Mabthera
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MABTHERA® (MABTHERA®)
Composition:
Active substance: rituximab;
1 ml of the preparation contains 10 mg of rituximab; 1 vial (10 ml) contains 100 mg of rituximab;
1 vial (50 ml) contains 500 mg of rituximab;
Excipients: sodium citrate dihydrate; polysorbate 80; sodium chloride; water for injections; hydrochloric acid or sodium hydroxide (to pH 6.5)
or
sodium citrate dihydrate; citric acid anhydrous; polysorbate 80; sodium chloride; water for injections; hydrochloric acid or sodium hydroxide (to pH 6.5)
Pharmaceutical form. Concentrate for solution for infusion.
Main physicochemical properties: liquid, from clear to opalescent, colorless to pale yellow.
Pharmacotherapeutic group.
Antineoplastic agents. Monoclonal antibodies and antibody-drug conjugates. CD20 (cluster of differentiation 20) inhibitors.
ATC code L01F A01.
Pharmacological Properties
Pharmacodynamics
Mechanism of Action
Rituximab is a genetically engineered chimeric monoclonal antibody of mouse/human origin, which is a glycosylated immunoglobulin with sequences from the human IgG1 constant domain and variable domain heavy and light chains from mouse. The antibodies are produced by a mammalian cell suspension culture (Chinese hamster ovary cells) and purified using affinity chromatography and ion exchange, along with specific viral inactivation and removal procedures. Rituximab specifically binds to the transmembrane CD20 antigen, a nonglycosylated phosphoprotein located on pre-B lymphocytes and mature B lymphocytes. This antigen is expressed in more than 95% of all B-cell non-Hodgkin's lymphomas.
CD20 is present on both normal and malignant B cells, but is absent on hematopoietic stem cells, pro-B cells, healthy plasma cells, and healthy cells of other tissues. After binding with the antibody, CD20 is neither internalized nor shed into the extracellular environment from the cell membrane. CD20 does not circulate in plasma as a free antigen and therefore does not compete for antibody binding.
The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes, while the Fc domain initiates immunological reactions leading to B-cell lysis. Possible mechanisms of cellular lysis include complement-dependent cytotoxicity (CDC) due to C1q binding, and antibody-dependent cellular cytotoxicity (ADCC), mediated by one or more Fcγ receptors on the surface of granulocytes, macrophages, and NK cells. It has also been demonstrated that binding of rituximab to the CD20 antigen on B lymphocytes induces cell death via apoptosis.
The number of B cells in peripheral blood decreases below normal levels after the first administration of the drug. In patients treated for hematologic malignancies, B-cell counts begin to recover after 6 months and return to normal within 12 months after completion of therapy; however, in some patients, the B-cell recovery period may be longer (on average, 23 months after induction therapy). In patients with rheumatoid arthritis, rapid depletion of the B-cell population in peripheral blood was observed after two 1000 mg infusions of MabThera®, administered 14 days apart. B-cell counts began to increase by week 24, and signs of population recovery were observed in most patients by week 40, regardless of whether MabThera® was administered as monotherapy or in combination with methotrexate. In a small number of patients, prolonged reduction in peripheral B-cell counts lasting up to 2 years or more after the last dose of MabThera® was observed. In patients with granulomatosis with polyangiitis or microscopic polyangiitis, peripheral blood B-cell counts decreased to <10 cells/μL after two infusions of MabThera® at 375 mg/m² administered weekly, and remained at this level in most patients for up to 6 months. Most patients (81%) showed signs of B-cell recovery, with B-cell counts >10 cells/μL by month 12 and 87% by month 18.
Pharmacokinetics
Non-Hodgkin’s Lymphoma
According to population pharmacokinetic analysis in 298 patients with non-Hodgkin’s lymphoma receiving MabThera® as monotherapy or in combination with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone) with rituximab doses ranging from 100 to 500 mg/m², the nonspecific clearance (CL1), specific clearance (CL2) (likely related to B cells or tumor burden), and central volume of distribution (V1) were 0.14 L/day, 0.59 L/day, and 2.71 L, respectively. The median terminal half-life of rituximab was 22 days (ranging from 6.1 to 52 days). Baseline CD19-positive cell levels and tumor size influenced CL2 of rituximab at a dose of 375 mg/m² administered intravenously once weekly for 4 weeks (data from 161 patients). CL2 was higher in patients with higher CD19-positive cell counts or larger tumor size. However, individual variability in CL2 persists even after adjusting for tumor size and CD19-positive cell levels. Relatively small changes in V1 depend on body surface area (1.53–2.32 m²) and concomitant CHOP chemotherapy. The variability in V1 (27.1% and 19.0%) due to fluctuations in body surface area (1.53–2.32 m²) and concurrent CHOP therapy, respectively, was relatively minor. Age, sex, and WHO performance status had no notable effect on rituximab pharmacokinetics. There is no reason to expect significant changes in rituximab pharmacokinetic parameters with dose adjustments based on any of the studied covariates.
MabThera® administered by intravenous infusion at 375 mg/m² weekly (total of 4 doses) to 203 patients with non-Hodgkin’s lymphoma who had not previously received MabThera® resulted in a mean Cmax after the fourth infusion of 486 μg/mL (range: 77.5 to 996.6 μg/mL). Rituximab was detectable in patient serum 3–6 months after completion of the last treatment course.
When MabThera® was administered at 375 mg/m² by intravenous infusion weekly (total of 8 doses) to 37 patients with non-Hodgkin’s lymphoma, mean Cmax increased with each subsequent infusion, rising from a mean of 243 μg/mL (range: 16 to 582 μg/mL) after the first infusion to 550 μg/mL (range: 171 to 1177 μg/mL) after the eighth infusion.
The pharmacokinetic profile of MabThera® (6 infusions at 375 mg/m²) in combination with 6 cycles of CHOP chemotherapy was practically identical to that observed with monotherapy.
Children with B-ALCL/B-ALL/B-LBL/PLL
In a clinical study involving children with B-ALCL/B-ALL/B-LBL/PLL, pharmacokinetics were evaluated in a subgroup of 35 patients aged 3 years and older. Pharmacokinetic parameters were comparable between the two age groups (patients aged ≥3 to <12 years and ≥12 to <18 years). After two intravenous infusions of MabThera® at 375 mg/m² in each of two induction cycles (cycles 1 and 2), followed by one intravenous infusion of MabThera® at 375 mg/m² in each consolidation cycle (cycles 3 and 4), the maximum concentration was highest after the fourth infusion (cycle 2), with a geometric mean of 347 μg/mL, followed by a lower geometric mean maximum concentration (cycle 4: 247 μg/mL). With this dosing regimen, trough levels were maintained at geometric mean values of 41.8 μg/mL (pre-dose, cycle 2; after 1 cycle), 67.7 μg/mL (pre-dose, cycle 3; after 2 cycles), and 58.5 μg/mL (pre-dose, cycle 4; after 3 cycles). The mean elimination half-life in children aged 3 years and older was 26 days.
The pharmacokinetic characteristics of MabThera® in children with B-ALCL/B-ALL/B-LBL/PLL were similar to those observed in adult patients with NHL.
For the age group ≥6 months to <3 years, pharmacokinetic data are lacking; however, population pharmacokinetic modeling supports comparable systemic exposure (AUC, Ctrough) in this age group to that in the ≥3 years group (Table 1). Smaller baseline tumor size is associated with higher exposure due to lower time-dependent clearance; however, systemic exposure influenced by varying tumor size remains within the range shown to be effective and with an acceptable safety profile.
Table 1. Predicted pharmacokinetic parameters after rituximab dosing regimen in children with B-ALCL/B-ALL/B-LBL/PLL
| Age group |
≥ 6 months – < 3 years |
≥ 3 – < 12 years |
≥ 12 – < 18 years |
| Cmin (μg/mL) |
47.5 (0.01–179) |
51.4 (0.00–182) |
44.1 (0.00–149) |
| AUC1–4 cycles (μg*day/mL) |
13,501 (278–31,070) |
11,609 (135–31,157) |
11,467 (110–27,066) |
Results are presented as median (minimum – maximum); Cmin is pre-dose of cycle 4.
Chronic lymphocytic leukemia
MabThera® was administered by intravenous infusion: the first dose of cycle was 375 mg/m², increased to 500 mg/m² each cycle in a 5-dose regimen in combination with fludarabine and cyclophosphamide in chronic lymphocytic leukemia. The mean maximum concentration (Cmax) (N=15) after the fifth infusion of rituximab at a dose of 500 mg/m² was 408 µg/ml (range 97–764 µg/ml), and the mean terminal half-life was 32 days (range 14 to 62 days).
Rheumatoid arthritis
After two intravenous infusions of MabThera® at a dose of 1000 mg given two weeks apart, the mean terminal half-life was 20.8 days (range 8.58 to 35.9 days), mean systemic clearance was 0.23 l/day (range 0.091 to 0.67 l/day), and mean volume of distribution at steady state was 4.61 l (range 1.7 to 7.51 l). According to population pharmacokinetic analysis, systemic clearance and half-life were 0.26 l/day and 20.4 days, respectively. Population pharmacokinetic analysis showed that body surface area and sex were the most significant covariates explaining individual variability in pharmacokinetic parameters. After correction for body surface area, male patients had higher volume of distribution and clearance than female patients. Sex-related differences in pharmacokinetic parameters were not clinically significant; therefore, dose adjustment is not required. Pharmacokinetic data in patients with hepatic or renal impairment are lacking.
