Truxima

Limited data on rituximab excretion in breast milk indicate very low levels in milk (relative infant dose less than 0.4%). Several post-marketing reports describe normal growth and development in breastfed infants up to 2 years of age. However, since these data are limited and long-term outcomes in breastfed infants remain unknown, breastfeeding is not recommended during rituximab therapy and optimally for 6 months after its discontinuation.

Animal studies have not shown harmful effects of rituximab on reproductive organs.

Ability to influence the speed of reactions when driving or operating machinery.

Studies on the effect of Truxima on the ability to drive or operate machinery have not been conducted. The pharmacological properties and adverse reaction profile observed to date suggest that rituximab has no effect or a negligible effect on the ability to drive or operate machinery.

Administration and Dosage

Infusions of Truxima should be administered under the close supervision of experienced medical personnel in specialized units equipped to provide emergency care (see section "Special Precautions").

Medication Premedication and Prophylaxis

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

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

For children with non-Hodgkin's lymphoma, premedication with paracetamol and an H1-antihistamine (diphenhydramine or equivalent) should be administered 30–60 minutes prior to the start of rituximab infusion. Additionally, prednisone should be administered (see Table 2).

For patients with rheumatoid arthritis, premedication with 100 mg intravenous methylprednisolone should be completed 30 minutes prior to Truxima infusion to reduce the frequency and severity of infusion reactions.

For patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), intravenous methylprednisolone at a dose of 1000 mg/day for 1–3 days is recommended prior to the first Truxima infusion (the last dose of methylprednisolone may be administered on the same day as the first dose of Truxima). Subsequently, patients should receive oral prednisone at 1 mg/kg/day (not exceeding 80 mg/day), with dose tapering as rapidly as clinically feasible, during and after Truxima treatment.

Prophylaxis against Pneumocystis jirovecii pneumonia is recommended for patients with GPA/MPA during and after treatment with Truxima, in accordance with local clinical practice guidelines.

Dosage

Non-Hodgkin's Lymphoma

Follicular Non-Hodgkin's Lymphoma

Combination Therapy

The recommended dose of Truxima 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.

Truxima 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

For previously untreated patients who have responded to induction therapy, Truxima should be administered at a dose of 375 mg/m² body surface area once every 2 months (2 months after the last dose of induction therapy) until disease progression or for a maximum duration of 2 years (a total of 12 infusions).

Relapsed/Refractory Follicular Lymphoma

For patients with relapsed/refractory follicular lymphoma who have responded to induction therapy, Truxima should be administered at a dose of 375 mg/m² body surface area once every 3 months (3 months after the last dose of induction therapy) until disease progression or for a maximum duration of 2 years (a total of 8 infusions).

Monotherapy

Relapsed/Refractory Follicular Lymphoma

The recommended dose of Truxima when used 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 via intravenous infusion once weekly for 4 weeks.

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

Diffuse Large B-Cell Non-Hodgkin's Lymphoma

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

Dosage Adjustment During Therapy

Dose reduction of Truxima is not recommended. If Truxima is administered in combination with chemotherapy, standard guidelines for dose reduction of chemotherapeutic agents should be followed.

Chronic Lymphocytic Leukemia

For patients with chronic lymphocytic leukemia, adequate hydration and uric acid-lowering agents should be administered at least 48 hours prior to the first Truxima infusion to reduce the risk of tumor lysis syndrome.

If the lymphocyte count exceeds 25 × 10⁹/L, prednisone/prednisolone at a dose of 100 mg intravenously is recommended shortly before Truxima infusion to reduce the frequency and severity of acute infusion reactions and/or cytokine release syndrome.

The recommended dose of Truxima 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 a total of 6 cycles. Chemotherapy should be administered after Truxima infusion.

Rheumatoid Arthritis

A treatment course with Truxima consists of two intravenous infusions of 1000 mg each. The recommended dose of Truxima is 1000 mg intravenously, with the second infusion administered 2 weeks after the first.

The need for subsequent 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 in patients who do not show clear evidence of therapeutic benefit within this time period.

