Mabthera, 100 mg/10 ml 2 pcs

Pharmacodynamics

Antitumor and immunomodulatory drug. Rituximab is a chimeric mouse/human monoclonal antibody that binds specifically to the transmembrane antigen CD20. This antigen is located on pre-B-lymphocytes and mature B-lymphocytes, but is absent on hematopoietic stem cells, pro-B cells, normal plasma cells, cells of other tissues and is expressed in more than 95% of B-cell non-Hodgkin lymphomas. Cell-expressed CD20 is not internalized after binding to the antibody and is no longer transported from the cell membrane into the extracellular space. CD20 does not circulate in the plasma as a free antigen and therefore does not compete for binding to the antibody.

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

The number of B-cells in peripheral blood decreases below normal after the first administration of the drug and begins to recover in patients with hematologic malignancies after 6 months, reaching normal values 12 months after completion of therapy, but in some cases the duration of B-cell recovery may be longer.

In patients with rheumatoid arthritis, the duration of decline in B-cell counts varies, with most patients receiving follow-up therapy until their numbers are fully restored. In a small number of patients there is a long-term decrease in the number of B-cells (for 2 years or more after the last dose of therapy).

In patients with granulomatosis with polyangiitis and microscopic polyangiitis, a decrease in CD19-positive B cells to less than 10 cells/μL occurs after the first two infusions of rituximab and in most patients remains at this level for 6 months.

Antichimeric antibodies were detected in 1.1% of patients with non-Hodgkin’s lymphoma and in 10% of patients with rheumatoid arthritis. Anti-mouse antibodies were not detected in the examined patients.

Pharmacokinetics

Non-Hodgkin’s lymphoma

. According to population pharmacokinetic analysis in patients with non-Hodgkin’s lymphoma when administered once or multiple times with Mabthera® as monotherapy or in combination with chemotherapy according to the CHOP regimen (cyclosporine, doxorubicin, vincristine, prednisolone) non-specific clearance (CL1), specific clearance (CL2), (probably related to B-cells or tumor burden), and plasma volume distribution (V1) are 0.14 L/day, 0.59 L/day and 2.7 L respectively. The median terminal T1/2 is 22 days. The baseline level of CD19-positive cells and tumor site size affect the CL2 of rituximab 375 mg/m2 v/v once weekly, for 4 weeks. CL2 was higher in patients with higher levels of CD19-positive cells or larger tumor nidus size. Individual variability in CL2 persisted even after correction of tumor focus size and CD19-positive cell levels. Relatively small changes in V1 depend on body surface area (1.53-2.32 m2) and on CHOP chemotherapy and are 27.1% and 19%, respectively. Age, sex, race, and general health according to the WHO scale have no effect on rituximab pharmacokinetics. Thus, adjusting the dose of rituximab according to the factors listed above does not significantly affect pharmacokinetic variability.

The mean Cmax increases after each infusion: 243 µg/ml after the first infusion, 486 µg/ml after the fourth infusion, and 550 µg/ml after the eighth infusion. Cmin and Cmax of the drug inversely correlate with the initial number of CD19-positive B-cells and tumor burden. With effective treatment, the median Css of the drug is higher. The median Css of the drug is higher in patients with histological subtypes of tumor B, C and D (IWF classification – International Working Formulation) than with subtype A. Traces of rituximab can be detected in the body for 3-6 months after the last infusion.

The pharmacokinetic profile of rituximab (6 infusions of 375 mg/m2) in combination with 6 cycles of SNR chemotherapy was almost identical to that of monotherapy.

Cronic lympholeukemia

The mean Cmax after the fifth infusion of rituximab at a dose of 500 mg/m2 is 408 mcg/mL.

Rheumatoid arthritis

After two 1,000-mg infusions by IV with a 2-week break, the mean Cmax of rituximab is 369 mcg/mL, mean T1/2 is 19.2-20.8 days, mean systemic clearance is 0.23 L/day and Vd in equilibrium is 4.6 L. After the second infusion, the mean Cmax was 16-19% higher compared to the first infusion. On retreatment, the pharmacokinetic parameters of rituximab are comparable to the first course of treatment.

Granulomatosis with polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis

After four infusions of rituximab at 375 mg/m2 once weekly, median T1/2 was 23 days, mean clearance was 0.313 L/day and Vd was 4.5 L, based on population pharmacokinetic analysis. The pharmacokinetic parameters of rituximab in granulomatosis with polyangiitis and microscopic polyangiitis were almost the same as in rheumatoid arthritis.

Pharmacokinetics in selected patient groups

The Vd and clearance of rituximab adjusted for body surface area are slightly greater in men than in women; no dose adjustment of rituximab is required. No pharmacokinetic data are available in patients with renal and hepatic impairment.