Pharmacokinetics of rituximab were evaluated after two intravenous administrations of 500 mg and 1000 mg on Day 1 and Day 15 in four studies. Rituximab pharmacokinetics were dose-proportional within the limited dose range studied. Mean Cmax values of rituximab in serum after the first infusion ranged from 157 to 171 µg/ml for two 500 mg doses and from 298 to 341 µg/ml for two 1000 mg doses. After the second infusion, mean Cmax ranged from 183 to 198 µg/ml for two 500 mg doses and from 355 to 404 µg/ml for two 1000 mg doses. Mean terminal half-life ranged from 15 to 16 days with two 500 mg doses and from 17 to 21 days with two 1000 mg doses. Mean Cmax was 16–19% higher after the second infusion compared to the first infusion for both dose levels.
Pharmacokinetics of rituximab were evaluated after two intravenous infusions of two 500 mg doses and two 1000 mg doses during the second treatment course. Mean Cmax of rituximab in serum after the first infusion was 170 to 175 µg/ml for two 500 mg doses and 317 to 370 µg/ml for two 1000 mg doses. Cmax after the second infusion was 207 µg/ml for two 500 mg doses and ranged from 377 to 386 µg/ml for two 1000 mg doses. Mean terminal half-life after the second infusion of the second course was 19 days for two 500 mg doses and ranged from 21 to 22 days for two 1000 mg doses. Pharmacokinetic parameters of rituximab were comparable across the two treatment courses.
Pharmacokinetic parameters in the population of patients who had inadequate response to tumor necrosis factor inhibitor therapy, after administration of the same treatment regimen (two 1000 mg intravenous infusions given two weeks apart), were similar, with a mean Cmax in serum of 369 µg/ml and a mean terminal half-life of 19.2 days.
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)
Adults
Population pharmacokinetic analysis of data from 197 patients with granulomatosis with polyangiitis and microscopic polyangiitis who received four weekly doses of MabThera® at 375 mg/m² showed that the mean terminal half-life was 23 days (range 9–49 days). Mean rituximab clearance and volume of distribution were 0.313 l/day (range 0.116–0.726 l/day) and 4.50 l (range 2.25–7.39 l), respectively. Maximum concentration during the first 180 days (Cmax), minimum concentration on day 180 (C180), and cumulative area under the curve over 180 days (AUC180) were (median [range]) 372.6 (252.3–533.5) µg/ml, 2.1 (0–29.3) µg/ml, and 10302 (3653–21874) µg/ml*days, respectively. Pharmacokinetic parameters of rituximab in adult patients with GPA and MPA are similar to those observed in patients with rheumatoid arthritis.
Clinical characteristics.
Indications.
Non-Hodgkin's lymphomas
Monotherapy in adult patients with stage III–IV follicular lymphomas who are refractory to chemotherapy or in second or subsequent relapse following chemotherapy.
Treatment of CD20-positive diffuse large B-cell non-Hodgkin's lymphoma in combination with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) in adults.
Treatment of previously untreated stage III–IV follicular lymphoma in combination with chemotherapy in adults.
Maintenance therapy in adult patients with follicular lymphomas following response to induction therapy.
MabThera® in combination with chemotherapy is indicated for the treatment of children (aged ≥ 6 months – < 18 years) with previously untreated advanced CD20-positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL)/Burkitt leukemia (acute leukemia of mature B-cells) (BLL), or Burkitt-like lymphoma (BLL).
Chronic lymphocytic leukemia
Treatment of previously untreated and relapsed/refractory chronic lymphocytic leukemia in combination with chemotherapy. There are limited data on the efficacy and safety of use in patients previously treated with monoclonal antibodies, including MabThera®, or in patients refractory to prior treatment with MabThera® plus chemotherapy.
Rheumatoid arthritis
Treatment of severe rheumatoid arthritis (active form) in adults in combination with methotrexate when treatment with other disease-modifying antirheumatic drugs, including one or more tumor necrosis factor inhibitors, has failed or is not tolerated.
When used in combination with methotrexate, MabThera® reduces the rate of progression of radiologically evident joint damage and improves physical function.
Granulomatosis with polyangiitis and microscopic polyangiitis
Treatment of severe active granulomatosis with polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis in adults in combination with glucocorticoids for remission induction.
Contraindications.
Hypersensitivity to the active substance or to mouse proteins or to any other excipient (see section "Composition").
Active severe infections (see section "Special precautions").
Marked immunodeficiency.
Severe heart failure (NYHA functional class IV) or severe decompensated heart disease are contraindications for use in rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis (see section "Special precautions" regarding other cardiovascular diseases).
Interaction with other medicinal products and other forms of interaction.
Data on interactions of MabThera® with other medicinal products are currently limited. In patients with chronic lymphocytic leukemia, concomitant administration with rituximab did not affect the pharmacokinetics of fludarabine or cyclophosphamide. No apparent effect of fludarabine and cyclophosphamide on the pharmacokinetics of MabThera® was observed.
Concomitant administration with methotrexate in patients with rheumatoid arthritis does not affect the pharmacokinetics of MabThera®.
Allergic or hypersensitivity reactions may occur upon administration of other monoclonal antibodies for diagnostic or therapeutic purposes in patients with titers of human anti-mouse antibodies (HAMA) or antibodies to the medicinal product (ADA).
Among patients with rheumatoid arthritis, 283 patients received sequential therapy with biological disease-modifying antirheumatic drugs after treatment with MabThera®. The rate of clinically significant infections during MabThera® treatment in patients with rheumatoid arthritis was 6.01 per 100 patient-years compared to 4.97 per 100 patient-years after treatment with biological disease-modifying antirheumatic drugs.
Special precautions for use.
Tracking
To improve the traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly documented.
Progressive multifocal leukoencephalopathy (PML)
All patients receiving MabThera® for rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis must be provided with patient alert cards at each infusion. These alert cards contain important safety information for patients regarding the risk of infections, including progressive multifocal leukoencephalopathy.
Very rare cases of PML with fatal outcomes have been reported following MabThera® use for the treatment of rheumatoid arthritis and autoimmune diseases (including systemic lupus erythematosus (SLE) and vasculitis), as well as during post-marketing use of MabThera® in NHL and CLL (where most patients received MabThera® in combination with chemotherapy or within hematopoietic stem cell transplantation programs).
Patients should be regularly monitored for any new or worsening neurological symptoms that may indicate PML. If PML is suspected, treatment should be suspended until PML is ruled out. Clinicians should evaluate patients to determine whether symptoms suggest neurological dysfunction and, if so, whether these symptoms could indicate PML. Neurological consultation should be considered as clinically indicated.
If there is any uncertainty, consideration should be given to performing additional investigations, including MRI scanning (preferably with contrast), analysis of cerebrospinal fluid for John Cunningham (JC) virus DNA, and repeat neurological evaluation.
Physicians must pay special attention to symptoms suggestive of PML that the patient may not notice (e.g., cognitive, neurological, or psychiatric disturbances). Patients should also be advised to inform their family members and close contacts about their treatment, as these individuals may notice symptoms the patient has not observed.
If PML develops, treatment with MabThera® must be permanently discontinued.
In patients with PML who had immunosuppression, stabilization or improvement of the condition has been observed after immune system recovery. It is currently unknown whether early detection of PML and suspension of MabThera® therapy could lead to similar stabilization or improvement.
Cardiac symptoms. Treatment with MabThera® has been associated with cases of angina and cardiac rhythm disturbances, such as atrial fibrillation and flutter, heart failure, and/or myocardial infarction. Therefore, patients with a history of cardiac disease and/or after cardiotoxic chemotherapy require careful monitoring (see below "Infusion reactions").
Infections. Due to the mechanism of action of MabThera® and the important role of B-cells in maintaining normal immune response, there is an increased risk of infections in patients treated with MabThera®. Serious infections, including fatal cases, may occur during MabThera® therapy (see section "Adverse reactions"). MabThera® should not be administered to patients with acute, severe infections (e.g., tuberculosis, sepsis, and opportunistic infections) or to patients with significantly impaired immunity (e.g., very low CD4 or CD8 levels) (see section "Contraindications"). Physicians should exercise particular caution when considering the use of MabThera® in patients with a history of recurrent or chronic infections or underlying conditions that may increase susceptibility to serious infections, such as hypogammaglobulinemia (see section "Adverse reactions"). Measurement of immunoglobulin levels in patients prior to starting MabThera® therapy is recommended.
Patients who develop symptoms of infection after MabThera® therapy should be promptly evaluated and appropriate treatment initiated. Prior to the next course of MabThera® therapy, patients should be re-evaluated for any potential risk of infection development.
For information on progressive multifocal leukoencephalopathy (PML), see above "Progressive multifocal leukoencephalopathy."
Cases of enteroviral meningioencephalitis, including fatal cases, have been reported after rituximab administration.
Hepatitis B virus
Cases of hepatitis B reactivation, including fatal cases, have been reported in patients receiving MabThera®. Most of these patients were also undergoing cytotoxic chemotherapy. Limited data from one study involving patients with relapsed/refractory CLL suggest that MabThera® therapy may also worsen outcomes of primary hepatitis B infections.
All patients should undergo screening for hepatitis B virus (HBV) prior to starting MabThera® therapy, including at minimum testing for HBsAg and HBcAb, and possibly supplemented with other markers according to local guidelines. MabThera® should not be used in patients with active hepatitis B. Patients with positive serological test results for hepatitis B virus (HBsAg or HBcAb) should consult with liver disease specialists prior to starting therapy. These patients should be monitored and managed according to local medical standards to prevent hepatitis B virus reactivation.
False-negative results in serological tests for infections. Due to the risk of false-negative results in serological testing for infections, alternative diagnostic methods should be considered if symptoms suggestive of rare infections arise, particularly West Nile virus and neuroborreliosis.
