Redditux

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT REDDITUX (ReDditux)

Composition:

Active substance: rituximab;

1 ml of concentrate for solution for infusion contains 10 mg of rituximab;

Excipients: sodium citrate, polysorbate 80, sodium chloride, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: from clear to opalescent (not exceeding reference standard III), from colorless to slightly yellowish (not exceeding reference standard Y5) solution, practically free from visible particles.

Pharmacotherapeutic group. Antineoplastic agents. Rituximab. Monoclonal antibodies. ATC code L01X C02.

Pharmacological Properties.

Pharmacodynamics.

Rituximab is a genetically engineered chimeric murine/human monoclonal antibody, a glycosylated immunoglobulin consisting of constant IgG1 domains of human origin and variable domains of heavy and light chains of murine origin. The antibody is produced by mammalian cell culture (Chinese hamster ovary cells) in suspension and purified by affinity chromatography and ion exchange, using specific viral inactivation and removal procedures. Reditux specifically binds to the transmembrane CD20 antigen, a non-glycosylated phosphoprotein expressed on pre-B lymphocytes and mature B lymphocytes. This antigen is expressed in more than 95% of cases of 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, normal plasma cells, and cells of other healthy tissues. After binding with the antibody, CD20 is not internalized and is not shed into the extracellular environment. CD20 does not circulate in plasma as a free antigen and therefore does not compete with the antibody for binding.

The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes, while the Fc domain initiates immunological responses leading to B-cell lysis. Possible mechanisms of effector-mediated cell lysis include complement-dependent cytotoxicity due to C1q binding, and antibody-dependent cellular cytotoxicity mediated by one or more Fcγ receptors on the surface of granulocytes, macrophages, and NK cells. It has also been demonstrated that binding of rituximab to the CD20 antigen on B lymphocytes induces cell death via apoptosis. The number of B cells in peripheral blood decreases below normal levels after the first administration of the drug. In patients treated for hematologic malignancies, B-cell counts begin to recover after 6 months and return to normal within 12 months after completion of therapy; however, in some patients, the recovery period 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 weekly, and remained at this level in most patients for up to 6 months. B-cell recovery was observed in the majority of patients (81%), with B-cell counts exceeding 10 cells/μL by month 12 and in 87% by month 18.

Pharmacokinetics.

Non-Hodgkin’s Lymphoma

Based on population pharmacokinetic analysis in patients with non-Hodgkin’s lymphoma receiving single or multiple doses of rituximab as monotherapy or in combination with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone), the administered doses of rituximab ranged from 100 to 500 mg/m² body surface area. 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 2.7 L, respectively. The median terminal half-life of rituximab was 22 days (ranging from 6.1 to 52 days). Baseline CD19-positive cell count and tumor size influenced the variability of CL2 in patients treated with 375 mg/m² rituximab administered intravenously once weekly for 4 weeks. CL2 was higher in patients with higher CD19-positive cell counts or larger tumor burden. However, individual variability in CL2 persisted even after adjusting for tumor size and CD19-positive cell levels. Variability in V1 was dependent on body surface area (1.53–2.32 m²) and concomitant CHOP chemotherapy. The variability in V1 (27.1% and 19.0%) due to fluctuations in body surface area and concurrent CHOP therapy, respectively, was relatively minor. Age, sex, and performance status (as assessed by WHO) had no significant effect on rituximab pharmacokinetics. There is no basis to expect a significant reduction in rituximab pharmacokinetic parameters with dose adjustment based on any of the studied covariates. Rituximab administered as intravenous infusion at 375 mg/m² body surface area weekly (total of 4 doses) to 203 patients with previously untreated non-Hodgkin’s lymphoma resulted in a mean Cmax of 486 μg/mL (range: 77.5 to 996.6 μg/mL) after the fourth infusion. Rituximab was detectable in patient serum 3–6 months after completion of the last treatment course. When rituximab was administered at 375 mg/m² as weekly intravenous infusions (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 body surface area) in combination with 6 cycles of CHOP chemotherapy was practically identical to that observed with monotherapy.

Chronic Lymphocytic Leukemia

Rituximab was administered as intravenous infusion: the first dose of each cycle was 375 mg/m², increased to 500 mg/m² in each of 5 cycles, in combination with fludarabine and cyclophosphamide for chronic lymphocytic leukemia. The mean maximum concentration (Cmax) (N=15) after the fifth infusion of rituximab at 500 mg/m² was 408 μg/mL (range: 97–764 μg/mL), and the mean terminal half-life was 32 days (range: 14 to 62 days).

Granulomatosis with Polyangiitis and Microscopic Polyangiitis

Population pharmacokinetic analysis of data from 197 patients with granulomatosis with polyangiitis and microscopic polyangiitis who received 4 weekly doses of rituximab at 375 mg/m² established a mean terminal half-life of 23 days (range: 9–49 days). The mean clearance and volume of distribution of rituximab were 0.313 L/day (range: 0.116–0.726 L/day) and 4.50 L (range: 2.25–7.39 L), respectively.

Clinical characteristics.

Indications.

Non-Hodgkin's lymphomas (NHL).

Recurrent or chemotherapy-resistant B-cell, CD20-positive low-grade non-Hodgkin's lymphomas or follicular lymphomas; CD20-positive diffuse large B-cell non-Hodgkin's lymphomas, in combination with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone).

Stage III–IV follicular lymphomas that are refractory to chemotherapy or in second or subsequent relapse after chemotherapy.

Previously untreated stage III–IV follicular lymphomas, in combination with CVP chemotherapy.

Maintenance therapy for recurrent/refractory follicular lymphoma responding to induction therapy.

Chronic lymphocytic leukemia

Treatment of previously untreated and recurrent/refractory chronic lymphocytic leukemia in combination with chemotherapy. Data on efficacy and safety are limited 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) and microscopic polyangiitis in combination with glucocorticoids for induction of remission in adult patients.

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, 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 types of interactions.

Data on interactions between Redditux and other medicinal products are currently limited.

