Rixaton
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RIXATHON (RIXATHON)
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, sodium chloride, polysorbate 80, sodium hydroxide, hydrochloric acid, water for injections.
Pharmaceutical form. Concentrate for solution for infusion.
Main physicochemical properties: colorless or slightly yellowish solution.
Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Antineoplastic agents.
Monoclonal antibodies and antibody-drug conjugates. CD20 (cluster of differentiation 20) inhibitors. Rituximab.
ATC code L01F A01.
Pharmacological Properties
Pharmacodynamics
Rituximab is a genetically engineered chimeric monoclonal antibody of mouse/human origin, which is a glycosylated immunoglobulin containing human IgG1 constant region sequences and variable region sequences of mouse heavy and light chains. 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 non-glycosylated 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 to 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 cell lysis include complement-dependent cytotoxicity (CDC) mediated by C1q binding, and antibody-dependent cellular cytotoxicity (ADCC), mediated by one or more Fcγ receptors on the surface of granulocytes, macrophages, and NK cells. Additionally, binding of rituximab to the CD20 antigen on B lymphocytes has been shown to induce cell death via apoptosis.
Following the first administration of the drug, the number of B cells in peripheral blood decreases to below normal levels. 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 duration of B-cell recovery may be longer (on average, 23 months after induction therapy). In patients with granulomatosis with polyangiitis or microscopic polyangiitis, the number of peripheral B cells in blood decreased to <10 cells/μL after two infusions of rituximab at a dose of 375 mg/m² administered once weekly, and remained at this level in most patients up to 6 months. Most patients (81%) showed signs of B-cell recovery, with B-cell counts exceeding 10 cells/μL by month 12 in 81% of patients and by month 18 in 87% of patients.
Pharmacokinetics
Non-Hodgkin’s Lymphoma
Based on population pharmacokinetic analysis in 298 patients with non-Hodgkin’s lymphoma receiving rituximab as monotherapy or in combination with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) at 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 (range: 6.1 to 52 days). Baseline CD19-positive cell count and tumor size influenced CL2 of rituximab administered at 375 mg/m² 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 persisted even after adjusting for tumor size and CD19-positive cell levels. Relatively minor changes in V1 were associated with body surface area and concomitant CHOP chemotherapy. This variability in V1 (27.1% and 19.0%, respectively, due to fluctuations in body surface area ranging from 1.53 to 2.32 m² and concomitant CHOP therapy) was relatively small. Age, sex, and WHO performance status had no significant effect on the pharmacokinetics of rituximab. There is no reason to expect a clinically significant reduction in rituximab pharmacokinetic parameters due to dose adjustments based on any of the studied covariates.
In a study where rituximab was administered intravenously at 375 mg/m² weekly (total of 4 doses) to 203 patients with non-Hodgkin’s lymphoma who had not previously received rituximab, the mean Cmax after the fourth infusion was 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 rituximab was administered at 375 mg/m² intravenously 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 rituximab (6 infusions at 375 mg/m²) administered in combination with 6 cycles of CHOP chemotherapy was practically identical to that observed with monotherapy.
Children with BL/ALCL/LBCL/PL
In a clinical study evaluating children with BL/ALCL/LBCL/PL, pharmacokinetics were assessed in a subgroup of 35 patients aged ≥3 years. Pharmacokinetics were comparable between the two age groups (≥3 to <12 years vs. ≥12 to <18 years). After two intravenous infusions of 375 mg/m² rituximab in each of two induction cycles (cycles 1 and 2), followed by one intravenous infusion of 375 mg/m² rituximab in each consolidation cycle (cycles 3 and 4), peak concentration was observed after the fourth infusion (cycle 2), with a geometric mean value of 347 μg/mL, and subsequently decreased gradually (cycle 4: 247 μg/mL). With this dosing regimen, the following trough levels were maintained: geometric means of 41.8 μg/mL (cycle prior to dose 2; after 1 cycle), 67.7 μg/mL (cycle prior to dose 3; after 2 cycles), and 58.5 μg/mL (cycle prior to dose 4; after 3 cycles). The mean elimination half-life in patients aged ≥3 years was 26 days.
The pharmacokinetic characteristics of rituximab in children with BL/ALCL/LBCL/PL were similar to those observed in adult patients with NHL.
There are no pharmacokinetic data available for patients aged ≥6 months to <3 years; however, population pharmacokinetic modeling predictions indicate comparable systemic exposure (area under the concentration-time curve [AUC], Cmin) in this age group compared to patients aged ≥3 years (Table 1). Lower baseline tumor size is associated with higher drug exposure due to reduced time-dependent clearance; however, systemic exposure across varying tumor sizes remains within the range shown to be effective and with an acceptable safety profile.
Table 1. Predicted pharmacokinetic parameters under the rituximab dosing regimen in children with BL/ALCL/LBCL/PL
| Age group |
from ≥ 6 months to < 3 years |
from ≥ 3 years to < 12 years |
from ≥ 12 years to < 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) |
13501 (278–31070) |
11609 (135–31157) |
11467 (110–27066) |
Results are presented as median (min/max); Cmin is pre-dose of cycle 4.
Chronic Lymphocytic Leukemia
Rituximab was administered by intravenous infusion: the first dose was 375 mg/m², increased to 500 mg/m² in each cycle consisting of 5 doses, in combination with fludarabine and cyclophosphamide for chronic lymphocytic leukemia. The mean maximum concentration (Cmax) (N = 15) after the fifth infusion of 500 mg/m² rituximab was 408 µg/mL (range: 97–764 µg/mL), and the mean terminal half-life was 32 days (range: 14 to 62 days).
Granulomatosis with Polyangiitis and Microscopic Polyangiitis
Adults
A population pharmacokinetic analysis of data from 97 patients with granulomatosis with polyangiitis and microscopic polyangiitis who received four weekly doses of rituximab at 375 mg/m² showed a mean terminal half-life of 23 days (range: 9–49 days). The mean clearance of rituximab 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 concentration-time 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·day, respectively.
Children
A population pharmacokinetic analysis of data from 25 children (aged 6–17 years) with GPA and MPA who received four weekly doses of rituximab at 375 mg/m² showed a mean terminal half-life of 22 days (range: 11 to 42 days). The mean clearance and volume of distribution of rituximab were 0.221 L/day (range: 0.0996–0.381 L/day) and 2.27 L (range: 1.43–3.17 L), respectively. Maximum concentration during the first 180 days (Cmax), minimum concentration on day 180 (C180), and cumulative area under the concentration-time curve over 180 days (AUC180) were (median [range]) 382.8 (270.6–513.6) µg/mL, 0.9 (0–17.7) µg/mL, and 9787 (4838–20446) µg/mL·day, respectively. Pharmacokinetic parameters of rituximab in pediatric patients with GPA or MPA were similar to those in adults with GPA or MPA, taking into account the effect of body surface area on clearance and volume of distribution parameters.
Pemphigus Vulgaris
Pharmacokinetic parameters in adult patients with pemphigus vulgaris who received 1000 mg of rituximab on days 1, 15, 168, and 182 are summarized in Table 2.
Table 2. Population pharmacokinetic parameters in adult patients with pemphigus vulgaris from Study 2
| Parameter |
Infusion cycle |
|
| 1st cycle at 1000 mg |
2nd cycle at 1000 mg day 168 and day 182 |
|
| Elimination half-life (days) |
21.0 |
26.5 |
| Clearance (L/day) Mean (range) |
391 |
247 |
| Central volume of distribution (L) |
3.52 |
3.52 |
After the first two administrations of rituximab (on day 1 and day 15, corresponding to cycle 1), its pharmacokinetic parameters in patients with pemphigus vulgaris were similar to those in patients with GPA/MPA. Following the last two administrations (on day 168 and day 182, corresponding to cycle 2), rituximab clearance decreased, while the central volume of distribution remained unchanged.
After two intravenous infusions of Rixathon at a dose of 1000 mg with a two-week interval, the mean terminal half-life was 20.8 days (ranging from 8.58 to 35.9 days), the mean systemic clearance was 0.23 L/day (ranging from 0.091 to 0.67 L/day), and the mean volume of distribution at steady state was 4.61 L (ranging from 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 indicated that body surface area and patient sex were the most significant covariates explaining inter-individual variability in pharmacokinetic parameters. After dose adjustment for body surface area, male patients had higher volume of distribution and clearance compared to female patients. Sex-related differences in pharmacokinetic parameters were not clinically significant; therefore, dose adjustment is not required. Information on pharmacokinetic parameters in patients with impaired hepatic or renal function is not available.
Rituximab pharmacokinetics were evaluated after two intravenous administrations of 500 mg and 1000 mg on day 1 and day 15 across four studies. Rituximab pharmacokinetics were dose-proportional within the limited dose range studied. The mean Cmax 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, the 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. The 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. The mean Cmax was 16–19% higher after the second infusion compared to the first infusion for both dose levels.
Rituximab pharmacokinetics were also evaluated after two intravenous infusions of two 500 mg doses and two 1000 mg doses during the second treatment course. The mean Cmax of rituximab in serum after the first infusion was 170–175 µg/mL for two 500 mg doses and 317–370 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. The 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. Rituximab pharmacokinetic parameters were comparable between the two treatment courses.
Pharmacokinetic parameters in the population of patients who inadequately responded to tumor necrosis factor inhibitor therapy, after administration of the same treatment regimen (two 1000 mg intravenous infusions two weeks apart), were similar, with a mean serum Cmax of 369 µg/mL and a mean terminal half-life of 19.2 days.
Clinical characteristics.
Indications.
Non-Hodgkin's lymphomas (NHL)
Treatment of previously untreated follicular lymphoma stage III–IV in adults, in combination with chemotherapy.
Maintenance therapy for follicular lymphomas following response to induction therapy.
Monotherapy for patients with stage III–IV follicular lymphomas who are refractory to chemotherapy or in second or subsequent relapse after chemotherapy.
Treatment of CD20-positive diffuse large B-cell non-Hodgkin’s lymphoma, in combination with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone).
Treatment of previously untreated CD20-positive diffuse large B-cell lymphoma (DLBCL) at advanced stage, Burkitt lymphoma (BL)/Burkitt leukemia (mature B-cell acute leukemia) (B-AL), or Burkitt-like lymphoma (BLL) in children (aged ≥ 6 months to < 18 years), in combination with chemotherapy.
