Experience of using a biosimilar of a genetically engineered biological drug in patients with rheumatoid arthritis in real clinical practice | Zhilyaev E.V., Koltsova E.N., Schmidt E.I., Lytkina K.A., Lukina G.V.

Introduction

The introduction of genetically engineered biological drugs (GEBPs) into the treatment of rheumatoid arthritis (RA) has significantly improved results in patients who did not respond to traditional basic therapy.
However, the use of these drugs is associated with a significant increase in treatment costs. To date, the patents on most biologically active drugs used in rheumatology have expired, allowing these important drugs to be reproduced. The appearance of generic drugs on the market, as experience shows, leads to a significant reduction in treatment costs [1]. However, the reproduction of GIBP has a number of significant features. The reproduced low-molecular drug (generic) exactly repeats the chemical structure of the original. For protein molecules, such as GIBPs, the coincidence of the amino acid sequence does not guarantee the similarity of the three-dimensional structure of the protein, which determines its pharmacological properties. Therefore, when reproducing a biosimilar, a biosimilar is required not only to demonstrate the similarity of key chemical and physicochemical characteristics, but also to confirm therapeutic equivalence. To this end (as opposed to generics), putative biosimilars are studied in large phase III randomized clinical trials (RCTs) [1].

The first biosimilar for the treatment of RA (infliximab) was approved by the European Medicines Agency (EMA) in 2013 [2]. Since then, the number of biosimilar biosimilars has rapidly increased and they now play a significant role in the treatment of rheumatic diseases.

The drug rituximab, which is a chimeric monoclonal antibody against the surface molecule CD20 of B lymphocytes, was registered by the EMA for the treatment of RA in 2006. In 2022, the first Russian biosimilar of the drug Acellbia® was registered in the Russian Federation for the treatment of RA and ANCA-associated systemic vasculitis . The full development cycle of the drug, as well as its production, is carried out in the Russian Federation by BIOCAD. The large-scale 48-week phase III BIORA study did not reveal differences in the clinical efficacy and safety of the biosimilar Acellbiy® and the originator drug MabThera®, and revealed no effect of switching from one drug to another on the parameters of efficacy, safety and immunogenicity [3]. However, given the biological nature of the drugs, such differences are possible. Therefore, the accumulation of comparative data, especially in real practice, is of great interest.

Target

research: to evaluate the effectiveness and safety of switching from MabThera® (the original drug rituximab) to its biosimilar (Acellbia®) in patients with RA in real clinical practice.

Material and methods

Data from the Moscow Unified Register of Arthritis (MERA) was analyzed. The registry monitors patients receiving biologically active drugs or targeted synthetic anti-inflammatory drugs at the expense of budget funds, living in Moscow and giving informed consent to participate in the study.

The following patients were selected for analysis:

meeting the RA criteria of the American Rheumatism Association (ARA) 1987 or the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2010;

who received at least one course of treatment with the original drug rituximab and subsequently switched to treatment with a biosimilar;

who made at least one visit during treatment with the original drug rituximab after at least 6 months. after it started;

who made at least one visit during treatment with a biosimilar after at least 6 months. after it started.

Rituximab was administered as one or two (2-week intervals) infusions with a single dose of 500–1000 mg and intravenous premedication with methylprednisolone (100–250 mg).

The effectiveness of the drugs was assessed based on the data from the last completed visit during treatment with the corresponding drug. At each visit, patients were asked using a questionnaire about all clinically significant events that had occurred since the previous visit. Data on adverse events (AEs) were analyzed for the entire period of use of the corresponding drug. Reports of acute respiratory illnesses were excluded from the analysis.

During the visits, all patients underwent a standard examination, which included, among other things, determination of the number of swollen joints and the number of painful joints (NBP), a study of erythrocyte sedimentation rate, and C-reactive protein. The effectiveness of treatment was assessed using the DAS28 composite index and indicators of the HAQ-DI (Health Assessment Questionnaire disability index), RAPID-3 (Routine Assessment of Patient Index Data 3) questionnaires.

Patients with missing data were excluded from the analysis. The IBM SPSS Statistic 22 (2013) program was used to process the data. To assess the significance of differences in quantitative indicators before and after the switch, the T-test for related samples was used. The significance of the dynamics of qualitative indicators was assessed using Fisher's exact test. The significance of changes in drug dose was assessed using the nonparametric Pearson correlation method.

Acellbia®

To assess the frequency of adverse reactions, the following criteria are used: very often > 10%, often > 1% - < 10%, infrequently > 0.1% - < 1%.

Rituximab in the treatment of low-grade or follicular non-Hodgkin lymphoma - monotherapy/maintenance therapy.

Adverse reactions were reported up to 12 months after monotherapy and up to 1 month after rituximab maintenance therapy.

Infectious and parasitic diseases: very common

- bacterial and viral infections;
often -
respiratory tract infections*, pneumonia*, sepsis, herpes zoster*, infections accompanied by fever*, fungal infections, infections of unknown etiology.

Blood and lymphatic system disorders: very common

- leukopenia, neutropenia;
often -
thrombocytopenia, anemia;
uncommon
- lymphadenopathy, bleeding disorder, transient partial aplastic anemia, hemolytic anemia.

Disorders of the respiratory system, chest and mediastinal organs: often -

rhinitis, bronchospasm, cough, respiratory diseases, shortness of breath, chest pain;
uncommon
- hypoxia, impaired pulmonary function, bronchiolitis obliterans, bronchial asthma.

Immune system disorders:

very often - angioedema; often - hypersensitivity reactions.

Metabolic and nutritional disorders:

often - hyperglycemia, weight loss, peripheral edema, facial edema, increased LDH activity, hypocalcemia.

General disorders and disorders at the injection site: very often -

headache, fever, chills, asthenia;
often -
pain in tumor foci, flu-like syndrome, hot flashes, weakness;
Uncommon:
pain at the injection site.

Gastrointestinal disorders: very common -

nausea;
often -
vomiting, diarrhea, dyspepsia, lack of appetite, dysphagia, stomatitis, constipation, abdominal pain, sore throat; infrequently - abdominal enlargement.

Cardiovascular system disorders: often -

decreased blood pressure, increased blood pressure, orthostatic hypotension, tachycardia, arrhythmia, atrial fibrillation*, cardiac pathology*;
uncommon -
left ventricular heart failure*, ventricular and supraventricular tachycardia*, bradycardia, myocardial ischemia*, angina*.

Nervous system disorders: often -

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dizziness, paresthesia, hypoesthesia, sleep disturbance, anxiety, agitation, vasodilation;
infrequently -
perversion of taste.

