Acellbia 10 mg/ml 50 ml

Pharmacodynamics

The active component of Atsellbia® is rituximab, a chimeric mouse/human monoclonal antibody that binds specifically to the transmembrane antigen CD20. This antigen is located on pre-B-lymphocytes and mature B-lymphocytes, but is absent on hematopoietic stem cells, pro-B cells, normal plasma cells, cells of other tissues, and is expressed in more than 95% of B-cell non-Hodgkin lymphomas. CD20 expressed on the cell is not signaled after binding to the antibody and is no longer transported from the cell membrane into the extracellular space. CD20 does not circulate in plasma as a free antigen and therefore does not compete for binding to the antibody.

Rituximab binds to the CD20 antigen on B-lymphocytes and initiates immunological responses mediating B-cell lysis. Possible mechanisms of cell lysis include complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and apoptosis induction. Rituximab increases the sensitivity of human B-cell lymphoma cell lines to the cytotoxic effects of certain chemotherapeutic agents in vitro.

The number of B-cells in peripheral blood decreases below normal after the first administration of the drug and begins to recover in patients with hematologic malignancies after 6 months, reaching normal values 12 months after completion of therapy, but the recovery period of B-cell numbers may be longer.

Antichimeric antibodies were detected in 1.1% of patients with non-Hodgkin’s lymphoma examined. Anti-mouse antibodies were not detected in the examined patients.

Pharmacokinetics

Nehodgkin’s lymphoma

According to population pharmacokinetic analysis in patients with non-Hodgkin’s lymphoma when rituximab is administered once or repeatedly as monotherapy or in combination with chemotherapy according to the SPOR regimen (cyclophosphamide, doxorubicin, vincristine, prednisolope) non-specific clearance (CL1), specific clearance (CL2) (probably related to B-cell or tumor burden), and plasma volume distribution (V1) are 0.14 L/day, 0.59 L/day, and 2.7 L, respectively. The median terminal elimination half-life (T1/2) is 22 days. The baseline level of CD19-positive cells and tumor site size affect the CL2 of rituximab administered intravenously at a dose of 375 mg/m2 once weekly, for 4 weeks. CL2 was higher in patients with higher levels of CD19-positive cells or larger tumor foci. Individual variability in CL2 persisted even after correction of tumor lesion size and CD19-positive cell levels. Relatively small changes in V1 depend on body surface area (1.53-2.32 m2) and CHOP chemotherapy and were 27.1% and 19.0%, respectively. Age, sex, race, and general health according to the WHO (World Health Organization) scale had no effect on the pharmacokinetics of rituximab. Thus, adjusting the dose of rituximab depending on the above factors does not significantly affect the pharmacokinetic variability.

The mean maximum concentration (Cmax) increases after each infusion: after the first infusion is 243 µg/ml, after the fourth infusion is 486 µg/ml, and after the eighth infusion is 550 µg/ml. Minimum and maximum drug concentrations inversely correlate with the initial number of CD19-positive B-cells and tumor burden. With effective treatment, the median equilibrium concentration of the drug is higher. The median equilibrium concentration of the drug is higher in patients with histological subtypes of tumor B, C and D (IWF classification) than with subtype A. Traces of rituximab can be detected in the body for 3-6 months after the last infusion.

The pharmacokinetic profile of rituximab (6 infusions of 375 mg/m2) in combination with 6 cycles of CHOP chemotherapy was virtually the same as that of monotherapy.

According to our own comparative study of rituximab pharmacokinetics in patients with non-Hodgkin’s lymphoma of low malignancy, the area under the concentration-time curve in the Acellbia® drug group was 16170.57 (µg/mL)×h, with the Mabthera® drug 17608.42 (µg/mL)×h and rituximab clearance was 43.87 ml/(h×kg) and 43.17 ml/(h×kg), respectively. The maximum Cmax concentration of Acellbia® was 172.19 mcg/ml, and its time to reach Tmax was 31.17 h. In Mabthera® group the similar parameters were 190.68 mcg/ml and 37.47 h, respectively. The elimination half-life (T1/2) was 49.60 h in the Acellbia® group and 48.95 h in the Mabthera® group. The ratio of geometric mean AUC0-168 of Acellbia® and Mabthera® preparation was 80.13 -118.18%, the ratio of geometric mean Cmax of Acellbia® and Mabthera® preparation was 81.82 -115.82%, which indicates equivalence of pharmacokinetic properties of Acellbia® and Mabthera® when administered intravenously to patients.

Cronic lympholeukemia

The mean maximum concentration (Cmax) after the fifth infusion of rituximab at a dose of 500 mg/m2 is 408 µg/mL.