Chronic lymphocytic leukemia (CLL)
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 rituximab, or in patients refractory to prior treatment with rituximab plus chemotherapy.
Granulomatosis with polyangiitis and microscopic polyangiitis
Treatment of severe active granulomatosis with polyangiitis (Wegener’s granulomatosis) (GPA) and microscopic polyangiitis (MPA), in combination with glucocorticoids, for induction of remission in adult patients.
Treatment of severe active GPA and MPA, in combination with glucocorticoids, for induction of remission in pediatric patients (aged ≥ 2 to < 18 years).
Pemphigus vulgaris
Treatment of moderate to severe pemphigus vulgaris.
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, Rixathon reduces the rate of progression of joint damage as assessed radiologically and improves physical function.
Contraindications.
Contraindications for use in non-Hodgkin’s lymphoma and chronic lymphocytic leukemia
Hypersensitivity to the active substance or to mouse proteins or to any other excipient (see section "Composition").
Active severe infections (see section "Special precautions").
Severe immunodeficiency.
Contraindications for use in granulomatosis with polyangiitis and microscopic polyangiitis and pemphigus vulgaris
Hypersensitivity to the active substance or to mouse proteins or to any other excipient (see section "Composition").
Active severe infections (see section "Special precautions").
Severe immunodeficiency.
Severe heart failure (NYHA functional class IV) or severe decompensated cardiac disease (see section "Special precautions" regarding other cardiovascular conditions).
Interaction with other medicinal products and other forms of interaction.
Data on interactions of rituximab with other medicinal products are currently limited. In patients with CLL, concomitant administration with rituximab did not affect the pharmacokinetics of fludarabine or cyclophosphamide. Also, no apparent effect of fludarabine and cyclophosphamide on the pharmacokinetics of rituximab was observed.
In patients with human anti-mouse antibodies (HAMA) or antibodies to the medicinal product, allergic or hypersensitivity reactions may occur upon administration of other monoclonal antibodies for diagnostic or therapeutic purposes.
Special Warnings and Precautions for Use
To improve the traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly documented (or stated) in the patient's medical records.
Progressive Multifocal Leukoencephalopathy (PML)
All patients receiving Rituxan for rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), or pemphigus vulgaris (PV) 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 (PML).
Very rare cases of PML with fatal outcomes have been reported following rituximab administration. Patients should be monitored regularly for any new or worsening neurological symptoms that may indicate PML. If PML is suspected, treatment should be suspended until the diagnosis of PML is excluded. Clinicians should evaluate whether symptoms indicate neurological dysfunction and, if so, whether they may suggest PML. Neurological consultation should be considered as clinically indicated.
If there is any doubt, additional investigations should be considered, including MRI scanning (preferably with contrast), cerebrospinal fluid analysis for John Cunningham (JC) virus DNA, and repeat neurological evaluation.
Particular attention from the physician is required for patients suspected of having PML symptoms that the patient may not notice themselves (e.g., cognitive, neurological, or psychiatric symptoms). Patients should also be advised to inform their relatives and close contacts about their treatment, as these individuals may notice symptoms the patient has not recognized.
If PML develops, treatment with Rituxan must be permanently discontinued.
In patients with immunosuppression due to PML, stabilization or improvement of the condition has been observed after immune reconstitution. It is currently unknown whether early detection of PML and discontinuation of rituximab therapy may lead to similar stabilization or improvement.
Non-Hodgkin's Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL)
Infusion Reactions
The use of rituximab is associated with infusion reactions, which may be related to cytokine release and/or other chemical mediators. The cytokine release syndrome may be clinically indistinguishable from 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, severe and fatal infusion reactions have been reported following intravenous administration of rituximab, 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 severe 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 or two hours after the start of the first infusion. Patients with a history of respiratory insufficiency or with tumor infiltration of the lungs are at higher risk of an unfavorable outcome and therefore require heightened caution during treatment. In the event of severe cytokine release syndrome, the infusion should be immediately interrupted (see section "Method of Administration and Dosage") and intensive symptomatic treatment initiated. Since clinical symptoms may worsen after initial improvement, such patients require careful monitoring until tumor lysis syndrome and pulmonary infiltration are ruled out or resolved. Subsequent treatment of patients after complete resolution of symptoms rarely leads 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 CLL), who are at increased risk of particularly severe cytokine release syndrome, should be conducted with extreme caution. Such patients require especially careful monitoring throughout the first infusion. If, during the first or any subsequent cycle, the lymphocyte count remains > 25 × 10⁹/L, consideration should be given to reducing the infusion rate or splitting the dose over two days.
Infusion-related adverse reactions of all types were observed in 77% of patients receiving rituximab (including cytokine release syndrome associated with arterial hypotension and bronchospasm in 10% of patients) (see section "Adverse Reactions"). These symptoms are usually reversible upon interruption of the rituximab infusion and administration of antipyretics, antihistamines, and, in some cases, oxygen, intravenous saline, bronchodilators, and/or corticosteroids if necessary. Severe reactions related to cytokine release syndrome 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 the treatment of hypersensitivity reactions, such as epinephrine (adrenaline), antihistamines, and corticosteroids, must be available for immediate use in case of an allergic reaction during rituximab administration.
The clinical manifestations of anaphylaxis may resemble those of cytokine release syndrome (described above). Hypersensitivity reactions have been reported less frequently than cytokine release-related reactions.
In some cases, additional reactions have been reported, such as myocardial infarction, atrial fibrillation, pulmonary edema, and acute reversible thrombocytopenia.
Since arterial hypotension may occur during rituximab infusion, antihypertensive medications should be withheld for 12 hours before the Rituxan infusion.
Cardiac Disorders. During rituximab treatment, cases of angina pectoris, cardiac arrhythmias (e.g., atrial fibrillation and flutter), heart failure, and/or myocardial infarction have been observed. Therefore, patients with a history of cardiac disease and/or after cardiotoxic chemotherapy require careful monitoring.
Hematological Toxicity. Although rituximab as monotherapy does not cause myelosuppression, the drug should be used with caution in patients with neutrophil counts below 1.5 × 10⁹/L and/or platelet counts below 75 × 10⁹/L, as clinical experience with rituximab in such patients is limited. Rituximab has been administered to 21 patients undergoing autologous bone marrow transplantation and to other high-risk groups with potential bone marrow dysfunction without causing myelotoxic effects.
During therapy with Rituxan, complete blood counts with neutrophil and platelet counts should be performed regularly.
Infections. Serious infections, including fatal cases, may develop during rituximab therapy (see section "Adverse Reactions"). The drug should not be administered to patients with acute, severe infections (such as tuberculosis, sepsis, and opportunistic infections) (see section "Contraindications").
Physicians should exercise caution when considering the use of Rituxan in patients with a history of recurrent or chronic infections or underlying conditions that may increase susceptibility to severe infections (see section "Adverse Reactions").
Cases of hepatitis B reactivation have been reported in individuals receiving rituximab therapy, including fulminant hepatitis with fatal outcomes. Most of these patients were also receiving cytotoxic chemotherapy. Limited data from one study involving patients with relapsed/refractory CLL suggest that rituximab treatment may also worsen outcomes of primary hepatitis B virus infection. All patients should be screened for hepatitis B virus (HBV) before starting Rituxan therapy, including at minimum testing for HBsAg and HBcAb, and possibly additional markers according to local guidelines. Rituxan should not be used in patients with active hepatitis B. Patients with positive serological tests for hepatitis B virus (HBsAg or HBcAb) should consult with liver disease specialists before starting treatment. These patients should be monitored and managed according to local medical standards for prevention of hepatitis B virus reactivation.
During post-marketing use of rituximab in NHL and CLL, very rare cases of progressive multifocal leukoencephalopathy (PML) have been reported (see section "Adverse Reactions"). Most patients received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplantation program.
Cases of enteroviral meningoencephalitis, including fatal cases, have been reported after rituximab administration.
False-Negative Serological Testing for Infections. Due to the risk of false-negative serological test results for infections, alternative diagnostic methods should be considered for patients with symptoms suggestive of rare infectious diseases, such as West Nile virus and neuroborreliosis.
Immunization. The safety of immunization with live viral vaccines after rituximab therapy has not been studied in patients with NHL and CLL; therefore, vaccination with live viral vaccines is not recommended. Patients who have received Rituxan may receive vaccines that do not contain live viruses. However, the response rate may be reduced when non-live vaccines are used. In a non-randomized study, patients with relapsed low-grade NHL receiving rituximab monotherapy had lower response rates to tetanus toxoid (16% vs. 81%) and to the neoantigen keyhole limpet hemocyanin (KLH) (4% vs. 76% when evaluating for antibody titer increase greater than 2-fold) compared to healthy control volunteers. Given the similarity between the two diseases, similar results may be expected in patients with CLL, although no corresponding clinical studies have been conducted.
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 rituximab treatment.
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 rituximab use is suspected, treatment should be permanently discontinued.
Children
Data on treatment of patients under 3 years of age are limited. For additional information, see section "Pharmacodynamic Properties."
Rheumatoid Arthritis (RA), Granulomatosis with Polyangiitis (GPA), Microscopic Polyangiitis (MPA), and Pemphigus Vulgaris (PV)
Patient Populations with Rheumatoid Arthritis Previously Untreated with Methotrexate (MTX)
The use of rituximab is not recommended in patients who have not previously received methotrexate treatment, as the favorable benefit-risk ratio for this population has not been established.
Infusion Reactions (IR)
The use of rituximab is associated with IR, which may be caused by cytokine release and/or other chemical mediators.
During the post-marketing period, severe and fatal IR have been observed in patients with RA. In RA patients, most IR reported 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 reducing or interrupting the rituximab infusion and administering antipyretics, antihistamines, and, in some cases, oxygen, intravenous saline (9 mg/mL [0.9%]), bronchodilators, and/or corticosteroids if necessary. Close monitoring is required for patients with a history of cardiac 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 Rituxan therapy is recommended. In most cases, once symptoms are fully resolved, the infusion may be resumed at a 50% reduced rate (e.g., from 100 mg/h to 50 mg/h).
Medications for the treatment of hypersensitivity reactions, such as epinephrine (adrenaline), antihistamines, and corticosteroids, must be available for immediate use in case of an allergic reaction during Rituxan administration.