Granulomatosis with Polyangiitis and Microscopic Polyangiitis

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

Dosage in Special Situations

Children

Non-Hodgkin's Lymphoma

For children aged ≥6 months to <18 years with previously untreated advanced CD20-positive DLBCL/LB/B-LB/LPLB, rituximab should be used in combination with systemic LMB (Lymphome Malin B) chemotherapy (see Tables 2 and 3). 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 have not been established for indications other than previously untreated advanced CD20-positive DLBCL/LB/B-LB/LPLB. Data on use in children under 3 years of age are limited. Rituximab should not be administered to children under 6 months of age with CD20-positive diffuse large B-cell lymphoma.

Table 2. Dosing regimen of rituximab for children with non-Hodgkin's lymphoma

Table 3. Treatment schedule for children with non-Hodgkin's lymphoma: concomitant chemotherapy with rituximab

Elderly patients (>65 years of age). Dose adjustment is not required in elderly patients.

Route of administration

Truxima is administered intravenously by infusion (slowly) through a separate catheter.

Truxima must not be administered by intravenous bolus or rapid injection.

Patients must be closely monitored for the development of cytokine release syndrome (see section "Special precautions"). Patients who develop signs of severe reactions, including severe dyspnea, bronchospasm, or hypoxia, require immediate discontinuation of the infusion. After such reactions occur, patients with non-Hodgkin's lymphoma should be evaluated for signs of tumor lysis syndrome, including appropriate laboratory tests 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. Then, the infusion may be resumed at a rate not exceeding half the initial rate. If similar severe adverse reactions occur again, discontinuation of treatment should be seriously considered in the individual case.

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

First infusion

The recommended initial infusion rate is 50 mg/hour; after 30 minutes, the rate may be increased by 50 mg/hour every 30 minutes until the maximum rate of 400 mg/hour is reached.

Subsequent infusions

All indications

Subsequent infusions of Truxima may be started at a rate of 100 mg/hour, increasing by 100 mg/hour every 30 minutes until the maximum rate of 400 mg/hour is reached.

Children

Non-Hodgkin's lymphoma

First infusion

The recommended initial infusion rate is 0.5 mg/kg/hour (maximum 50 mg/hour); the infusion rate may be increased by 0.5 mg/kg/hour every 30 minutes in the absence of hypersensitivity or infusion reactions, up to a maximum of 400 mg/hour.

Subsequent infusions

Subsequent doses of rituximab may be administered starting at an initial rate of 1 mg/kg/hour (maximum 50 mg/hour); the infusion rate may be increased by 1 mg/kg/hour every 30 minutes, up to a maximum of 400 mg/hour.

Rheumatoid arthritis only

Alternative regimen for subsequent administration with higher infusion rate

If the patient has not experienced serious infusion reactions during the first or subsequent infusion of Truxima at a dose of 1000 mg administered according to the standard regimen, the second and subsequent infusions may be given at a higher 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 next 90 minutes. If the patient tolerates the higher infusion rate, the drug may be administered according to this regimen in subsequent infusions.

Patients with clinically significant cardiovascular diseases, including arrhythmias, or those who have experienced serious infusion reactions to previous administration of any biological medicinal product or rituximab, should not have the infusion rate increased.

Preparation and storage of the solution

Truxima is supplied in sterile, pyrogen-free single-use vials that do not contain preservatives.

The required amount of Truxima should be aseptically withdrawn and diluted to the calculated rituximab concentration (1–4 mg/ml) in an infusion bag (bottle) containing sterile, pyrogen-free 0.9% sodium chloride solution or 5% glucose solution. To mix the solution, the bag (bottle) should be gently inverted to avoid foaming. Sterility of the prepared solution must be maintained. Since the medicinal product contains no antibacterial preservatives or bacteriostatic agents, aseptic techniques must be followed. The solution should be inspected visually for particulate matter or discoloration prior to administration.