Skin reactions
Severe skin reactions, such as toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome (some with fatal outcomes), have been reported (see section "Adverse reactions"). If such skin reactions occur and a possible association with MabThera® use is suspected, treatment with this drug should be permanently discontinued.
Non-Hodgkin's lymphomas and chronic lymphocytic leukemia
Infusion reactions.
The use of MabThera® has been associated with infusion reactions, which may be related to cytokine release and/or other chemical mediators. Cytokine release syndrome may clinically resemble acute hypersensitivity reactions.
This spectrum of reactions, including cytokine release syndrome, tumor lysis syndrome, anaphylactic reactions, and hypersensitivity reactions, is described below.
During the post-marketing period, fatal severe infusion reactions have been reported following intravenous administration of MabThera®, occurring 30 minutes to 2 hours after the start of the first intravenous infusion. These reactions were characterized by pulmonary manifestations, and in some cases, rapid tumor lysis and signs of tumor lysis syndrome were observed in addition to fever, chills, rigors, hypotension, urticaria, angioedema, and other symptoms (see section "Adverse reactions").
Severe cytokine release syndrome is characterized by marked dyspnea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This syndrome may be associated with some features of tumor lysis syndrome, such as hyperuricemia, hyperkalemia, hypocalcemia, hyperphosphatemia, acute renal failure, elevated lactate dehydrogenase (LDH) levels, and may also be associated with acute respiratory failure and death. Acute respiratory failure may be accompanied by findings such as interstitial infiltration or pulmonary edema, detectable by chest X-ray. The syndrome often manifests within one to two hours after the start of the first infusion. Patients with a history of respiratory insufficiency or pulmonary tumor infiltration are at higher risk of an unfavorable outcome and therefore require heightened caution during treatment. In case of severe cytokine release syndrome, infusion should be immediately interrupted (see section "Method of administration and dosage") and intensive symptomatic treatment initiated. Because symptoms may reappear after initial improvement, such patients require careful monitoring until tumor lysis syndrome and pulmonary infiltration are ruled out or resolved. Subsequent treatment after complete symptom resolution has rarely led to recurrence of severe cytokine release syndrome.
Treatment of patients with high tumor burden or a large number (≥ 25 × 10⁹/L) of circulating malignant cells (e.g., patients with chronic lymphocytic leukemia), who are at increased risk of particularly severe cytokine release syndrome, should be conducted with extreme caution. Such patients require especially close monitoring throughout the first infusion. If lymphocyte counts remain > 25 × 10⁹/L during the first or any subsequent cycle, consideration should be given to reducing the infusion rate for the first infusion or splitting the dose over two days.
Infusion-related adverse reactions of all types were observed in 77% of patients receiving MabThera® therapy (including cytokine release syndrome associated with arterial hypotension and bronchospasm in 10% of patients) (see section "Adverse reactions"). These symptoms are usually reversible by interrupting the MabThera® infusion and administering antipyretics, antihistamines, and in some cases oxygen, intravenous saline, or bronchodilators, and glucocorticoids if necessary. Severe reactions are described above.
Anaphylactic and other hypersensitivity reactions have been reported after intravenous administration of protein-based agents. Unlike cytokine release syndrome, true hypersensitivity reactions usually develop within minutes after the start of infusion. Medications for treating hypersensitivity reactions, such as epinephrine, antihistamines, and glucocorticoids, should be readily available for immediate use in case of an allergic reaction during MabThera® administration. Clinical manifestations of anaphylaxis may resemble those of cytokine release syndrome. Hypersensitivity reactions have been reported less frequently than cytokine release-related reactions.
In some cases, additional reactions such as myocardial infarction, atrial fibrillation, pulmonary edema, and acute reversible thrombocytopenia have been reported.
Because arterial hypotension may occur during MabThera® infusion, antihypertensive medications should be withheld for 12 hours before and after MabThera® infusion.
Hematological toxicity. Although MabThera® as monotherapy does not cause myelosuppression, caution is advised when administering the drug to patients with neutrophil counts below 1.5 × 10⁹/L and/or platelet counts below 75 × 10⁹/L, as clinical experience with MabThera® in such patients is limited. MabThera® was administered to 21 patients who underwent autologous bone marrow transplantation and to other high-risk groups with potential bone marrow dysfunction, without causing myelotoxic effects.
Complete blood counts, including neutrophil and platelet counts, should be regularly performed during MabThera® therapy.
Immunization. The safety of live viral vaccines after MabThera® therapy has not been studied in patients with non-Hodgkin's lymphoma and chronic lymphocytic leukemia; therefore, vaccination with live viral vaccines is not recommended. Patients who have received MabThera® may receive non-live vaccines. However, response rates may be reduced with non-live vaccines. In an uncontrolled study, patients with relapsing low-grade non-Hodgkin's lymphomas receiving MabThera® monotherapy had lower response rates to tetanus toxoid (16% vs. 81%) and KLH-neoantigen (Keyhole Limpet Hemocyanin, KLH) (4% vs. 76% when assessing antibody titer increase by more than 2-fold) compared to healthy control volunteers. Given the similarity between the two diseases, similar results may be expected in patients with chronic lymphocytic leukemia, although no corresponding clinical studies have been conducted.
Mean antibody titers against a panel of antigens (Streptococcus pneumoniae, influenza A, mumps, rubella, varicella), measured before therapy, were maintained for up to 6 months after MabThera® treatment.
Children. Data on use in children under 3 years of age are limited.
Rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis
Patients with rheumatoid arthritis who have not previously received methotrexate therapy
The use of MabThera® in patients who have not previously received methotrexate therapy is not recommended, as the benefit-risk ratio for this population has not been established.
Infusion reactions
The use of MabThera® is associated with infusion-related reactions, which may be due to cytokine release and/or other chemical mediators. Premedication with an analgesic/antipyretic and an antihistamine should be administered before each MabThera® infusion. For patients with rheumatoid arthritis, glucocorticoid premedication should be administered before each MabThera® infusion to reduce the frequency and severity of infusion reactions (see sections "Method of administration and dosage" and "Adverse reactions").
During post-approval use of MabThera® in patients with rheumatoid arthritis, fatal severe infusion reactions have been observed. In patients with rheumatoid arthritis, most infusion reactions recorded in clinical trials were mild to moderate in severity. The most common symptoms were allergic reactions, including headache, pruritus, throat irritation, hyperemia, rash, urticaria, arterial hypertension, and hyperthermia. Overall, the number of patients experiencing any infusion reactions was higher after the first infusion than after the second infusion of any treatment cycle. The frequency of infusion reactions decreased with subsequent treatment courses (see section "Adverse reactions"). These reactions are usually reversible by slowing or interrupting the MabThera® infusion and administering antipyretics, antihistamines, and in some cases oxygen, intravenous saline, or bronchodilators, and glucocorticoids if necessary. Close monitoring is required for patients with a history of heart disease and for those who previously experienced cardiopulmonary adverse reactions. Depending on the severity of infusion reactions and the extent of required intervention, temporary interruption or discontinuation of MabThera® therapy is recommended. In most cases, once symptoms are fully resolved, the infusion can be resumed at a 50% reduced rate (e.g., from 100 mg/hour to 50 mg/hour).
Medications for treating hypersensitivity reactions, such as epinephrine, antihistamines, and glucocorticoids, should be readily available for immediate use in case of an allergic reaction during MabThera® administration.
Safety data on MabThera® use in patients with moderate heart failure (NYHA class III) or severe uncontrolled cardiovascular disease are lacking. In patients receiving MabThera® therapy, pre-existing ischemic heart disease has been observed to manifest clinically as angina, as well as atrial fibrillation and flutter. Therefore, the risk of cardiovascular complications due to infusion reactions should be carefully considered before initiating MabThera® therapy in patients with known cardiac disease or previous cardiopulmonary adverse reactions, and close monitoring should be ensured during drug administration. Because arterial hypotension may occur during MabThera® infusion, antihypertensive medications should be withheld for 12 hours before and after MabThera® infusion.
Infusion reactions in patients with granulomatosis with polyangiitis and microscopic polyangiitis were similar to those observed in patients with rheumatoid arthritis during clinical trials and the post-marketing period (see section "Adverse reactions").
Late-onset neutropenia
Neutrophil counts should be determined before each MabThera® treatment course and regularly monitored for 6 months after therapy discontinuation and in case of infection symptoms (see section "Adverse reactions").
Immunization
Physicians should review the patient's vaccination status and, if possible, ensure that the patient receives all recommended vaccinations before starting MabThera® therapy.
The safety of live viral vaccines after MabThera® therapy has not been studied. Therefore, vaccination with live viral vaccines during MabThera® therapy or during B-cell depletion is not recommended.
Patients who have received MabThera® therapy may receive non-live vaccines. However, response rates to vaccination may be reduced. In a randomized study, patients with rheumatoid arthritis who received MabThera® and methotrexate had a similar response rate to tetanus toxoid (39% vs. 42%), reduced response to pneumococcal polysaccharide vaccine (43% vs. 82% for at least 2 pneumococcal antibody serotypes), and reduced response to KLH-neoantigen (47% vs. 93%) when vaccinated 6 months after MabThera® administration compared to patients receiving only methotrexate. If non-live vaccination is needed during MabThera® therapy, vaccination should be completed at least 4 weeks before the next MabThera® treatment course.
From the overall experience of repeated MabThera® treatment over one year in patients with rheumatoid arthritis, the number of patients with positive antibody titers against S. pneumoniae, influenza, mumps, rubella, varicella, and tetanus toxoid was generally similar to the number at the beginning of treatment.
Concomitant/sequential use of other disease-modifying antirheumatic drugs in patients with rheumatoid arthritis
Concomitant use of MabThera® with antirheumatic drugs other than those mentioned in the sections describing the "rheumatoid arthritis" indication and dosage is not recommended.