Indications

Non-Hodgkin’s lymphoma:

Cronic lympholeukemia:

Rheumatoid arthritis:

Granulomatosis with polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis:

Active ingredient

Composition

1 ml (1 vial) contains:

Active ingredients:

rituximab 10 mg (100 mg).

Associates:

Sodium citrate dihydrate – 7.35 mg,

Polysorbate 80 – 0.7 mg,

Sodium chloride – 9 mg,

Hydrochloric acid or sodium hydroxide (up to pH 6.5),

d/i water – up to 1 ml.

How to take, the dosage

Regulations for solution preparation and storage

The required amount of the drug is taken under aseptic conditions and diluted to the calculated concentration (1-4 mg/ml) in the infusion bottle (bag) with 0.9% sodium chloride solution for infusion or 5% dextrose solution (solutions must be sterile and apyrogenic). For stirring carefully turn the bottle (package) to avoid foaming. Before administering, the solution should be inspected to make sure there are no foreign impurities or color changes.

The physician is responsible for the preparation, conditions and storage time of the prepared solution prior to use.

Because Mabthera® contains no preservatives, the prepared solution must be used immediately.

The prepared infusion solution of Mabthera® is physically and chemically stable for 12 hours at room temperature or for not more than 24 hours at 2° to 8°C.

Mabthera® is administered only as an IV infusion via a separate catheter! The drug should not be given by injection or bolus!

The recommended initial infusion rate for the first infusion is 50 mg/h and may be increased by 50 mg/h every 30 minutes thereafter, up to a maximum rate of 400 mg/h.

Subsequent infusions can be started at 100 mg/h and increased by 100 mg/h every 30 minutes to a maximum rate of 400 mg/h.

Dose adjustment during therapy

Dose reduction of rituximab is not recommended. If Mabthera® is administered in combination with chemotherapy, dose reduction of chemotherapy drugs is performed according to standard guidelines.

The standard dosing regimen

Non-Hodgkin’s lymphoma of low-grade malignancy or follicularity

A premedication (analgesic/antipyretic such as paracetamol; antihistamine such as diphenhydramine) should be given before each infusion of Mabthera®. If Mabthera® is not used in combination with chemotherapy containing GCS, premedication also includes GCS.

Initial therapy

Monotherapy in adult patients: 375 mg/m2 once weekly, for 4 weeks.

In combination with chemotherapy on any regimen: 375 mg/m2 on the first day of the chemotherapy cycle after IV administration of GCS as a component of therapy, for:

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

Supportive therapy (after response to induction therapy):

Diffuse B-cell non-Hodgkin’s lymphoma

Premedication (analgesic/antipyretic such as paracetamol; antihistamine such as diphenhydramine) should be given before each infusion of Mabthera®. If Mabthera® is not used in combination with chemotherapy containing GCS, premedication also includes GCS.

In combination with chemotherapy according to the CHOP regimen: 375 mg/m2 on the first day of each cycle of chemotherapy after IV administration of GCS, 8 cycles. The other components of the CHOP regimen (cyclophosphamide, doxorubicin and vincristine) are administered after Mabthera®.

Cronic lympholeukemia

Premedication (an analgesic/antipyretic such as paracetamol; an antihistamine such as diphenhydramine) must be given before each infusion of Mabthera®. If Mabthera® is not used in combination with chemotherapy containing GCS, premedication also includes GCS.

In combination with chemotherapy (in patients who have not previously received standard therapy and in relapsed/chemoresistant lymph leukemia): 375 mg/m2 on the first day of the first cycle, then 500 mg/m2 on the first day of each subsequent cycle, 6 cycles. Chemotherapy is given after administration of Mabthera®.

To reduce the risk of tumor lysis syndrome, prophylactic provision of adequate hydration and administration of uricostatics 48 hours before therapy is recommended. In patients with chronic lympholeukemia and lymphocyte counts of >25,000/μL, an IV infusion of prednisone/prednisolone at a dose of 100 mg 1 hour before infusion of Mabthera® is recommended to reduce the frequency and severity of acute infusion reactions and/or cytokine release syndrome.

Rheumatoid arthritis

Premedication (an analgesic/antipyretic such as paracetamol; an antihistamine such as diphenhydramine) should be given before each infusion of Mabthera®. GCS premedication should also be given to reduce the frequency and severity of infusion reactions. Patients should receive 100 mg of methylprednisolone by IV 30 min prior to each infusion of Mabthera®.

Initial therapy: 1000 mg by IV drip, slowly, once every 2 weeks, a course of 2 infusions.

Retreatment: The need for repeated courses of therapy is recommended to be evaluated 24 weeks after the previous course. Retreatment is carried out in case of residual disease activity or in case of disease activity increase more than 2.6 by DAS28-CoE (disease activity index by 28 joints and erythrocyte sedimentation rate). Repeat courses may be prescribed no earlier than 16 weeks after the previous course.