Safety data on the use of rituximab in patients with moderate heart failure (NYHA class III) or severe uncontrolled cardiovascular disease are lacking. In patients receiving rituximab therapy, pre-existing ischemic heart disease has been observed to manifest clinically as angina, atrial fibrillation, and atrial flutter. Therefore, the risk of cardiovascular complications due to infusion reactions should be carefully considered before initiating Rituxan therapy in patients with known cardiac disease or previous cardiopulmonary adverse reactions, and close monitoring during drug administration is essential. Since arterial hypotension may develop during rituximab infusion, antihypertensive medications should be withheld for 12 hours before the Rituxan infusion.
Infusion reaction rates in patients with GPA, MPA, and PV were similar to those in RA patients during clinical trials and in the post-marketing period (see section "Adverse Reactions").
Cardiac Disorders
Cases of angina pectoris, cardiac arrhythmias (including atrial fibrillation and flutter), heart failure, and/or myocardial infarction have been reported in patients receiving rituximab therapy. Therefore, patients with a history of cardiac disease should be carefully monitored (see subsection "Infusion Reactions (IR)" above).
Infections
Given the mechanism of action of rituximab and the important role of B-cells in maintaining normal immune response, patients are at increased risk of developing infections after rituximab therapy (see section "Pharmacodynamics"). Serious infections, including fatal cases, may occur during rituximab therapy (see section "Adverse Reactions"). Rituxan should not be prescribed to patients with active severe infections (such as tuberculosis, sepsis, and opportunistic infections) or to patients with significantly compromised immunity (e.g., with very low CD4 or CD8 levels) (see section "Contraindications"). Physicians should exercise particular caution when considering rituximab use 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"). Immunoglobulin levels should be determined before starting Rituxan therapy.
Patients showing signs and symptoms of infection after Rituxan therapy should be promptly evaluated and appropriate treatment initiated. Before starting the next course of Rituxan therapy, patients should be re-evaluated for any potential risk of infection.
Isolated cases of fatal PML have been reported after rituximab use for the treatment of RA and autoimmune diseases, including systemic lupus erythematosus (SLE) and vasculitis.
Cases of enteroviral meningoencephalitis, including fatal cases, have been reported after rituximab administration.
False-Negative Serological Testing for Infections
Due to the risk of false-negative serological test results for infections, alternative diagnostic methods should be considered for patients with symptoms suggestive of rare infectious diseases, such as West Nile virus and neuroborreliosis.
Hepatitis B Virus
Cases of hepatitis B reactivation, including fatal cases, have been reported in RA, GPA, and MPA patients receiving rituximab.
All patients should be screened for hepatitis B virus (HBV) before starting Rituxan therapy, including at minimum testing for HBsAg and HBcAb, and possibly additional markers according to local guidelines. Rituximab should not be used in patients with active hepatitis B. Patients with positive serological tests for hepatitis B virus (HBsAg or HBcAb) should consult with liver disease specialists before starting treatment. These patients should be monitored and managed according to local medical standards for prevention of hepatitis B virus reactivation.
Late-Onset Neutropenia
Neutrophil counts should be determined before each course of Rituxan therapy and regularly for up to 6 months after therapy discontinuation, and in case of infection symptoms (see section "Adverse Reactions").
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 Rituxan use is suspected, treatment should be permanently discontinued.
Immunization
Before starting Rituxan therapy, physicians should assess the patient's vaccination status, administer all necessary vaccinations, and follow current immunization guidelines. Vaccination should be completed at least 4 weeks before the first Rituxan dose.
The safety of immunization with live viral vaccines after rituximab therapy has not been studied. Therefore, vaccination with live viral vaccines during Rituxan therapy or during depletion of peripheral B-cells is not recommended.
Patients who have received Rituxan therapy may receive vaccines that do not contain live components. However, the response rate to vaccination may be reduced when non-live vaccines are used. In a randomized study, RA patients receiving rituximab and methotrexate had a similar response rate to tetanus antigen (39% vs. 42%), a reduced response rate to pneumococcal polysaccharide vaccine (43% vs. 82% for at least 2 pneumococcal antibody serotypes), and a reduced response to the neoantigen KLH (47% vs. 93%) when vaccinated 6 months after rituximab administration, compared to patients receiving only methotrexate. If vaccination with non-live vaccines is required during rituximab therapy, it should be completed at least 4 weeks before the next course of rituximab treatment.
From the overall experience of repeated rituximab treatment within one year in RA, the proportion of patients with positive antibody titers against S. pneumoniae, influenza, mumps, rubella, varicella, and tetanus was generally similar to that at the beginning of treatment.
Concomitant/Sequential Use of Other Disease-Modifying Antirheumatic Drugs (DMARDs) in Rheumatoid Arthritis
Concomitant use of Rituxan with antirheumatic medicinal products other than those specified in the sections describing the indication "rheumatoid arthritis (RA)" is not recommended.
Clinical trial data are too limited to fully assess the safety of sequential use of other disease-modifying antirheumatic drugs (DMARDs) (including tumor necrosis factor inhibitors and other biological agents) after rituximab therapy (see section "Interaction with Other Medicinal Products and Other Forms of Interaction"). Available data suggest that the frequency of clinically significant infections does not increase in patients previously treated with rituximab; however, such patients should be closely monitored for signs of infection when biological agents and/or DMARDs are used after rituximab therapy.
Malignancies
Immunomodulatory agents may increase the risk of malignancies. However, available data do not indicate an increased risk of malignancies with rituximab use in autoimmune diseases beyond the risk already associated with the underlying autoimmune condition.
Excipients
This medicinal product contains 2.3 mmol (or 52.6 mg) of sodium per 10 mL vial and 11.5 mmol (or 263.2 mg) of sodium per 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 for adults (2 g).
Use During Pregnancy or Breastfeeding
Women of Reproductive Potential / Contraception in Women
Given the prolonged persistence of rituximab in patients with B-cell depletion, women of childbearing potential should use effective contraceptive methods during treatment and for 12 months after completion of Rituxan therapy.
Pregnancy
It is known that IgG immunoglobulins cross the placental barrier.
The level of B-lymphocytes in newborns whose mothers received rituximab has not been studied in clinical trials. Adequate and well-controlled data from studies in pregnant women are lacking, although reports have been received of transient depletion of B-cell pools and lymphopenia in some infants whose mothers received rituximab during pregnancy. Similar effects were observed in animal studies. Therefore, Rituxan should not be administered to pregnant women unless the potential benefit outweighs the potential risk to the fetus.
Breastfeeding
It is unknown whether rituximab is excreted in human breast milk. However, since IgG immunoglobulins circulating in maternal blood are known to pass into breast milk and rituximab has been detected in the milk of lactating monkeys, women should not breastfeed during treatment and for 12 months after completion of Rituxan therapy.
Animal studies did not reveal any harmful effects of rituximab on reproductive organs.
Fertility
Animal studies did not reveal any statistically significant effect of rituximab on reproductive organs.
Ability to Affect Reaction Speed When Driving or Operating Machinery
Rituximab may have a minor influence on the ability to drive or operate machinery. Dizziness may occur after administration of rituximab.
Method of Administration and Dosage
Infusions should be administered under the close supervision of experienced medical personnel in specialized units equipped to provide emergency care (see section "Special Precautions").
Pre-medication and Prophylactic Measures
Prior to each administration of Rixathon, pre-medication with an antipyretic and an antihistamine, such as paracetamol and diphenhydramine, should always be administered.
For adult patients with non-Hodgkin's lymphoma and chronic lymphocytic leukemia, consider pre-medication with corticosteroids if Rixathon is not used in combination with chemotherapy regimens containing corticosteroids.
For adult patients with non-Hodgkin's lymphoma and chronic lymphocytic leukemia receiving Rixathon via a 90-minute infusion, consider the use of corticosteroids if Rixathon is not administered in combination with chemotherapy containing corticosteroids.
Children with NHL should receive pre-medication with paracetamol and an H1 antihistamine (dimenhydrinate or equivalent) 30–60 minutes prior to the start of rituximab infusion. Additionally, prednisone should be administered as indicated in Table 3.
Patients with chronic lymphocytic leukemia require prophylaxis with adequate hydration and agents that reduce uric acid levels, initiated 48 hours before starting therapy, to reduce the risk of tumor lysis syndrome. For patients with chronic lymphocytic leukemia and lymphocyte counts exceeding 25 × 10⁹/L, administration of prednisone/prednisolone at a dose of 100 mg intravenously shortly before rituximab infusion is recommended to reduce the frequency and severity of acute infusion reactions and/or cytokine release syndrome.
For patients with GPA, MPA, or pemphigus vulgaris, pre-medication with intravenous methylprednisolone 100 mg should be completed 30 minutes prior to Rixathon infusion to reduce the frequency and severity of infusion-related adverse reactions.
Adult patients with GPA or MPA should receive intravenous methylprednisolone at a dose of 1000 mg/day for 1–3 days prior to the first Rixathon infusion (the last dose of methylprednisolone may be administered on the same day as the first dose of Rixathon). Subsequently, patients should receive oral prednisone at 1 mg/kg/day (not exceeding 80 mg/day), with dose tapering initiated as soon as possible based on clinical need, during and after the 4-week induction treatment course with Rixathon.
If necessary, adult patients with GPA/MPA or pemphigus vulgaris should receive prophylaxis for Pneumocystis jirovecii pneumonia (PCP) during and after rituximab therapy, in accordance with local clinical practice guidelines.
Children
Children with GPA or MPA should receive intravenous methylprednisolone at a dose of 30 mg/kg/day (not exceeding 1 g/day) to prevent severe vasculitis symptoms prior to the first rituximab infusion. Up to three additional daily doses of 30 mg/kg intravenous methylprednisolone may be administered before the first rituximab infusion.
After completion of intravenous methylprednisolone administration, patients should receive oral prednisone at 1 mg/kg/day (not exceeding 60 mg/day), with dose tapering initiated as soon as possible based on clinical need.
Prophylaxis for Pneumocystis jirovecii pneumonia (PCP) is recommended for children with GPA or MPA during and after rituximab treatment, depending on clinical need.
Dosage
Check the labels on the medicinal product packaging to ensure that the patient receives the prescribed dose.