In patients who have antibodies to mouse proteins or to other antichimeric antibodies (HAMA/HACA), hypersensitivity reactions or allergic reactions may occur upon administration of other diagnostic or therapeutic monoclonal antibodies.

The safety of concomitant or sequential administration of rituximab with agents that may reduce the number of healthy B-cells (other than CHOP or CVP regimens) has not been established.

In patients with chronic lymphocytic leukemia, concomitant administration with rituximab did not affect the pharmacokinetics of fludarabine or cyclophosphamide. Likewise, no apparent effect of fludarabine and cyclophosphamide on the pharmacokinetics of Redditux was observed.

Renal toxicity has been reported in patients experiencing tumor lysis syndrome (TLS), as well as in patients with non-Hodgkin's lymphomas (NHL) receiving concomitant therapy with cisplatin during clinical trials.

The combination of cisplatin and rituximab is not an approved treatment regimen. Signs of renal impairment should be closely monitored, and rituximab administration should be discontinued in patients with elevated serum creatinine levels or oliguria.

Special precautions for use.

Administration of rituximab should be performed under close supervision of experienced medical personnel in specialized units where emergency assistance can be provided.

To improve traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly documented (or specified) in the patient's medical records.

Progressive multifocal leukoencephalopathy (PML).

The use of rituximab may be associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML).

Very rare cases of PML with fatal outcome have been reported following administration of the drug.

Patients should be monitored regularly for the onset of any new neurological symptoms or worsening of existing ones, which may indicate PML. If PML is suspected, further administration of rituximab should be suspended until PML has been excluded.

The physician should evaluate the patient's condition to determine whether the observed symptoms indicate neurological dysfunction and may suggest PML. Consultation with a neurologist should be considered as clinically indicated.

If any doubts exist, further investigations should be considered, including MRI scanning, preferably with contrast, analysis of cerebrospinal fluid for John Cunningham (JC) virus DNA, and repeat neurological examination. The physician should remain particularly vigilant for PML symptoms that the patient may not notice (e.g., cognitive, neurological, or psychiatric symptoms). Patients should also be advised to inform their family members and close contacts about their treatment, as they may notice symptoms the patient is unaware of. If a patient develops PML, rituximab treatment should be permanently discontinued. In patients with PML who have underlying immunodeficiency, stabilization or improvement of clinical parameters has been observed after immune system recovery. It is currently unknown whether early detection of PML and discontinuation of rituximab therapy may lead to similar stabilization or improvement of clinical parameters.

Non-Hodgkin's lymphoma.

Infusion reactions.

The use of the drug is associated with infusion reactions, which may be related to cytokine release and/or other chemical mediators. Cytokine release syndrome may clinically resemble acute hypersensitivity reactions. Reactions are independent of the route of administration.

This spectrum of reactions, including cytokine release syndrome, tumor lysis syndrome, anaphylactic reactions, and hypersensitivity reactions, is described below. During the post-marketing period, cases of severe infusion reactions with fatal outcomes have been reported following intravenous administration of rituximab, occurring 30 minutes to 2 hours after the start of the first intravenous infusion. These 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 pronounced 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 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 pulmonary tumor infiltration have a higher risk of an unfavorable outcome and therefore require heightened caution during treatment. In case of severe cytokine release syndrome, drug administration should be immediately stopped (see section "Instructions for use 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 after complete symptom resolution 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 chronic lymphocytic leukemia), who are at increased risk of particularly severe cytokine release syndrome, should be conducted with exceptional caution. Such patients require particularly close monitoring throughout the first infusion. If, during the first cycle or any subsequent cycle, lymphocyte count remains >25 × 10⁹/L, consideration should be given to reducing the infusion rate for the first infusion or splitting drug administration over two days.

Infusion-related adverse reactions of all types were observed in 77% of patients receiving rituximab therapy (including cytokine release syndrome accompanied by arterial hypotension and bronchospasm in 10% of patients) (see section "Adverse reactions").

These symptoms are usually reversible upon interruption of the infusion and administration of antipyretics, antihistamines, and, in individual cases, oxygen, intravenous saline, bronchodilators, and corticosteroids if necessary. Severe reactions are described above.

Anaphylactic and other hypersensitivity reactions have been reported after intravenous administration of protein-based agents. Unlike cytokine release syndrome, true hypersensitivity reactions usually develop within minutes after the start of infusion. Medications for treating hypersensitivity reactions, such as epinephrine, antihistamines, and corticosteroids, should be readily available for immediate use in case of allergic reaction during drug administration. Clinical manifestations of anaphylaxis may resemble those of cytokine release syndrome. Hypersensitivity reactions have been reported less frequently than cytokine release-related reactions. In some cases, additional reactions such as myocardial infarction, atrial fibrillation, pulmonary edema, and acute reversible thrombocytopenia have been reported. Since arterial hypotension may occur during drug infusion, antihypertensive medications should be withheld for 12 hours before and after infusion.

Cardiac symptoms. Angina pectoris and cardiac rhythm disturbances, such as atrial flutter and fibrillation, heart failure, and/or myocardial infarction, have been observed during rituximab therapy. 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 administered with caution to 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. The drug was administered to 21 patients who underwent autologous bone marrow transplantation and to patients in other risk groups with potential bone marrow dysfunction, with no myelotoxicity observed.

Complete blood counts, including neutrophil and platelet counts, should be performed regularly during therapy.

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 carefully consider the use of rituximab in patients with a history of recurrent or chronic infections or underlying conditions that may increase the risk of 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 also received cytotoxic chemotherapy. All patients should be screened for hepatitis B virus (HBV) before starting treatment, including at minimum testing for HBsAg and HBcAb, and possibly supplemented with other markers according to local recommendations. 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. Such patients should be monitored and managed according to local medical standards to prevent hepatitis B virus reactivation. During post-marketing use of rituximab in non-Hodgkin's lymphoma and chronic lymphocytic leukemia, very rare cases of progressive multifocal leukoencephalopathy (PML) have been reported (see section "Adverse reactions"). Most patients received rituximab in combination with chemotherapy or within hematopoietic stem cell transplantation programs.