The recommended dosing regimen for repeated use is 1000 mg once every 2 weeks, the course is 2 infusions.

Granulomatosis with polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis

Pre-medication (analgesic/antipyretic such as paracetamol; antihistamine such as diphenhydramine) should be given before each infusion of Mabthera®.

The recommended dosing regimen:

During and after completion of therapy with Mabthera® in patients with granulomatosis with polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis, prevention of pneumocystis pneumonia (caused by Pneumocystis jiroveci) is recommended.

Dosage in special cases

Dose adjustment is not required in patients over 65 years of age.

Interaction

There are limited data on drug interactions of Mabthera®.

In patients with chronic lympholeukemia, concomitant use of Mabthera® , fludarabine and cyclophosphamide does not change pharmacokinetic parameters.

The concomitant administration of methotrexate has no effect on the pharmacokinetics of rituximab in patients with rheumatoid arthritis.

The risk of allergic reactions increases when administered with other monoclonal antibodies for diagnostic or therapeutic purposes in patients who have antibodies against mouse proteins or anti-chimeric antibodies.

In patients with rheumatoid arthritis, the rate of serious infections during therapy with Mabthera® (before therapy with other biological basal anti-inflammatory drugs (BBBs)) is 6.1 per 100 patient-years, while during subsequent therapy with other BBBs it is 4.9 per 100 patient-years.

PVC or polyethylene infusion systems or bags may be used when administering Mabthera® because of material compatibility with the drug.

Special Instructions

The patient’s medical records should include the brand name of the drug (Mabthera®). Substitution with any other biologic medication must be approved by the attending physician. The information in this leaflet refers only to the drug Mabthera®.

The drug Mabthera® is given under the close supervision of an oncologist, hematologist, or rheumatologist with the necessary conditions for resuscitation.

Non-Hodgkin’s lymphoma and chronic lympholeukemia

Infusion reactions. The development of infusion reactions may be due to the release of cytokines and/or other mediators. Severe infusion reactions are difficult to distinguish from hypersensitivity reactions or cytokine release syndrome. There have been reports of fatal infusion reactions described during post-registration use of the drug. Most patients experience fever with chills or shivering within 0.5-2 hours after the start of the first infusion of Mabthera®. Severe reactions include pulmonary symptoms, decreased BP, urticaria, angioedema, nausea, vomiting, weakness, headache, itching, tongue irritation or pharyngeal edema (swelling), rhinitis, hot flashes, pain in the nidi and, in some cases, signs of rapid tumor lysis syndrome. Infusion reactions disappear after interruption of Mabthera® and drug therapy (including intravenous administration of 0.9% sodium chloride solution, diphenhydramine and acetaminophen, bronchodilators, GCS, etc.). In most cases, once symptoms have completely disappeared, infusion can be resumed at a rate 50% of the previous rate (e.g., 50 mg/h instead of 100 mg/h). In most patients with non-life-threatening infusion reactions, treatment with rituximab has been completed. Continuation of therapy after complete disappearance of symptoms is rarely accompanied by a recurrence of severe infusion reactions.

Because of the potential for anaphylactic reactions and other hypersensitivity reactions with IV administration of protein drugs, it is necessary to have the means for their control: adrenaline, antihistamines and GCS.

Lung side effects. Hypoxia, pulmonary infiltrates and acute respiratory failure. Some of these phenomena were preceded by severe bronchospasm and dyspnea. There may be an increase in symptoms over time or clinical deterioration after initial improvement. Patients with pulmonary symptoms or other severe infusion reactions should be closely monitored until symptoms have resolved. Acute respiratory failure may be accompanied by formation of interstitial lung infiltrates or pulmonary edema, often manifested within the first 1-2 h after the start of the first infusion. If severe pulmonary reactions develop, rituximab infusion should be stopped immediately and intensive symptomatic therapy should be administered. Because initial improvement in clinical symptoms may be followed by worsening, patients should be closely monitored until pulmonary symptoms resolve.

The rapid tumor lysis syndrome. Mabthera® mediates rapid lysis of benign or malignant CD20-positive cells. Tumor lysis syndrome is possible 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 a high tumor burden or with a circulating malignant cell count of >25,000/μL, such as those with chronic lympholeukemia or mantle cell lymphoma) require close medical monitoring and regular laboratory examination. If symptoms of rapid tumor lysis develop, appropriate therapy is given. After complete resolution of symptoms in a limited number of cases, therapy with Mabthera® was continued in combination with prophylaxis for rapid tumor lysis syndrome.

Patients with a high number of circulating malignant cells (>25,000/μL) or a high tumor burden (e.g., chronic lympholeukemia or mantle cell lymphoma) in whom the risk of extremely severe infusion reactions may be particularly high should use Mabthera® with extreme caution and close monitoring. The first infusion of the drug should be given at a slower rate in such patients or the dose should be divided over 2 days during the first cycle of therapy and every subsequent cycle thereafter if the number of circulating malignant cells remains >25,000/μL.