Non-Hodgkin's Lymphoma
Follicular Non-Hodgkin's Lymphoma
Combination Therapy
The recommended dose of Rixathon 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, for a total treatment duration of up to 8 cycles.
Rixathon should be administered on day 1 of each chemotherapy cycle, after intravenous administration of the glucocorticosteroid component of chemotherapy, if included in the treatment regimen.
Maintenance Therapy
Previously Untreated Follicular Lymphoma
Previously untreated patients who have responded to induction therapy should receive Rixathon 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 period of 2 years (a total of 12 infusions).
Relapsed/Refractory Follicular Lymphoma
Patients with relapsed/refractory disease who have responded to induction therapy should receive Rixathon 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 period of 2 years (a total of 8 infusions).
Monotherapy
Relapsed/Refractory Follicular Lymphoma
The recommended dose of Rixathon when used 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 via intravenous infusion once weekly for 4 weeks.
The recommended dose for retreatment with Rixathon as monotherapy in patients who previously responded to rituximab monotherapy for relapsed/refractory follicular lymphoma is 375 mg/m² body surface area, administered via intravenous infusion once weekly for 4 weeks (see section "Pharmacodynamics").
Diffuse Large B-Cell Non-Hodgkin's Lymphoma in Adults
Rixathon should be used in combination with CHOP chemotherapy regimen. The recommended dose is 375 mg/m² body surface area, administered on day 1 of each of the 8 chemotherapy cycles, after intravenous administration of the glucocorticosteroid component of the CHOP regimen. The safety and efficacy of rituximab in combination with other chemotherapeutic agents for the treatment of diffuse large B-cell non-Hodgkin's lymphomas have not been established.
Dosage Adjustment During Therapy
Dose reduction of Rixathon is not recommended. If Rixathon is administered in combination with chemotherapy, standard guidelines for dose reduction of chemotherapeutic agents should be followed.
Chronic Lymphocytic Leukemia
The recommended dose of Rixathon in combination with chemotherapy for previously untreated patients and patients with relapsed/refractory chronic lymphocytic leukemia is 375 mg/m² body surface area on day 0 of the first cycle, followed by 500 mg/m² body surface area on day 1 of each subsequent cycle for 6 cycles. Chemotherapy should be administered after Rixathon infusion.
Rheumatoid Arthritis
Patients receiving Rixathon infusions should be provided with a patient reminder card at each infusion.
A treatment course with Rixathon consists of two intravenous infusions of 1000 mg each, administered 2 weeks apart.
The need for further treatment courses should be assessed 24 weeks after the previous course. Retreatment should be administered if residual disease activity persists; otherwise, retreatment should be delayed until disease activity reappears.
Available data indicate that clinical response is typically achieved within 16–24 weeks after the initial treatment course. The continuation of therapy should be re-evaluated for patients who show no clear evidence of therapeutic benefit during this period.
Granulomatosis with Polyangiitis and Microscopic Polyangiitis
Prior to each infusion, patients receiving rituximab should be provided with a patient reminder card.
Induction of Remission in Adults
The recommended dose of Rixathon for induction of remission in adult patients with GPA or MPA is 375 mg/m² body surface area, administered via intravenous infusion once weekly for 4 weeks (a total of 4 infusions).
Maintenance Therapy in Adults
After remission induction with rituximab, maintenance therapy in adult patients with GPA or MPA should be initiated within 16 weeks after the last rituximab infusion.
After remission induction with other standard immunosuppressive therapy, maintenance therapy with rituximab should be initiated within 4 weeks after disease remission.
Rituximab should be administered via two intravenous infusions of 500 mg each, 2 weeks apart, followed by intravenous infusions of 500 mg every 6 months. Patients should receive rituximab for at least 24 months after achieving remission (absence of clinical signs and symptoms). Physicians should consider a longer duration of maintenance therapy with rituximab (up to 5 years) for patients at high risk of disease relapse.
Pemphigus Vulgaris
Prior to each infusion, patients receiving rituximab should be provided with a patient reminder card.
The recommended dose of rituximab for the treatment of pemphigus vulgaris is 1000 mg administered via intravenous infusion, followed by a second dose of 1000 mg via intravenous infusion 2 weeks later, in combination with a tapering course of glucocorticoids.
Maintenance Therapy
Maintenance intravenous infusions of 500 mg should be administered at months 12 and 18, and then, if necessary, regularly every 6 months based on clinical assessment.
Relapse Treatment
In case of relapse, patients may receive 1000 mg intravenously. The healthcare provider should also consider reinitiating or increasing the dose of glucocorticoids based on clinical assessment.
Further infusions may be administered no sooner than 16 weeks after the previous infusion.
Dosage in Special Situations
Children
Non-Hodgkin's Lymphoma
Rituximab should be administered in combination with systemic chemotherapy according to the pediatric malignant lymphoma B protocol for children aged ≥6 months to <18 years with previously untreated advanced CD20-positive DLBCL/BL/ Burkitt-like lymphoma/ Burkitt lymphoma (see Tables 3 and 4). The recommended dose of rituximab is 375 mg/m² body surface area, administered via intravenous infusion. Dose adjustment of rituximab, other than based on body surface area, is not required.
The safety and efficacy of rituximab in children aged ≥6 months to <18 years for indications other than previously untreated CD20-positive DLBCL/BL/ Burkitt-like lymphoma/ Burkitt lymphoma have not been established. Limited data are available for patients under 3 years of age.
Rituximab should not be administered to children from birth to <6 months of age with CD20-positive diffuse large B-cell lymphoma.
Table 3. Rituximab Dosage for Children with Non-Hodgkin's Lymphoma
| Cycle |
Treatment day |
Administration details |
| Preliminary phase (COP) |
Rituximab is not administered |
- |
| Induction course 1 (COPDAM1) |
Day 2 (corresponds to day 6 of the preliminary phase) 1st rituximab infusion |
During the 1st induction course, prednisone is administered as part of the chemotherapy regimen given prior to rituximab. |
| Day 1 2nd rituximab infusion |
Rituximab is administered 48 hours after the first rituximab infusion. |
|
| Induction course 2 (COPDAM2) |
Day 2 3rd rituximab infusion |
During the second induction course, prednisone is not administered during rituximab administration. |
| Day 1 4th rituximab infusion |
Rituximab is administered 48 hours after the third rituximab infusion. |
|
| Consolidation course 1 (CYM/CYVE) |
Day 1 5th rituximab infusion |
Prednisone is not administered during rituximab administration. |
| Consolidation course 2 (CYM/CYVE) |
Day 1 6th rituximab infusion |
Prednisone is not administered during rituximab administration. |
| Maintenance course 1 (M1) |
Day 25–28 of consolidation course 2 (CYVE) Rituximab is not administered |
Initiated after recovery of peripheral B-cell count following consolidation course 2 (CYVE), with ANC > 1.0 × 109/L and platelets > 100 × 109/L |
| Maintenance course 2 (M2) |
Day 28 of maintenance course 1 (M1) Rituximab is not administered |
- |
| ANC – absolute neutrophil count; COP – cyclophosphamide, vincristine, prednisone; COPDAM – cyclophosphamide, vincristine, prednisolone, doxorubicin, methotrexate; CYM – cytarabine (cytosine arabinoside, Ara-C), methotrexate; CYVE – cytarabine (cytosine arabinoside, Ara-C), vepesid (VP16) |
||
Table 4. Treatment regimen for children with non-Hodgkin lymphoma: concomitant chemotherapy with rituximab
| Treatment plan |
Stage |
Administration details |
| Group B |
Stage III with high LDH level (> N × 2), Stage IV, CNS-negative |
Preliminary phase followed by 4 courses: 2 induction courses (COPADM) with HD-MTX 3 g/m2 and 2 consolidation courses (CYM) |
| Group C |
Group C1: CNS-negative B-ALL, stage IV, and CNS-positive and CSF-negative B-ALL |
Preliminary phase followed by 6 courses: 2 induction courses (COPADM) with HD-MTX 8 g/m2, 2 consolidation courses (CYVE) and 2 maintenance courses (M1 and M2) |
| Group C3: CSF-positive B-ALL, stage IV, CSF-positive |
||
| The sequential courses should be administered as soon as blood counts recover, as soon as the patient's condition allows, except for the maintenance courses, which are administered at 28-day intervals. |
||
| B-ALL – Burkitt leukemia (mature B-cell acute leukemia); CSF – cerebrospinal fluid; CNS – central nervous system; HD-MTX – high-dose methotrexate; LDH – lactate dehydrogenase |
||
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)
Induction of remission
The recommended dose of rituximab for induction of remission in children with severe active GPA or MPA is 375 mg/m² body surface area, administered by intravenous infusion once weekly for 4 weeks.
The safety and efficacy of rituximab in children aged ≥2 to <18 years for indications other than severe active GPA or MPA have not been established.
Rituximab should not be used in children under 2 years of age with severe active GPA or MPA due to the likelihood of inadequate immune response to routine childhood vaccinations (such as measles, mumps, rubella, and polio).
Elderly patients (>65 years of age)
Dose adjustment is not required in elderly patients.
Method of administration
Rixathon is administered by intravenous infusion (slowly) through a separate catheter.
The drug must not be administered by intravenous push or bolus injection.
Patients should be closely monitored for signs of cytokine release syndrome (see section "Special precautions"). 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 tumor lysis syndrome, including appropriate laboratory tests, and 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. The infusion may then be resumed at a rate not exceeding half the initial rate. If similar severe adverse reactions recur, discontinuation of treatment should be seriously considered.
Mild or moderate infusion-related reactions (see section "Adverse reactions") usually resolve with a reduction in infusion rate. The infusion rate may be increased once symptoms have improved.
First infusion
The recommended initial infusion rate is 50 mg/hour; after 30 minutes, it may be increased by 50 mg/hour every 30 minutes up to a maximum rate of 400 mg/hour.
Subsequent infusions
All indications
Subsequent infusions of Rixathon may be initiated at a rate of 100 mg/hour, increasing by 100 mg/hour every 30 minutes until a maximum rate of 400 mg/hour is reached.
Non-Hodgkin's lymphoma in children
First infusion
The recommended initial infusion rate is 0.5 mg/kg/hour (maximum 50 mg/hour); in the absence of hypersensitivity or infusion reactions, the rate may be increased by 0.5 mg/kg/hour every 30 minutes until a maximum rate of 400 mg/hour is reached.