Falsely negative results of serological infection tests. Due to the risk of false-negative serological test results for infections, alternative diagnostic methods should be considered if symptoms suggestive of rare infections arise, including West Nile virus and neuroborreliosis.

Immunization. The safety of live viral vaccines after rituximab therapy in patients with non-Hodgkin's lymphoma and chronic lymphocytic leukemia has not been studied; therefore, vaccination with live viral vaccines is not recommended. Patients who have received rituximab may receive non-live vaccines. However, response rates may be reduced when using inactivated vaccines. In an uncontrolled study, patients with relapsing low-grade non-Hodgkin's lymphomas who received rituximab monotherapy had lower response rates to tetanus toxoid (16% vs. 81%) and keyhole limpet hemocyanin (KLH) neoantigen (4% vs. 76% when evaluating antibody titer increase by more than 2-fold) compared to healthy control volunteers.

Average 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.

Granulomatosis with polyangiitis and microscopic polyangiitis

Infusion reactions

The use of Reddix is associated with infusion-related reactions, which may be caused by cytokine release and/or other chemical mediators. Premedication with an analgesic/antipyretic and an antihistamine should be administered before each Reddix infusion.

Safety data for Reddix use in patients with moderate heart failure (NYHA class III) or severe uncontrolled cardiovascular disease are lacking. In patients receiving Reddix therapy, pre-existing ischemic heart disease has been observed to manifest clinically as angina, as well as atrial flutter and fibrillation. Therefore, the risk of cardiovascular complications due to infusion reactions should be carefully considered before initiating Reddix therapy in patients with known cardiac disease or a history of cardiopulmonary adverse reactions, and such patients should be closely monitored during drug administration. Since arterial hypotension may develop during Reddix administration, antihypertensive medications should be withheld for 12 hours before infusion.

Cardiac disorders

Cases of angina, cardiac arrhythmias (including atrial flutter and fibrillation), heart failure, and/or myocardial infarction have been reported in patients receiving Reddix therapy. Therefore, patients with a history of cardiac disease should be closely monitored.

Infections

Given the mechanism of action of Reddix and the important role of B-cells in maintaining normal immune response, patients are at increased risk of infections after Reddix therapy. Serious infections, including fatal cases, may develop during Reddix therapy (see section "Adverse reactions"). The drug should not be prescribed to patients with acute, severe infections (e.g., tuberculosis, sepsis, opportunistic infections) or patients with severely compromised immunity (e.g., very low CD4 or CD8 levels) (see section "Contraindications"). Physicians should exercise particular caution when considering Reddix 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 effects"). Immunoglobulin levels should be determined before starting Reddix therapy.

Patients who develop signs of infection after Reddix therapy should be promptly evaluated and appropriate treatment initiated. Before starting the next Reddix treatment cycle, patients should be re-evaluated for any potential risk of infection development.

Cases of enteroviral meningoencephalitis, including fatal cases, have been reported after rituximab use.

Hepatitis B virus

Cases of hepatitis B reactivation, including fatal cases, have been reported in patients with granulomatosis with polyangiitis and microscopic polyangiitis receiving Reddix.

All patients should be screened for hepatitis B virus (HBV) before starting Reddix therapy, including at minimum testing for HBsAg and HBcAb, and possibly supplemented with other markers according to local recommendations. Reddix 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 therapy. Such patients should be monitored and managed according to local medical standards to prevent hepatitis B virus reactivation.

Late-onset neutropenia

Neutrophil count should be determined before each Reddix treatment cycle and regularly for 6 months after therapy discontinuation, and whenever infection symptoms occur (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 Reddix use is suspected, treatment should be permanently discontinued.

Immunization

Before starting Reddix therapy, physicians should assess the patient's vaccination status and follow current immunization recommendations. Vaccination should be completed at least 4 weeks before the first Reddix dose.

The safety of live viral vaccines after Reddix therapy has not been studied. Therefore, vaccination with live viral vaccines during Reddix therapy or while peripheral B-cell counts are reduced is not recommended.

Patients who have received Reddix therapy may receive vaccines that do not contain live components. However, response rates to vaccination may be reduced when using inactivated vaccines.

Malignant neoplasms

Immunomodulatory agents may increase the risk of malignant neoplasms. However, available data do not indicate an increased risk of malignancy with rituximab use in patients with autoimmune diseases, beyond the malignancy risk already associated with the underlying autoimmune disease.

Disposal of unused or expired medication: Environmental contamination should be minimized. The drug should not be disposed of in wastewater or household waste. "Waste collection systems" should be used for disposal if available.

Excipients: This medicinal product contains 2.27 mmol (or 52.26 mg) of sodium per 10 mL vial and 11.36 mmol (or 261.34 mg) of sodium per 50 mL vial. Caution should be exercised when administering to patients on sodium-restricted diets.

Use during pregnancy or breastfeeding.

Contraception in men and women

Given the prolonged retention of rituximab in patients with B-cell depletion, women of childbearing potential should use effective contraception methods during treatment and for 12 months after completion of Reddix therapy.

Pregnancy. Adequate and well-controlled studies in pregnant women are lacking. It is known that IgG immunoglobulins can cross the placental barrier. The harmful effects of Reddix on the fetus and its impact on reproductive function are unknown; however, transient B-cell depletion and lymphopenia have been reported in some infants whose mothers received treatment during pregnancy. Similar effects were observed in animal studies. Therefore, Reddix should not be administered during pregnancy unless the potential benefit outweighs the potential risk.

Breastfeeding period. Limited data on rituximab excretion in breast milk indicate very low levels in breast milk (relative infant dose less than 0.4%). Several follow-up cases of breastfed infants describe normal growth and development up to 1.5 years of age. However, since these data are limited and long-term outcomes for breastfed infants remain unknown, breastfeeding is not recommended during rituximab therapy and optimally for 12 months after its discontinuation.