Clinical data are too limited to fully assess the safety of sequential use of other disease-modifying antirheumatic drugs (including tumor necrosis factor inhibitors and other biological agents) after MabThera® therapy (see section "Interaction with other medicinal products and other forms of interaction"). Available data suggest that the frequency of clinically significant infections remains unchanged when these drugs are used in patients previously treated with MabThera®; however, careful monitoring for signs of infection is required if biological agents and/or disease-modifying antirheumatic drugs are used after MabThera® therapy.
Malignant neoplasms
Immunomodulatory drugs may increase the risk of developing malignant neoplasms. However, available data indicate that when rituximab is used for autoimmune indications, there is no increased risk of malignancies, except those associated with the underlying autoimmune disease.
Excipients
This medicinal product contains 2.3 mmol (or 52.6 mg) of sodium in the 10 mL vial and 11.5 mmol (or 263.2 mg) of sodium in the 50 mL vial, equivalent to 2.6% (for the 10 mL vial) and 13.2% (for the 50 mL vial) of the WHO recommended maximum daily sodium intake of 2 g for adults.
Use during pregnancy or breastfeeding.
Use of contraception by men and women
Due to the long persistence of rituximab in patients with B-cell depletion, women of childbearing potential should use effective contraceptive methods during therapy and for 12 months after completion of MabThera® therapy.
It is known that IgG immunoglobulins cross the placental barrier. The level of B-lymphocytes in newborns whose mothers received MabThera® during pregnancy has not been studied in clinical trials. Adequate and well-controlled data from studies in pregnant women are lacking, although reports have described transient depletion of B-cell pools and lymphopenia in some infants whose mothers received MabThera® during pregnancy. Similar effects were observed in animal studies. Therefore, MabThera® should not be administered to pregnant women unless the potential benefit of therapy outweighs the potential risk to the fetus.
Limited data on rituximab excretion in breast milk indicate very low concentrations of rituximab in breast milk (relative infant dose less than 0.4%). Several follow-up cases of breastfed infants describe normal growth and development up to 2 years of age. However, since these data are limited and long-term outcomes in breastfed infants remain unknown, breastfeeding is not recommended during rituximab therapy and optimally for 6 months after rituximab therapy.
Animal studies did not show harmful effects of rituximab on reproductive organs.
Ability to affect reaction speed when driving or operating machinery.
Studies on the effect of MabThera® on the ability to drive or operate machinery have not been conducted. The pharmacological properties and the adverse reaction profile reported to date suggest that MabThera® will have no effect or a negligible effect on the ability to drive or operate machinery.
Method of Administration and Dosage
Infusions of MabThera® should be administered under the close supervision of experienced medical personnel in specialized units equipped to provide emergency care (see section "Special Precautions").
Medication Premedication and Prophylaxis
All Indications
Premedication with an antipyretic and an antihistamine, such as paracetamol and diphenhydramine, should always be administered prior to each infusion of MabThera®.
Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
For adult patients with non-Hodgkin’s lymphoma and chronic lymphocytic leukemia, consider the use of glucocorticoids if MabThera® is not administered in combination with chemotherapy regimens containing glucocorticoids.
For children with non-Hodgkin’s lymphoma, premedication with paracetamol and an H1 antihistamine (diphenhydramine or equivalent) should be administered 30–60 minutes prior to the start of rituximab (MabThera®) infusion. In addition, prednisone should be administered (see Table 2).
Rheumatoid Arthritis, Granulomatosis with Polyangiitis, and Microscopic Polyangiitis
For patients with rheumatoid arthritis, premedication with 100 mg of methylprednisolone intravenously should be completed 30 minutes prior to MabThera® infusion to reduce the frequency and severity of infusion reactions.
For patients with granulomatosis with polyangiitis (Wegener’s granulomatosis) or microscopic polyangiitis, intravenous methylprednisolone at a dose of 1000 mg/day for 1–3 days is recommended prior to the first MabThera® infusion (the last dose of prednisone may be administered on the same day as the first dose of MabThera®). Thereafter, patients should receive oral prednisone at 1 mg/kg/day (not exceeding 80 mg/day), tapered as rapidly as clinically feasible during and after MabThera® treatment.
Prophylaxis against Pneumocystis jirovecii pneumonia is recommended for patients with GPA/MPA during and after MabThera® treatment, in accordance with local clinical guidelines.
Dosage
Check the drug label to ensure that the correct formulation (for intravenous or subcutaneous administration) has been prescribed and is being administered to the patient.
Dosage Adjustment During Therapy
Reduction of the MabThera® dose is not recommended. If MabThera® is administered in combination with chemotherapy, standard guidelines for dose reduction of chemotherapeutic agents should be followed.
Non-Hodgkin’s Lymphoma
Follicular Non-Hodgkin’s Lymphoma
Combination Therapy
The recommended dose of MabThera® in combination with chemotherapy for induction treatment of previously untreated patients or patients with relapsed/refractory follicular lymphomas is 375 mg/m² body surface area per cycle, with a total treatment duration of up to 8 cycles.
MabThera® should be administered on day 1 of each chemotherapy cycle, after intravenous administration of the corticosteroid component of chemotherapy, if included in the treatment regimen.
Consolidation Therapy
Previously Untreated Follicular Lymphoma
For previously untreated patients who have responded to induction therapy, MabThera® should be administered at a dose of 375 mg/m² body surface area once every 2 months (2 months after the last dose of induction therapy) until disease progression or for a maximum of 2 years (a total of 12 infusions).
Relapsed/Refractory Follicular Lymphoma
For patients with relapsed/refractory disease who have responded to induction therapy, MabThera® should be administered at a dose of 375 mg/m² body surface area once every 3 months (3 months after the last dose of induction therapy) until disease progression or for a maximum of 2 years (a total of 8 infusions).
Monotherapy
Relapsed/Refractory Follicular Lymphoma
The recommended dose of MabThera® as monotherapy for induction treatment of adult patients with stage III–IV follicular lymphomas who are chemotherapy-resistant or in second or subsequent relapse after chemotherapy is 375 mg/m² body surface area administered by intravenous infusion once weekly for 4 weeks.
The recommended dose for retreatment with MabThera® as monotherapy in patients who previously responded to MabThera® monotherapy for relapsed/refractory follicular lymphoma is 375 mg/m² body surface area administered by intravenous infusion once weekly for 4 weeks.
Diffuse Large B-Cell Non-Hodgkin’s Lymphoma
MabThera® should be used in combination with CHOP chemotherapy. The recommended dose of MabThera® is 375 mg/m² body surface area administered on day 1 of each of 8 chemotherapy cycles, after intravenous administration of the corticosteroid component of the CHOP regimen. The safety and efficacy of MabThera® in combination with other chemotherapeutic regimens for the treatment of diffuse large B-cell non-Hodgkin’s lymphoma have not been established.
Chronic Lymphocytic Leukemia
In patients with chronic lymphocytic leukemia, prophylactic measures including adequate hydration and uric acid-lowering agents should be initiated 48 hours before the first MabThera® infusion to reduce the risk of tumor lysis syndrome.
If the lymphocyte count exceeds 25 × 10⁹/L, prednisone/prednisolone at a dose of 100 mg intravenously is recommended shortly before the MabThera® infusion to reduce the frequency and severity of acute infusion reactions and/or cytokine release syndrome.
The recommended dose of MabThera® in combination with chemotherapy for previously untreated patients and patients with relapsed/refractory chronic lymphocytic leukemia is 375 mg/m² body surface area administered on day 0 of the first cycle, followed by 500 mg/m² body surface area on day 1 of each subsequent cycle for a total of 6 cycles. Chemotherapy should be administered after the MabThera® infusion.
Rheumatoid Arthritis
A treatment course with MabThera® consists of two intravenous infusions of 1000 mg each. The recommended dose of MabThera® is 1000 mg intravenously, with the second infusion administered 2 weeks after the first.
The need for further treatment courses should be evaluated 24 weeks after the previous course. Retreatment should be administered if residual disease activity persists; otherwise, retreatment should be delayed until disease activity resumes.
Available data indicate that clinical response is typically achieved within 16–24 weeks after the initial treatment course. The continuation of therapy should be reconsidered in patients who show no clear evidence of therapeutic benefit within this time period.
Granulomatosis with Polyangiitis and Microscopic Polyangiitis
The recommended dose of MabThera® for induction of remission in granulomatosis with polyangiitis and microscopic polyangiitis is 375 mg/m² body surface area administered by intravenous infusion once weekly for 4 weeks (a total of 4 infusions).
Dosage in Special Situations
Children
Non-Hodgkin’s Lymphoma
For children aged ≥6 months to <18 years with previously untreated advanced CD20-positive DLBCL/LB/BALB/PLBL, MabThera® should be used in combination with systemic LMB (Lymphome Malin B) chemotherapy (see Tables 2 and 3). The recommended dose of MabThera® is 375 mg/m² body surface area administered by intravenous infusion. Dose adjustment of MabThera® (other than by body surface area) is not required.
The safety and efficacy of MabThera® in children aged ≥6 months to <18 years have not been established for indications other than previously untreated advanced CD20-positive DLBCL/LB/BALB/PLBL. Data on use in children under 3 years of age are limited. MabThera® should not be used in children under 6 months of age with CD20-positive diffuse large B-cell lymphoma.