Mental disorders: uncommon -

nervousness, depression.

Musculoskeletal and connective tissue disorders: common

- myalgia, arthralgia, muscle hypertonicity, back pain, neck pain, pain.
Disorders of the skin and subcutaneous tissues: very often -
itching, rash;
often -
urticaria, increased sweating at night, sweating, alopecia*.
Visual disturbances: often
- lacrimation disorders, conjunctivitis.
Hearing and labyrinthine disorders
: often - pain and tinnitus.
Laboratory and instrumental data: very often -
a decrease in the level of immunoglobulins G (IgG).

* - frequency is indicated only for adverse reactions > 3 severity in accordance with the toxicity criteria of the National Cancer Institute (NCI-CTC).

Rituximab in combination with chemotherapy
( R - CHOP , R - CVP , R - FC ) for non-Hodgkin's lymphoma and chronic lymphocytic leukemia
The following are severe adverse reactions in addition to those observed with monotherapy/maintenance therapy and/or occurring at a higher frequency.

Infectious and parasitic diseases: very often -

bronchitis;
often -
acute bronchitis, sinusitis, hepatitis B* (exacerbation and primary infection).

Blood and lymphatic system disorders: very common -

neutropenia**, febrile neutropenia, thrombocytopenia;
often -
pancytopenia, granulocytopenia.

Skin and subcutaneous tissue disorders: very common -

alopecia;
often -
skin diseases.

General disorders and disorders at the injection site: often -

fatigue, chills. * — frequency is indicated based on observations during the treatment of relapsed/chemoresistant chronic lymphocytic leukemia according to the R-FC regimen.

**prolonged and/or delayed neutropenia has been observed after completion of R-FC therapy in previously untreated patients or in patients with relapsed/chemoresistant chronic lymphocytic leukemia.

The following are adverse events that occurred with the same frequency (or less frequently) during rituximab therapy compared to the control group: hematotoxicity, neutropenic infections, urinary tract infections, septic shock, pulmonary superinfections, implant infections, staphylococcal septicemia, mucous nasal discharge, edema lungs, heart failure, sensitivity disorders, venous thrombosis, incl. deep vein thrombosis of the extremities, mucositis, edema of the lower extremities, decreased left ventricular ejection fraction, increased temperature, deterioration of general health, bacteremia, multiple organ failure, decompensation of diabetes mellitus.

The safety profile of rituximab in combination with chemotherapy regimens MCP, CHVP-IFN does not differ from that in combination with CVP, CHOP or FC in relevant populations.

Infusion reactions

Rituximab monotherapy (for 4 weeks)

More than 50% of patients experienced events resembling infusion reactions, most often during the first infusions. Infusion reactions include chills, trembling, weakness, shortness of breath, nausea, rash, hot flashes, low blood pressure, fever, itching, urticaria, irritation of the tongue or swelling of the larynx (angioedema), rhinitis, vomiting, pain in tumor areas, headache, bronchospasm. The development of signs of tumor lysis syndrome has been reported.

Rituximab in combination with chemotherapy according to the following regimens:
R - CVP for non-Hodgkin's lymphoma; R - CHOP for diffuse large B-cell non-Hodgkin's lymphoma; R - FC in chronic lymphocytic leukemia
Grade 3 and 4 infusion reactions during infusion or within 24 hours after rituximab infusion were observed during the first cycle of chemotherapy in 12% of patients.

The incidence of infusion reactions decreased with each subsequent cycle and by the 8th cycle of chemotherapy, the incidence of infusion reactions decreased to less than 1%. Infusion reactions in addition to those mentioned above (with rituximab monotherapy) included: dyspepsia, rash, increased blood pressure, tachycardia, signs of tumor lysis syndrome, in some cases - myocardial infarction, atrial fibrillation, pulmonary edema and acute reversible thrombocytopenia.

Infections

Rituximab monotherapy (for 4 weeks)

Rituximab causes depletion of the B cell pool in 70-80% of patients and a decrease in serum immunoglobulin concentrations in a small number of patients. Bacterial, viral, fungal infections and infections of unspecified etiology (all, regardless of cause) develop in 30.3% of patients. Severe infections (grades 3 and 4), including sepsis, were noted in 3.9% of patients.

Maintenance therapy (non-Hodgkin's lymphoma) up to 2 years

An increase in the overall incidence of infections, including grade 3-4 infections, was observed with rituximab therapy. There was no increase in the incidence of infectious complications with maintenance therapy lasting 2 years.

Fatal progressive multifocal leukoencephalopathy (PML) has been reported in patients with non-Hodgkin's lymphoma after disease progression and re-treatment.

Rituximab in combination with chemotherapy according to the following regimens:
R - CVP for non-Hodgkin's lymphoma; R - CHOP for diffuse B-cell non-Hodgkin's lymphoma; R - FC in chronic lymphocytic leukemia
There was no increase in the incidence of infections or invasions with rituximab therapy according to the R-CVP regimen. Upper respiratory tract infections were the most common (12.3% in the R-CVP group). Serious infections occurred in 4.3% of patients receiving R-CVP chemotherapy; No life-threatening infections were reported. The proportion of patients with grade 2-4 infections and/or febrile neutropenia in the R-CHOP group was 55.4%. The overall incidence of grade 2–4 infections in the R-CHOP group was 45.5%. The incidence of grade 2-4 fungal infections in the R-CHOP group was higher than in the CHOP group due to a higher incidence of local candidiasis and amounted to 4.5%. The incidence of grade 2-4 herpes infection was higher in the R-CHOP group than in the CHOP group and was 4.5%.

In patients with chronic lymphocytic leukemia, the incidence of hepatitis B (exacerbation and primary infection) of grade 3-4 in the R-FC group was 2%

From the blood system

Pituximab monotherapy (for 4 weeks)

Severe thrombocytopenia (grade 3 and 4) was observed in 1.7% of patients, severe neutropenia - in 4.2% of patients, and severe anemia (grade 3 and 4) - in 1.1% of patients.

Maintenance therapy (non-Hodgkin's lymphoma) up to 2 years

Leukopenia (grades 3 and 4) was observed in 5% of patients, and neutropenia (grades 3 and 4) in 10% of patients receiving rituximab. The incidence of thrombocytopenia (grade 3-4 severity) was low and amounted to <1%.

Approximately 50% of patients for whom B-cell recovery data were available took 12 months or more to recover B-cell counts to normal levels after completion of rituximab induction therapy.