Cardiovascular side effects. During infusion, close monitoring of patients with a history of cardiovascular disease is required due to the possibility of developing angina pectoris, arrhythmia (atrial flutter and fibrillation), heart failure or myocardial infarction. Because of the possibility of development of hypotension at least 12 hours before infusion of Mabthera® drug, antihypertensive drugs should be cancelled.

Control of blood cells. Although Mabthera® monotherapy has no myelosuppressive effect, caution should be exercised when administering the drug in neutropenia less than 1500/μL and/or thrombocytopenia less than 75,000/μL, since there is limited experience of its clinical use in such patients. Mabthera® has been used in patients after autologous bone marrow transplantation and in other risk groups with possible bone marrow dysfunction without causing myelotoxicity. Routine peripheral blood counts, including platelet counts, should be determined routinely during treatment.

Infections. Mabthera® should not be administered to patients with severe acute infections.

Hepatitis B. Reactivation of hepatitis B virus or fulminant hepatitis (including fatal) has been reported when combining Mabthera® with chemotherapy. Predisposing factors included both the stage of the underlying disease and cytotoxic chemotherapy.

Contraindications

Side effects

The following criteria are used to evaluate the frequency of adverse reactions:

The drug’s experience with oncohematologic diseases

Mabthera® in therapy of low-grade non-Hodgkin lymphoma or follicular lymphoma – monotherapy/supportive therapy

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Adverse reactions have been reported up to 12 months after monotherapy and up to 1 month after Mabthera® maintenance therapy.

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

The blood and lymphatic system: very common – leukopenia, neutropenia; common – thrombocytopenia, anemia; infrequent – lymphadenopathy, blood clotting disorder, transient partial aplastic anemia, hemolytic anemia.

Respiratory system, thoracic and mediastinal organs: frequently – rhinitis, bronchospasm, cough, respiratory disorders, dyspnea, chest pain; infrequently – hypoxia, pulmonary dysfunction, bronchiolitis obliterans, bronchial asthma.

The immune system: very common – angioedema; frequent – hypersensitivity reactions.

Metabolism and nutrition: often – hyperglycemia, weight loss, peripheral edema, facial edema, increased LDH activity, hypocalcemia.

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

Gastrointestinal disorders: very common – nausea; common – vomiting, diarrhea, dyspepsia, lack of appetite, dysphagia, stomatitis, constipation, abdominal pain, sore throat; infrequent – abdominal enlargement.

Cardiovascular system disorders: frequent – BP lowering, BP increasing, orthostatic hypotension, tachycardia, arrhythmia, atrial fibrillation*, myocardial infarction*, cardiac pathology*; infrequent – left ventricular heart failure*, ventricular and supraventricular tachycardia*, bradycardia, myocardial ischemia*, angina pectoris*.

Nervous system disorders: frequently – dizziness, paresthesia, hypoesthesia, sleep disturbance, anxiety, agitation, vasodilation; infrequently – perversion of taste.

Psychiatric disorders: infrequent – nervousness, depression.

Muscular and connective tissue disorders: often – myalgia, arthralgia, muscle hypertonicity, back pain, neck pain, pain.

Skin and subcutaneous tissue: very often – itching, rash; often – urticaria, increased sweating at night, sweating, alopecia*.

An organ of vision: often – tear production disorders, conjunctivitis.

Hearing organ and labyrinth disorders: often – pain and tinnitus.

Laboratory and instrumental data: very common – decreased concentration of immunoglobulin G (IgG). * Frequency is indicated only for adverse reactions of ≥3 severity according to National Cancer Institute (NCI-CTC) toxicity criteria.

Mabthera® in combination with chemotherapy (R-CHOP, R-CVP, R-FC) in non-Hodgkin’s lymphoma and chronic lymph leukemia

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

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

The blood and lymphatic system: very common – neutropenia**, febrile neutropenia, thrombocytopenia; common – pancytopenia, granulocytopenia.

Skin and subcutaneous tissue: very common – alopecia; common – skin diseases.

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

* – frequency is based on observations during therapy of relapsed/chemoresistant chronic lympholeukemia with the R-FC regimen.

** – prolonged and/or delayed neutropenia was observed after completion of R-FC therapy in previously untreated patients or in patients with relapsed/chemoresistant chronic lympholeukemia.

The following are the adverse reactions that occurred with Mabthera® therapy at the same rate (or less frequently) compared to the control group Hematotoxicity, neutropenic infections, urinary tract infections, septic shock, pulmonary superinfections, implant infection, staphylococcal septicemia, nasal mucous discharge, pulmonary edema, heart failure, sensory disorders, venous thrombosis, includingincluding deep vein thrombosis of the extremities, mucositis, edema of the lower extremities, decreased left ventricular ejection fraction, increased body temperature, worsening of general well-being, falling, multiple organ failure, bacteremia, decompensation of diabetes mellitus.