The prepared infusion solution in 0.9% sodium chloride solution remains physically and chemically stable for 30 days when stored at 2–8°C and for 24 hours at room temperature (not exceeding 30°C). The prepared infusion solution in 5% glucose solution remains physically and chemically stable for 24 hours when stored at 2–8°C and for 12 hours at room temperature (not exceeding 30°C). From a microbiological standpoint, the prepared infusion solution should be used immediately. If not used immediately after vial opening, the duration and conditions of storage are the responsibility of the user; storage for up to 24 hours at 2–8°C is acceptable, except when dilution is performed under validated, controlled aseptic conditions.

Overdose

Clinical experience with rituximab doses higher than those recommended for intravenous administration is limited. To date, the highest intravenous dose of rituximab studied in humans was 5000 mg (2250 mg/m²). This dose was administered in a dose-escalation clinical trial to patients with chronic lymphocytic leukemia. No additional safety concerns were identified.

In case of overdose, the infusion should be immediately discontinued 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 after administration of rituximab at a dose of 1.8 g, and respiratory failure with fatal outcome was reported after administration of rituximab at a dose of 2 g.

Adverse Reactions

Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

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) or in combination with chemotherapy.

The most common adverse reactions in patients receiving rituximab were infusion-related and occurred in the majority of patients during the first infusion. The incidence of infusion-related adverse reactions significantly decreases with subsequent infusions and is less than 1% after the eighth dose of rituximab.

Infections (predominantly bacterial and viral) were observed during clinical trials in approximately 30–55% of patients with non-Hodgkin’s lymphoma and in 30–50% of patients with chronic lymphocytic leukemia.

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 in combination with chemotherapy. Within each category, adverse reactions are listed in order of decreasing severity. The following categories are used to describe the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data). Adverse reactions identified only during post-marketing surveillance, whose frequency cannot be calculated, 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; uncommon – serious viral infections2, Pneumocystis jirovecii pneumonia; rare – progressive multifocal leukoencephalopathy; frequency not known – enteroviral meningoencephalitis2,8.

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 levels; frequency not known – late-onset neutropenia3.

Immune system disorders: very common – infusion reactions4, angioedema; common – hypersensitivity; uncommon – anaphylaxis; rare – tumor lysis syndrome, cytokine release syndrome4, serum sickness-like reaction; frequency not known – acute infusion-related thrombocytopenia4.

Metabolism and nutrition disorders: common – hyperglycemia, weight loss, peripheral edema, facial edema, increased lactate dehydrogenase activity, hypocalcemia.

Psychiatric disorders: uncommon – depression, nervousness.

Nervous system disorders: common – paresthesia, hypoesthesia, anxiety, insomnia, vasodilation, dizziness, restlessness; uncommon – taste disturbance; rare – peripheral neuropathy, facial nerve paralysis5; frequency not known – cranial neuropathy, loss of other sensory functions5.

Eye disorders: common – lacrimation disorder, conjunctivitis; rare – severe vision loss5.

Ear and labyrinth disorders: common – tinnitus, ear pain; frequency not known – hearing loss5.

Cardiac disorders: common – myocardial infarction4,6,*, arrhythmia*, atrial fibrillation*, tachycardia*, cardiac disorders*; uncommon – left ventricular dysfunction*, supraventricular tachycardia*, ventricular tachycardia*, angina pectoris*, myocardial ischemia*, bradycardia; uncommon – severe cardiac disorders4,6; rare – cardiac failure4,6.

Vascular disorders: common – arterial hypertension, orthostatic hypotension, arterial hypotension; rare – vasculitis (predominantly cutaneous), leukocytoclastic vasculitis.

Respiratory, thoracic and mediastinal disorders: common – bronchospasm4, respiratory disorder, chest pain, dyspnea, increased cough, rhinitis; uncommon – asthma, obliterative bronchiolitis, lung disorders, 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; uncommon – abdominal distension; rare – gastrointestinal perforation7.

Skin and subcutaneous tissue disorders: very common – pruritus, rash, alopecia*; common – urticaria, sweating, night sweats, skin disorders*; rare – severe bullous skin reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome)7.

Musculoskeletal and connective tissue disorders: common – muscle hypertonia, myalgia, arthralgia, back pain, neck pain, pain.

Renal and urinary disorders: rare – renal failure4.