Rituximab in combination with chemotherapy according to the following regimens:
R - CVP for Hodgkin's lymphoma; R — CHOP for diffuse large B-cell non-Hodgkin lymphoma; R - FC in chronic lymphocytic leukemia
Severe neutropenia and leukopenia:

in patients receiving rituximab in combination with chemotherapy, leukopenia of grades 3 and 4 was observed more often compared to patients receiving chemotherapy alone. The incidence of severe leukopenia was 88% in patients receiving R-CHOP and 23% in patients receiving R-FC. The incidence of severe neutropenia was 24% in the R-CVP group, 97% in the R-CHOP group, and 30% in the R-FC group in previously untreated chronic lymphocytic leukemia. The higher incidence of neutropenia in patients receiving rituximab and chemotherapy was not associated with an increased incidence of infections and infestations compared with patients receiving chemotherapy alone. In patients with recurrent or chemoresistant chronic lymphocytic leukemia after treatment according to the R-FC regimen, in some cases, neutropenia was characterized by a long course and later manifestations.

Severe anemia and thrombocytopenia (grades 3 and 4):

There was no significant difference in the incidence of anemia of grades 3 and 4 in the groups. In the R-FC group, in the first line of treatment for chronic lymphocytic leukemia, anemia of grades 3 and 4 occurred in 4% of patients, thrombocytopenia of grades 3 and 4 - in 7% of patients. In the R-FC group with recurrent or chronic lymphocytic leukemia, anemia of grades 3 and 4 occurred in 12% of patients, thrombocytopenia of grades 3 and 4 - in 11% of patients.

From the cardiovascular system

Rituximab monotherapy (for 4 weeks)

Side effects from the cardiovascular system were noted in 18.8%. The most common are increased and decreased blood pressure. In isolated cases, cardiac arrhythmias of grade 3 and 4 were observed (including ventricular and supraventricular tachycardia) and angina pectoris.

Maintenance therapy (non-Hodgkin's lymphoma) up to 2 years

The incidence of grade 3 and 4 cardiovascular events was similar in patients receiving rituximab and those not receiving it. Serious cardiovascular events occurred in less than 1% of patients not receiving rituximab and in 3% of patients receiving the drug (atrial fibrillation in 1%, myocardial infarction in 1%, left ventricular failure in <1%, myocardial ischemia in <1% ).

Rituximab in combination with chemotherapy according to the following regimens:
R - CVP for non-Hodgkin's lymphoma; R — CHOP for diffuse large B-cell Pehodgkin lymphoma; R - FC in chronic lymphocytic leukemia
The frequency of heart rhythm disturbances of grade 3 and 4, mainly supraventricular arrhythmias (tachycardia, atrial flutter and fibrillation), was higher in the R-CHOP group and amounted to 6.9%. All arrhythmias developed either in connection with rituximab infusion or were associated with predisposing conditions such as fever, infection, acute myocardial infarction, or concomitant diseases of the respiratory and cardiovascular systems. The R-CHOP and CHOP groups did not differ in the incidence of other grade 3 and 4 cardiac adverse events, including heart failure, myocardial disease, and manifestation of coronary artery disease.

The overall incidence of grade 3 and 4 cardiovascular events was low both in first-line treatment of chronic lymphocytic leukemia (4% in the R-FC group) and in the treatment of relapsed/chemoresistant chronic lymphocytic leukemia (4% in the R-FC group).

Nervous system

Rituximab in combination with chemotherapy according to the following regimens:
R - CVP for non-Hodgkin's lymphoma; R — CHOP for diffuse large B-cell non-Hodgkin lymphoma; R - FC in chronic lymphocytic leukemia
Patients (2%) in the R-CHOP group with cardiovascular risk factors developed thromboembolic cerebrovascular accidents during the first cycle of therapy, in contrast to patients in the CHOP group who developed cerebrovascular accidents during observation without treatment. There was no difference between groups in the incidence of other thromboembolism.

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

IgG
concentration Maintenance therapy (non-Hodgkin's lymphoma) up to 2 years

After induction therapy, IgG concentrations were below the lower limit of normal (<7 g/L) in the rituximab-treated and non-rituximab groups. In the group not receiving rituximab, the median IgG level consistently increased and exceeded the lower limit of normal, while the median IgG level did not change in the group receiving rituximab. In 60% of patients receiving rituximab for 2 years, IgG levels remained below the lower limit. In the group without rituximab therapy, IgG levels remained below the lower limit in 36% of patients after 2 years.

Special categories of patients

Rituximab monotherapy (for 4 weeks)

Elderly age

(>65 years): frequency and severity of all adverse reactions and

grade 3 and 4 adverse reactions are no different from those in younger patients.

Combination therapy

Elderly age

(65 years and older): In first-line therapy and in treatment of relapsed/chemoresistant chronic lymphocytic leukemia, the incidence of grade 3 and 4 hematopoietic and lymphatic adverse events was higher compared to younger patients.

High tumor burden

(diameter of single lesions more than 10 cm): increased frequency of adverse reactions of grade 3 and 4.

Repeat therapy

: the frequency and severity of adverse reactions do not differ from those during initial therapy.

Information on the post-registration use of rituximab for non-Hodgkin's lymphoma and chronic lymphocytic leukemia

From the cardiovascular system:

severe cardiovascular events associated with infusion reactions, such as heart failure and myocardial infarction, mainly in patients with a history of cardiovascular disease and/or receiving cytotoxic chemotherapy;
very rarely
- vasculitis, mainly cutaneous (leukocytoclastic).

From the respiratory system:

respiratory failure and pulmonary infiltrates caused by infusion reactions; In addition to pulmonary adverse events due to infusion reactions, interstitial lung disease, in some cases fatal, has been observed.

From the circulatory and lymphatic system:

reversible acute thrombocytopenia associated with infusion reactions.

From the skin and its appendages: rarely

- severe bullous reactions, toxic epidermal necrolysis and Stevens-Johnson syndrome, in some cases fatal.

From the nervous system: rarely -

neuropathy of the cranial nerves in combination with peripheral neuropathy or without it (marked decrease in visual acuity, hearing, damage to other sensory organs, paresis of the facial nerve) during various periods of therapy up to several months after completion of treatment with rituximab. Cases of posterior reversible encephalopathy (P11E8)/posterior reversible leukoencephalopathy syndrome (PRLS) have been reported in patients treated with rituximab. Symptoms included blurred vision, headache, seizures and mental disturbances, with or without increased blood pressure. The diagnosis of PRES/PRLS can be confirmed using brain imaging techniques. In the cases described, patients had risk factors for developing PRES/PRLS, such as underlying disease, elevated blood pressure, immunosuppressive therapy and/or chemotherapy.