The safety profile of Mabthera® in combination with chemotherapy with MSR, CHVP-IFN regimens is not different from that of combining the drug with CVP, CHOP or FC in the respective populations.

Infusion reactions

Mabthera® monotherapy (for 4 weeks)

More than 50% of patients experienced phenomena resembling infusion reactions, most commonly in the first infusions. Infusion reactions include chills, shivering, weakness, shortness of breath, nausea, rash, hot flashes, decreased BP, fever, itching, urticaria, sensation of tongue irritation or laryngeal edema (angioedema), rhinitis, vomiting, pain in tumor foci, headache, bronchospasm. The development of signs of tumor lysis syndrome has been reported.

Mabthera® in combination with chemotherapy according to the following regimens: R-CVP for non-Hodgkin’s lymphoma; R-CHOP for diffuse B-cell non-Hodgkin’s lymphoma; R-FC for chronic lymph leukemia

Infusion reactions of grade 3 and 4 severity during infusion or within 24 hours after infusion of Mabthera® were noted during the first cycle of chemotherapy in 12% of patients. The frequency of infusion reactions decreased with each subsequent cycle and by the 8th cycle of chemotherapy, the frequency of infusion reactions reached less than 1%. In addition to those mentioned above (when treated with Mabthera® monotherapy), infusion reactions included: dyspepsia, rash, increased BP, tachycardia, signs of tumor lysis syndrome, in some cases – myocardial infarction, atrial fibrillation, pulmonary edema and acute reversible thrombocytopenia.

Infections

Mabthera® monotherapy (for 4 weeks)

Mabthera® causes depletion of the B-cell pool in 70-80% of patients and decreased serum immunoglobulin concentrations in a small number of patients. Bacterial, viral, fungal infections and infections without a definite etiology (all, regardless of the cause) develop in 30.3% of patients. Severe infections (3 and 4 degrees of severity), including sepsis, are noted in 3.9% of patients.

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

In therapy with Mabthera® there was an increase in the overall rate of infections, including infections of grade 3-4 severity. No increase in cases of infectious complications was observed with maintenance therapy of 2 years. Cases of progressive multifocal leukoencephalopathy (PML) with fatal outcome in patients with non-Hodgkin’s lymphoma after disease progression and retreatment have been reported.

Mabthera® in combination with chemotherapy on the following regimens: R-CVP for non-Hodgkin’s lymphoma; R-CHOP for diffuse B-cell non-Hodgkin’s lymphoma; R-FC for chronic lympholeukemia

There was no increase in the frequency of infections or invasions with Mabthera® therapy with the R-CVP regimen. Upper respiratory tract infections were the most frequent (12.3% in the R-CVP group). Serious infections were observed in 4.3% of patients receiving R-CVP chemotherapy; no life-threatening infections were reported.

The proportion of patients with grade 2-4 infections and/or febrile neutropenia in the R-CHOP group was 55.4%. The cumulative incidence of grade 2-4 infections in the R-CHOP group was 45.5%. The incidence of grade 2-4 fungal infections in the R-CHOP group was higher than in the CHOP group due to a higher incidence of local candidiasis and was 4.5%. The incidence of herpetic infections of grade 2-4 severity was higher in the R-CHOP group compared with the CHOP group and was 4.5%.

In patients with chronic lymph leukemia, the incidence of hepatitis B (hepatitis B virus reactivation and primary infection) of grade 3-4 severity was 2% in the R-FC group.

Hematopoietic system disorders

Monotherapy with Mabthera® (for 4 weeks)

1.7% – severe thrombocytopenia (3rd and 4th degree severity); 4.2% – severe neutropenia; 1.1% – severe anemia (3rd and 4th degree severity).

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

Leukopenia (grade 3 and 4 severity) was observed in 5% of patients; neutropenia (grade 3 and 4 severity) in 10% of patients treated with Mabthera®. Frequency of thrombocytopenia (3rd-4th degree of severity) during therapy with Mabthera® was low and amounted to < 1%.

About 50% of patients for whom B-cell count recovery was available took 12 months or more after completion of Mabthera® induction therapy to restore B-cell count to normal levels.

Mabthera® in combination with chemotherapy according to the following regimens: R-CVP for non-Hodgkin lymphoma; R-CHOP for diffuse B-cell non-Hodgkin lymphoma; R-FC for chronic lympholeukemia

Severe neutropenia and leukopenia (3rd and 4th degree severity): Grade 3 and 4 leukopenia were more common in patients who received Mabthera® in combination with chemotherapy compared to patients who received chemotherapy alone. The incidence of severe leukopenia was 88% in patients receiving R-CHOP and 23% in patients receiving R-FC. The incidence of severe neutropenia was 24% in the R-CVP group, 97% in the R-CHOP group, and 30% in the R-FC group for previously untreated chronic lymph leukemia. The higher rate of neutropenia in patients who received Mabthera® and chemotherapy was not associated with an increased rate of infections and invasions compared to patients who received chemotherapy alone. In patients with relapsed or chemoresistant chronic lymph leukemia after R-FC therapy, neutropenia was occasionally characterized by a prolonged course or later manifestation.