General disorders and administration site conditions: very common – pyrexia, chills, asthenia, headache; common – tumor pain, hot flushes, malaise, cold-like symptoms, weakness*, tremor*, multi-organ failure4*; uncommon – infusion site pain.

Investigations: very common – decreased IgG levels.

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

1 Includes 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 See section "Blood-related adverse reactions" below.

4 See section "Infusion reactions" below. Fatal cases have been rarely reported.

5 Symptoms of cranial neuropathy. Observed at various times, from during treatment to several months after completion of rituximab therapy.

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

7 Including fatal cases.

8 Observed during post-marketing use.

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 symptoms 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 flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, arterial hypertension, arterial hypotension, dyspnea, dyspepsia, asthenia, and signs of tumor lysis syndrome. Severe infusion reactions (such as bronchospasm, arterial hypotension) occurred in approximately 12% of patients. Myocardial infarction, atrial fibrillation, pulmonary edema, and acute reversible thrombocytopenia were reported in some cases. Exacerbation of pre-existing cardiac conditions (e.g., angina pectoris or congestive heart failure), severe cardiac events (heart failure, myocardial infarction, atrial fibrillation), pulmonary edema, multi-organ failure, tumor lysis syndrome, cytokine release syndrome, renal failure, and respiratory failure were observed at lower or unknown frequencies. The incidence of infusion-related symptoms significantly decreased during subsequent infusions and was <1% of patients 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 treatment associated with decreased serum immunoglobulin levels.

Cases of localized candidiasis and herpes zoster were reported at higher frequencies in patient groups receiving rituximab in randomized trials. Serious infections developed in approximately 4% of patients receiving rituximab as monotherapy. A higher overall incidence of infections, including grade 3 or 4 infections, was observed during maintenance therapy with rituximab over a period of up to 2 years compared to the observation group. No cumulative infection-related toxicity was observed during the two-year treatment period. Additionally, other serious viral infections—first occurrence, reactivation, or exacerbation—have been reported during rituximab treatment, sometimes with fatal outcomes. 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), JC virus (progressive multifocal leukoencephalopathy (PML)), and hepatitis C virus. Fatal cases of PML occurring after disease progression and retreatment were also observed during clinical trials. Cases of hepatitis B reactivation have been reported, most commonly in patients receiving rituximab in combination with cytotoxic chemotherapy. In patients with relapsed/refractory chronic lymphocytic leukemia, the incidence of grade 3/4 hepatitis B (reactivation or 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 fewer patients and were usually mild and reversible. Severe (grade 3/4) neutropenia occurred in 4.2% of patients, anemia in 1.1%, and thrombocytopenia in 1.7%. During maintenance therapy with rituximab over a period of 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 incidence of thrombocytopenia was low (<1%, grade 3/4) and did not differ between treatment groups. In trials of rituximab in combination with chemotherapy, grade 3/4 leukopenia (rituximab-CHOP 88% vs. CHOP 79%; R-FC 23% vs. FC 12%), neutropenia (rituximab-cyclophosphamide, vincristine, prednisolone (CVP) 24% vs. CVP 14%; R-CHOP 97% vs. CHOP 88%; R-FC 30% vs. FC 19% in previously untreated chronic lymphocytic leukemia), and pancytopenia (R-FC 3% vs. FC 1% in previously untreated chronic lymphocytic leukemia) were generally observed at higher frequencies compared to chemotherapy alone. However, the higher incidence of neutropenia in patients receiving rituximab with chemotherapy was not associated with a higher incidence of infections and parasitic diseases compared to patients receiving chemotherapy alone. In trials involving previously untreated CLL patients and patients with relapsed/refractory CLL, 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 following the last dose in patients without prior prolonged neutropenia or with neutrophil recovery by day 42) neutropenia occurred in 25% of patients treated with R-FC. No differences in anemia incidence were reported. Cases of late-onset neutropenia occurring more than four weeks after the last rituximab infusion have been reported. In a first-line therapy trial in chronic lymphocytic leukemia patients with Binet stage C, a higher incidence of adverse reactions was observed in the R-FC group compared to the FC group (R-FC 83% vs. FC 71%). In a trial for relapsed/refractory chronic lymphocytic leukemia, grade 3/4 thrombocytopenia occurred in 11% of patients in the R-FC group compared to 9% in the FC group.