Fertility.

Animal studies did not reveal any harmful effects of rituximab on reproductive organs.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of rituximab on the ability to drive or operate machinery have not been conducted; however, currently known pharmacological activity and adverse effects suggest that such an effect is unlikely.

Method of Administration and Dosage

Infusions of Reddix should be administered under the close supervision of experienced medical personnel in specialized units where emergency assistance is available (see section "Special Precautions").

Prior to each administration of Reddix, premedication with an antipyretic and antihistamine agent, such as paracetamol and diphenhydramine, should always be administered.

For patients with non-Hodgkin's lymphoma and chronic lymphocytic leukemia, consider the use of glucocorticoids if Reddix is not administered in combination with chemotherapy containing glucocorticoids.

Patients with granulomatosis with polyangiitis (Wegener’s granulomatosis) or microscopic polyangiitis should receive intravenous methylprednisolone at a dose of 1000 mg/day for 1–3 days prior to the first infusion of Reddix (the last dose of prednisolone may be administered on the same day as the first dose of Reddix). Subsequently, patients should receive oral prednisone at 1 mg/kg/day (not exceeding 80 mg/day), tapered as rapidly as clinically possible, during and after Reddix treatment.

Prophylaxis with adequate hydration and uric acid-lowering agents, initiated 48 hours before starting therapy, is recommended for patients with CLL to reduce the risk of tumor lysis syndrome. Patients with CLL and lymphocyte counts >25 × 10⁹/L should receive intravenous prednisone/prednisolone 100 mg shortly before rituximab administration to reduce the rate and severity of acute infusion reactions and/or cytokine release syndrome.

Prophylaxis of Pneumocystis jirovecii pneumonia (PCP) is recommended for patients with granulomatosis with polyangiitis (Wegener’s granulomatosis), microscopic polyangiitis, or pemphigus vulgaris during and after treatment with Reddix, in accordance with local clinical guidelines.

Dosage

Check the drug label to ensure that the correct formulation (for intravenous or subcutaneous administration) is being administered to the patient.

Non-Hodgkin's Lymphoma

Follicular Non-Hodgkin's Lymphoma

Combination Therapy

The recommended dose of Reddix in combination with chemotherapy for induction treatment of previously untreated patients or patients with relapsed/refractory follicular lymphomas is 375 mg/m² body surface area per cycle, with a total treatment duration of up to 8 cycles.

Reddix should be administered on day 1 of each chemotherapy cycle, after intravenous administration of the corticosteroid component of chemotherapy, if included in the treatment regimen.

Maintenance Therapy

Previously Untreated Follicular Lymphoma

Previously untreated patients who have responded to induction therapy should receive Reddix at a dose of 375 mg/m² body surface area every 2 months (2 months after the last dose of induction therapy) until disease progression or for a maximum of 2 years.

Relapsed/Refractory Follicular Lymphoma

Patients with relapsed/refractory disease who have responded to induction therapy should receive Reddix at a dose of 375 mg/m² body surface area every 3 months (3 months after the last dose of induction therapy) until disease progression or for a maximum of 2 years.

Monotherapy

Relapsed/Refractory Follicular Lymphoma

The recommended dose of Reddix as monotherapy for induction treatment of adult patients with stage III–IV follicular lymphomas who are chemotherapy-resistant or in second or later relapse after chemotherapy is 375 mg/m² body surface area administered as an intravenous infusion once weekly for 4 weeks.

The recommended dose for retreatment with Reddix as monotherapy in patients who previously responded to prior monotherapy with Reddix for relapsed/refractory follicular lymphoma is 375 mg/m² body surface area administered as an intravenous infusion once weekly for 4 weeks.

Diffuse Large B-Cell Non-Hodgkin's Lymphoma

Reddix should be used in combination with CHOP chemotherapy. The recommended dose of Reddix is 375 mg/m² body surface area administered on day 1 of each cycle of an 8-cycle CHOP chemotherapy regimen, after intravenous administration of the corticosteroid component of CHOP. The safety and efficacy of Reddix in combination with other chemotherapy regimens for the treatment of diffuse large B-cell non-Hodgkin's lymphomas have not been established.

Dose Adjustment During Therapy. Dose reduction of Reddix is not recommended. If Reddix is administered in combination with CHOP or CVP chemotherapy, standard dose-reduction guidelines for chemotherapy agents should be followed.

Chronic Lymphocytic Leukemia (CLL)

In patients with chronic lymphocytic leukemia, prophylaxis with adequate hydration and uric acid-lowering agents should be initiated 48 hours before the start of Reddix infusion to reduce the risk of tumor lysis syndrome.

For patients with lymphocyte counts >25 × 10⁹/L, intravenous prednisone/prednisolone 100 mg is recommended shortly before Reddix infusion to reduce the frequency and severity of acute infusion reactions and/or cytokine release syndrome.

The recommended dose of Reddix in combination with chemotherapy for previously untreated patients and patients with relapsed/refractory chronic lymphocytic leukemia is 375 mg/m² body surface area administered on day 0 of the first cycle, followed by 500 mg/m² body surface area administered on day 1 of each subsequent cycle for 6 cycles. Chemotherapy should be administered after Reddix infusion.

Granulomatosis with Polyangiitis and Microscopic Polyangiitis

The recommended dose of Reddix for induction of remission in granulomatosis with polyangiitis and microscopic polyangiitis is 375 mg/m² body surface area administered as an intravenous infusion once weekly for 4 weeks (a total of 4 infusions).

Prophylaxis of Pneumocystis jirovecii pneumonia is recommended during and after Reddix therapy in patients with granulomatosis with polyangiitis or microscopic polyangiitis.

Maintenance Therapy

After remission induction with Reddix, maintenance therapy should not begin earlier than 16 weeks after the last Reddix infusion.

After remission induction with other standard immunosuppressive agents, maintenance therapy with Reddix should begin within a 4-week period following disease remission.