Pharmacokinetics in selected patient groups

Gender: The volume of distribution and clearance of rituximab adjusted for body surface area is slightly greater in men than in women, no adjustment of rituximab dose is required.

Patients with renal and hepatic impairment: No pharmacokinetic data in patients with renal and hepatic impairment.

Indications

Hodgkin’s lymphoma

Chronic lymph leukemia

Active ingredient

Composition

The active ingredient is rituximab 10 mg.

How to take, the dosage

Principles of solution preparation and storage

The necessary amount of Acellbia® drug is taken under aseptic conditions and diluted to the calculated concentration (1-4 mg/ml) in an infusion bottle (bag) with 0.9% sodium chloride solution for infusion or 5% dextrose solution (solutions must be sterile and apyrogenic). The vial (package) is carefully turned over to avoid pricing to mix. Before administering, the solution should be inspected to make sure there are no foreign impurities or color changes. The physician is responsible for the preparation, conditions and storage time of the prepared solution prior to use.

Since Acellbia® contains no preservatives, the prepared solution must be used immediately.

The prepared infusion solution is physically and chemically stable for 12 h at room temperature or for not more than 24 h at 2° to 8°C.

The prepared solution of Acellbia® is administered only intravenously, dropwise, through a separate catheter! The drug should not be given intravenously by trickle or bolus!

The recommended initial rate of the first infusion is 50 mg/h, which may be increased by 50 mg/h every 30 minutes thereafter, up to a maximum rate of 400 mg/h. Subsequent infusions may be started at 100 mg/h and increased by 100 mg/h every 30 minutes to a maximum rate of 400 mg/h.

Dose adjustment during therapy

It is not recommended to decrease the dose of Acellbia®. If Acellbia® is administered in combination with chemotherapy, dosage reduction of chemotherapeutic agents is done according to standard guidelines.

Standard dosing regimen

Nehodgkin’s lymphoma of low-grade malignancy or follicular

.A premedication (an analgesic/antipyretic such as paracetamol; an antihistamine such as diphenhydramine) must be given before each infusion of Acellbia®. If Acellbia® is not used in combination with chemotherapy containing glucocorticosteroids, premedication also includes glucocorticosteroids.

Initial therapy:

Monotherapy in adult patients: 375 mg/m2 once weekly, for 4 weeks;

In combination with chemotherapy on any regimen: 375 mg/m2 on the first day of the chemotherapy cycle after intravenous glucocorticosteroid as a component of therapy, for:

Retreatment in case of relapse (in patients who have responded to the first course of therapy): 375 mg/m2 once weekly, for 4 weeks.

Supportive therapy (after response to induction therapy):

Diffuse B-cell non-Hodgkin’s lymphoma

Pre-medication (analgesic/antipyretic such as paracetamol; antihistamine such as diphenhydramine) should be given before each infusion of Acellbia®. If Acellbia® is not used in combination with chemotherapy containing glucocorticosteroids, premedication also includes glucocorticosteroids.

In combination with chemotherapy under the CHOP regimen: 375 mg/m2 on the first day of each chemotherapy cycle after intravenous glucocorticosteroid administration, 8 cycles. The other components of the CHOP regimen (cyclophosphamide, doxorubicin and vincristine) are administered after administration of Acellbia®.

Dosage in Special Cases

Individuals over 65 years of age do not require dose adjustments.

Interaction

Data on drug interactions of rituximab are limited. In patients with chronic lympholeukemia, concomitant use of rituximab, fludarabine and cyclophosphamide does not change pharmacokinetic parameters. There are no data from clinical studies on the presence of synergistic effects when Acellbia® is used in combination with chemotherapy.

The risk of allergic reactions increases when used with other monoclonal antibodies for diagnostic or therapeutic purposes in patients who have antibodies against mouse proteins or anti-chimeric antibodies.

PVC or polyethylene infusion systems or bags may be used when administering Acellbia® due to material compatibility with the drug.

Special Instructions

Acellbia® is administered under the close supervision of an oncologist or hematologist with the necessary conditions for resuscitation.