Severe anemia and thrombocytopenia (grade 3 and 4 severity): there was no significant difference in the incidence of grade 3 and 4 anemia between the groups. In the R-FC group of first-line therapy for chronic lymph leukemia, grade 3 and 4 anemia occurred in 4% of patients, and grade 3 and 4 thrombocytopenia in 7% of patients. In the R-FC group for relapsed or chemoresistant chronic lympholeukemia, grade 3 and 4 anemia occurred in 12% of patients and grade 3 and 4 thrombocytopenia occurred in 11% of patients.

Nervous system disorders

Mabthera® in combination with chemotherapy according to the following regimens: R-CVP for non-Hodgkin’s lymphoma; R-CHOP for diffuse B-cell non-Hodgkin’s lymphoma; R-FC for chronic lympholeukemia

Patients (2%) in the R-CHOP group with cardiovascular risk factors developed cerebral thromboembolic circulatory disorders during the first cycle of therapy, in contrast to patients in the CHOP group, who developed cerebral circulatory disorders during follow-up without treatment. There was no difference between the groups in the incidence of other thromboemboli.

The overall incidence of grade 3 and 4 neurologic impairment was low in both first-line therapy for chronic lymph leukemia (4% in the R-FC group) and therapy for relapsed/chemoresistant chronic lymph leukemia (3% in the R-FC group).

IgG concentrations

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

After induction therapy, IgG concentrations were below the lower limit of normal ( < 7 g/L) in the group receiving Mabthera® and in the group not receiving the drug. In the group that did not receive Mabthera®, the median IgG concentration consistently increased and exceeded the lower limit of normal, while the median IgG concentration was unchanged in the Mabthera®-treated group. In 60% of patients treated with Mabthera® for 2 years, the IgG concentration remained below the lower limit. In the group without Mabthera® therapy, after 2 years, the IgG concentration remained below the lower limit in 36% of patients.

Particular categories of patients

Mabthera® monotherapy (for 4 weeks)

In elderly patients (65 years and older), the frequency and severity of all adverse reactions and side effects of grade 3 and 4 do not differ from that in younger patients.

Combination therapy

In elderly patients (65 years and older), the incidence of grade 3 and 4 adverse reactions from the blood and lymphatic system was higher in first-line therapy as well as in therapy of relapsed/chemoresistant chronic lympholeukemia compared to younger patients.

The incidence of grade 3 and 4 adverse reactions was increased in high tumor burden (single foci greater than 10 cm in diameter).

The incidence and severity of adverse reactions are not different with repeated therapy than with initial therapy.

The experience with the drug in rheumatoid arthritis

The following are the adverse reactions that occurred with therapy with Mabthera® with a frequency of at least 2% and at least a 2% difference compared to the control group.

Immune system, general disorders and disorders at the site of administration: very common – infusion reactions* (common – increased and decreased BP, flushes, rash, urticaria, pruritus, chills, fever, nausea, rhinitis, feeling of throat fart, tachycardia, weakness, pain in the mouth and throat, peripheral edema, erythema).

* – The following clinically significant infusion reactions have also been observed infrequently: generalized edema, bronchospasm, wheezing, laryngeal edema, angioedema, generalized pruritus, anaphylaxis, anaphylactoid reaction. Infectious and parasitic diseases: very often – urinary tract infections, upper respiratory tract infections; often – bronchitis, sinusitis, gastroenteritis, foot dermatophytosis.

The digestive system: frequently – dyspepsia, diarrhea, gastroesophageal reflux, oral mucosa ulceration, pain in the right upper quadrant of the abdomen.

Nervous system disorders: very common – headache; common – migraine, paresthesia, dizziness, sciatica.

Psychiatric disorders: often – depression, anxiety.

Musculoskeletal and connective tissue disorders: often – arthralgia, musculoskeletal pain, osteoarthritis, bursitis.

Skin and subcutaneous tissue: often – alopecia.

Laboratory and instrumental data: often – hypercholesterolemia.

Retreatment: the profile of adverse reactions with repeated use is not different from that with initial therapy. The safety profile improved with each subsequent course of therapy and was characterized by a decrease in the incidence of infusion reactions, infections, and exacerbations, which were most common in the first 6 months of therapy.