Reddix should be administered as two intravenous infusions of 500 mg, two weeks apart, followed by 500 mg intravenously every 6 months. Patients should receive Reddix for a minimum of 24 months after achieving remission (absence of clinical signs and symptoms). For patients at higher risk of relapse, physicians should consider longer maintenance therapy with Reddix, up to 5 years.

Dosage in Special Situations

Elderly Patients (aged 65 years and older). Dose adjustment for elderly patients is not required.

Preparation and Storage of Solution

The required amount of Reddix should be diluted aseptically to a calculated rituximab concentration of 1–4 mg/mL in an infusion vial (bag) with sterile, non-pyrogenic 0.9% sodium chloride solution or 5% glucose solution. The container should be gently inverted to mix (avoiding foaming).

The solution should be visually inspected for particulate matter or discoloration prior to administration. Since Reddix contains no preservatives, the prepared solution should be used immediately. Prepared infusion solutions of Reddix are stable for 12 hours at room temperature or up to 24 hours at 2–8°C.

Sterility of the prepared solution must be maintained. As the product contains no antimicrobial preservatives or bacteriostatic agents, aseptic techniques must be strictly followed.

From a microbiological standpoint, the prepared solution should be used immediately.

If not used immediately, the time and conditions of storage of the prepared solution are the responsibility of the user and should not exceed 24 hours at 2–8°C, and only if the solution was prepared under controlled and validated aseptic conditions.

Method of Administration

Standard Dosing Regimen. The prepared rituximab solution at a dose of 375 mg/m² should be administered intravenously as a slow infusion through a separate catheter once weekly. Intravenous bolus or push administration is not permitted.

Method of Administration

Reddix is administered intravenously as a slow infusion through a separate catheter.

The drug must not be administered intravenously as a bolus or by push injection.

Patients must 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, 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 resolved and laboratory parameters and chest X-ray findings have normalized. The infusion may then be resumed at a rate no greater than half the initial rate. If similar severe adverse reactions occur again, discontinuation of treatment should be seriously considered.

Mild or moderate infusion-related reactions (see section "Special Precautions") usually resolve with a reduction in infusion rate. The infusion rate may be increased once symptoms have improved.

First Infusion of Each Course. The recommended initial infusion rate is 50 mg/hour; after the first 30 minutes, the rate may be increased by 50 mg/hour every 30 minutes up to a maximum of 400 mg/hour.

Subsequent Infusions

All Indications

Subsequent doses of rituximab may be infused at an initial rate of 100 mg/hour, increasing by 100 mg/hour every 30 minutes up to a maximum of 400 mg/hour.

Patients with clinically significant cardiovascular disease, including arrhythmias, or those who have experienced serious infusion reactions to any prior biological agent or rituximab, should not have the infusion rate increased.

Children. Rituximab is not recommended for use in children due to lack of data on safety and efficacy.

Overdose

Clinical experience with Reddix at doses higher than those approved for intravenous administration is limited. The highest intravenous dose of rituximab studied in humans to date is 5000 mg (2250 mg/m²), 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 immediately stopped and the patient 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 with a dose of 1.8 g, and respiratory failure with fatal outcome was reported with a dose of 2 g.

Adverse Reactions

Non-Hodgkin's lymphoma and chronic lymphocytic leukemia

Overall safety profile

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 rituximab either as monotherapy (for induction or maintenance therapy following induction therapy) or in combination with chemotherapy.

The most common adverse reactions in patients receiving rituximab were infusion-related reactions, which occurred predominantly during the first infusion. The frequency of infusion-related adverse reactions significantly decreased with subsequent infusions and was less than 1% after administration of the eighth dose.

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 included infusion-related reactions (including cytokine release syndrome, tumor lysis syndrome); infections; cardiovascular adverse reactions (see section "Special precautions").

Other serious adverse reactions included hepatitis B reactivation and progressive multifocal leukoencephalopathy (PML) (see section "Special precautions").

The following adverse reactions were observed during monotherapy with rituximab or in combination with chemotherapy. Within each category, adverse reactions are listed in decreasing order of severity.

The following frequency categories are used to describe the incidence of adverse reactions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data). Adverse reactions identified only during post-marketing surveillance, for which frequency cannot be estimated, are listed under the category "frequency not known".

Infusion reactions. Common – chills, malaise, dyspnea, dyspepsia, nausea, vomiting, weakness, headache, flushing, hypotension, hypertension, fever, pruritus, urticaria, rash, throat irritation, rhinitis, bronchospasm, tachycardia, asthenia, and signs of tumor lysis syndrome. In individual cases during R-CHOP chemotherapy regimen – myocardial infarction, atrial fibrillation, and pulmonary edema.

During studies, more than 50% of patients experienced symptoms indicating infusion reactions, which occurred predominantly during the first infusion and usually within the first 1–2 hours. These symptoms most commonly included fever, chills, and rigors. Other symptoms included flushing, 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. In some cases, myocardial infarction, atrial fibrillation, pulmonary edema, and acute reversible thrombocytopenia were reported. Exacerbation of pre-existing cardiac conditions (e.g., angina pectoris or congestive heart failure), 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 with subsequent infusions and was <1% of patients during the eighth treatment cycle including the drug.

Infections and infestations.

Very common – bacterial infections, viral infections, bronchitis*;

common – sepsis, pneumonia*, febrile infection*, herpes zoster*, respiratory tract infections*, fungal infections, infections of unknown etiology, acute bronchitis*, sinusitis*, hepatitis B1; uncommon – serious viral infections2, Pneumocystis jirovecii pneumonia; rare – progressive multifocal leukoencephalopathy (PML); frequency not known – enteroviral meningoencephalitis2,8

Immune system disorders.

Very common – infusion reactions4, angioedema; common – hypersensitivity;

uncommon – anaphylaxis; rare – tumor lysis syndrome, cytokine release syndrome4, serum sickness; frequency not known – acute reversible thrombocytopenia associated with infusion4.

Blood and lymphatic system disorders.