In trials 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. IgM levels typically returned to at least baseline values within 4 months.

Cardiovascular adverse reactions

Cardiovascular events were reported in 18.8% of patients during clinical trials of rituximab monotherapy, with the most frequent events being arterial hypotension and hypertension. Arrhythmias of grade 3 or 4 (including ventricular and supraventricular tachycardia) and angina pectoris were reported during infusions. The incidence of grade 3/4 cardiac disorders during maintenance therapy 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 patients receiving rituximab compared to <1% in the observation group. In trials of rituximab in combination with chemotherapy, the incidence of grade 3/4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardia and atrial fibrillation/flutter, was higher in the R-CHOP group (14 patients, 6.9%) compared to the CHOP group (3 patients, 1.5%). These arrhythmias occurred either during rituximab infusion or were associated with precipitating conditions such as fever, infection, acute myocardial infarction, or pre-existing respiratory and cardiovascular diseases. No differences in the incidence of grade 3/4 cardiac events, including heart failure, myocardial disorders, and ischemic heart disease, were observed between the R-CHOP and CHOP groups. In chronic lymphocytic leukemia, the overall incidence of grade 3/4 cardiac disorders was low in both the first-line therapy trial (4% with R-FC, 3% with FC) and the relapsed/refractory disease trial (4% with R-FC, 4% with FC).

Respiratory disorders

Cases of interstitial lung disease, some fatal, have been reported.

Neurological disorders

During treatment (initial phase of R-CHOP regimen, up to 8 cycles), four patients (2%) receiving R-CHOP, all with cardiovascular risk factors, developed acute thromboembolic cerebrovascular events during the first treatment cycle. No differences in the incidence of other thromboembolic events were observed between treatment groups. For comparison, cerebrovascular events occurred in three patients (1.5%) in the CHOP group during the follow-up period. In chronic lymphocytic leukemia, the overall incidence of grade 3/4 nervous system disorders was low in both the first-line therapy trial (4% with R-FC, 4% with FC) and the relapsed/refractory disease trials (3% with R-FC, 3% with FC).

Posterior reversible encephalopathy syndrome (PRES)/posterior reversible leukoencephalopathy syndrome (PRLS) has been reported. Symptoms included visual disturbances, headache, seizures, and altered mental status, with or without arterial hypertension. Diagnosis of PRES/PRLS requires confirmation by brain imaging. In reported cases, risk factors for PRES/PRLS were identified, including underlying patient conditions, arterial 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. Most of these patients received rituximab in combination with chemotherapy.

IgG levels

In clinical trials of maintenance rituximab 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 group. The proportion of patients with IgG levels below the lower limit of normal was approximately 60% in the rituximab group throughout 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 (reported from spontaneous reports and published case descriptions) have been observed in children treated with rituximab. In some cases, hypogammaglobulinemia was severe and required 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 have been reported, some of which were fatal.

Subpopulations of Patients (Rituximab Monotherapy)

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

High tumor burden

The frequency of grade 3/4 adverse reactions was higher in patients with high tumor burden compared to those without high tumor burden (25.6% vs. 15.4%). The frequency of adverse reactions of all grades was similar in both patient groups.

Retreatment

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

Subpopulations of Patients (Combination Therapy with Rituximab)

Elderly patients (≥ 65 years)

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

Experience in pediatric patients with BL/B-AL/B-NHL/LBL

Summary of Safety Profile

A multicenter, open-label, randomized trial of LMB (Lymphome Malin B) chemotherapy with or without rituximab was conducted in children (aged ≥6 months to <18 years) with previously untreated advanced CD20-positive BL/B-AL/B-NHL/LBL.

Overall, 309 children received rituximab and were included in the safety population analysis. Children randomized to the LMB chemotherapy plus rituximab group or enrolled 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 in each of two induction cycles and one in each of two consolidation cycles according to the LMB protocol).