Infusion reactions: Infusion reactions were the most common adverse reaction with Mabthera®. At least one infusion reaction was observed in 35% of patients, with serious infusion reactions occurring in less than 1% of patients, regardless of dose. The majority of infusion reactions were grade 1 and 2 severe. The proportion of grade 3 infusion reactions and infusion reactions leading to discontinuation of therapy decreased with each subsequent course of treatment, and, starting with course 3, such reactions were rare. No grade 4 infusion reactions or deaths were detected as a result of their development.

The following symptoms of infusion reactions occurred in 23% of patients after the first administration of Mabthera®: nausea, itching, fever, urticaria/rash, chills, shivering, sneezing, angioedema, pharyngeal irritation, cough and bronchospasm with or without increased or decreased BP. Premedication with IV GCS significantly reduces the frequency and severity of these events.

Infections: During therapy with Mabthera® the overall incidence of infections, which were predominantly mild to moderate in severity (most common were upper respiratory tract infections and urinary tract infections) was 97 per 100 patient-years. The incidence of severe infections, some of which were fatal, was 4 per 100 patient-years. Among the clinically significant serious adverse events, pneumonia was also observed (1.9%).

Malignant disease: The incidence of malignant disease after administration of Mabthera® does not exceed the rates in the age- and sex-matched population, at 0.8 per 100 patient-years.

Laboratory parameters: hypogammaglobulinemia (decrease of IgG and IgM immunoglobulin concentrations below the lower limit of normal) with no increase in the overall incidence or rate of serious infections. During the first course of Mabthera® therapy, including several months after completion of therapy, cases of neutropenia, mostly transient and of mild to moderate severity, have been reported. The incidence of severe neutropenia (grade 3 and 4) was 0.94% compared to 0.27% in the non-treated group.

. Given that the rate of severe neutropenia after the first course of Mabthera® therapy was 1.06 per 100 patient-years compared to 0.53 per 100 patient-years with no such therapy, and the rate of severe neutropenia after repeated use was 0.97 per 100 patient-years compared to 0.88 per 100 patient-years with no such therapy, severe neutropenia can be considered an adverse reaction only for the first course of Mabthera® therapy. The timing of neutropenia manifestation varied. Neutropenia was not associated with an increased incidence of serious infections, and in most cases patients received repeated courses of Mabthera® after episodes of neutropenia.

The drug’s experience with granulomatosis with polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis

. The following are adverse events that occurred with Mabthera® with an incidence of ≥10% (very common) compared to the incidence of adverse reactions with cyclophosphamide (allowed for cross-medication or change to another therapy based on a weighted clinical decision).

Infectious and parasitic diseases: infections, including the most common upper respiratory tract infections, urinary tract infections, herpes zoster – 61.6% (in the comparison group – 46.9%).

Gastrointestinal disorders: nausea – 18.2% (comparison group – 20.4%), diarrhea – 17.2% (comparison group – 12.2%).

Nervous system disorders: headache – 17.2% (comparison group -19.4%).

Musculoskeletal and connective tissue disorders: muscle cramps – 17.2% (comparison group – 15.3%), arthralgia – 13.1% (comparison group – 9.2%).

Blood and lymphatic system disorders: anemia – 16.2% (in comparison group – 20.4%), leukopenia – 10.1% (in comparison group – 26.5%).

General disorders and disorders at the injection site: peripheral edema – 16.2% (comparison group – 6.1%), weakness – 13.1% (comparison group – 21.4%).

Immune system disorders: infusion reactions, including the most common, cytokine release syndrome, redness, throat irritation, tremor – 12.1% (comparison group – 11.2%).

Mental disorders: insomnia – 14.1% (comparison group – 12.2%).

Laboratory and instrumental findings: increased ALT activity – 13.1% (comparison group – 15.3%).

Respiratory system, chest and mediastinal organs: cough – 13.1% (comparison group – 11.2%), nasal bleeding 11.1% (comparison group – 6.1%), dyspnea – 10.1% (comparison group – 11.2%).

Cardiovascular system: increase in BP – 12.1% (in comparison group – 5.1%).

Skin and subcutaneous tissue: rash – 10.1% (comparison group – 17.3%).

Infusion reactions: all infusion reactions observed during infusion of Mabthera® or within 24 h after it were of 1 and 2 severity. The most frequently observed were cytokine release syndrome, redness, throat irritation and tremor. The use of Mabthera® in combination with an IV GCS may have reduced the frequency and severity of the adverse reactions described.

Infections: The overall incidence of infections with Mabthera® was 210 per 100 patient-years. Infections were predominantly mild to moderate in severity and most commonly included upper respiratory tract infections, urinary tract infections and herpes zoster. The incidence of serious infections with Mabthera® was 25 per 100 patient-years. Among serious infections, pneumonia was the most commonly reported with Mabthera® (4%).

Malignant diseases: The incidence of new cases of malignant diseases with Mabthera® is consistent with that in the population and is 2.05 per 100 patient-years.