From the body as a whole, reactions at the injection site: rare

- serum sickness.

Infections:

reactivation of viral hepatitis B (in most cases with a combination of rituximab and cytotoxic chemotherapy); as well as other severe viral infections (primary infection, viral reactivation or exacerbation), some of which were fatal, caused by cytomegalovirus, Varicella zoster, Herpes simplex, JC polyomavirus (PML), hepatitis C virus.

When rituximab was prescribed for indications not covered by the instructions for medical use, sarcoma progression was observed in patients with previously diagnosed Kaposi's sarcoma (most patients were HIV-positive).

From the gastrointestinal tract:

perforation of the stomach and/or intestines (possibly fatal) when rituximab is combined with chemotherapy for non-Hodgkin's lymphoma.

From the blood and lymphatic system: rarely -

neutropenia occurring 4 weeks after the last administration of rituximab; a transient increase in IgM levels in patients with Waldenström's macroglobulinemia, followed by a return to its original value after 4 months.

results

The study included 46 outpatients who were prescribed the original drug rituximab at the beginning of treatment, and then the patients were switched to a biosimilar. The average duration of therapy on the original drug rituximab before switching was 36.8±26.8 months. The average follow-up period for patients on biosimilar therapy was 12.2±6.18 months. The follow-up period for treatment with the original drug rituximab and the biosimilar was 141 and 46 patient-years, respectively (total volume - 187 patient-years). 20 patients (43.5%) had previously reported ineffectiveness or intolerance to other GEBDs .

The proportion of patients receiving concomitant glucocorticoid therapy was 19.6% (9 patients), 43.5% (20 patients) received methotrexate in various dosages. The clinical characteristics of the patients are shown in Table 1. The dose of rituximab changed during treatment: it was reduced in the case of sustained low disease activity or remission and could be increased in the case of an increase in the level of disease activity above the target during treatment. Table 1 shows the doses of rituximab at the time of the last completed visit at which the clinical effectiveness of treatment was assessed. There was a statistically significant reduction in the dose of rituximab after switching (p=0.002).

When assessing the dynamics of DAS28, HAQ-DI and RAPID3 indicators, it was found that switching from the original drug rituximab to a biosimilar was not accompanied by a decrease in the effectiveness of treatment (Table 2). Moreover, the numerically average values of these activity and functional capacity indices were slightly lower during ongoing biosimilar therapy. However, no significant differences were recorded. There was a statistically significant increase in the number of patients with low disease activity (DAS28 <3.2) and remission (DAS28 <2.6). The proportion of people with low disease activity after switching increased from 39.1% to 52.2%, and the percentage of patients in remission - from 17.4% to 23.9% (see Table 2). The increase in the rate of positive response to treatment is apparently associated with the duration of use of rituximab in general, and not with switching from one drug to another.

No patient had a biosimilar discontinued due to lack of efficacy.

A brief description of the observed AEs is given in Table 3. During the period of use of the original drug rituximab, 13 AEs were recorded in the analyzed patients (incidence - 9.22 per 100 patient-years) in 5 patients (10.9%), of which 2 were regarded as serious. During treatment with the biosimilar, 5 AEs (10.9 per 100 patient-years) were observed in 4 patients (8.7%), none of which were considered serious. There were no significant infusion reactions, AEs requiring treatment discontinuation, or deaths.

Acellbia

To assess the frequency of adverse reactions, the following criteria are used: very often >10%, often >1% - 0.1% -

Rituximab for the treatment of low-grade or follicular non-Hodgkin lymphoma - monotherapy/maintenance therapy

Adverse reactions were reported up to 12 months after monotherapy and up to 1 month after rituximab maintenance therapy.

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

Disorders of the blood and lymphatic system: very often - leukopenia, neutropenia; often - thrombocytopenia, anemia; uncommon - lymphadenopathy, bleeding disorder, transient partial aplastic anemia, hemolytic anemia.

Disorders of the respiratory system, chest and mediastinal organs: often - rhinitis, brochospasm, cough, respiratory diseases, shortness of breath, chest pain; uncommon - hypoxia, impaired pulmonary function, bronchiolitis obliterans, bronchial asthma.

Immune system disorders: very often - angioedema; often - hypersensitivity reactions.

Metabolic and nutritional disorders: often - hyperglycemia, weight loss, peripheral edema, facial edema, increased LDH activity, hypocalcemia.

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

Gastrointestinal disorders: very often - nausea; often - vomiting, diarrhea, dyspepsia, lack of appetite, dysphagia, stomatitis, constipation, abdominal pain, sore throat; infrequently - abdominal enlargement.

Disorders of the cardiovascular system: often - decreased blood pressure, increased blood pressure, orthostatic hypotension, tachycardia, arrhythmia, atrial fibrillation*, cardiac pathology*; uncommon - left ventricular heart failure*, ventricular and supraventricular tachycardia*, bradycardia, myocardial ischemia*, angina*.

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

Mental disorders: infrequently - nervousness, depression.

Musculoskeletal and connective tissue disorders: often - myalgia, arthralgia, muscle hypertonicity, back pain, neck pain, pain.

Disorders of the skin and subcutaneous tissues: very often - itching, rash; often - urticaria, increased sweating at night, sweating, alopecia*.

Visual disturbances: often - lacrimation disorders, conjunctivitis.

Hearing and labyrinthine disorders: often - pain and tinnitus.

Laboratory and instrumental data: very often - a decrease in the level of immunoglobulins G (IgG).

* - frequency is indicated only for adverse reactions of grade 3 in accordance with the toxicity criteria of the National Cancer Institute (NCI-CTC).

Rituximab in combination with chemotherapy (R-CHOP, R-CVP, R-FC) for non-Hodgkin's lymphoma and chronic lymphocytic leukemia

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

Infectious and parasitic diseases: very often - bronchitis; often - acute bronchitis, sinusitis, hepatitis B* (exacerbation and primary infection).

Disorders of the blood and lymphatic system: very often - neutropenia**, febrile neutropenia, thrombocytopenia; often - pancytopenia, granulocytopenia.

Disorders of the skin and subcutaneous tissues: very often - alopecia; often - skin diseases.

General disorders and disorders at the injection site: often - fatigue, chills.

* — frequency is indicated based on observations during the treatment of recurrent/chemoresistant chronic lymphocytic leukemia according to the R-FC regimen.

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

The following are adverse events that occurred with the same frequency (or less frequently) during rituximab therapy compared to the control group: hematotoxicity, neutropenic infections, urinary tract infections, septic shock, pulmonary superinfections, implant infections, staphylococcal septicemia, mucous nasal discharge, edema lungs, heart failure, sensory disturbances, venous thrombosis, including deep vein thrombosis of the extremities, mucositis, edema of the lower extremities, decreased left ventricular ejection fraction, increased temperature, deterioration of general health, bacteremia, multiple organ failure, decompensation of diabetes mellitus.