Non-Hodgkin’s lymphoma and chronic lympholeukemia

Infusion reactions. The development of infusion reactions may be due to the release of cytokines and/or other mediators. Severe infusion reactions are difficult to distinguish from hypersensitivity reactions or cytokine release syndrome. There have been reports of fatal infusion reactions described during post-registration use of the drug. Most patients experience fever with chills or shivering within 30 minutes to 2 hours after the start of the first rituximab infusion. Severe reactions include pulmonary symptoms, low blood pressure, urticaria, angioneurotic edema, nausea, vomiting, weakness, headache, itching, tongue irritation or pharyngeal edema (vasculopathy), rhinitis, flushes, pain in foci, and, in some cases, signs of rapid tumor lysis syndrome. Infusion reactions disappear after interruption of rituximab administration and drug therapy (intravenous administration of 0.9% sodium chloride solution, diphenhydramine and acetamipophen, bronchodilators, glucocorticosteroids, etc.). In most cases, once symptoms have completely disappeared, the infusion can be resumed at a rate 50% of the previous rate (e.g., 50 mg/h instead of 100 mg/h). In most patients with non-life-threatening infusion reactions, treatment with rituximab has been completed. Continuation of therapy after complete disappearance of symptoms is rarely accompanied by a recurrence of severe infusion reactions.

Because of the potential for anaphylactic reactions and other hypersensitivity reactions with intravenous administration of proteinaceous drugs, it is necessary to have means for their control: adrenaline, antihistamines and glucocorticosteroid drugs.

Lung side effects. Hypoxia, pulmonary infiltrates and acute respiratory failure. Some of these phenomena were preceded by severe bronchospasm and dyspnea. There may be an increase in symptomatology over time or clinical deterioration after initial improvement. Patients with pulmonary symptoms or other severe infusion reactions should be closely monitored until symptoms have resolved. Acute respiratory failure may be accompanied by formation of interstitial lung infiltrates or pulmonary edema, often manifesting in the first 1-2 h after the start of the first infusion. If severe pulmonary reactions develop, rituximab infusion should be stopped immediately and intensive symptomatic therapy should be administered. Since the initial improvement in clinical symptoms may be followed by worsening, patients should be closely monitored until pulmonary symptoms resolve.

The rapid tumor lysis syndrome. Rituximab mediates rapid lysis of benign or malignant CD20-positive cells. Tumor lysis syndrome is possible after the first infusion of rituximab in patients with a high number of circulating malignant lymphocytes. Tumor lysis syndrome includes: hyperuricemia, hyperkalemia, hypocalcemia, hyperphosphatemia, acute renal failure, increased LDH level. Patients at risk (patients with a high tumor burden or a high number of circulating malignant cells ( > 25 ×109/l), such as those with chronic lympholeukemia or mantle cell lymphoma) require close medical monitoring and regular laboratory examination. If symptoms of rapid tumor lysis develop, appropriate therapy is given. After complete resolution of symptoms in a limited number of cases, therapy with rituximab was continued in combination with prophylaxis for rapid tumor lysis syndrome.

Patients with a high number of circulating malignant cells (>25×109/l) or a high tumor burden (e.g., with chronic lympholeukemia or mantle cell lymphoma) in whom the risk of extremely severe infusion reactions may be particularly high, Atsellbia® should be administered with extreme caution, under close supervision. The first infusion of the drug should be administered at a slower rate in such patients or the dose should be divided over two days during the first cycle of therapy and in each subsequent cycle if the number of circulating malignant cells remains > 25×10 /l.

Cardiovascular side effects. During infusion, close monitoring of patients with a history of cardiovascular disease is required due to the possibility of developing angina pectoris, arrhythmia (atrial flutter and fibrillation), heart failure or myocardial infarction. Because of the possibility of hypotension, antihypertensive medications should be withdrawn at least 12 hours before rituximab infusion.

Blood cell monitoring. Although rituximab monotherapy has no myelosuppressive effect, caution should be exercised when prescribing the drug for neutropenia less than 1.5×109/l and/or thrombocytopenia less than 75×109/l, as experience with its clinical use in such patients is limited. Rituximab has been used in patients after autologous bone marrow transplantation and in other risk groups with possible bone marrow dysfunction without causing myelotoxicity. In the course of treatment it is necessary to determine regularly a detailed analysis of peripheral blood, including platelet counts according to routine practice. Acellbia® should not be administered to patients with severe acute infections.

Hepatitis B. All patients should be screened for hepatitis B before administration of rituximab. A minimum set of tests should include HbsAg and HbcAb determination; the tests may be supplemented according to local guidelines. Acellbia® should not be used in patients with active hepatitis B. Patients with positive hepatitis B serologic markers should consult a hepatologist before using rituximab; these patients should be appropriately monitored and measures taken to prevent hepatitis B virus reactivation in accordance with local standards.