Very common – leukopenia, neutropenia, febrile neutropenia*, thrombocytopenia*; common – anemia, pancytopenia*, granulocytopenia*; uncommon – coagulation disorders, aplastic anemia, hemolytic anemia, lymphadenopathy; rare – transient increase in serum IgM levels3; frequency not known – late-onset neutropenia3.

Respiratory, thoracic and mediastinal disorders.

Common – bronchospasm4, respiratory disorders, chest pain, dyspnea, increased cough, nasal congestion, rhinitis, acute respiratory failure, pulmonary infiltrates; uncommon – asthma, obliterative bronchiolitis, pulmonary function disorder, hypoxia; uncommon – interstitial lung disease7; rare – respiratory failure4; frequency not known – pulmonary infiltrates.

Gastrointestinal disorders.

Very common – nausea; common – vomiting, diarrhea, abdominal pain, dysphagia, stomatitis, constipation, dyspepsia, anorexia, throat irritation, loss of appetite, taste disturbances;

uncommon – abdominal distension; rare – gastrointestinal perforation7

Cardiac disorders:

common – myocardial infarction*,4 and 6, arrhythmia (including ventricular and supraventricular tachycardia, atrial flutter)*, atrial fibrillation*, tachycardia*, cardiac disorders*; uncommon – left ventricular dysfunction*, supraventricular tachycardia*, ventricular tachycardia*, angina pectoris*, myocardial ischemia*, bradycardia; uncommon – severe cardiac disorders4 and 6; rare – heart failure4 and 6.

Vascular disorders: common – hypertension, orthostatic hypotension, hypotension, vasodilation; rare – vasculitis (mainly cutaneous), leukocytoclastic vasculitis, venous thrombosis, including deep vein thrombosis of the lower extremities.

Nervous system disorders.

Common – paresthesia, hypoesthesia, excitement, insomnia, vasodilation, dizziness, anxiety; headache, migraine; uncommon – dysgeusia; rare – peripheral neuropathy, facial nerve paralysis5, cranial nerve neuropathy, decreased visual, auditory, or other sensory acuity, ischemic cerebrovascular events; frequency not known – cranial neuropathy, loss of other sensation5,

Psychiatric disorders. Common – confusion; uncommon – depression, nervousness, syncope

Metabolism and nutrition disorders. Common – hyperglycemia, weight loss, peripheral edema, increased LDH activity, hypocalcemia, decompensation of diabetes mellitus, facial edema.

Musculoskeletal and connective tissue disorders. Common – hypertonia, myalgia, arthralgia, pain, back pain, neck pain, chest pain, muscle spasms, osteoarthritis.

Skin and subcutaneous tissue disorders. Very common – pruritus, rash, alopecia, skin irritation; common – urticaria, increased sweating, night sweats, skin disorders*; rare – severe bullous skin reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome7), potentially fatal.

Eye disorders. Common – lacrimation disorders, conjunctivitis; rare – severe vision loss.

Ear and labyrinth disorders. Common – ear pain and tinnitus; frequency not known – hearing loss5.

Renal and urinary disorders. Rare – renal failure4.

Investigations. Common – increased LDH activity, hypocalcemia, hypercholesterolemia, hyperkalemia, bacteremia, decreased IgG level.

General disorders and administration site reactions: very common – fever, chills, asthenia, headache; common – tumor pain, flushing, malaise, cold-like symptoms, weakness*, tremor*, multi-organ failure4*; uncommon – infusion site pain; frequency not known – mucositis, rapid tumor lysis syndrome.

For each adverse reaction, the frequency was calculated based on reactions of all severity grades (from mild to severe), except for adverse reactions marked with «*», for which the frequency was calculated based only on severe reactions (≥ grade 3 according to the National Cancer Institute (NCI) Common Toxicity Criteria).

1 Including reactivation and primary infections; frequency with R-FC regimen (rituximab-fludarabine and cyclophosphamide) in relapsed/refractory chronic lymphocytic leukemia.

2 See also section "Infections" below.

3 See also section "Blood disorders" below.

4 See also section "Infusion reactions" below. Fatal cases were rarely reported.

5 Symptoms of cranial neuropathy. Observed at various times up to several months after completion of rituximab therapy.

6 Observed predominantly in patients with prior cardiac disease and/or cardiotoxic chemotherapy, and primarily associated with infusion-related reactions.

7 Including cases with fatal outcome.

8 Observed during post-marketing use.

Description of selected adverse reactions

Infections

Rituximab induces B-cell depletion in approximately 70–80% of patients, but only in a small number of patients was treatment 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. Severe infections developed in approximately 4% of patients receiving the drug as monotherapy. A higher overall infection rate, including grade 3 or 4 infections, was observed during maintenance rituximab therapy over a period of up to 2 years compared to the observation group. No cumulative toxicity regarding infections was observed during the two-year treatment period. Additionally, other serious viral infections (first occurrence, reactivation, or exacerbation) were reported during rituximab therapy, sometimes with fatal outcomes. Most patients received rituximab in combination with chemotherapy or in the context of hematopoietic stem cell transplantation. Examples of such serious viral infections include herpes viruses (cytomegalovirus, varicella-zoster virus, herpes simplex virus), JC virus (progressive multifocal leukoencephalopathy (PML)), enterovirus (meningoencephalitis), and hepatitis C virus. Fatal cases of PML occurring after disease progression and re-treatment were also observed in clinical trials. Cases of hepatitis B virus reactivation were reported, most occurring in patients receiving the drug in combination with cytotoxic chemotherapy. Kaposi's sarcoma progression was observed in patients with pre-existing Kaposi's sarcoma receiving rituximab. These cases occurred with off-label use of the drug, and most patients were HIV-positive.

Hematological adverse reactions

In clinical trials of rituximab monotherapy administered over 4 weeks, hematological abnormalities were observed in fewer patients and were generally mild and reversible. Severe (grade 3/4) neutropenia occurred in 4.2% of patients, anemia in 1.1%, and thrombocytopenia in 1.7%. During maintenance rituximab therapy over up to 2 years, 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 frequency of thrombocytopenia was low (<1%, grade 3/4) and did not differ between treatment groups.