The safety profile of rituximab in combination with chemotherapy regimens MCP, CHVP-IFN does not differ from that when the drug is combined with CVP, CHOP or FC in relevant populations.

Infusion reactions

Rituximab monotherapy (for 4 weeks)

Rituximab in combination with chemotherapy according to the following regimens: K-CVP for non-Hodgkin's lymphoma; R-CHOP for diffuse large B-cell non-Hodgkin lymphoma: R-FC for chronic lymphocytic leukemia

Grade 3 and 4 infusion reactions during infusion or within 24 hours after rituximab infusion were observed during the first cycle of chemotherapy in 12% of patients.

Infections

Rituximab monotherapy (for 4 weeks)

Rituximab causes depletion of the B cell pool in 70-80% of patients and a decrease in serum immunoglobulin concentrations in a small number of patients. Bacterial, viral, fungal infections and infections of unspecified etiology (weight, regardless of cause) develop in 30.3% of patients. Severe infections (grades 3 and 4), including sepsis, were noted in 3.9% of patients.

Maintenance therapy (non-Hodgkin's lymphoma) up to 2 years

Fatal progressive multifocal leukoencephalopathy (PML) has been reported in patients with non-Hodgkin's lymphoma after disease progression and re-treatment.

Rituximab in combination with chemotherapy according to the following regimens: R-CVP for non-Hodgkin's lymphoma; R-CHOP for diffuse large B-cell non-Hodgkin lymphoma; R-FC for chronic lymphocytic leukemia

There was no increase in the incidence of infections or infestations with rituximab R-CVP regimen. Upper respiratory tract infections were the most common (12.3% in the R-CVP group). Serious infections occurred in 4.3% of patients receiving R-CVP chemotherapy; No life-threatening infections were reported. The proportion of patients with grade 2-4 infections and/or febrile neutropenia in the R-CHOP group was 55.4%. The total incidence of grade 2-4 infections in the R-CHOP group was 45.5%. The frequency of fungal infections of grade 2-4 in the R-CHOP group was higher than in the CHOP group due to a higher frequency of local candidiasis and amounted to 4.5%. The incidence of grade 2-4 herpes infection was higher in the R-CHOP group than in the CHOP group and was 4.5%.

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

From the blood system

Rituximab monotherapy (for 4 weeks)

Severe thrombocytopenia (grades 3 and 4) was observed in 1.7% of patients, severe neutropenia - in 4.2% of patients, and severe anemia (grades 3 and 4) - in 1.1% of patients.

Maintenance therapy (non-Hodgkin's lymphoma) up to 2 years

Leukopenia (grades 3 and 4) was observed in 5% of patients, and neutropenia (grades 3 and 4) in 10% of patients receiving rituximab. The incidence of thrombocytopenia (grade 3-4) was low and amounted to

Approximately 50% of patients for whom B-cell recovery data were available took 12 months or more to recover B-cell counts to normal levels after completion of rituximab induction therapy.

Severe neutropenia and leukopenia: In patients receiving rituximab in combination with chemotherapy, grades 3 and 4 leukopenia were observed more often than in patients receiving chemotherapy alone. The incidence of severe leukopenia was 88% in patients receiving R-CHOP and 23% in patients receiving R-FC. The incidence of severe neutropenia was 24% in the R-CVP group, 97% in the R-CHOP group, and 30% in the R-FC group in previously untreated chronic lymphocytic leukemia. The higher incidence of neutropenia in patients receiving rituximab and chemotherapy was not associated with an increased incidence of infections and infestations compared with patients receiving chemotherapy alone. In patients with recurrent or chemoresistant chronic lymphocytic leukemia after treatment according to the R-FC regimen, in some cases, neutropenia was characterized by a long course and later manifestations.

Severe anemia and thrombocytopenia (grades 3 and 4): there was no significant difference in the incidence of anemia of grades 3 and 4 between groups. In the R-FC group, in the first line of treatment for chronic lymphocytic leukemia, anemia of grades 3 and 4 occurred in 4% of patients, thrombocytopenia of grades 3 and 4 - in 7% of patients. In the R-FC group with recurrent or chronic lymphocytic leukemia, anemia of grades 3 and 4 occurred in 12% of patients, thrombocytopenia of grades 3 and 4 - in 11% of patients.

From the cardiovascular system

Rituximab monotherapy (for 4 weeks)

Maintenance therapy (non-Hodgkin's lymphoma) up to 2 years

Rituximab and combinations with chemotherapy according to the following regimens: R-CVP for non-Hodgkin's lymphoma; R-CHOP for diffuse large B-cell non-Hodgkin lymphoma; R-FC for chronic lymphocytic leukemia

The incidence of grade 3 and 4 cardiac arrhythmias, mainly supraventricular arrhythmias (tachycardia, atrial flutter and atrial fibrillation), was higher in the R-CHOP group and amounted to 6.9%. All arrhythmias developed either in connection with rituximab infusion or were associated with predisposing conditions such as fever, infection, acute myocardial infarction, or concomitant diseases of the respiratory and cardiovascular systems. The R-CHOP and CHOP groups did not differ in the incidence of other grade 3 and 4 cardiac adverse events, including heart failure, myocardial disease, and manifestation of coronary artery disease.

Nervous system

Patients (2%) in the R-CHOP group with cardiovascular risk factors developed cerebroembolic events during the first cycle of therapy, in contrast to patients in the CHOP group who developed cerebroembolic events during the observation period without treatment. There was no difference between groups in the incidence of other thromboembolism.

IgG concentration

Maintenance therapy (non-Hodgkin's lymphoma) up to 2 years

After induction therapy, the IgG concentration was below the lower limit of normal (

Special categories of patients

Rituximab monotherapy (for 4 weeks)

Elderly age (>65 years): the frequency and severity of all adverse reactions and grade 3 and 4 adverse reactions does not differ from that in younger patients.

Combination therapy

Older age (65 years and older): In first-line therapy and in treatment of relapsed/chemoresistant chronic lymphocytic leukemia, the incidence of grade 3 and 4 side effects from the blood and lymphatic system was higher compared to younger patients.

High tumor load (diameter of single lesions more than 10 cm): increased frequency of grade 3 and 4 adverse reactions.

Repeated therapy: the frequency and severity of adverse reactions do not differ from those during initial therapy.

