, prednisolone) with non-Hodgkin's lymphoma; R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) with diffuse B-large-cell non-Hodgkin's lymphoma

    Infusion reactions 3 and 4 severity during infusion or within 24 hours after infusion of the drug Mabtera® observed during the first cycle of chemotherapy in 12% of patients. The frequency of infusion reactions decreased with each subsequent cycle and the 8th cycle frequency chemotherapy infusion reactions was less than 1%. Infusion reactions, in addition to the above (with monotherapy Mabtera®) included: dyspepsia, rash, hypertension, tachycardia, signs of tumor lysis syndrome, in some cases - myocardial infarction, atrial fibrillation, pulmonary edema and acute reversible thrombocytopenia.

    Infections

    Monotherapy with MabThera® (within 4 weeks)

    MabThera® causes depletion of the B-cell pool in 70-80% of patients and a decrease in serum immunoglobulin concentrations in a small number of patients. Bacterial, viral, fungal infections and infections of unspecified etiology (all, regardless of cause) develop in 30.3% of patients.Severe infections (grade 3 and 4), including sepsis, were noted in 3.9% of patients.

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

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

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

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

    On the part of the blood system

    Monotherapy with MabThera® (within 4 weeks)

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

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

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

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

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

    Severe neutropenia and leukopenia (grade 3 and 4): in patients who received

    MabThera preparation in combination with chemotherapy, leukopenia of 3 and 4 severity was noted more often compared to patients receiving chemotherapy alone. The incidence of severe leukopenia was 88% in patients who received R-CHOP. The incidence of severe neutropenia was 24% in the group R-CVP, 97% of the group R-CHOP. A higher incidence of neutropenia in patients treated with MabThera 5 and chemotherapy, was not associated with an increased incidence of infections and invasions compared to patients receiving chemotherapy alone.

    Severe anemia and thrombocytopenia (grade 3 and 4): There was no significant difference in the incidence of anemia and thrombocytopenia in grade 3 and 4.

    From the side of the cardiovascular system

    Monotherapy with MabThera® (within 4 weeks)

    Side effects from the cardiovascular system were noted in 18.8%. The most common decrease and increase in blood pressure.In rare cases, there was a disturbance of cardiac rhythm of 3 and 4 degrees of severity (including, ventricular and supraventricular tachycardia) and angina.

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

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

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

    Nervous system

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

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

    Concentration IgG

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

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

    Special categories of patients

    Monotherapy with MabThera® (within 4 weeks)

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

    Combination Therapy

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

    Repeated therapy: the frequency and severity of adverse reactions does not differ from those in the initial therapy.

    Post-marketing application of MabThera in a dosage form "concentrate for the preparation of a solution for infusions" with non-Hodgkin's lymphoma and chronic lymphocytic leukemia

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

    predominantly cutaneous (leukocytoclastic).

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

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

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

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

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

    When MabThera is prescribed according to indications not provided for in the medical instruction manual,In patients with previously diagnosed Kaposi's sarcoma, progression of the sarcoma was observed (most patients were HIV-positive).

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

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

    Overdose:
    An episode of a random overdose with iv dose introduction of 2280 mg of MabThera preparation in the dosage form "solution for subcutaneous administration" was recorded, without any consequences. In the case of an overdose of MabThera in the dosage form of a "subcutaneous injection solution" or medical error, the patient's condition should be monitored.

    In connection with the increased risk of infectious complications when the B-lymphocyte pool is depleted, the need to conduct a detaileda common blood test.
    Interaction:Data on drug interactions of MabThera® are limited. When administered with other monoclonal antibodies for diagnostic or therapeutic purposes, patients with antibodies against mouse proteins or anti-chimera antibodies increase the risk of developing allergic reactions.
    Special instructions:

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

    The drug MabThera in the dosage form "solution for subcutaneous administration" is administered only subcutaneously, under the careful supervision of an oncologist or hematologist, provided there are necessary conditions for resuscitation.

    Reactions associated with the administration of the drug

    The reactions associated with the administration of the drug include undesirable phenomena that occurred within 24 hours after the administration of the study drug and regarded as associated with the MabThera preparation.

    When MabThera was used, the development of reactions associated with the administration of the drug was observed, which may be due to the release of cytokines and / or other mediators. The release of cytokines is difficult to distinguish from acute hypersensitivity reactions.

    When using the MabThera preparation in the dosage form of a "subcutaneous injection solution," local skin reactions (including reactions at the site of administration) were in most cases mild or moderate in severity and did not require any therapy. Such reactions can develop at any time during therapy and include pain, swelling, tightness, bleeding, erythema, pruritus and rash.

    The first administration of MabThera should be carried out in the form of IV infusion (dosage form "concentrate for the preparation of a solution for infusions"), which allows to effectively control possible reactions associated with the administration of the drug, by slowing or interrupting the infusion. The risk of developing such reactions is highest during the first cycle of therapy. The drug in the dosage form "solution for subcutaneous administration" should be used, starting not earlier than from the second cycle.Patients who failed to receive the full dose of the drug with iv introduction, in the following cycles should continue to receive the drug in a dosage form intended for intravenous administration. Patients who received a full dose of the drug with iv introduction, in the following cycles can receive the drug in the dosage form intended for the SC administration.

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

    After the injection of MabThera in the dosage form, the solution for subcutaneous administration should be observed for at least 15 minutes. Patients at increased risk of developing hypersensitivity reactions may need a longer follow-up period.