Subsequent infusions
Subsequent rituximab infusions may be initiated at a rate of 1 mg/kg/hour (maximum 50 mg/hour) and increased by 1 mg/kg/hour every 30 minutes until a maximum rate of 400 mg/hour is reached.
Non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) in adult patients
If patients have not experienced grade 3 or 4 infusion-related adverse events during cycle 1, a 90-minute infusion may be administered in cycle 2 with a chemotherapy regimen containing glucocorticoids. The infusion should begin at 20% of the total dose over the first 30 minutes, followed by the remaining 80% over the next 60 minutes. If the 90-minute infusion is well tolerated in cycle 2, the same rate may be used for the remainder of the treatment regimen (through cycle 6 or 8).
Patients with clinically significant cardiovascular disease, including arrhythmia, or prior serious infusion reactions to any previous biological therapy or rituximab should not receive infusion at an accelerated rate.
Rheumatoid arthritis only
Alternative regimen for subsequent administration with faster infusion rate
If a patient has not experienced serious infusion reactions during the first or subsequent infusion of Rixathon 1000 mg administered under the standard regimen, subsequent infusions may be administered at a faster rate, using the same concentration as in previous infusions (4 mg/mL in a volume of 250 mL). The drug should be administered at a rate of 250 mg/hour for the first 30 minutes and 600 mg/hour for the following 90 minutes. If the patient tolerates the faster infusion rate, this regimen may be used for subsequent infusions.
Patients with clinically significant cardiovascular disease, including arrhythmia, or those who have experienced serious infusion reactions to prior biological agents or rituximab should not have the infusion rate increased.
Preparation and storage of the solution
Rixathon is supplied in sterile, preservative-free, pyrogen-free vials for single use.
Aseptic preparation
Aseptic conditions must be maintained during solution preparation. Preparation should be performed:
- by trained personnel under aseptic conditions in accordance with accepted standards, taking into account aseptic preparation of parenteral solutions;
- in a laminar flow hood or biological safety cabinet, using standard precautions for safe handling of intravenous drugs.
The required amount of Rixathon should be drawn aseptically and diluted to the calculated rituximab concentration (1–4 mg/mL) in an infusion bag (bottle) with 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 strictly followed. The solution should be visually inspected for particulate matter or discoloration before administration.
Any unused medicinal product or waste should be disposed of in accordance with local requirements.
Children
This medicinal product is indicated for the treatment of children (aged ≥6 months to <18 years) with previously untreated CD20-positive diffuse large B-cell lymphoma (DLBCL) at advanced stage, Burkitt lymphoma (BL)/Burkitt leukemia (mature B-cell acute leukemia) (B-AL), or Burkitt-like lymphoma (BLL) in combination with chemotherapy, and for induction of remission in children (aged ≥2 to <18 years) with severe active GPA and MPA in combination with glucocorticoids.
Overdose
Experience with rituximab at doses higher than those approved for intravenous administration in clinical trials is limited. The highest intravenous dose of rituximab studied in humans to date is 5000 mg (2250 mg/m²), which was administered in a dose-escalation clinical trial to patients with chronic lymphocytic leukemia. No additional safety risks were identified.
In case of overdose, the infusion should be stopped immediately 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 lymphomas and chronic lymphocytic leukemia in adults
The overall safety profile of rituximab in non-Hodgkin's lymphoma and chronic lymphocytic leukemia is based on data from clinical trials and post-marketing surveillance. Patients received treatment with rituximab either as monotherapy (for induction or maintenance therapy following induction) or in combination with chemotherapy.
The most common adverse reactions in patients receiving rituximab were infusion-related reactions, occurring in the majority of patients during the first infusion. The frequency of infusion-related adverse reactions significantly decreases during subsequent infusions and is less than 1% after the eighth dose of rituximab.
Infections (predominantly bacterial and viral) were observed 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 infusion-related 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").
The following adverse reactions were observed during monotherapy with rituximab or combination therapy with chemotherapy. The frequency categories used are: 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 order of decreasing severity. Adverse reactions identified only during post-marketing surveillance, for which frequency cannot be estimated, are listed under "frequency not known."
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; rare – serious viral infections2, Pneumocystis jirovecii pneumonia; very 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; rare – anaphylaxis; very 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 decreased, peripheral edema, facial edema, increased lactate dehydrogenase activity, hypocalcemia.
Psychiatric disorders: uncommon – depression, restlessness.
Nervous system disorders: common – paresthesia, hypoesthesia, anxiety, insomnia, vasodilatation, dizziness, restlessness; uncommon – taste distortion; rare – peripheral neuropathy, facial nerve paralysis6; frequency not known – cranial neuropathy, loss of other sensation6.
Eye disorders: common – lacrimation disorder, conjunctivitis; very rare – severe vision loss6.
Ear and labyrinth disorders: common – tinnitus, ear pain; frequency not known – hearing loss6.
Cardiac disorders: common – myocardial infarction5 and 7*, arrhythmia*, atrial fibrillation*, tachycardia*, cardiac disorder*; uncommon – left ventricular dysfunction*, supraventricular tachycardia*, ventricular tachycardia*, angina pectoris*, myocardial ischemia*, bradycardia; rare – severe cardiac disorders5 and 7; very rare – cardiac failure5 and 7.
Vascular disorders: common – hypertension, orthostatic hypotension, hypotension; very rare – vasculitis (mainly cutaneous), leukocytoclastic vasculitis.
Respiratory, thoracic and mediastinal disorders: common – bronchospasm5, respiratory disorder, chest pain, dyspnea, cough increased, rhinitis; uncommon – asthma, obliterative bronchiolitis, lung disorder, hypoxia; rare – interstitial lung disease8; very 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; very rare – gastrointestinal perforation8.
Skin and subcutaneous tissue disorders: very common – pruritus, rash, alopecia*; common – urticaria, sweating, night sweats, skin disorders*; very 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: very rare – renal failure5.
General disorders and administration site conditions: very common – pyrexia, chills, asthenia, headache; common – tumor pain, hot flushes, malaise, cold-like syndrome, weakness*, tremor*, multi-organ failure5*; rare – infusion site pain.
Investigations: very common – decreased IgG level.
For each adverse reaction, the frequency was calculated based on all-grade reactions (mild to severe), except for adverse reactions marked with «*», for which frequency was calculated based on severe reactions only (≥ grade 3 according to National Cancer Institute Common Toxicity Criteria).
1 Including reactivation and primary infections; frequency observed with R-FC regimen (rituximab-fludarabine and cyclophosphamide) in relapsed/refractory chronic lymphocytic leukemia.
2 See section "Infections" below.
3 Observed during post-marketing surveillance.
4 See section "Blood-related adverse reactions" below.
5 See section "Infusion reactions" below. Fatal cases have been rarely reported.
6 Signs and symptoms of cranial neuropathy. Observed at various times, up to several months after completion of rituximab therapy.
7 Observed primarily in patients with pre-existing cardiac conditions and/or cardiotoxic chemotherapy, and mostly associated with infusion-related reactions.
8 Including fatal cases.
During clinical trials, the following adverse events were reported (with similar or lower frequency in the rituximab treatment group compared to control groups): hematotoxicity, neutropenic infection, urinary tract infection, sensory disorder, hyperthermia.
During clinical trials, infusion-related reactions were reported in more than 50% of patients, predominantly during the first infusion and usually within the first 1–2 hours. These symptoms most commonly included fever, chills, and tremors. Other symptoms included hot flushes, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnea, dyspepsia, asthenia, and signs of tumor lysis syndrome. Severe infusion reactions (such as bronchospasm, hypotension) occurred in approximately 12% of patients.
Additional reactions reported in some cases included myocardial infarction, atrial fibrillation, pulmonary edema, and acute reversible thrombocytopenia. Exacerbation of pre-existing cardiac conditions, such as angina or congestive heart failure, or 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 frequency of infusion-related symptoms significantly decreased during subsequent infusions and was <1% during the eighth treatment cycle including rituximab.
Description of selected adverse reactions
Infections
Rituximab 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 rituximab in randomized trials. Serious infections occurred in approximately 4% of patients receiving rituximab as monotherapy. A higher incidence of infections, including grade 3 or 4 infections, was observed during rituximab maintenance therapy over a period of up to 2 years compared to the observation group. No cumulative toxicity regarding infections was observed during the 2-year treatment period. Additionally, other serious viral infections, both new and reactivated or exacerbated, sometimes fatal, have been reported with rituximab treatment. Most patients received rituximab 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), John Cunningham virus (JC) (progressive multifocal leukoencephalopathy [PML]), and hepatitis C virus. Fatal cases of PML occurring after disease progression and retreatment were also observed in clinical trials. Cases of hepatitis B reactivation have been reported, mostly in patients receiving rituximab in combination with cytotoxic chemotherapy. In patients with relapsed/refractory chronic lymphocytic leukemia, the incidence of grade 3/4 viral hepatitis B (reactivation and primary infection) was 2% with the R-FC regimen (rituximab, fludarabine, cyclophosphamide) compared to 0% with the 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 rituximab monotherapy administered over 4 weeks, hematological abnormalities were observed in a minority of patients, 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 rituximab maintenance therapy 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. During combination therapy trials with rituximab and chemotherapy, grade 3/4 leukopenia (rituximab [R]-CHOP 88% vs CHOP 79%; R-FC 23% vs FC 12%), neutropenia (R-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 more frequently than with chemotherapy alone. However, the higher frequency of neutropenia in patients receiving rituximab with chemotherapy was not associated with a higher incidence of infections and infestations compared to patients receiving chemotherapy alone. In trials involving previously untreated CLL patients and relapsed/refractory CLL patients, prolonged (neutrophil count remained below 1 × 10⁹/L between days 24 and 42 after the last dose) or late-onset (neutrophil count below 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 the R-FC regimen after rituximab combined with FC regimen. No differences in anemia incidence were reported. Isolated cases of late-onset neutropenia developing more than four weeks after the last rituximab infusion have been reported. In a first-line CLL trial in patients with Binet stage C, a higher frequency of adverse reactions was observed in the R-FC group compared to the FC group (R-FC 83% vs FC 71%). In a relapsed/refractory CLL trial, grade 3/4 thrombocytopenia was observed in 11% of patients in the R-FC group compared to 9% in the FC group.