Information on the post-registration use of rituximab for non-Hodgkin's lymphoma and chronic lymphocytic leukemia

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

From the respiratory system: respiratory failure and pulmonary infiltrates caused by infusion reactions; In addition to pulmonary adverse events due to infusion reactions, interstitial lung disease, in some cases fatal, has been observed.

From the circulatory and lymphatic system: reversible acute thrombocytopenia associated with infusion reactions.

From the skin and its appendages: rarely - severe bullous reactions, toxic epidermal necrolysis and Stevens-Johnson syndrome, in some cases with death.

From the nervous system: rarely - neuropathy of the cranial nerves in combination with peripheral neuropathy or without it (marked decrease in visual acuity, hearing, damage to other sensory organs, paresis of the facial nerve) during various periods of therapy up to several months after completion of the course of treatment with rituximab . Cases of posterior reversible encephalopathy (PRES)/posterior reversible leukoencephalopathy syndrome (PRLS) have been reported in patients treated with rituximab. Symptoms included blurred vision, headache, seizures and mental disturbances, with or without increased blood pressure. The diagnosis of PRES/PRLS can be confirmed using brain imaging techniques. In the cases described, patients had risk factors for developing PRES/PRLS, such as underlying disease, elevated blood pressure, immunosuppressive therapy and/or chemotherapy.

From the body as a whole, reactions at the injection site: rarely - serum sickness.

Infections: reactivation of hepatitis B virus (in most cases with a combination of rituximab and cytotoxic chemotherapy); as well as other severe viral infections (primary infection, viral reactivation or exacerbation), some of which were fatal, caused by cytomegalovirus, Varicella zoster, Herpes simplex, JC polyomavirus (PML), hepatitis C virus.

From the gastrointestinal tract: perforation of the stomach and/or intestines (possibly fatal) when rituximab is combined with chemotherapy for non-Hodgkin's lymphoma.

From the blood and lymphatic system: rarely - neutropenia that occurred 4 weeks after the last administration of rituximab; a transient increase in IgM levels in patients with Waldenström's macroglobulinemia, followed by a return to its original value after 4 months.

Cases of overdose in humans have not been observed. Single doses of rituximab above 1000 mg have not been studied. The maximum dose of 5000 mg was prescribed to patients with chronic lymphocytic leukemia, no additional safety data were obtained. Due to the increased risk of infectious complications when the pool of B-lymphocytes is depleted, infusions should be canceled or reduced, and the need for a comprehensive general blood test should be considered.

Discussion

In the present study, based on the analysis of data from the registry of patients with RA, the preservation of the clinical effect was demonstrated after switching patients from therapy with the original drug rituximab to a biosimilar. Disease activity and functional capacity scores at least did not worsen after the switch.

Moreover, the proportion of patients achieving low disease activity and remission according to the DAS28 criterion has increased. Such dynamics cannot be considered as the superiority of the biosimilar over the original drug rituximab. It should be borne in mind that in all cases the biosimilar was used after the original drug. Across different cohorts, there was a decrease in disease activity and an increase in the proportion of patients achieving target activity over follow-up [3]. Such changes were observed previously in the MERA registry as a whole [4].

To assess the safety of a drug, real-world studies are the most valuable source. On the one hand, they tend to be longer and, as a result, may have a larger follow-up and may detect complications, the frequency of which increases with long-term treatment. Thus, in our study, the total observation volume was 187 patient-years (in the phase III RCT BIORA it was about 148 patient-years) [5]. On the other hand, RCTs typically have strict selection criteria that exclude patients at increased risk of AEs. Therefore, the safety profile in real practice may differ slightly from that in RCTs. The safety analysis did not reveal significant differences between the study drugs. The overall incidence of AEs was almost comparable.

Acellbia, 10 mg/ml, concentrate for solution for infusion, 50 ml, 1 pc.

To assess the frequency of adverse reactions, the following criteria are used: very often (≥10%); often (≥1% - <10%); uncommon (≥0.1% - <1%).

Rituximab in the treatment of low-grade or follicular non-Hodgkin lymphoma - monotherapy/maintenance therapy.

Adverse reactions were reported up to 12 months after monotherapy and up to 1 month after rituximab maintenance therapy.

Infectious and parasitic diseases:

very often - bacterial and viral infections; often - respiratory tract infections*, pneumonia*, sepsis, herpes zoster*, infections accompanied by fever*, fungal infections, infections of unknown etiology.

From the blood and lymphatic system:

very often - leukopenia, neutropenia; often - thrombocytopenia, anemia; uncommon - lymphadenopathy, bleeding disorder, transient partial aplastic anemia, hemolytic anemia.

From the respiratory system, chest and mediastinal organs:

often - rhinitis, bronchospasm, cough, respiratory diseases, shortness of breath, chest pain; uncommon - hypoxia, impaired pulmonary function, bronchiolitis obliterans, bronchial asthma.

From the immune system:

very often - angioedema; often - hypersensitivity reactions.

Metabolism and nutrition:

often - hyperglycemia, weight loss, peripheral edema, facial edema, increased LDH activity, hypocalcemia.

General disorders and disorders at the injection site:

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

From the gastrointestinal tract:

very often - nausea; often - vomiting, diarrhea, dyspepsia, lack of appetite, dysphagia, stomatitis, constipation, abdominal pain, sore throat; infrequently - abdominal enlargement.

From the SSS side:

often - decreased blood pressure, increased blood pressure, orthostatic hypotension, tachycardia, arrhythmia, atrial fibrillation*, cardiac pathology*; uncommon - left ventricular heart failure*, ventricular and supraventricular tachycardia*, bradycardia, myocardial ischemia*, angina*.

From the nervous system:

often - dizziness, paresthesia, hypoesthesia, sleep disturbance, anxiety, agitation, vasodilation; infrequently - perversion of taste.

Mental disorders:

infrequently - nervousness, depression.

From the musculoskeletal system:

often - myalgia, arthralgia, muscle hypertonicity, back pain, neck pain, pain.

For the skin and subcutaneous tissues:

very often - itching, rash; often - urticaria, increased sweating at night, sweating, alopecia*.

From the side of the organ of vision:

often - lacrimation disorders, conjunctivitis.

Hearing and labyrinth disorders:

often - pain and noise in the ears.

Laboratory and instrumental data:

very often - a decrease in
IgG
.

*Frequencies are only for adverse reactions grade ≥3 according to National Cancer Institute Toxicity Criteria ( NCI-CTC)

Rituximab in combination with chemotherapy ( R-CHOP

,
R-CVP
,
R-FC
) for non-Hodgkin's lymphoma and chronic lymphocytic leukemia

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

Infectious and parasitic diseases:

very often - bronchitis; often - acute bronchitis, sinusitis, hepatitis B* (exacerbation and primary infection).