In rituximab combination chemotherapy trials, grade 3/4 leukopenia (rituximab-CHOP 88% vs CHOP 79%; R-FC 23% vs FC 12%), neutropenia (rituximab-cyclophosphamide, vincristine, prednisolone (CVP) 24% vs CVP 14%; R-CHOP 97% vs CHOP 88%; R-FC 30% vs FC 19% in previously untreated chronic lymphocytic leukemia), pancytopenia (R-FC 3% vs FC 1% in previously untreated chronic lymphocytic leukemia) were generally observed at higher frequencies compared to chemotherapy alone.

However, the higher frequency of neutropenia in patients receiving rituximab with chemotherapy was not associated with a higher frequency of infections and parasitic diseases compared to patients receiving chemotherapy alone. In trials in previously untreated CLL patients and patients with relapsed/refractory CLL, prolonged neutropenia (i.e., neutrophil count remained below 1 x 10⁹/L between days 24 and 42 after the last dose) or late-onset neutropenia (i.e., neutrophil count below 1 x 10⁹/L after day 42 in patients without prior prolonged neutropenia or who had recovered by day 42) occurred in 25% of patients receiving the R-FC regimen after rituximab in combination with FC regimen. No differences in anemia frequency were reported. Isolated cases of late-onset neutropenia developing more than four weeks after the last drug infusion were reported. In a trial of the drug as first-line treatment in chronic lymphocytic leukemia patients with Binet stage C, a higher frequency of adverse reactions was observed in the R-FC treatment group compared to the FC group (R-FC 83% vs FC 71%). In a trial for relapsed/refractory chronic lymphocytic leukemia, grade 3/4 thrombocytopenia was observed in 11% of patients in the R-FC group compared to 9% in the FC group.

In trials involving patients with Waldenström's macroglobulinemia, transient increases in serum IgM levels were observed after initiation of treatment, which may be associated with increased blood viscosity and related symptoms. Transient IgM level elevation usually returned to at least baseline levels within 4 months.

Cardiovascular adverse reactions

Cardiovascular reactions were reported in 18.8% of patients during clinical trials of rituximab monotherapy, with most reports involving hypotension and hypertension. Cases of grade 3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectoris were reported during infusions. The frequency of grade 3/4 cardiac disorders during maintenance therapy was comparable between patients receiving the drug and the observation group. Serious cardiac adverse events (including atrial fibrillation, myocardial infarction, left ventricular dysfunction, myocardial ischemia) were reported in 3% of patients receiving the drug compared to <1% in the observation group. In trials of the drug in combination with chemotherapy, the frequency of grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardia and atrial flutter/fibrillation, was higher in the R-CHOP group (6.9% of patients) compared to the CHOP group (1.5% of patients). These arrhythmias occurred either during drug 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 treatment groups were observed regarding the frequency of grade 3 and 4 cardiac events, including heart failure, myocardial disorders, and ischemic heart disease manifestations.

In chronic lymphocytic leukemia, the overall frequency of grade 3 or 4 cardiac disorders was low both in the trial of the drug as first-line treatment (4% for R-FC regimen, 3% for FC regimen) and in the trial for relapsed/refractory disease (4% for R-FC regimen, 4% for FC regimen).

Respiratory disorders

Cases of interstitial lung disease, some fatal, were reported.

Neurological disorders

During therapy (initial phase of R-CHOP regimen for up to 8 cycles), acute thromboembolic cerebrovascular events occurred in patients receiving R-CHOP therapy, all of whom had cardiovascular risk factors, during the first treatment cycle. No differences between treatment groups were observed regarding the frequency of other thromboembolic events. For comparison, cerebrovascular events occurred in CHOP treatment group patients during the follow-up period. Posterior reversible encephalopathy syndrome / posterior reversible leukoencephalopathy syndrome was reported. Symptoms included visual disturbances, headache, seizures, and mental status changes, with or without hypertension. Diagnosis of posterior reversible encephalopathy syndrome / posterior reversible leukoencephalopathy syndrome requires confirmation by brain imaging. In reported cases, recognized risk factors for posterior reversible encephalopathy syndrome / posterior reversible leukoencephalopathy syndrome were present, including underlying patient disease, hypertension, immunosuppressive therapy and/or chemotherapy.

Gastrointestinal disorders

In some cases, gastrointestinal tract perforation, sometimes fatal, was observed in patients receiving the drug for non-Hodgkin's lymphoma treatment. In most such cases, the drug 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 (LLN) (<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 LLN, but remained unchanged in the rituximab treatment group. The proportion of patients with IgG levels below LLN 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).

In children receiving rituximab therapy, a small number of cases of hypogammaglobulinemia (spontaneous and described in literature) were observed, sometimes severe and requiring prolonged immunoglobulin replacement therapy. The consequences of prolonged B-cell depletion in children are unknown.

Skin reactions

Very rarely, cases of toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome were reported, some of which were fatal.

Patient subpopulations (monotherapy with Redditux)

Elderly patients (≥65 years): the frequency of adverse reactions of all severity grades and grade 3/4 adverse reactions in elderly patients was similar to that in younger patients (<65 years).

High tumor burden

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 5.4%). The frequency of adverse reactions of all grades was similar in both patient groups.

Re-treatment

The number of patients reporting adverse reactions during re-treatment with additional rituximab courses was similar to the number reporting adverse reactions during initial treatment (adverse reactions of all grades and grade 3/4).

Patient subpopulations (combination therapy with Redditux)

Elderly patients (≥65 years)

The frequency of grade 3/4 adverse events related to blood and lymphatic system was higher in elderly patients compared to younger patients (<65 years) in trials of previously untreated or relapsed/refractory chronic lymphocytic leukemia.