In rituximab trials involving 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. The transiently elevated IgM levels usually returned to at least baseline levels within 4 months.
Cardiovascular adverse reactions
During clinical trials of rituximab monotherapy, cardiovascular reactions were reported in 18.8% of patients, most commonly hypotension and hypertension. During infusions, grade 3 or 4 arrhythmias (including ventricular and supraventricular tachycardia) and angina were reported. During maintenance therapy, the frequency of grade 3/4 cardiac disorders was comparable between rituximab-treated patients and the observation group. Cardiac events were reported as serious adverse events (including atrial fibrillation, myocardial infarction, left ventricular dysfunction, myocardial ischemia) in 3% of rituximab-treated patients compared to <1% in the observation group. In trials of rituximab combined with chemotherapy, the frequency of grade 3 and 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%). All arrhythmias occurred either during rituximab infusion or were associated with provoking conditions such as fever, infection, acute myocardial infarction, or pre-existing respiratory and cardiovascular diseases. No differences between R-CHOP and CHOP groups were observed regarding the frequency of grade 3 and 4 cardiac events, including heart failure, myocardial disorders, and ischemic heart disease manifestations. In CLL, the overall frequency of grade 3 or 4 cardiac disorders was low both in the first-line treatment trial (4% R-FC, 3% FC) and in the relapsed/refractory disease trial (4% R-FC, 4% FC).
Respiratory disorders
Cases of interstitial lung disease, some fatal, have been reported.
Neurological disorders
During treatment (initial phase of R-CHOP therapy, up to 8 cycles), acute thromboembolic cerebrovascular events occurred in four patients (2%) receiving R-CHOP therapy who had cardiovascular risk factors, during the first treatment cycle. No differences between treatment groups were observed regarding the frequency of other thromboembolic events. Conversely, cerebrovascular events occurred in three patients (1.5%) in the CHOP group during the follow-up period. In CLL, the overall frequency of grade 3 or 4 nervous system disorders was low in both the first-line trial (4% R-FC, 4% FC) and relapsed/refractory disease trials (3% R-FC, 3% FC).
Cases of reversible posterior leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual disturbances, headache, seizures, and mental status changes, with or without hypertension. RPLS diagnosis requires confirmation by brain imaging. In reported cases, established risk factors for RPLS were present, including underlying patient conditions, hypertension, immunosuppressive therapy, and/or chemotherapy.
Gastrointestinal disorders
In some patients receiving rituximab for non-Hodgkin's lymphoma, gastrointestinal tract perforation, sometimes fatal, has been observed. In most such cases, rituximab was administered with chemotherapy.
IgG levels
In clinical trials of rituximab 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 rituximab treatment groups. In the observation group, median IgG levels subsequently increased, reaching values above the lower limit of normal, but remained unchanged in the rituximab treatment group. The proportion of patients with IgG levels below the lower limit of normal was approximately 60% in the rituximab group over the 2-year treatment period, while a decrease was observed 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 rituximab, some of which were severe and required prolonged immunoglobulin replacement therapy. The consequences of prolonged B-cell depletion in children are unknown.
Skin and subcutaneous tissue reactions
Very rare cases of toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome have been reported, some of which were fatal.
Patient subpopulations (rituximab monotherapy)
Elderly patients (≥ 65 years): The frequency of adverse reactions of all grades and grade 3/4 adverse reactions in elderly patients was similar to that in younger patients (<65 years).
High tumor burden
In patients with high tumor burden, the frequency of grade 3/4 adverse reactions was higher compared to patients 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 proportion of patients reporting adverse reactions during retreatment with additional rituximab courses was similar to the number of patients reporting adverse reactions during initial treatment (adverse reactions of all grades and grade 3/4).
Patient subpopulations (combination therapy with rituximab)
Elderly patients (≥ 65 years)
The frequency of grade 3/4 blood and lymphatic system disorders in previously untreated or relapsed/refractory CLL was higher in elderly patients compared to younger patients (<65 years).
Rituximab in pediatric treatment of DLBCL/BL/ALL/B-ALCL
A multicenter, open-label, randomized trial of Lymphome Malin B (LMB) chemotherapy protocol with rituximab was conducted in children (aged ≥6 months to <18 years) with previously untreated advanced CD20-positive DLBCL/BL/ALL/B-ALCL.
Overall, 309 children received rituximab and were included in the safety analysis. Children randomized to the LMB chemotherapy with rituximab group or included in the single-arm part of the study received rituximab at a dose of 375 mg/m² body surface area and received a total of six intravenous rituximab infusions (two during each of two induction therapy courses and one during each of two consolidation therapy courses according to the LMB protocol).
The safety profile of rituximab in children (aged ≥6 months to <18 years) with previously untreated advanced CD20-positive DLBCL/BL/ALL/B-ALCL was generally similar in type, nature, and severity of adverse reactions to the known safety profile in adult patients with NHL and CLL. However, adding rituximab to chemotherapy increased the risk of certain adverse reactions, particularly infections (including sepsis), compared to chemotherapy alone.
Rheumatoid arthritis treatment experience
The overall safety profile of rituximab for rheumatoid arthritis is based on data from clinical trials and post-marketing surveillance.
The safety profile of rituximab in patients with moderate to severe rheumatoid arthritis (RA) 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 receiving 5 or more courses. Safety information collected during post-marketing surveillance reflects the expected profile of adverse reactions observed in clinical trials of rituximab (see section "Contraindications").
In addition to methotrexate (10–25 mg/week), patients received two courses of 1000 mg rituximab with a two-week interval. Rituximab infusions were administered after intravenous infusion of 100 mg methylprednisolone; patients also received oral prednisolone for 15 days.
The following adverse reactions were recorded during clinical trials or post-marketing surveillance in patients with rheumatoid arthritis receiving rituximab. Frequency categories used are: 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 order of decreasing severity.
The most common adverse reactions to rituximab were infusion reactions (IRs). The overall frequency of IRs in clinical trials was 23% during the first infusion and decreased during subsequent infusions. Serious IRs were uncommon (0.5% of patients) and occurred primarily 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 (PML) (see section "Contraindications") and serum sickness-like reactions.
Infections and infestations: very common – upper respiratory tract infections, urinary tract infections; common – bronchitis, sinusitis, gastroenteritis, herpes zoster; very rare – PML, hepatitis B reactivation; frequency not known: serious viral infection1, enteroviral meningoencephalitis2.
Blood and lymphatic system disorders: common – neutropenia2; rare: late-onset neutropenia3; very rare: serum sickness-like reaction.
Immune system disorders, general disorders and administration site conditions: very common – infusion reactions5 (hypertension, nausea, rash, hyperthermia, pruritus, urticaria, throat irritation, hot flushes, hypotension, rhinitis, chills, tachycardia, fatigue, oropharyngeal 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.
Psychiatric disorders: common – depression, anxiety.
Nervous system disorders: very common – headache; common – paresthesia, migraine, dizziness, sciatica.
Cardiac disorders: rare – angina pectoris, atrial fibrillation, cardiac failure, myocardial infarction; very rare – atrial flutter.
Gastrointestinal disorders: common – dyspepsia, diarrhea, gastroesophageal reflux, oral ulceration, upper abdominal pain.
Skin and subcutaneous tissue disorders: common – alopecia; very rare – toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome7.
Musculoskeletal and connective tissue disorders: common – arthralgia/musculoskeletal pain, osteoarthritis, bursitis.
Investigations: very common – decreased IgM levels6; common – decreased IgG levels6.
1 See section "Infections" below.
2 Observed during post-marketing surveillance.
3 Frequency category based on laboratory findings collected during routine laboratory monitoring in clinical trials.
4 Frequency category based on post-marketing data.
5 Reactions occurring during or within 24 hours after infusion. See section "Infusion reactions" below. Infusion reactions may occur due to hypersensitivity and/or related to the drug's mechanism of action.
6 Includes observations collected during routine laboratory monitoring.
7 Including fatal cases.
Multiple treatment courses
The adverse reaction profile with multiple treatment courses is similar to that observed after the first course. The frequency of all adverse reactions after the first rituximab treatment course was highest during the first 6 months and then decreased. The most commonly observed events were infusion reactions (predominantly during the first treatment course), rheumatoid arthritis exacerbation, and infections; all occurred more frequently during the first 6 months of treatment.
Selected adverse reactions
Infusion reactions
The most common adverse reactions after rituximab administration in clinical trials were infusion reactions (IRs). Among 3189 patients receiving rituximab treatment, 1135 (36%) developed at least one IR, and 733 of 3189 (23%) developed an IR after the first infusion or first treatment course. The frequency of IRs decreased with subsequent infusions. In clinical trials, serious IRs occurred in less than 1% (17 of 3189) of patients. No grade 4 IRs according to Common Toxicity Criteria (CTC) or fatal cases due to IRs were reported during clinical trials. The proportion of grade 3 CTC reactions and IRs leading to treatment discontinuation decreased with each course and became rare starting from the third course. Premedication with intravenous glucocorticoids significantly reduced the frequency and severity of IRs (see sections "Contraindications" and "Special Warnings and Precautions for Use"). In the post-marketing period, serious IRs with fatal outcomes have been reported.
In a study evaluating the safety of rapid rituximab infusion in patients with rheumatoid arthritis (RA), patients with active moderate to severe RA who did not experience serious IRs during or within 24 hours after the first study infusion were allowed to receive the drug as a 2-hour intravenous infusion. Patients with a history of serious IRs to biological agents for RA treatment were excluded from the study. The frequency, types, and severity of IRs were consistent with previously obtained data. No serious IRs were observed.
Infections
The overall frequency of infections reported during clinical trials was approximately 94 per 100 patient-years in patients receiving rituximab. Most of these infections were mild or moderate in severity and primarily included upper respiratory tract infections and urinary tract infections. The frequency of serious infections or infections requiring intravenous antibiotics was approximately 4 per 100 patient-years. No significant increase in serious infection frequency after multiple rituximab treatment courses was observed. During clinical trials, lower respiratory tract infections (including pneumonia) were reported at similar frequencies in rituximab treatment and control groups.
During post-marketing surveillance, serious viral infections have been reported in RA patients receiving rituximab.