From the blood and lymphatic system:

very often - neutropenia**, febrile neutropenia, thrombocytopenia; often - pancytopenia, granulocytopenia.

For the skin and subcutaneous tissues:

very often - alopecia; often - skin diseases.

General disorders and disorders at the injection site:

often - fatigue, chills.

* Frequency is indicated based on observations during the treatment of relapsed/chemoresistant chronic lymphocytic leukemia according to the R-FC

R-FC therapy

previously untreated patients or in patients with relapsed/chemoresistant chronic lymphocytic leukemia.

The following are adverse events that occurred during rituximab therapy with equal frequency (or less frequently) compared to the control group: hematotoxicity, neutropenic infections, urinary tract infections, septic shock, pulmonary superinfections, implant infections, staphylococcal septicemia, mucous nasal discharge, pulmonary edema , heart failure, sensitivity disorders, venous thrombosis, incl. deep vein thrombosis of the extremities, mucositis, edema of the lower extremities, decreased left ventricular ejection fraction, increased temperature, deterioration of general health, bacteremia, multiple organ failure, decompensation of diabetes mellitus.

Safety profile of rituximab in combination with chemotherapy according to MCP

CHVP-IFN
does not differ from that when the drug is combined with
CVP
,
CHOP
or
FC
in matched populations

Infusion reactions

Rituximab monotherapy (for 4 weeks)

More than 50% of patients experienced events resembling infusion reactions, most often during the first infusions. Infusion reactions include chills, trembling, weakness, shortness of breath, nausea, rash, hot flashes, decreased blood pressure, fever, itching, urticaria, irritation of the tongue or swelling of the larynx (angioedema), rhinitis, vomiting, pain in tumor areas, headache, bronchospasm . The development of signs of tumor lysis syndrome has been reported.

Rituximab in combination with chemotherapy according to the following regimens: R-CVP

- for non-Hodgkin's lymphoma;
R-CHOP
- for diffuse large B-cell non-Hodgkin lymphoma;
R-FC
- for chronic lymphocytic leukemia

Grade 3 and 4 infusion reactions during infusion or within 24 hours after rituximab infusion were observed during the first cycle of chemotherapy in 12% of patients. The incidence of infusion reactions decreased with each subsequent cycle and by the 8th cycle of chemotherapy, the incidence of infusion reactions decreased to less than 1%. Infusion reactions, in addition to those mentioned above (with rituximab monotherapy), included: dyspepsia, rash, increased blood pressure, tachycardia, signs of tumor lysis syndrome, in some cases - myocardial infarction, atrial fibrillation, pulmonary edema and acute reversible thrombocytopenia.

Infections

Rituximab monotherapy (for 4 weeks)

Rituximab causes B-cell depletion in 70–80% of patients and a decrease in serum immunoglobulin concentrations in a small number of patients. Bacterial, viral, fungal infections and infections of unspecified etiology (all, regardless of cause) develop in 30.3% of patients. Severe infections (grade 3 and 4), including sepsis, were noted in 3.9% of patients.

Maintenance therapy (non-Hodgkin's lymphoma) up to 2 years

During rituximab therapy, an increase in the overall incidence of infections was observed, incl. infections of 3 - 4 degrees of severity. There was no increase in the incidence of infectious complications with maintenance therapy lasting 2 years.

Cases of progressive multifocal leukoencephalopathy (PML)

with a fatal outcome in patients with non-Hodgkin's lymphoma after disease progression and re-treatment.

Rituximab in combination with chemotherapy according to the following regimens: R-CVP

- for non-Hodgkin's lymphoma;
R-CHOP
- for diffuse large B-cell non-Hodgkin lymphoma;
R-FC
- for chronic lymphocytic leukemia

During rituximab therapy according to the R-CVP

no increase in the incidence of infections or infestations was observed.

The most common infections were upper respiratory tract infections (12.3% in the R-CVP

).
Serious infections occurred in 4.3% of patients receiving R-CVP
;
No life-threatening infections were reported. The proportion of patients with grade 2–4 infections and/or febrile neutropenia in the R-CHOP
was 55.4%.
The overall rate of grade 2–4 infections in the R-CHOP
was 45.5%.
The frequency of fungal infections of 2–4 degrees of severity in the R-CHOP
was higher than in
the CHOP
due to a higher frequency of local candidiasis and amounted to 4.5%.
The incidence of grade 2–4 herpes infection was higher in the R-CHOP
than in
the CHOP
and amounted to 4.5%.

In patients with chronic lymphocytic leukemia, the incidence of hepatitis B (exacerbation and primary infection) of grade 3–4 in the R-FC

amounted to 2%.

From the blood system

Monotherapy with rituximab (for 4 weeks)

Severe thrombocytopenia (grade 3 and 4) was observed in 1.7% of patients, severe neutropenia - in 4.2% of patients, and severe anemia (grade 3 and 4) - in 1. 1% of patients.

Maintenance therapy (non-Hodgkin's lymphoma) up to 2 years

Leukopenia (grades 3 and 4) was observed in 5% of patients and neutropenia (grades 3 and 4) in 10% of patients receiving rituximab. The incidence of thrombocytopenia (grade 3–4) was low and was <1%.

Approximately 50% of patients for whom B-cell recovery data were available took 12 months or more to recover B-cell counts to normal levels after completion of rituximab induction therapy.

Rituximab in combination with chemotherapy according to the following regimens: R-CVP

- for non-Hodgkin's lymphoma;
R-CHOP
- for diffuse large B-cell non-Hodgkin lymphoma;
R-FC
- for chronic lymphocytic leukemia

Severe neutropenia and leukopenia:

In patients receiving rituximab in combination with chemotherapy, grade 3 and 4 leukopenia were observed more often than in patients receiving chemotherapy alone.
The incidence of severe leukopenia was 88% in patients receiving R-CHOP
and 23% in patients receiving
R-FC
.
The incidence of severe neutropenia was 24% in the R-CVP
, 97% in the
R-CHOP
, and 30% in the
R-FC
in previously untreated chronic lymphocytic leukemia.
The higher incidence of neutropenia in patients receiving rituximab and chemotherapy was not associated with an increased incidence of infections and infestations compared with patients receiving chemotherapy alone. In patients with recurrent or chemoresistant chronic lymphocytic leukemia after treatment according to the R-FC
, in some cases, neutropenia was characterized by a long course and later manifestations.