The safety profile of rituximab in children (aged ≥6 months to <18 years) with previously untreated advanced CD20-positive BL/B-AL/B-NHL/LBL was generally consistent in type, nature, and severity with the known safety profile in adult patients with non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. The addition of rituximab to chemotherapy increased the risk of certain events, including infections (including sepsis), compared to chemotherapy alone.

Rituximab in the Treatment of Rheumatoid Arthritis

The overall safety profile of rituximab in 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 is summarized in the section below. In clinical trials, over 3,100 patients received at least one course of treatment and were followed for periods ranging from 6 months to over 5 years; approximately 2,400 patients received two or more courses, including over 1,000 patients who received 5 or more courses. Safety information collected during post-marketing surveillance reflects the expected profile of adverse reactions observed in clinical trials of rituximab (see section "Special Warnings and Precautions for Use").

In addition to methotrexate (10–25 mg/week), patients received two courses of 1,000 mg rituximab, separated by a two-week interval. Rituximab infusions were administered after intravenous infusion of 100 mg methylprednisolone; patients also received oral prednisone for 15 days. The following categories are used to describe the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000), very rare (< 1/10,000). Within each frequency category, adverse reactions are listed in order of decreasing severity.

The most common adverse reactions associated with rituximab were infusion reactions. The overall incidence of infusion reactions in clinical trials was 23% during the first infusion and decreased with subsequent infusions. Serious infusion reactions were uncommon (0.5% of patients) and occurred predominantly during the initial treatment course. In addition to adverse reactions observed in clinical trials of rituximab for rheumatoid arthritis, post-marketing surveillance reported progressive multifocal leukoencephalopathy (see section "Special Warnings and Precautions for Use") and serum sickness-like reactions.

Infections and infestations: very common – upper respiratory tract infections, urinary tract infections; common – bronchitis, sinusitis, gastroenteritis, tinea pedis; rare – progressive multifocal leukoencephalopathy, hepatitis B reactivation; frequency not known – serious viral infection1, enteroviral meningoencephalitis7.

Blood and lymphatic system disorders: common – neutropenia2; uncommon – late-onset neutropenia3; rare – serum sickness-like reaction.

Cardiac disorders: uncommon – angina pectoris, atrial fibrillation, heart failure, myocardial infarction; rare – atrial flutter.

Immune system disorders/General disorders and administration site conditions: very common – infusion reactions4 (arterial hypertension, nausea, rash, hyperthermia, pruritus, urticaria, throat irritation, hot flushes, arterial hypotension, rhinitis, chills, tachycardia, fatigue, oral and pharyngeal pain, peripheral edema, erythema); uncommon – infusion reactions4 (generalized edema, bronchospasm, wheezing, laryngeal edema, angioedema, generalized pruritus, anaphylaxis, anaphylactoid reaction).

Metabolism and nutrition disorders: common – hypercholesterolemia.

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

Skin and subcutaneous tissue disorders: common – alopecia; rare – Stevens-Johnson syndrome6, toxic epidermal necrolysis (Lyell’s syndrome).

Psychiatric disorders: common – depression, anxiety.

Gastrointestinal disorders: common – dyspepsia, diarrhea, gastroesophageal reflux, oral ulceration, upper abdominal pain.

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

Investigations: very common – decreased IgM levels5; common – decreased IgG levels5.

1 See section "Infections" below.

2 Frequency calculated based on laboratory data collected during routine laboratory monitoring in clinical trials.

3 Frequency determined from post-marketing data.

4 Reactions observed during or within 24 hours after infusion. See "Infusion reactions" below. Infusion-related reactions may result from hypersensitivity and/or mechanisms of drug action.

5 Including observations collected during routine laboratory monitoring.

6 Including fatal cases.

7 Observed during post-marketing use.

Multiple Treatment Courses

Multiple treatment courses are associated with an adverse reaction profile similar to that observed after the first treatment course. The frequency of all adverse reactions after the first rituximab treatment course was highest during the first 6 months and then decreased. Infusion reactions (predominantly during the first treatment course), rheumatoid arthritis flares, and infections were most commonly observed, with all events occurring more frequently during the first 6 months of treatment.