In the laboratory indexes: hypogammaglobulinemia (decrease of immunoglobulins’ concentration below the lower limit of normality) IgA, IgG and IgM on the 6th month of therapy in the Mabthera® group was 27%, 58% and 51%, respectively, in comparison with 25%, 50% and 46% in comparison group. Patients with low IgA, IgG and IgM concentrations showed no increase in overall infection rates or incidence of serious infections.

Grade 3 and 4 neutropenia was observed in 24% of patients in the Mabthera® group and 23% of patients in the comparison group. Patients who received rituximab had no increase in the incidence of serious infections associated with neutropenia. The effect of rituximab on the development of neuropenia with repeated use has not been investigated.

Post-registration use of Mabthera® in non-Hodgkin’s lymphoma and chronic lympholeukemia

Cardiovascular system effects: Severe cardiovascular events associated with infusion reactions, such as heart failure and myocardial infarction, mostly in patients with a history of cardiovascular disease and/or receiving cytotoxic chemotherapy; very rarely, vasculitis, mostly cutaneous (leukocytoclastic).

Respiratory system disorders: respiratory failure and pulmonary infiltrates due to infusion reactions; in addition to adverse pulmonary reactions due to infusion reactions, interstitial lung disease, in some cases with a fatal outcome, has been observed.

Blood and lymphatic system disorders: reversible acute thrombocytopenia associated with infusion reactions.

Skin and its appendages: rare – severe bullous reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome, in some cases with fatal outcome.

Nervous system disorders: rare – cranial nerve neuropathy in combination with peripheral neuropathy or without it (marked decrease of visual acuity, hearing, other sensory organs affection, facial nerve paresis) during various periods of therapy up to several months after therapy with Mabthera®. Patients treated with Mabthera® had cases of reversible encephalopathy with posterior brain injury (PRES)/reversible leukoencephalopathy with posterior brain injury (PRLS) syndrome. Symptomatology included visual impairment, headache, seizures, and psychiatric disturbances, with or without elevated BP. The diagnosis of PRES/PRLS could be confirmed by brain imaging techniques. In the cases described, patients had risk factors for PRES/PRLS, such as underlying disease, elevated BP, immunosuppressive therapy and/or chemotherapy.

Body and injection site reactions: rarely, serum sickness.

Infections: Reactivation of viral hepatitis B (in most cases with the combination of Mabthera® and cytotoxic chemotherapy); and other severe viral infections (primary infection, virus reactivation or exacerbation), some of which were fatal, caused by cytomegalovirus, Varicella zoster, Herpes simplex, polyomavirus JC (PML), hepatitis C virus. When Mabthera® was administered for indications not provided for in the instructions for medical use, progression of sarcoma was observed in patients with previously diagnosed Kaposi sarcoma (most patients were HIV-positive).

Gastrointestinal disorders: gastric and/or intestinal perforation (possibly fatal) when combining Mabthera® with chemotherapy for non-Hodgkin’s lymphoma.

With the blood and lymphatic system: rare – neutropenia occurring 4 weeks after the last administration of rituximab; transient increase of IgM concentration in patients with Waldenstrom macroglobulinemia with subsequent return to the initial value in 4 months.

Post-registration use of Mabthera® in rheumatoid arthritis, granulomatosis with polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis

. The following are adverse reactions that have been observed in patients with rheumatoid arthritis during postmarketing use of Mabthera® and are also expected or observed in patients with granulomatosis with polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis.

Infections: PML, hepatitis B virus reactivation.

In general, reactions at the site of administration: serum-like reactions; severe infusion reactions, in some cases with fatal outcome.

Skin and its appendages: very rare – toxic epidermal necrolysis and Stevens-Johnson syndrome, in some cases with fatal outcome.

With the blood and lymphatic system: rarely – neutropenia (including severe cases with late manifestation and cases of prolonged neutropenia), some of which have been associated with fatal infections.

Nervous system disorders: cases of PRES/PRLS have been observed in patients treated with Mabthera®. Symptoms have included visual disturbances, headache, seizures, and psychiatric disorders, with or without elevated BP. The diagnosis of PRES/PRLS could be confirmed using brain imaging techniques. In the cases described, patients had risk factors for PRES/PRLS, such as elevated BP, immunosuppressive therapy, and/or other concomitant therapy.

Overdose

No human cases of overdose have been observed.

Dose doses of rituximab greater than 1000 mg have not been studied.

The maximum dose of 5,000 mg has been administered to patients with chronic lympholeukemia; no additional safety data are available.

Due to increased risk of infectious complications in case of depletion of B-lymphocyte pool the Mabthera® infusion should be stopped, the patient should be monitored and a detailed blood count should be performed.

Pregnancy use

Immunoglobulin G (IgG) is capable of crossing the placental barrier.

B-cell levels in newborns when Mabthera® was administered to women during pregnancy have not been studied.