    Patients should be informed of the need to seek immediate medical attention in the event of symptoms of severe hypersensitivity reactions or syndromerelease of cytokines after application of MabThera preparation, regardless of the time of their occurrence.

    During the period of post-marketing application of the MabThera preparation in a medicinal form intended for intravenous administration, fatal infusion reactions were reported. Severe infusion reactions include symptoms from the side of the lungs, lowering blood pressure, hives, angioedema, nausea, vomiting, weakness, go headache, itching, irritation of the tongue or swelling of the pharynx (vascular edema), rhinitis, "hot flashes", pain in the foci of the disease and, in some cases, signs of fast tumor lysis syndrome. Very often for 30 min-2h After the first infusion of the MabThera drug, a fever with chills or tremors occurs. In case of development of infusion reactions, the introduction of MabThera should be discontinued and medical therapy should be prescribed (iv injection of 0.9% solution of sodium chloride, diphenhydramine and acetaminophen, bronchodilators, glucocorticosteroids, etc.). In most cases, after complete disappearance of the symptomatology, the infusion can be resumed at a rate of 50% of the preceding (eg 50 mg / h instead of 100 mg / h).In most cases of development of infusion reactions, not life-threatening, the course of treatment with rituximab was completely completed. Continuation of therapy after complete disappearance of symptoms is rarely accompanied by repeated development of severe infusion reactions. With intravenous administration of protein preparations, cases of development of anaphylactic reactions and other hypersensitivity reactions have been described. When using MabThera it is necessary to have the means for their relief: adrenaline, antihistamine and glucocorticosteroid preparations.

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

    Syndrome of rapid lysis of the tumor. MabThera mediates the rapid lysis of benign or malignant C020-positive cells. Tumor lysis syndrome was observed after the first infusion of MabThera in patients with a large number of circulating malignant lymphocytes. Tumor lysis syndrome includes hyperuricemia, hyperkalemia, hypocalcemia, hyperphosphatemia, acute renal failure, increased LDH activity. Patients at risk (patients with high tumor burden or a large number of circulating malignant cells (> 25 thousand / μL)) need careful medical supervision and regular laboratory testing. With the development of symptoms of rapid lysis of the tumor, appropriate therapy is carried out. After complete relief of symptoms in a limited number of cases, MabThera treatment indrug form for iv administration continued in conjunction with the prevention of rapid tumor lysis syndrome.

    Patients with a large number of circulating malignant cells (> 25 thousand / μL) or high tumor load (eg, chronic lymphocytic leukemia or mantle cell lymphoma), in which the risk of extremely severe reactions associated with the administration of the drug may be particularly high, the MabThera preparation should be administered with extreme caution, under close supervision. The first infusion of the drug in such patients should be administered at a lower rate or divided the dose of the drug for two days during the first cycle of therapy and every subsequent cycle if the number of circulating malignant cells remains> 25 thousand / μL.

    Side effect of the cardiovascular system. During the use of MabThera, careful monitoring of patients with cardiovascular diseases in history is required in connection with the possibility of angina pectoris, arrhythmia (flutter and atrial fibrillation), heart failure or myocardial infarction.Because of the possibility of developing hypotension, antihypertensive drugs should be discontinued no less than 12 hours before MabThera® is used.

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

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

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

    Hepatitis B. When MabThera was administered in a dosage form for intravenous administration in combination with chemotherapy, reactivation of the hepatitis B virus or fulminant hepatitis (includingfatal outcome). Predisposing factors included both the stage of the underlying disease and cytotoxic chemotherapy. Before prescribing MabThera, all patients should be screened for Patits B according to local recommendations. MabThera should not be used in patients with active hepatitis B. Patients with positive serological markers of hepatitis B should consult a hepatologist before using MabThera; in respect of such patients, it is necessary to conduct appropriate monitoring and take measures to prevent the reactivation of the hepatitis B virus in accordance with local standards.

    Progressive multifocal leukoencephalopathy (PML). When using the drug

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

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

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

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

    With and / or the introduction of MabThera®, polypropylene or polycarbonate syringes, double-ended and injection needles made of stainless steel can be used due to the compatibility of the material with the preparation.

    Needles and syringes can not be reused. Used needles and syringes are placed in a puncture-proof container (container). Dispose of MabThera® and consumables in accordance with local regulations.

    Effect on the ability to drive transp. cf. and fur:Does rituximab on the ability to manage and work with machines and mechanisms - is unknown, although the pharmacological activity and the described undesirable phenomena do not give grounds for assuming such an effect.
    Form release / dosage:
    A solution for subcutaneous administration of 1400 mg / 11.7 ml

    Packaging:
    For 1400 mg / 11.7 ml of the drug in a bottle of colorless glass (hydrolytic class 1 EF), sealed with a stopper made of butyl rubber laminated with fluoropolymer, crimped with an aluminum cap and closed with a plastic lid.

    1 The vial with the preparation together with the instruction for use is placed in a cardboard box.
    Storage conditions:At a temperature of 2-8 ° C in a place protected from light and inaccessible to children. Do not freeze.
    Shelf life:
    2 year 6 months.

    Do not use after the expiration date printed on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-002575
    Date of registration:13.08.2014/06.03.2015
    Date of cancellation:2019-08-13
    The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland
    Manufacturer: & nbsp
    Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland
    Information update date: & nbsp30.04.2016
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