Infusion Reactions

The most common adverse reactions following rituximab administration in clinical trials were infusion reactions. Among 3,189 patients receiving rituximab treatment, 1,135 (36%) developed at least one infusion reaction, with 733 of 3,189 (23%) experiencing an infusion reaction after the first infusion of the first treatment course. The incidence of infusion reactions decreased with subsequent infusions. In clinical trials, serious infusion reactions occurred in less than 1% (17 of 3,189) of patients. No grade 4 infusion reactions according to Common Toxicity Criteria (CTC) or deaths due to infusion reactions were observed during clinical trials. The number of grade 3 CTC reactions and infusion reactions leading to treatment discontinuation decreased with subsequent courses and were rare starting from the third course. Premedication with intravenous glucocorticoids significantly reduced the frequency and severity of infusion reactions (see sections "Dosage and Administration", "Special Warnings and Precautions for Use"). During post-marketing use of rituximab, cases of severe infusion reactions with fatal outcomes have been reported.

In a safety study of faster rituximab infusion in patients with rheumatoid arthritis (RA), patients with moderate to severe active RA who did not experience serious infusion reactions during the first studied infusion or within 24 hours thereafter were allowed to receive the drug via a 2-hour intravenous infusion. Patients with a history of serious infusion reactions to biological agents for RA treatment were excluded from the study. The frequency, type, and severity of infusion reactions were consistent with previously obtained data. No serious infusion reactions were observed.

Description of Selected Adverse Reactions

Infections

The overall infection rate was approximately 94 cases per 100 patient-years in patients receiving rituximab treatment. Infections were predominantly mild to moderate in severity and mainly included upper respiratory tract infections and urinary tract infections. The rate of infections that were serious or required intravenous antibiotics was approximately 4 cases per 100 patient-years. No significant increase in the frequency of serious infections was observed after multiple courses of rituximab treatment. Lower respiratory tract infections (including pneumonia) were reported during clinical trials with similar frequency in rituximab treatment and control groups.

Serious viral infections have been reported in patients with rheumatoid arthritis receiving rituximab during post-marketing surveillance.

Fatal cases of progressive multifocal leukoencephalopathy have been reported after rituximab use in the treatment of autoimmune diseases (rheumatoid arthritis and unapproved autoimmune conditions, including systemic lupus erythematosus and vasculitis).

Cases of hepatitis B reactivation have been documented in patients with non-Hodgkin’s lymphoma receiving rituximab in combination with cytotoxic chemotherapy. Isolated cases of reactivation of hepatitis B virus infection have also been reported in patients with rheumatoid arthritis receiving rituximab treatment (see section "Special Warnings and Precautions for Use").

Cardiovascular events

Serious cardiovascular events were reported at a rate of 1.3 cases per 100 patient-years in patients receiving rituximab treatment, compared to 1.3 cases per 100 patient-years in patients receiving placebo. No increase in the number of patients developing cardiovascular events (all or serious) was observed during multiple treatment courses.

Neurological events

Cases of posterior reversible encephalopathy syndrome (PRES)/posterior reversible leukoencephalopathy syndrome (PRLS) have been reported. 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.

Neutropenia

Neutropenia has been reported with rituximab use, which in most cases was transient and mild to moderate in severity. Neutropenia may occur several months after rituximab administration (see section "Special Warnings and Precautions for Use").

During placebo-controlled periods of clinical trials, severe neutropenia developed in 0.94% (13 of 1,382) of patients receiving rituximab and in 0.27% (2 of 731) of patients in the placebo group.

Neutropenic events, including severe late-onset neutropenia and persistent neutropenia, have been rarely reported during post-marketing use. Some of these events were associated with fatal infections.

Skin and subcutaneous tissue reactions

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

Laboratory abnormalities

Hypogammaglobulinemia (IgG or IgM levels below the lower limit of normal) was observed in patients with rheumatoid arthritis receiving rituximab treatment. No increase in the overall frequency of infections or serious infections was observed after decreased IgG or IgM levels (see section "Special Warnings and Precautions for Use").