Table 2. Dosing Regimen of MabThera® for Children with Non-Hodgkin’s Lymphoma
| Cycle |
Treatment day |
Detailed administration information |
| Pre-phase (COP) |
Rituximab is not administered |
- |
| Induction course 1 (COPDAM1) |
Day 2 (corresponds to day 6 of pre-phase) First infusion of Rituximab |
During the first induction course, prednisone is used as part of the chemotherapy regimen. Prednisone should be administered prior to Rituximab infusion. |
| Day 1 Second infusion of Rituximab |
Rituximab should be administered 48 hours after the first Rituximab infusion. |
|
| Induction course 2 (COPDAM2) |
Day 2 Third infusion of Rituximab |
In the second induction course, prednisone is not used during Rituximab administration. |
| Day 1 Fourth infusion of Rituximab |
Rituximab should be administered 48 hours after the third Rituximab infusion. |
|
| Consolidation course 1 (CYM/CYVE) |
Day 1 Fifth infusion of Rituximab |
Prednisone is not used during Rituximab administration. |
| Consolidation course 2 (CYM/CYVE) |
Day 1 Sixth infusion of Rituximab |
Prednisone is not used during Rituximab administration. |
| First maintenance therapy course (M1) |
Days 25–28 of consolidation course 2 (CYVE) Rituximab is not administered |
Initiate when peripheral blood ANC recovery occurs after consolidation course 2 (CYVE), with ANC > 1.0 × 10⁹/L and platelets > 100 × 10⁹/L. |
| Second maintenance therapy course (M2) |
Day 28 of first maintenance therapy course (M1) Rituximab is not administered |
|
| ANC – absolute neutrophil count; COP – cyclophosphamide, vincristine, prednisone; COPDAM – cyclophosphamide, vincristine, prednisone, doxorubicin, methotrexate; CYM – cytarabine (cytosine arabinoside, ara-C), methotrexate; CYVE – cytarabine (cytosine arabinoside, ara-C), etoposide (VP16) |
||
Table 3. Treatment regimen for children with non-Hodgkin's lymphoma: concomitant chemotherapy with Mabthera®
| Treatment plan |
Disease stage |
Details of administration |
| Group B |
Stage III with high LDH (> 2 × ULN), |
Preface followed by 4 courses: |
| Group C |
group C1: |
Preface followed by 6 courses: |
| group C3: |
||
| The sequential courses should be administered immediately after recovery of blood cell counts and if the patient's condition allows, except for maintenance therapy courses, which are administered at 28-day intervals. |
||
| BL – Burkitt leukemia (acute mature B-cell leukemia); CSF – cerebrospinal fluid; CNS – central nervous system; HDMTX – high-dose methotrexate; LDH – lactate dehydrogenase. |
||
Elderly patients (>65 years of age). Dose adjustment is not required in elderly patients.
Administration method
All indications
MabThera® must be administered by intravenous infusion (slowly) through a separate catheter.
MabThera® must not be administered by intravenous bolus or rapid injection.
Patients must be closely monitored for the development of cytokine release syndrome (see section "Special warnings and precautions for use"). Patients who develop severe reactions, including marked dyspnea, bronchospasm, or hypoxia, require immediate interruption of the infusion. After such reactions occur, patients with non-Hodgkin's lymphoma should be evaluated for signs of tumor lysis syndrome, including appropriate laboratory tests, as well as chest X-ray to detect pulmonary infiltrates. Infusions should not be resumed until all symptoms have completely resolved and laboratory parameters and chest X-ray findings have normalized. Then, the infusion may be resumed at a rate no greater than half the initial rate. If similar severe adverse reactions occur again, discontinuation of treatment should be seriously considered in the individual case.
Mild or moderate infusion-related reactions (see section "Special warnings and precautions for use") usually resolve with a reduction in the infusion rate. The infusion rate may be increased once symptoms have improved.
Non-Hodgkin's lymphoma in adults, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis
First infusion
The recommended initial infusion rate is 50 mg/hour; after 30 minutes, the rate may be increased by 50 mg/hour every 30 minutes up to a maximum rate of 400 mg/hour.
Subsequent infusions
Subsequent infusions of MabThera® may begin at a rate of 100 mg/hour and be increased by 100 mg/hour every 30 minutes up to a maximum rate of 400 mg/hour.
Children
Non-Hodgkin's lymphoma
First infusion
The recommended initial infusion rate is 0.5 mg/kg/hour (maximum 50 mg/hour); the infusion rate may be increased by 0.5 mg/kg/hour every 30 minutes in the absence of hypersensitivity or infusion reactions, up to a maximum of 400 mg/hour.
Subsequent infusions
Subsequent doses of MabThera® may be administered starting at an initial rate of 1 mg/kg/hour (maximum 50 mg/hour); the infusion rate may be increased by 1 mg/kg/hour every 30 minutes, up to a maximum of 400 mg/hour.
Rheumatoid arthritis
Alternative regimen with faster infusion rate
If a patient has not experienced serious infusion reactions during the first or subsequent infusions of MabThera® 1000 mg administered according to the standard regimen, the second and subsequent infusions may be given at a faster rate, using the same concentration as in previous infusions (4 mg/ml in a volume of 250 ml). The drug is administered at a rate of 250 mg/hour for the first 30 minutes and at a rate of 600 mg/hour for the following 90 minutes. If the patient tolerates the faster infusion rate, subsequent infusions may be administered according to this regimen.
Patients with clinically significant cardiovascular diseases, including arrhythmias, or those who have experienced serious infusion reactions to previous administration of any biological medicinal product or rituximab, should not have the infusion rate increased.
Preparation and storage instructions for the solution
MabThera® is supplied in sterile, preservative-free, pyrogen-free single-use vials.
Sterile needles and syringes should be used to prepare MabThera® for administration.
The required amount of MabThera® should be withdrawn under aseptic conditions and diluted to the calculated rituximab concentration (1–4 mg/ml) in an infusion bag (bottle) containing sterile, pyrogen-free 0.9% sodium chloride solution or 5% glucose solution. To mix the solution, the bag (bottle) should be gently inverted to avoid foaming. Sterility of the prepared solution must be maintained. Since the medicinal product contains no antibacterial preservatives or bacteriostatic agents, aseptic techniques must be followed. The solution should be visually inspected for particulate matter and discoloration prior to administration.
The prepared MabThera® infusion solution remains physically and chemically stable for 24 hours at 2–8 °C and for 12 hours at room temperature.
From a microbiological standpoint, the prepared solution should be used immediately.
If not used immediately, the storage time and conditions prior to use are the responsibility of the user and should not exceed 24 hours at 2–8 °C, and only if the solution was prepared under controlled and validated aseptic conditions.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
No incompatibility has been observed between MabThera® and polyvinyl chloride or polyethylene bags or infusion systems.
Overdose
Clinical experience with MabThera® administered at doses higher than the approved intravenous doses is limited. The highest intravenous dose of MabThera® studied in humans to date is 5000 mg (2250 mg/m²), which was administered in a dose-escalation clinical trial in patients with chronic lymphocytic leukemia. No additional patient safety risks were identified.
In case of overdose, the infusion should be immediately stopped and the patient should be closely monitored.
During post-marketing surveillance, five cases of rituximab overdose have been reported. In three cases, no adverse events were reported. In the other two cases, flu-like symptoms were reported following administration of rituximab at a dose of 1.8 g, and respiratory failure with fatal outcome was reported following administration of rituximab at a dose of 2 g.
Adverse Reactions
Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia
The overall safety profile of MabThera® in non-Hodgkin’s lymphoma and chronic lymphocytic leukemia is based on data from clinical trials and post-marketing surveillance. Patients received treatment with MabThera® either as monotherapy (for induction or maintenance therapy following induction) or in combination with chemotherapy.
The most common adverse reactions in patients receiving MabThera® were infusion-related and occurred in the majority of patients during the first infusion. The incidence of infusion-related adverse reactions significantly decreases with subsequent infusions and is less than 1% after administration of the eighth dose of MabThera®.
Infections (predominantly bacterial and viral) occurred in approximately 30–55% of patients with non-Hodgkin’s lymphoma and in 30–50% of patients with chronic lymphocytic leukemia during clinical trials.
The most common serious adverse reactions were those related to infusion reactions (including cytokine release syndrome, tumor lysis syndrome); infections; and cardiovascular events (see section "Special Warnings and Precautions for Use").
Other serious adverse reactions included hepatitis B reactivation and progressive multifocal leukoencephalopathy (PML) (see section "Special Warnings and Precautions for Use").
Below are adverse reactions observed during monotherapy with MabThera® or combination therapy with chemotherapy. Within each category, adverse reactions are listed in decreasing order of severity. The following frequency categories are used: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in decreasing order of severity.
Infections and infestations: very common – bacterial infections, viral infections, bronchitis*; common – sepsis, pneumonia*, febrile infection*, herpes zoster*, respiratory tract infections*, fungal infections, infections of unknown etiology, acute bronchitis*, sinusitis*, hepatitis B1; uncommon – serious viral infections2, Pneumocystis jirovecii pneumonia; rare – progressive multifocal leukoencephalopathy; frequency not known – enteroviral meningoencephalitis2,3.
Blood and lymphatic system disorders: very common – neutropenia, leukopenia, febrile neutropenia*, thrombocytopenia*; common – anemia, pancytopenia*, granulocytopenia*; uncommon – coagulation disorders, aplastic anemia, hemolytic anemia, lymphadenopathy; rare – transient increase in serum IgM levels4; frequency not known – late-onset neutropenia4.
Immune system disorders: very common – infusion reactions5, angioedema; common – hypersensitivity; uncommon – anaphylaxis; rare – tumor lysis syndrome, cytokine release syndrome5, serum sickness-like reaction; frequency not known – acute reversible thrombocytopenia associated with infusion5.
Metabolism and nutrition disorders: common – hyperglycemia, weight loss, peripheral edema, facial edema, increased lactate dehydrogenase activity, hypocalcemia.
Psychiatric disorders: uncommon – depression, nervousness.