Fatal cases of progressive multifocal leukoencephalopathy have been reported after rituximab use for autoimmune diseases, including rheumatoid arthritis (RA) and non-approved autoimmune conditions such as systemic lupus erythematosus (SLE) and vasculitis.
Cases of hepatitis B reactivation have been reported in patients with non-Hodgkin's lymphoma receiving rituximab in combination with cytotoxic chemotherapy (see subsection "Non-Hodgkin's lymphoma"). Isolated cases of hepatitis B virus infection reactivation have also been reported in RA patients receiving rituximab (see section "Special Warnings and Precautions for Use").
Cardiovascular adverse reactions
Serious cardiovascular reactions were reported at a rate of 1.3 per 100 patient-years in patients receiving rituximab compared to 1.3 per 100 patient-years in placebo-treated patients. An increase in the number of patients developing cardiovascular reactions (all or serious) during multiple treatment courses was not observed.
Neurological reactions
Cases of reversible posterior encephalopathy syndrome (RPES)/reversible posterior leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual disturbances, headache, seizures, and mental status changes, with or without hypertension. RPES/RPLS diagnosis must be confirmed by brain imaging. In reported cases, established risk factors for RPES/RPLS were present, including underlying patient conditions, hypertension, immunosuppressive therapy, and/or chemotherapy.
Neutropenia
Cases of neutropenia were observed during rituximab treatment, most of which were transient and mild or moderate in severity. Neutropenia may occur several months after rituximab administration (see section "Contraindications").
During placebo-controlled periods of clinical trials, severe neutropenia developed in 0.94% (13 of 1382) of patients receiving rituximab and in 0.27% (2 of 731) of placebo group patients.
During the post-marketing period, neutropenic events, including severe late-onset neutropenia and persistent neutropenia, were rarely reported, some associated with fatal infections.
Skin and subcutaneous tissue disorders
Very rare cases of toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome have been reported, some of which were fatal.
Laboratory test abnormalities
Hypogammaglobulinemia (IgG or IgM below the lower limit of normal) was observed in patients with rheumatoid arthritis receiving rituximab. No increase in overall infection frequency or serious infections was observed after decreased IgG or IgM levels (see section "Contraindications").
A small number of spontaneous and literature-reported cases of hypogammaglobulinemia were observed in children receiving rituximab. Some of these cases were severe and required prolonged immunoglobulin replacement therapy. The consequences of prolonged B-cell depletion in children are unknown.
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)
Induction of remission in adults (study 1 GPA/MPA)
In clinical study 1 GPA and MPA, 99 adult patients received treatment for induction of remission of GPA and MPA with rituximab (375 mg/m² once weekly for 4 weeks) and glucocorticoids.
The following adverse reactions were observed in ≥5% of adult patients in the rituximab group during 6 months and had a higher frequency than in the comparator group in study 1 GPA/MPA (rituximab, n=99) or during post-marketing surveillance. Adverse reactions are grouped by MedDRA system organ classes.
Infections and infestations: urinary tract infections (7%), bronchitis (5%), herpes zoster (5%), nasopharyngitis (5%), serious viral infection1,2 (frequency not known), enteroviral meningoencephalitis1 (frequency not known).
Blood and lymphatic system disorders: thrombocytopenia (7%).
Immune system disorders: cytokine release syndrome (5%).
Metabolism and nutrition disorders: hyperkalemia (5%).
Psychiatric disorders: insomnia (14%).
Nervous system disorders: dizziness (10%), tremor (10%).
Vascular disorders: hypertension (12%), hot flushes (5%).
Respiratory, thoracic and mediastinal disorders: cough (12%), dyspnea (11%), epistaxis (11%), nasal congestion (6%).
Gastrointestinal disorders: diarrhea (18%), dyspepsia (6%), constipation (5%).
Skin and subcutaneous tissue disorders: acne (7%).
Musculoskeletal and connective tissue disorders: muscle spasms (18%), arthralgia (15%), back pain (10%), muscle weakness (5%), bone and muscle pain (5%), limb pain (5%).
General disorders and administration site conditions: peripheral edema (16%).
Investigations: decreased hemoglobin level (6%).
1 Observed during post-marketing surveillance.
2 See also section "Infections" below.
Maintenance therapy in adults (study 2 GPA/MPA)
In study 2 GPA/MPA, a total of 57 adult patients with severe active GPA and MPA received rituximab treatment for maintenance of remission.
The following adverse reactions occurred in ≥5% of adult patients in the rituximab group and had a higher frequency than in the comparator group in study 2 GPA/MPA (rituximab, n=57) or during post-marketing surveillance.
Infections and infestations: bronchitis (14%), rhinitis (5%), serious viral infection1,2 (frequency not known), enteroviral meningoencephalitis1 (frequency not known).
Respiratory, thoracic and mediastinal disorders: dyspnea (9%).
Gastrointestinal disorders: diarrhea (7%).
General disorders and administration site conditions: pyrexia (9%), influenza-like symptoms (5%), peripheral edema (5%).
Injury, poisoning and procedural complications: infusion reactions3 (12%).
1 Observed during post-marketing surveillance.
2 See also subsection "Infections" below.
3 Detailed information on infusion reactions is provided in the section "Description of selected adverse reactions."
The overall safety profile corresponded to the established safety profile of rituximab for approved autoimmune indications, including granulomatosis with polyangiitis and microscopic polyangiitis. Overall, 4% of patients in the rituximab group experienced adverse reactions leading to treatment discontinuation. Most adverse reactions in the rituximab group were mild or moderate in severity. No fatal adverse reactions were recorded in the rituximab group.
The most common adverse reactions were infusion-related reactions and infections.
Long-term follow-up (study 3 GPA/MPA)
In a long-term observational safety study, 97 patients with GPA and MPA received rituximab treatment (mean 8 infusions [range 1–28]) over a period of up to 4 years according to standard practice and physician assessment. The overall safety profile corresponded to the established safety profile of rituximab in patients with GPA and MPA. No new adverse reactions were recorded.
Children
An open-label single-group study was conducted in 25 children with severe active GPA or MPA. The overall study period consisted of a 6-month remission induction phase with a minimum 18-month observation period, totaling up to 4.5 years. During the observation phase, rituximab was administered at the investigator's discretion (17 of 25 patients received additional rituximab treatment). Concomitant immunosuppressive therapy was allowed.
Adverse reactions considered as events occurring with frequency ≥10% included: infections (17 patients [68%] during remission induction phase; 23 patients [92%] during the overall study period), infusion reactions (15 patients [60%] during remission induction phase; 17 patients [68%] during the overall study period), and nausea (4 patients [16%] during remission induction phase; 5 patients [20%] during the overall study period).
Throughout the entire study period, the safety profile of rituximab corresponded to the established profile during remission induction.
The safety profile of rituximab in children with GPA or MPA corresponded in type, nature, and severity to the known safety profile in adult patients for approved autoimmune indications, including GPA or MPA in adult patients.
Infusion reactions
Infusion reactions in study 1 GPA/MPA (remission induction study in adults) were defined as any adverse reaction developing within 24 hours after infusion and considered by the investigator as infusion-related in the safety evaluation population. 99 patients received rituximab treatment, and 12 (12%) developed at least one infusion reaction. All infusion reactions were grade 1 or 2 according to CTC criteria. The most common infusion reactions were cytokine release syndrome, hot flushes, throat irritation, and tremor. Rituximab was administered in combination with intravenous glucocorticoids, which may reduce the frequency and severity of infusion reactions.
In study 2 GPA/MPA (maintenance therapy study in adults), at least one infusion reaction was observed in 7 of 57 (12%) patients in the rituximab group. The frequency of infusion reactions was highest during or after the first infusion (9%) and decreased with subsequent infusions (<4%). All infusion reaction symptoms were mild or moderate in severity, and most involved respiratory, thoracic and mediastinal disorders and skin and subcutaneous tissue disorders.
In the clinical study in children with GPA or MPA, infusion reactions were reported predominantly during the first infusion (8 patients [32%]), and their frequency decreased over time with each subsequent rituximab infusion (20% during second infusion, 12% during third infusion, 8% during fourth infusion). The most commonly reported infusion reaction symptoms during the remission induction phase were: headache, rash, rhinorrhea, and hyperthermia (8% for each symptom). Observed infusion reaction symptoms were similar to those known in adult patients with GPA or MPA receiving rituximab. Most infusion reactions were grade 1 or 2; two non-serious grade 3 infusion reactions were reported, and no grade 4 or 5 infusion reactions were reported. One patient experienced one serious grade 2 infusion reaction (generalized edema, which resolved with treatment).
Infections
In study 1 GPA/MPA, the overall infection frequency was approximately 237 per 100 patient-years (95% CI 197–285) at 6 months as the primary endpoint. Most infections were mild or moderate in severity and primarily included upper respiratory tract infections, herpes zoster, and urinary tract infections. The frequency of serious infections was approximately 25 per 100 patient-years. The most common serious infection in the rituximab group was pneumonia with a frequency of 4%.
In study 2 GPA/MPA, infections were observed in 30 of 57 (53%) patients in the rituximab group. The frequency of infections of all severity grades was similar in both groups. Infections were predominantly mild or moderate in severity. The most common infections in the rituximab group were upper respiratory tract infections, gastroenteritis, urinary tract infections, and herpes zoster. The frequency of serious infections was similar in both groups (approximately 12%). The most common serious infection in the rituximab group was bronchitis of mild or moderate severity.
In the clinical study in children with severe active GPA and MPA, 91% of recorded infections were non-serious, and 90% were mild or moderate in severity.
The most common infections during the overall phase were: upper respiratory tract infections (URTI) (48%), influenza (24%), conjunctivitis (20%), nasopharyngitis (20%), lower respiratory tract infections (16%), sinusitis (16%), viral URTI (16%), ear infections (12%), gastroenteritis (12%), pharyngitis (12%), urinary tract infections (12%). Serious infections were recorded in 7 patients (28%) and included influenza (2 patients [8%]) and lower respiratory tract infections (2 patients [8%]), which were most frequently reported.
During the post-marketing period, serious viral infections have been reported in GPA/MPA patients receiving rituximab treatment.
Malignant neoplasms
In the remission induction clinical study, the malignancy incidence rate in patients with granulomatosis with polyangiitis and microscopic polyangiitis receiving rituximab treatment was 2.00 per 100 patient-years at study completion (when the last patient completed the follow-up period). According to standardized incidence ratios, the malignancy rate was similar to that in patients with antineutrophil cytoplasmic antibody-associated vasculitis.