A small number of cases of hypogammaglobulinemia (known from spontaneous reports and published case descriptions) have been observed in children receiving rituximab treatment, sometimes severe and requiring prolonged immunoglobulin replacement therapy. The consequences of prolonged B-cell depletion in children are unknown.

Rituximab in the Treatment of Granulomatosis with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA)

In a clinical trial of GPA and MPA, 99 patients received rituximab (375 mg/m² once weekly for 4 weeks) and glucocorticoids for induction of remission of GPA and MPA.

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

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

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

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

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

Infections and infestations: urinary tract infections (7%), bronchitis (5%), herpes zoster (5%), nasopharyngitis (5%), serious viral infection (frequency not known)1,2, enteroviral meningoencephalitis (frequency not known).

Investigations: decreased hemoglobin levels (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: arterial hypertension (12%), hot flushes (5%).

1 Observed during post-marketing period.

2 See also subsection "Infections" below.

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 after infusion and considered by the investigator to be infusion-related in the safety evaluation population. Ninety-nine patients received rituximab treatment, and 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, hot flushes, throat irritation, and tremor. Rituximab was administered in combination with intravenous glucocorticoids, which may reduce the frequency and severity of infusion reactions.

Infections

In the GPA/MPA clinical trial involving 99 patients receiving rituximab, the overall infection rate was approximately 237 cases per 100 patient-years (95% CI: 197–285) at the primary endpoint of 6 months. Infections were predominantly mild to moderate and included upper respiratory tract infections, herpes zoster, and urinary tract infections. The incidence of serious infections was approximately 25 cases per 100 patient-years. The most commonly reported serious infection in the rituximab group was pneumonia, with an incidence of 4%.

Malignant Neoplasms

In the GPA/MPA clinical trial, the incidence of malignant neoplasms in patients with granulomatosis with polyangiitis and microscopic polyangiitis receiving rituximab treatment was 2 cases per 100 patient-years at the end of the study (when the last patient completed the observation period). According to standardized incidence ratios, the rate of malignancies was similar to that in patients with antineutrophil cytoplasmic antibody-associated vasculitis.

Cardiovascular Adverse Reactions

In the GPA/MPA clinical trial, cardiac disorders were observed at a rate of approximately 273 cases per 100 patient-years (95% CI: 149–470) at 6 months as the primary endpoint. The incidence 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 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 have been observed, sometimes with fatal outcomes.

Hypogammaglobulinemia

Hypogammaglobulinemia (decreased IgA, IgG, or IgM levels below the lower limit of normal) was observed in patients with granulomatosis with polyangiitis and microscopic polyangiitis receiving rituximab treatment. The frequency of total infections or serious infections did not increase after decreased IgA, IgG, or IgM levels.

At 6 months in the GPA/MPA clinical 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. No increase in the frequency of total or serious infections was observed in patients with low IgA, IgG, or IgM levels.

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 in 23% of patients in the cyclophosphamide group. Neutropenia was not associated with a significant 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 in 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 have been reported, some of which were fatal.

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after drug authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf life. 4 years.

The prepared infusion solution in 0.9% sodium chloride solution remains physically and chemically stable for 30 days at 2–8°C and for 24 hours at room temperature (not exceeding 30°C). The prepared infusion solution in 5% glucose solution remains physically and chemically stable for 24 hours at 2–8°C and for 12 hours at room temperature (not exceeding 30°C). From a microbiological standpoint, the prepared infusion solution should be used immediately. If not used immediately after vial opening, storage duration and conditions are the responsibility of the user; storage for up to 24 hours at 2–8°C is acceptable, except when dilution is performed under validated controlled aseptic conditions.

Storage conditions. Store at 2–8°C in the original carton to protect from light. Keep out of reach of children.

Packaging. 50 mL in a vial, 1 vial in a carton; 10 mL in a vial, 2 vials in a carton.

Prescription status. Prescription only.

Manufacturer. Novartis France SARL.

Manufacturer's address. 2400, Route des Colles, 06410, Biot, France.