Nervous system disorders: common – paresthesia, hypoesthesia, anxiety, insomnia, vasodilation, dizziness, restlessness; uncommon – taste disturbance; rare – peripheral neuropathy, facial nerve paralysis6; frequency not known – cranial neuropathy, loss of other sensation6.
Eye disorders: common – lacrimation disorders, conjunctivitis; rare – severe vision loss6.
Ear and labyrinth disorders: common – tinnitus, ear pain; frequency not known – hearing loss6.
Cardiac disorders: common – myocardial infarction5, 7*, arrhythmia*, atrial fibrillation*, tachycardia*, cardiac disorders*; uncommon – left ventricular dysfunction*, supraventricular tachycardia*, ventricular tachycardia*, angina pectoris*, myocardial ischemia*, bradycardia; uncommon – severe cardiac disorders5, 7; rare – heart failure5, 7.
Vascular disorders: common – arterial hypertension, orthostatic hypotension, arterial hypotension; rare – vasculitis (mainly cutaneous), leukocytoclastic vasculitis.
Respiratory, thoracic and mediastinal disorders: common – bronchospasm5, respiratory disorders, chest pain, dyspnea, increased cough, rhinitis; uncommon – asthma, obliterative bronchiolitis, lung disorders, hypoxia; uncommon – interstitial lung disease8; rare – respiratory failure5; frequency not known – pulmonary infiltrates.
Gastrointestinal disorders: very common – nausea; common – vomiting, diarrhea, abdominal pain, dysphagia, stomatitis, constipation, dyspepsia, anorexia, throat irritation; uncommon – abdominal distension; rare – gastrointestinal perforation8.
Skin and subcutaneous tissue disorders: very common – pruritus, rash, alopecia*; common – urticaria, sweating, night sweats, skin disorders*; rare – severe bullous skin reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome)8.
Musculoskeletal and connective tissue disorders: common – muscle hypertonia, myalgia, arthralgia, back pain, neck pain, pain.
Renal and urinary disorders: rare – renal failure5.
General disorders and administration site conditions: very common – fever, chills, asthenia, headache; common – tumor pain, hot flushes, malaise, cold-like symptoms, weakness*, tremor*, multi-organ failure5*; uncommon – infusion site pain.
Investigations: very common – decreased IgG levels.
For each adverse reaction, the frequency was calculated based on reactions of all severity grades (from mild to severe), except for adverse reactions marked with «*», for which the frequency was calculated based on severe reactions only (≥ grade 3 according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events).
1Includes reactivation and primary infections; frequency observed with R-FC regimen (rituximab–fludarabine and cyclophosphamide) in relapsed/refractory chronic lymphocytic leukemia.
2See section "Infections" below.
3Observed during post-marketing use.
4See section "Blood-related adverse reactions" below.
5See section "Infusion reactions" below. Fatal cases have been rarely reported.
6Symptoms of cranial neuropathy. Observed at various times, from during treatment to several months after completion of MabThera® therapy.
7Mainly observed in patients with prior cardiac disease and/or cardiotoxic chemotherapy, and primarily associated with infusion-related reactions.
8Including cases with fatal outcome.
During clinical trials, the following adverse reactions were reported (with similar or lower frequency in the MabThera® treatment group compared to control groups): hematotoxicity, neutropenic infection, urinary tract infection, sensory disorder, hyperthermia.
During clinical trials, infusion-related symptoms were observed in more than 50% of patients, predominantly during the first infusion and usually within the first 1–2 hours. These symptoms typically included fever, chills, and shivering. Other symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, arterial hypertension, arterial hypotension, dyspnea, dyspepsia, asthenia, and signs of tumor lysis syndrome. Severe infusion reactions (such as bronchospasm, arterial hypotension) occurred in approximately 12% of patients. In some cases, myocardial infarction, atrial fibrillation, pulmonary edema, and acute reversible thrombocytopenia were reported. Exacerbation of pre-existing cardiac conditions (e.g., angina pectoris or congestive heart failure), severe cardiac events (heart failure, myocardial infarction, atrial fibrillation), pulmonary edema, multi-organ failure, tumor lysis syndrome, cytokine release syndrome, renal failure, and respiratory failure were observed at lower or unknown frequencies. The incidence of infusion-related symptoms significantly decreased with subsequent infusions and was <1% of patients during the eighth treatment cycle including MabThera®.
Description of Selected Adverse Reactions
Infections
MabThera® induces B-cell depletion in approximately 70–80% of patients, but only in a minority of patients is this associated with decreased serum immunoglobulin levels.
Cases of localized candidiasis and herpes zoster were reported more frequently in patient groups receiving MabThera® in randomized trials. Severe infections developed in approximately 4% of patients receiving MabThera® as monotherapy. A higher overall incidence of infections, including grade 3 or 4 infections, was observed during maintenance therapy with MabThera® over a period of up to 2 years compared to the observation group. No cumulative infection-related toxicity was observed during the 2-year treatment period. Additionally, other serious viral infections—first occurrence, reactivation, or exacerbation—have been reported with MabThera® treatment, sometimes with fatal outcomes. Most patients received MabThera® in combination with chemotherapy or within hematopoietic stem cell transplantation programs. Examples of such serious viral infections include herpesviruses (cytomegalovirus, varicella-zoster virus, herpes simplex virus), JC virus (progressive multifocal leukoencephalopathy (PML)), enterovirus (meningoencephalitis), and hepatitis C virus (see section "Special Warnings and Precautions for Use"). Fatal cases of PML occurring after disease progression and retreatment were also observed in clinical trials. Cases of hepatitis B reactivation have been reported, most occurring in patients receiving MabThera® in combination with cytotoxic chemotherapy. In patients with relapsed/refractory chronic lymphocytic leukemia, the incidence of grade 3/4 hepatitis B (reactivation and primary infection) was 2% with R-FC regimen (rituximab, fludarabine, cyclophosphamide) compared to 0% with FC regimen (fludarabine, cyclophosphamide). Kaposi's sarcoma progression was observed in patients with pre-existing Kaposi's sarcoma receiving rituximab. These cases occurred with off-label use, and most patients were HIV-positive.
Blood-related adverse reactions
In clinical trials of MabThera® monotherapy administered over 4 weeks, hematological abnormalities were observed in a minority of patients and were usually mild and reversible. Severe (grade 3/4) neutropenia occurred in 4.2% of patients, anemia in 1.1%, and thrombocytopenia in 1.7%. During maintenance therapy with MabThera® over a 2-year treatment period, leukopenia (5% vs 2%, grade 3/4) and neutropenia (10% vs 4%, grade 3/4) were reported more frequently than in the observation group. The incidence of thrombocytopenia was low (<1%, grade 3/4) and did not differ between treatment groups. In trials of MabThera® in combination with chemotherapy, grade 3/4 leukopenia (rituximab–CHOP 88% vs CHOP 79%; R-FC 23% vs FC 12%), neutropenia (rituximab–cyclophosphamide, vincristine, prednisolone (CVP) 24% vs CVP 14%; R-CHOP 97% vs CHOP 88%; R-FC 30% vs FC 19% in previously untreated chronic lymphocytic leukemia), and pancytopenia (R-FC 3% vs FC 1% in previously untreated chronic lymphocytic leukemia) were generally observed at higher frequencies compared to chemotherapy alone. However, the higher incidence of neutropenia in patients receiving MabThera® with chemotherapy was not associated with a higher incidence of infections and parasitic diseases compared to patients receiving chemotherapy alone. In trials in previously untreated CLL patients and relapsed/refractory CLL patients, prolonged (neutrophil count <1 × 10⁹/L between days 24 and 42 after last dose) or late-onset (neutrophil count <1 × 10⁹/L after day 42 in patients without prior prolonged neutropenia or with neutrophil recovery by day 42) neutropenia occurred in 25% of patients receiving R-FC regimen after treatment with MabThera® in combination with FC regimen. No differences in anemia incidence were reported. Isolated cases of late-onset neutropenia developing more than four weeks after the last MabThera® infusion have been reported. In a first-line treatment trial in chronic lymphocytic leukemia patients with Binet stage C, a higher incidence of adverse reactions was observed in the R-FC group compared to the FC group (R-FC 83% vs FC 71%). In a trial in relapsed/refractory chronic lymphocytic leukemia, grade 3/4 thrombocytopenia occurred in 11% of patients in the R-FC group compared to 9% in the FC group.
In trials of MabThera® in patients with Waldenström's macroglobulinemia, transient increases in serum IgM levels were observed after treatment initiation, which may be associated with increased blood viscosity and related symptoms. Transient IgM elevation typically returned to at least baseline levels within 4 months.
Cardiovascular adverse reactions
Cardiovascular events were reported in 18.8% of patients during clinical trials of MabThera® monotherapy, with most reports involving arterial hypotension and hypertension. Arrhythmias of grade 3 or 4 (including ventricular and supraventricular tachycardia) and angina pectoris were reported during infusions. During maintenance therapy, the incidence of grade 3/4 cardiac disorders was comparable between patients receiving MabThera® and the observation group. Cardiac events were reported as serious adverse reactions (including atrial fibrillation, myocardial infarction, left ventricular dysfunction, myocardial ischemia) in 3% of patients receiving MabThera® compared to <1% in the observation group. In trials of MabThera® in combination with chemotherapy, the incidence of grade 3/4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardia and atrial fibrillation/flutter, was higher in the R-CHOP group (14 patients, 6.9%) compared to the CHOP group (3 patients, 1.5%). These arrhythmias occurred either during MabThera® infusion or were associated with precipitating conditions such as fever, infection, acute myocardial infarction, or pre-existing respiratory and cardiovascular diseases. No differences were observed between R-CHOP and CHOP groups in the incidence of grade 3/4 cardiac events, including heart failure, myocardial disorders, and ischemic heart disease manifestations. In chronic lymphocytic leukemia, the overall incidence of grade 3/4 cardiac disorders was low in both the first-line treatment trial (4% for R-FC regimen, 3% for FC regimen) and the relapsed/refractory disease trial (4% for R-FC regimen, 4% for FC regimen).