Redditux in the treatment of granulomatosis with polyangiitis and microscopic polyangiitis

In a clinical trial of granulomatosis with polyangiitis and microscopic polyangiitis, 99 patients received rituximab (375 mg/m² once weekly for 4 weeks) and glucocorticoids.

The following adverse reactions were observed during 6 months in ≥5% of patients receiving the drug and at higher frequency than in the comparator group in the pilot clinical trial.

Blood and lymphatic system disorders: thrombocytopenia (7%).

Gastrointestinal disorders: diarrhea (18%), dyspepsia (6%), constipation (5%).

General disorders and administration site reactions: peripheral edema (16%).

Immune system disorders: cytokine release syndrome (5%).

Infections and infestations: urinary tract infections (7%), bronchitis (5%), herpes zoster (5%), nasopharyngitis (5%).

Investigations: decreased hemoglobin level (6%).

Metabolism and nutrition disorders: hyperkalemia (5%).

Musculoskeletal and connective tissue disorders: muscle spasms (18%), arthralgia (15%), back pain (10%), muscle weakness (5%), muscle and bone pain (5%), limb pain (5%).

Nervous system disorders: dizziness (10%), tremor (10%).

Psychiatric disorders: insomnia (14%).

Respiratory, thoracic and mediastinal disorders: cough (12%), dyspnea (11%), epistaxis (11%), nasal congestion (6%).

Skin and subcutaneous tissue disorders: acne (7%).

Vascular disorders: hypertension (12%), flushing (5%).

Selected adverse reactions

Infusion reactions

Infusion reactions in the clinical trial of granulomatosis with polyangiitis and microscopic polyangiitis were defined as any adverse event occurring within 24 hours of infusion and considered by the investigator as infusion-related in the safety evaluation cohort. Of 99 patients receiving rituximab, 12% developed at least one infusion reaction. All infusion reactions were grade 1 or 2 according to CTC criteria. The most common infusion reactions included cytokine release syndrome, flushing, throat irritation, and tremor. Rituximab was administered in combination with intravenous glucocorticoids, which may reduce the frequency and severity of infusion reactions.

Infections

Among 99 patients receiving rituximab, the overall infection rate was approximately 237 per 100 patient-years (95% confidence interval 197–285) at 6 months as the primary endpoint. Infections were predominantly mild or moderate in severity and consisted mainly of upper respiratory tract infections, herpes zoster, and urinary tract infections. The rate of serious infections was approximately 25 per 100 patient-years. The most common serious infection in the rituximab treatment group was pneumonia (4%).

Malignant neoplasms

The incidence rate of malignant neoplasms in the clinical trial of patients with granulomatosis with polyangiitis and microscopic polyangiitis receiving rituximab was 2.00 per 100 patient-years at study completion (when the last patient completed the observation period). According to standardized incidence ratios, the rate of malignant neoplasms was similar to that in patients with antineutrophil cytoplasmic antibody-associated vasculitis.

Cardiovascular adverse reactions

Cardiac disorders were observed at a rate of approximately 273 per 100 patient-years (95% confidence interval 149–470) at 6 months as the primary endpoint. The rate of serious cardiac events was 2.1 per 100 patient-years (95% confidence interval 3–15). Tachycardia (4%) and atrial fibrillation (3%) were most frequently reported (see section "Special precautions").

Neurological disorders

Cases of posterior reversible encephalopathy syndrome (PRES)/posterior reversible leukoencephalopathy syndrome (PRLS) have been reported in autoimmune diseases. Symptoms included visual disturbances, headache, seizures, and altered mental status with or without hypertension. Diagnosis of PRES/PRLS must be confirmed by brain imaging. In reported cases, recognized risk factors for PRES/PRLS were present, including concomitant disease, hypertension, immunosuppressive therapy and/or chemotherapy.

Hepatitis B reactivation

During post-marketing use of rituximab in patients with granulomatosis with polyangiitis and microscopic polyangiitis, cases of hepatitis B reactivation, sometimes fatal, were observed.

Hypogammaglobulinemia

Hypogammaglobulinemia (decreased IgA, IgG, or IgM levels below the lower limit of normal) was observed in patients with granulomatosis with polyangiitis and microscopic polyangiitis receiving rituximab. At 6 months in an active-controlled, randomized, double-blind, multicenter non-inferiority trial, in the rituximab treatment group, 27%, 58%, and 51% of patients with normal baseline immunoglobulin levels experienced decreased IgA, IgG, or IgM levels, respectively, compared to 25%, 50%, and 46% in the cyclophosphamide group. In patients with low IgA, IgG, or IgM levels, no increase in the frequency of overall infections or serious infections was observed.

Neutropenia

In an active-controlled, randomized, double-blind, multicenter non-inferiority trial, grade 3 or higher neutropenia according to CTC criteria developed in 24% of patients in the rituximab group (one course) and 23% in the cyclophosphamide group. Neutropenia was not associated with a notable increase in the frequency of serious infections in patients receiving rituximab. The impact of multiple rituximab treatment courses on neutropenia development was not studied in clinical trials of patients with granulomatosis with polyangiitis and microscopic polyangiitis.

Skin and subcutaneous tissue reactions

Very rarely, cases of toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome were reported, some of which were fatal.

Shelf life. 3 years.

Storage conditions. Store out of reach of children, protected from light, at 2–8°C. Do not freeze.

Incompatibilities.

No incompatibilities between Redditux and polyvinyl chloride or polyethylene infusion systems or bags have been observed.

Packaging. 10 ml (100 mg) or 50 ml (500 mg) in a vial; 1 vial per cardboard box; 1 cardboard box per plastic bag.

Prescription status. Prescription only.

Manufacturer. Dr. Reddy’s Laboratories Ltd, India.

Manufacturer’s address. Biologics, Plot No. 47 & 44p, Bachupally, Bachupally Mandal, Medchal-Malkajgiri District, 500090, Telangana State, India.

To report an adverse reaction or lack of efficacy when using the medicinal product, please call (24/7): +380 44 207 51 97 or +380 50 414 39 39;

or email: [email protected]