Severe anemia and thrombocytopenia (grade 3 and 4):

There was no significant difference in the frequency of anemia of the 3rd and 4th severity in the groups.
In the R-FC
, in the first line of treatment for chronic lymphocytic leukemia, anemia of the 3rd and 4th severity was found in 4% of patients, thrombocytopenia of the 3rd and 4th severity - in 7% of patients.
In the R-FC
with recurrent or chronic lymphocytic leukemia, anemia of the 3rd and 4th severity occurred in 12% of patients, thrombocytopenia of the 3rd and 4th severity - in 11% of patients.

From the SSS side

Rituximab monotherapy (for 4 weeks)

Side effects from the cardiovascular system were noted in 18.8%. The most common occurrences are increases and decreases in blood pressure. In isolated cases, cardiac arrhythmias of the 3rd and 4th degree of severity (including ventricular and supraventricular tachycardia) and angina pectoris were observed.

Maintenance therapy (non-Hodgkin's lymphoma) up to 2 years

The incidence of grade 3 and 4 cardiovascular events was similar in patients receiving rituximab and those not receiving it. Serious cardiovascular events occurred in less than 1% of patients not receiving rituximab and in 3% of patients receiving the drug (atrial fibrillation - 1%, myocardial infarction - 1%, left ventricular failure - <1%, myocardial ischemia - y <1%).

Rituximab in combination with chemotherapy according to the following regimens: R-CVP

- for non-Hodgkin's lymphoma;
R-CHOP
- for diffuse large B-cell non-Hodgkin lymphoma;
R-FC
- for chronic lymphocytic leukemia

Frequency of heart rhythm disturbances of the 3rd and 4th severity, mainly supraventricular arrhythmias (tachycardia, flutter and atrial fibrillation), in the R-CHOP

was higher and amounted to 6.9%.
All arrhythmias developed either in connection with rituximab infusion or were associated with predisposing conditions such as fever, infection, acute myocardial infarction, or concomitant diseases of the respiratory system and cardiovascular system. The R-CHOP
and
CHOP
groups did not differ in the incidence of other grade 3 and 4 cardiac adverse events, including heart failure, myocardial disease, and manifestations of coronary artery disease.

The overall incidence of grade 3 and 4 cardiovascular events was low as in first-line treatment for chronic lymphocytic leukemia (4% in the R-FC

), and in the treatment of recurrent/chemoresistant chronic lymphocytic leukemia (4% in the
R-FC
).

Nervous system

Rituximab in combination with chemotherapy according to the following regimens: R-CVP

for non-Hodgkin's lymphoma;
R-CHOP
for diffuse large B-cell non-Hodgkin lymphoma;
R-FC
for chronic lymphocytic leukemia

In patients (2%) from the R-CHOP

with cardiovascular risk factors developed cerebroembolic events during the first cycle of therapy, in contrast to patients in the
CHOP
who developed cerebroembolic events during the observation period without treatment. There was no difference between groups in the incidence of other thromboembolism.

The overall incidence of grade 3 and 4 neurological impairment was low as in first-line therapy for chronic lymphocytic leukemia (4% in the R-FC

), and in the treatment of recurrent/chemoresistant chronic lymphocytic leukemia (3% in the
R-FC
).

IgG concentration

Maintenance therapy (non-Hodgkin's lymphoma) up to 2 years

After induction therapy, IgG

was below the lower limit of normal (<7 g/l) in the group receiving rituximab and in the group not receiving the drug.
In the group not receiving rituximab, the median IgG
consistently increased and exceeded the lower limit of normal, while the median
IgG
did not change in the group receiving rituximab.
In 60% of patients receiving rituximab for 2 years, IgG
remained below the lower limit.
In the group without rituximab therapy, IgG
remained below the lower limit in 36% of patients after 2 years.

Special categories of patients

Rituximab monotherapy (for 4 weeks)

Old age (≥65 years):

the frequency and severity of all adverse reactions and grade 3 and 4 adverse reactions did not differ from those in younger patients.

Combination therapy

Old age (65 years and older):

in first-line therapy, as well as in the treatment of relapsed/chemoresistant chronic lymphocytic leukemia, the incidence of grade 3 and 4 side effects from the blood and lymphatic system was higher compared to younger patients.

High tumor load (diameter of single lesions more than 10 cm):

the frequency of adverse reactions of the 3rd and 4th severity is increased.

Repeat therapy:

the frequency and severity of adverse reactions does not differ from those during initial therapy.

Information on the post-registration use of rituximab for non-Hodgkin's lymphoma and chronic lymphocytic leukemia

From the SSS side:

severe cardiovascular events associated with infusion reactions, such as heart failure and myocardial infarction, mainly in patients with a history of cardiovascular disease and/or receiving cytotoxic chemotherapy; very rarely - vasculitis, mainly cutaneous (leukocytoclastic).

From the respiratory system:

From the circulatory and lymphatic system:

reversible acute thrombocytopenia associated with infusion reactions.

From the skin and its appendages:

rarely - severe bullous reactions, toxic epidermal necrolysis and Stevens-Johnson syndrome, in some cases with death.

From the nervous system:

rarely - neuropathy of the cranial nerves in combination with peripheral neuropathy or without it (marked decrease in visual acuity, hearing, damage to other sensory organs, paresis of the facial nerve) during various periods of therapy up to several months after completion of the course of treatment with rituximab.
Cases of posterior reversible encephalopathy ( PRES
)/posterior reversible leukoencephalopathy syndrome (
PRLS
) have been reported in patients treated with rituximab. Symptoms included blurred vision, headache, seizures and mental disturbances, with or without increased blood pressure.

Confirm diagnosis of PRES/PRLS

possible using brain imaging techniques.
In the cases described, patients had risk factors for developing PRES/PRLS
, such as underlying disease, hypertension, immunosuppressive therapy and/or chemotherapy.

From the body as a whole, reactions at the injection site:

rarely - serum sickness.

Infections:

reactivation of viral hepatitis B (in most cases with a combination of rituximab and cytotoxic chemotherapy);
as well as other severe viral infections (primary infection, viral reactivation or exacerbation), some of which were fatal, caused by cytomegalovirus, Varicella zoster
,
Herpes simplex

JC
polyomavirus (
PML
), hepatitis C virus.

From the gastrointestinal tract:

perforation of the stomach and/or intestines (possibly fatal) when rituximab is combined with chemotherapy for non-Hodgkin's lymphoma.

From the blood and lymphatic system:

rarely - neutropenia that occurred 4 weeks after the last administration of rituximab;
a transient increase in IgM
in patients with Waldenström's macroglobulinemia, followed by a return to its original value after 4 months.