Respiratory disorders
Cases of interstitial lung disease, some fatal, have been reported.
Neurological disorders
During treatment (initial phase within R-CHOP regimen, up to 8 cycles), acute thromboembolic cerebrovascular events occurred in four patients (2%) receiving R-CHOP, all with cardiovascular risk factors, during the first treatment cycle. No differences in the incidence of other thromboembolic events were observed between treatment groups. For comparison, cerebrovascular events occurred in three patients (1.5%) in the CHOP group during the follow-up period. In chronic lymphocytic leukemia, the overall incidence of grade 3/4 nervous system disorders was low in both the first-line trial (4% for R-FC regimen, 4% for FC regimen) and the relapsed/refractory disease trials (3% for R-FC regimen, 3% for FC regimen).
Posterior reversible encephalopathy syndrome (PRES)/posterior reversible leukoencephalopathy syndrome (PRLS) has been reported. Symptoms included visual disturbances, headache, seizures, and altered mental status, with or without hypertension. Diagnosis of PRES/PRLS requires confirmation by brain imaging. In reported cases, recognized risk factors for PRES/PRLS were present, including underlying patient conditions, hypertension, immunosuppressive therapy, and/or chemotherapy.
Gastrointestinal disorders
In some patients receiving MabThera® for non-Hodgkin’s lymphoma, gastrointestinal tract perforation, sometimes fatal, has been observed. In most such cases, MabThera® was administered with chemotherapy.
IgG levels
In clinical trials of MabThera® maintenance therapy in relapsed/refractory follicular lymphoma, median IgG levels were below the lower limit of normal (<7 g/L) after induction therapy in both the observation and MabThera® treatment groups. In the observation group, median IgG levels subsequently increased, reaching values above the lower limit of normal, but remained unchanged in the MabThera® treatment group. The proportion of patients with IgG levels below the lower limit of normal was approximately 60% in the MabThera® group over the 2-year treatment period, while it decreased in the observation group (36% after 2 years).
A small number of cases of hypogammaglobulinemia (spontaneous and reported in literature) have been observed in children receiving MabThera®, some of which were severe and required prolonged immunoglobulin replacement therapy. The consequences of prolonged B-cell depletion in children are unknown.
Skin reactions
Very rare cases of toxic epidermal necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome have been reported, some with fatal outcomes.
Subpopulations (MabThera® monotherapy)
Elderly patients (≥ 65 years): The frequency of adverse reactions of all severity grades and grade 3/4 adverse reactions in elderly patients was similar to that in younger patients (<65 years).
High tumor burden
The frequency of grade 3/4 adverse reactions was higher in patients with high tumor burden compared to those without high tumor burden (25.6% vs 15.4%). The frequency of adverse reactions of all grades was similar in both patient groups.
Retreatment
The number of patients reporting adverse reactions during retreatment with additional MabThera® courses was similar to the number reporting adverse reactions during initial treatment (adverse reactions of all grades and grade 3/4).
Subpopulations (MabThera® combination therapy)
Elderly patients (≥ 65 years)
The incidence of grade 3/4 hematological and lymphatic system disorders in previously untreated or relapsed/refractory chronic lymphocytic leukemia was higher in elderly patients compared to younger patients (<65 years).
Pediatric experience in DLBCL/BL/B-AL/PLL
Summary of safety profile
A multicenter, open-label, randomized trial of LMB (Lymphome Malin B) chemotherapy with or without MabThera® was conducted in children (aged ≥6 months to <18 years) with previously untreated advanced CD20-positive DLBCL/BL/B-AL/PLL.
A total of 309 children received MabThera® and were included in the safety population analysis. Children randomized to the LMB chemotherapy plus MabThera® group or enrolled in the single-arm part of the study received MabThera® at a dose of 375 mg/m² body surface area and received a total of six intravenous infusions of MabThera® (two in each of two induction cycles and one in each of two consolidation cycles according to the LMB regimen).
The safety profile of MabThera® in children (aged ≥6 months to <18 years) with previously untreated advanced CD20-positive DLBCL/BL/B-AL/PLL was generally consistent in type, nature, and severity with the known safety profile in adult patients with non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Adding MabThera® to chemotherapy increased the risk of certain events, including infections (including sepsis), compared to chemotherapy alone.
MabThera® in the treatment of Rheumatoid Arthritis
The overall safety profile of MabThera® in rheumatoid arthritis is based on data from clinical trials and post-marketing surveillance.
The safety profile of MabThera® in patients with moderate to severe rheumatoid arthritis is summarized in the section below. In clinical trials, over 3100 patients received at least one course of treatment and were followed for periods ranging from 6 months to over 5 years; approximately 2400 patients received two or more courses, including over 1000 patients who received 5 or more courses. Safety information collected during post-marketing surveillance reflects the expected profile of adverse reactions observed in clinical trials of MabThera® (see section "Special Warnings and Precautions for Use").
Patients received two courses of 1000 mg MabThera®, separated by a 2-week interval, in addition to methotrexate (10–25 mg/week). MabThera® infusions were administered after intravenous infusion of 100 mg methylprednisolone; patients also received oral prednisone for 15 days. The following frequency categories are used: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in decreasing order of severity.
Adverse reactions identified only during post-marketing use, for which frequency could not be estimated, are listed under "frequency not known" (see footnotes).
The most common adverse reactions associated with MabThera® were infusion reactions. The overall incidence of infusion reactions in clinical trials was 23% during the first infusion and decreased with subsequent infusions. Serious infusion reactions were uncommon (0.5% of patients) and occurred predominantly during the initial treatment course. In addition to adverse reactions observed in clinical trials of rituximab for rheumatoid arthritis, post-marketing surveillance reported progressive multifocal leukoencephalopathy (see section "Special Warnings and Precautions for Use") and serum sickness-like reactions.
Infections and infestations: very common – upper respiratory tract infections, urinary tract infections; common – bronchitis, sinusitis, gastroenteritis, tinea pedis; rare – progressive multifocal leukoencephalopathy, hepatitis B reactivation; frequency not known – serious viral infection1, enteroviral meningoencephalitis2.
Blood and lymphatic system disorders: common – neutropenia3; uncommon – late-onset neutropenia4; rare – serum sickness-like reaction.
Cardiac disorders: uncommon – angina pectoris, atrial fibrillation, heart failure, myocardial infarction; rare – atrial flutter.
Immune system disorders / General disorders and administration site reactions: very common – infusion reactions5 (arterial hypertension, nausea, rash, hyperthermia, pruritus, urticaria, throat irritation, hot flushes, arterial hypotension, rhinitis, chills, tachycardia, fatigue, oral and pharyngeal pain, peripheral edema, erythema); uncommon – infusion reactions5 (generalized edema, bronchospasm, wheezing, laryngeal edema, angioedema, generalized pruritus, anaphylaxis, anaphylactoid reaction).
Metabolism and nutrition disorders: common – hypercholesterolemia.
Nervous system disorders: very common – headache; common – paresthesia, migraine, dizziness, sciatica.
Skin and subcutaneous tissue disorders: common – alopecia; rare – Stevens-Johnson syndrome7, toxic epidermal necrolysis (Lyell’s syndrome).
Psychiatric disorders: common – depression, anxiety.
Gastrointestinal disorders: common – dyspepsia, diarrhea, gastroesophageal reflux, oral ulceration, upper abdominal pain.
Musculoskeletal and connective tissue disorders: common – arthralgia/musculoskeletal pain, osteoarthritis, bursitis.
Investigations: very common – decreased IgM levels6; common – decreased IgG levels6.
1See also subsection "Infections" below.
2Observed during post-marketing use.
3Frequency category calculated based on laboratory data collected during routine laboratory monitoring in clinical trials.
4Frequency category derived from post-marketing data.
5Reactions observed during or within 24 hours after infusion. See also "Infusion reactions" below. Infusion-related reactions may result from hypersensitivity and/or the mechanism of action of the drug.
6Including observations collected during routine laboratory monitoring.
7Including fatal cases.
Multiple treatment courses
Multiple treatment courses are associated with an adverse reaction profile similar to that observed after the first treatment course. The frequency of all adverse reactions after the first MabThera® course was highest during the first 6 months and then decreased. The most commonly observed events were infusion reactions (most frequently during the first treatment course), rheumatoid arthritis flares, and infections, all occurring more frequently during the first 6 months of treatment.
Description of Selected Adverse Reactions
Infusion reactions
The most common adverse reactions following MabThera® administration in clinical trials were infusion reactions. Of 3189 patients receiving MabThera® treatment, 1135 (36%) experienced at least one infusion reaction, with 733 of 3189 (23%) experiencing an infusion reaction after the first infusion of the first treatment course. The frequency of infusion reactions decreased with subsequent infusions. In clinical trials, serious infusion reactions occurred in less than 1% (17 of 3189) of patients. No grade 4 infusion reactions according to Common Toxicity Criteria (CTC) or fatal outcomes due to infusion reactions were observed during clinical trials. The number of grade 3 CTC reactions and infusion reactions leading to treatment discontinuation decreased with subsequent courses and became rare starting from the third course. Premedication with intravenous glucocorticoids significantly reduced the frequency and severity of infusion reactions (see sections "Dosage and Administration", "Special Warnings and Precautions for Use"). During post-marketing use of MabThera®, cases of severe infusion reactions with fatal outcomes have been reported.