In the pediatric clinical trial, no malignancy cases were recorded during the 54-month observation period.
Cardiovascular adverse reactions
In the remission induction clinical study, cardiac disorders were observed at a rate of approximately 273 cases per 100 patient-years (95% CI 149–470) at the 6-month primary endpoint. The frequency of serious cardiac events was 2.1 cases 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 reversible posterior encephalopathy syndrome (RPES)/reversible posterior leukoencephalopathy syndrome (RPLS) have been reported in autoimmune diseases. Symptoms included visual disturbances, headache, seizures, and mental status changes with or without hypertension. RPES/RPLS diagnosis must be confirmed by brain imaging. In reported cases, established risk factors for RPES/RPLS were present, including comorbid conditions, hypertension, immunosuppressive therapy, and/or chemotherapy.
Hepatitis B reactivation
During the post-marketing period, cases of hepatitis B reactivation were observed in patients with granulomatosis with polyangiitis and microscopic polyangiitis receiving rituximab, sometimes fatal.
Hypogammaglobulinemia
Hypogammaglobulinemia (decreased IgA, IgG, or IgM levels below the lower limit of normal) was observed in adult and pediatric patients with granulomatosis with polyangiitis and microscopic polyangiitis receiving rituximab treatment.
In study 1 GPA/MPA, at 6 months, 27%, 58%, and 51% of patients in the rituximab 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. The frequency of overall and serious infections did not increase after decreased IgA, IgG, or IgM levels.
In study 2 GPA/MPA, no clinically significant differences were observed between the two treatment groups or decreased levels of total immunoglobulin, IgG, IgM, or IgA throughout the study.
In the pediatric clinical trial, hypogammaglobulinemia was observed in 3 of 25 (12%) patients throughout the study period, 18 patients (72%) had prolonged IgG level decrease (i.e., Ig level below the lower limit of normal for at least 4 months), of whom 15 also had prolonged IgM level decrease. Three patients received intravenous immunoglobulin therapy (IV-IG). Due to limited data, definitive conclusions cannot be made regarding whether prolonged IgG and IgM level decreases led to increased risk of serious infections in these patients. The consequences of prolonged B-cell depletion in children are unknown.
Neutropenia
In study 1 GPA/MPA, grade 3 or higher neutropenia according to CTC criteria developed in 24% of patients in the rituximab group (one course) and in 23% of patients in the cyclophosphamide group. Neutropenia was not associated with increased frequency of serious infections in patients receiving rituximab.
In study 2 GPA/MPA, the frequency of neutropenia of any grade was 0% in the rituximab group compared to 5% in the azathioprine group.
Skin and subcutaneous tissue reactions
Very rare cases of toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome have been reported, some of which were fatal.
Pemphigus vulgaris
Summary of safety profile in PV-study 1 and PV-study 2
The safety profile of rituximab in combination with short-term low-dose glucocorticoids for the treatment of patients with pemphigus vulgaris was evaluated in a randomized, controlled, multicenter, open-label phase 3 study in patients with pemphigus vulgaris (PV), including 38 patients with pemphigus vulgaris randomized to the rituximab group (PV-study 1). Patients randomized to the rituximab group received an initial dose of 1000 mg intravenously on day 1 of the study and a second dose of 1000 mg intravenously on day 15 of the study. Maintenance doses of 500 mg intravenously were administered at 12 and 18 months. Patients could receive 1000 mg intravenously at relapse.
In PV-study 2 (randomized, double-blind, double-dummy, active-comparator, multicenter study of efficacy and safety of rituximab compared to mycophenolate mofetil [MMF] in patients with moderate to severe PV requiring oral corticosteroids), 67 patients with PV received rituximab (initially 1000 mg intravenously on day 1, then 1000 mg intravenously on day 15, repeated at weeks 24 and 26) over 52 weeks.
The safety profile of rituximab in patients with pemphigus vulgaris was consistent with that in patients with granulomatosis with polyangiitis and microscopic polyangiitis.
List of adverse reactions
The adverse reactions listed below were observed with frequency ≥5% in patients with pemphigus vulgaris receiving rituximab, with an absolute frequency difference of ≥2% between the rituximab group and the prednisone standard-dose group up to 24 months. No patient discontinued treatment due to adverse reactions.
Adverse reactions observed in patients receiving rituximab for the treatment of pemphigus vulgaris during PV-study 1 up to 24 months and PV-study 2 up to 52 weeks:
Infections and infestations: very common – upper respiratory tract infections; common – herpesvirus infection, herpes zoster, oral herpes, conjunctivitis, nasopharyngitis, oral candidiasis, urinary tract infections; frequency not known – serious viral infection1,2, enteroviral meningoencephalitis1.
Benign, malignant and unspecified neoplasms (including cysts and polyps): common – skin papilloma.
Psychiatric disorders: very common – persistent depressive disorder; common – major depressive disorder, irritability.
Nervous system disorders: very common – headache; common – dizziness.
Cardiac disorders: common – tachycardia.
Gastrointestinal disorders: common – upper abdominal pain.
Skin and subcutaneous tissue disorders: very common – alopecia; common – pruritus, urticaria, skin disorder.
Musculoskeletal and connective tissue disorders: common – bone and muscle pain, arthralgia, back pain.
General disorders and administration site conditions: common – fatigue, asthenia, pyrexia.
Injury, poisoning and procedural complications: very common – infusion reactions3.
1 Observed during post-marketing surveillance.
2 See also subsection "Infections" below.
3 Infusion reactions in PV-study 1 included symptoms collected at the next scheduled visit after each infusion and adverse reactions observed on the day or day after infusion. The most common infusion reactions/predominant terms included headache, chills, high blood pressure, nausea, asthenia, and pain.
The most common infusion reaction symptoms (predominant terms) in PV-study 2 included dyspnea, erythema, hyperhidrosis, hot flushes/hot flashes, hypotension/low blood pressure, and rash/itchy rash.
Description of selected adverse reactions
Infusion reactions
During PV-study 1, infusion reactions were common (58%). Almost all infusion reactions were mild or moderate in severity. The number of patients experiencing infusion reactions was 29% (11 patients), 40% (15 patients), 13% (5 patients), and 10% (4 patients) after the first, second, third, and fourth infusion, respectively. No patient discontinued treatment due to infusion reactions. The type and severity of infusion reaction symptoms were similar to those observed in patients with granulomatosis with polyangiitis and microscopic polyangiitis.
In PV-study 2, infusion reactions occurred predominantly during the first infusion, and their frequency decreased with subsequent infusions: 17.9%, 4.5%, 3%, and 3% of patients experienced infusion reactions during the first, second, third, and fourth infusions, respectively.
Infusion reactions, at least one of which was observed in 11/15 patients, were grade 1 or 2 in severity.
In 4/15 patients, infusion reactions ≥ grade 3 were reported, leading to discontinuation of rituximab treatment; in 3 of 4 patients, serious (life-threatening) infusion reactions were observed. Serious infusion reactions occurred during the first (2 patients) or second (1 patient) infusion and resolved with symptomatic treatment.
Infections
During PV-study 1, treatment-related infections were recorded in 14 patients (37%) in the rituximab group compared to 15 patients (42%) in the standard-dose prednisone group. The most common infections in the rituximab group included herpes simplex virus and herpesvirus infections, bronchitis, urinary tract infections, fungal infections, and conjunctivitis. Five serious infections (Pneumocystis jirovecii pneumonia, infectious thrombosis, intervertebral discitis, pulmonary infection, staphylococcal sepsis) were recorded in 3 patients (8%) in the rituximab group. One serious infection (Pneumocystis jirovecii pneumonia) was recorded in 1 patient (3%) in the standard-dose prednisone group.
In PV-study 2, infections occurred in 42 patients (62.7%) in the rituximab group. The most common infections in the rituximab group were upper respiratory tract infections, nasopharyngitis, oral candidiasis, and urinary tract infections. Serious infections were recorded in 6 patients (9%) in the rituximab group.
During the post-marketing period, serious viral infections have been reported in PV patients receiving rituximab.
Laboratory test abnormalities
In PV-study 2, transient decrease in lymphocyte count, due to decreased peripheral T-cell populations, and transient decrease in phosphorus levels after infusion were very commonly observed in the rituximab group. These reactions were considered related to intravenous methylprednisolone infusion during premedication.
In PV-study 2, decreased IgG levels were commonly observed and decreased IgM levels were very commonly observed in the rituximab group, but there was no evidence of increased risk of serious infections after decreased IgG or IgM levels.
Reporting of adverse reactions after marketing authorization is important. This allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.
Shelf life. 36 months.
Shelf life of the reconstituted infusion solution:
- After aseptic dilution in sodium chloride solution
Chemical and physical stability of Rixathon diluted in 0.9% sodium chloride solution has been demonstrated for 30 days when stored at 2–8°C and for 24 hours thereafter at room temperature (≤25°C).
- After aseptic dilution in glucose solution
Chemical and physical stability of Rixathon diluted in 5% glucose solution has been demonstrated for 24 hours when stored at 2–8°C and for 12 hours thereafter at room temperature (≤25°C).
From a microbiological point of view, the reconstituted infusion solution should be used immediately. If not used immediately, the shelf life and storage conditions before use are the responsibility of the user and should not normally exceed 24 hours at 2–8°C, except in cases where reconstitution was performed under controlled and validated aseptic conditions.
Storage conditions. Store at 2–8°C in the outer carton to protect from light. Keep out of reach of children. May be stored without refrigeration in the outer carton at 30°C for up to 7 days, but not exceeding the shelf life of the finished product.
For storage conditions of the medicinal product after dilution, see section "Shelf life of the reconstituted infusion solution."
Packaging. 10 ml (100 mg) or 50 ml (500 mg) in a vial;
2 or 3 vials of 10 ml in a cardboard box;
1 or 2 vials of 50 ml in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
- Sandoz GmbH – Business Division Technological Development and Manufacturing of Biological Medicinal Products Sandoz (BTDM DPS).
- Lek Pharmaceuticals d.d.
Manufacturer's address.
- Biochemistrasse 10, 6336 Langkampfen, Austria.
- Verovskova 57, 1526 Ljubljana, Slovenia.