In a safety study of faster MabThera® infusion in patients with rheumatoid arthritis (RA), patients with moderate to severe active RA who did not experience serious infusion reactions during or within 24 hours after the first study infusion were allowed to receive the drug via a 2-hour intravenous infusion. Patients with a history of serious infusion reactions to biological agents for RA treatment were excluded from the study. The frequency, type, and severity of infusion reactions were consistent with previously reported data. No serious infusion reactions were observed.
Infections
The overall incidence of reported infections in clinical trials was approximately 94 per 100 patient-years in patients receiving MabThera® treatment. Infections were predominantly mild to moderate in severity and mainly included upper respiratory tract infections and urinary tract infections. The incidence of serious infections or infections requiring intravenous antibiotics was approximately 4 per 100 patient-years. No significant increase in the frequency of serious infections was observed after multiple MabThera® treatment courses. Lower respiratory tract infections (including pneumonia) were reported during clinical trials with similar frequency in MabThera® treatment groups and control groups.
During the post-marketing period, serious viral infections have been reported in RA patients receiving rituximab treatment.
Fatal cases of progressive multifocal leukoencephalopathy have been reported after MabThera® use for autoimmune diseases (rheumatoid arthritis and non-approved autoimmune conditions including systemic lupus erythematosus and vasculitis).
Cases of hepatitis B reactivation have been reported in patients with non-Hodgkin’s lymphoma receiving rituximab in combination with cytotoxic chemotherapy. Isolated cases of hepatitis B virus infection reactivation have also been reported in patients with rheumatoid arthritis receiving MabThera® (see section "Special Warnings and Precautions for Use").
Cardiovascular events
Serious cardiovascular events were reported at a rate of 1.3 per 100 patient-years in patients receiving MabThera® treatment, compared to 1.3 per 100 patient-years in placebo-treated patients. No increase in the number of patients developing cardiovascular events (all or serious) was observed during multiple treatment courses.
Neurological events
Cases of posterior reversible encephalopathy syndrome (PRES)/posterior reversible leukoencephalopathy syndrome (PRLS) have been reported. Signs and symptoms included visual disturbances, headache, seizures, and altered mental status with or without hypertension. Diagnosis of PRES/PRLS requires confirmation by brain imaging. In reported cases, recognized risk factors for PRES/PRLS were present, including comorbid conditions, hypertension, immunosuppressive therapy, and/or chemotherapy.
Neutropenia
Cases of neutropenia have been reported with MabThera® use, most of which were transient and mild to moderate in severity. Neutropenia may occur several months after MabThera® administration (see section "Special Warnings and Precautions for Use").
During placebo-controlled periods of clinical trials, severe neutropenia developed in 0.94% (13/1382) of patients receiving rituximab and in 0.27% (2/731) of placebo group patients.
Neutropenic events, including severe late-onset neutropenia and persistent neutropenia, have been rarely reported during post-marketing use. Some of these events were associated with fatal infections.
Skin and subcutaneous tissue reactions
Very rare cases of toxic epidermal necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome have been reported, some with fatal outcomes.
Laboratory abnormalities
Hypogammaglobulinemia (IgG or IgM levels below the lower limit of normal) was observed in patients with rheumatoid arthritis receiving MabThera® treatment. No increase in the overall frequency of infections or serious infections was observed after decreased IgG or IgM levels (see section "Special Warnings and Precautions for Use").
A small number of cases of hypogammaglobulinemia (spontaneous and reported in literature) have been observed in children receiving MabThera® treatment, some of which were severe and required prolonged immunoglobulin replacement therapy. The consequences of prolonged B-cell depletion in children are unknown.
MabThera® in the treatment of Granulomatosis with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA)
The overall safety profile of MabThera® in adults with GPA/MPA is based on data from 3 clinical trials and post-marketing use.
In GPA/MPA Study 1, 99 adult patients received MabThera® (375 mg/m² once weekly for 4 weeks) and glucocorticoids for induction of remission of GPA and MPA. Adverse reactions from GPA/MPA Study 1 listed below under "common" or "very common" occurred with a frequency ≥5% in the MabThera® group and at a higher frequency than in the comparator group.
Adverse reactions identified only during post-marketing use, for which frequency could not be estimated, are listed under "frequency not known" (see footnotes).
Below are adverse reactions occurring within 6 months in ≥5% of adult patients receiving MabThera® in the GPA/MPA study (99 patients received rituximab), with higher frequency compared to the comparator group or during the post-marketing period.
Blood and lymphatic system disorders: common – thrombocytopenia.
Gastrointestinal disorders: very common – diarrhea; common – dyspepsia, constipation.
General disorders and administration site conditions: very common – peripheral edema.
Immune system disorders: common – cytokine release syndrome.
Infections and infestations: common – urinary tract infections, bronchitis, herpes zoster, nasopharyngitis; frequency not known – serious viral infection1,2, enteroviral meningoencephalitis1.
Investigations: common – decreased hemoglobin levels.
Metabolism and nutrition disorders: common – hyperkalemia.
Musculoskeletal and connective tissue disorders: very common – muscle spasms, arthralgia, back pain; common – muscle weakness, myalgia and bone pain, limb pain.
Nervous system disorders: very common – dizziness, tremor.
Psychiatric disorders: very common – insomnia.
Respiratory, thoracic and mediastinal disorders: very common – cough, dyspnea, epistaxis; common – nasal congestion.
Skin and subcutaneous tissue disorders: common – acne.
Vascular disorders: very common – arterial hypertension; common – hot flushes.
1Observed during post-marketing period.
2See also subsection "Infections" below.
Selected adverse reactions
Infusion reactions
In GPA/MPA Study 1 (remission induction study in adults), infusion reactions were defined as any adverse event occurring within 24 hours of infusion and considered by the investigator as infusion-related in the safety evaluation population. Of 99 patients receiving MabThera® treatment, 12% experienced at least one infusion reaction. All infusion reactions were grade 1 or 2 according to CTC criteria. The most common infusion reactions included cytokine release syndrome, hot flushes, throat irritation, and tremor. MabThera® was used in combination with intravenous glucocorticoids, which may reduce the frequency and severity of infusion reactions.
Infections
In GPA/MPA Study 1, the overall infection rate was approximately 237 per 100 patient-years (95% CI 197–285) at the primary endpoint of 6 months. Infections were predominantly mild to moderate in severity and mainly included upper respiratory tract infections, herpes zoster, and urinary tract infections. The rate of serious infections was approximately 25 per 100 patient-years. The most common serious infection in the MabThera® treatment group was pneumonia (4%).
During the post-marketing period, serious viral infections have been reported in GPA/MPA patients receiving rituximab treatment.
Malignant neoplasms
In GPA/MPA Study 1, the incidence of malignancies in patients receiving MabThera® in the GPA and MPA clinical trial was 2 per 100 patient-years at the overall data cutoff date (when follow-up ended for the last patient). The standardized incidence rate was similar to that in patients with ANCA-associated vasculitis.
Cardiovascular adverse reactions
In GPA/MPA Study 1, cardiac events occurred at a rate of approximately 273 per 100 patient-years (95% CI 149–470) at the primary endpoint of 6 months. The rate of serious cardiac events was 2.1 per 100 patient-years (95% CI 3–15). Tachycardia (4%) and atrial fibrillation (3%) were most frequently reported (see section "Special Warnings and Precautions for Use").
Neurological events
Cases of posterior reversible encephalopathy syndrome (PRES)/posterior reversible leukoencephalopathy syndrome (PRLS) have been reported in autoimmune diseases. Symptoms included visual disturbances, headache, seizures, and altered mental status with or without hypertension. Diagnosis of PRES/PRLS requires confirmation by brain imaging. In reported cases, recognized risk factors for PRES/PRLS were present, including comorbid conditions, hypertension, immunosuppressive therapy, and/or chemotherapy.
Hepatitis B reactivation
During post-marketing use of MabThera® in patients with granulomatosis with polyangiitis and microscopic polyangiitis, cases of hepatitis B reactivation have been observed, sometimes with fatal outcomes.
Hypogammaglobulinemia
Hypogammaglobulinemia (decreased IgA, IgG, or IgM levels below the lower limit of normal) was observed in patients with granulomatosis with polyangiitis and microscopic polyangiitis receiving MabThera® treatment. In GPA/MPA Study 1, at month 6, 27%, 58%, and 51% of patients in the MabThera® group with normal immunoglobulin levels at baseline had low IgA, IgG, and IgM levels, respectively, compared to 25%, 50%, and 46% in the cyclophosphamide group. Patients with low IgA, IgG, or IgM levels did not show increased frequency of overall infections or serious infections.
Neutropenia
In GPA/MPA Study 1, grade 3 or higher neutropenia (CTC criteria) occurred in 24% of patients in the MabThera® group (one course) and in 23% of patients in the cyclophosphamide group. Neutropenia was not associated with a significant increase in serious infections in patients receiving MabThera®. The impact of multiple MabThera® treatment courses on neutropenia development has not been studied in clinical trials in patients with granulomatosis with polyangiitis and microscopic polyangiitis.
Skin and subcutaneous tissue reactions
Very rare cases of toxic epidermal necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome have been reported, some with fatal outcomes.
Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life: 3 years.
Storage conditions: Store at 2–8°C in the outer carton to protect from light. Keep out of reach of children.
Packaging: Vials of 100 mg/10 mL № 2, 500 mg/50 mL № 1 in a cardboard box.
Prescription status: Prescription only.
Manufacturer:
F. Hoffmann-La Roche Ltd
Roche Diagnostics GmbH
Manufacturer's address and place of business:
Wurmisweg, 4303 Kaiseraugst, Switzerland
Sandhofer Strasse 116, 68305 Mannheim, Germany