Patients with progressive multifocal leukoencephalopathy (PML). PML has been observed in patients with non-Hodgkin’s lymphoma and chronic lymph leukemia when using rituximab. Most patients received rituximab in combination with chemotherapy or in combination with hematopoietic stem cell transplantation. If neurologic symptoms occur in such patients, a differential diagnosis to rule out PML and consultation with a neurologist should be performed.

Skin reactions. There have been recorded cases of severe skin reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome, in some cases with fatal outcome. If these reactions are detected, the drug Acellbia® should be discontinued. Resumption of rituximab should be considered on a case-by-case basis, taking into account the benefit-risk ratio for each individual patient.

Immunization. The safety and efficacy of immunization with live viral vaccines after rituximab treatment has not been studied. Immunization with live viral vaccines is not recommended. Vaccination with inactivated vaccines is possible, but response rates may decrease. Patients with recurrent non-Hodgkin’s lymphoma of low malignancy had a decreased response rate to tetanus toxoid and KHL-neoantigen (KHL-hemocyanin of the molluscan fissure) administration compared with patients not receiving rituximab (16% vs 81% and 4% vs 69% (evaluation criteria of more than 2-fold increase in antibody titer), respectively). However, the mean antibody titer to a set of antigens (Streptococcus pneumonia, Influenza A, mumps, rubella, varicella) did not change for at least 6 months after rituximab therapy (when compared with antibody titers before treatment).

Influence on ability to drive and operate vehicles and other mechanisms requiring increased concentration

If Atsellbia® affects the ability to drive and operate machinery is unknown, although the pharmacological activity and adverse events described do not suggest such an effect.

Contraindications

With caution: history of respiratory failure or lung tumor infiltration; circulating malignant cell count >25×109/l or high tumor burden; neutropenia (less than 1.5×109/l), thrombocytopenia (less than 75×109/l); chronic infections.

Side effects

The following criteria are used to assess the incidence of adverse reactions:

Rituximab in therapy for non-Hodgkin’s lymphoma of low malignancy or follicularity – monotherapy/supportive therapy

Adverse reactions have been reported at 12 months after ionotherapy and up to 1 month after rituximab maintenance therapy.

Infectious and parasitic diseases: very common – bacterial and viral infections; common – 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; common – thrombocytopenia, anemia; infrequent – lymphoadenopathy, coagulation disorders, transient partial aplastic anemia, hemolytic anemia.

Disorders of the respiratory system, thorax and mediastinum: frequently – rhinitis, bronchospasm, cough, respiratory disorders, dyspnea, chest pain; infrequently – hypoxia, lung function abnormalities, bronchiolitis obliterans, bronchial asthma.

Immune system disorders: very common – angioedema; frequent – hypersensitivity reactions.

Disorders of 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 the tumor foci, flu-like syndrome, hot flashes, weakness; infrequently – pain at the injection site.

Gastrointestinal disorders: very common – nausea; common – vomiting, diarrhea, dyspepsia, lack of appetite, dysphagia, stomatitis, constipation, abdominal pain, scratchy throat; infrequent – abdominal enlargement.

Cardiovascular system disorders: frequent – decreased blood pressure, increased blood pressure, orthostatic hypotension, tachycardia, arrhythmia, atrial fibrillation*, cardiac pathology*; infrequent – left ventricular heart failure*, ventricular and supraventricular tachycardia*, bradycardia, myocardial ischemia*, angina pectoris*.

Nervous system disorders: frequently – dizziness, paresthesia, hypoesthesia, sleep disturbance, anxiety, agitation, vasodilatation; rarely – perversion of taste.

Mental disorders: infrequent – nervousness, depression.

Muscular and connective tissue disorders: frequent – myalgia, arthralgia, muscle hypertonicity, back pain, neck pain, pain.

Skin and subcutaneous tissue disorders: very often – itching, rash; often – urticaria, increased sweating at night, sweating, alopecia*.

Sight organ disorders: frequent – tear production disorders, conjunctivitis.

Hearing organ and labyrinth disorders: frequent – pain and tinnitus.

Laboratory and instrumental findings: very common – decreased levels of class G immunoglobulins (IgG).

* – frequency is indicated only for adverse reactions ≥3 severity according to National Cancer Institute (NCI-CTC) toxicity criteria.

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

Severe adverse reactions in addition to those observed with monotherapy/supportive therapy and/or occurring at higher rates are listed below.

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

Blood and lymphatic system disorders: very common – neutropenia**, febrile neutropenia, thrombocytopenia; common – pancytopenia, granulocytopenia.

Skin and subcutaneous tissue disorders: very common – alopecia; common – skin disorders.

General disorders and disorders at the site of administration: common – fatigue, chills.

* – frequency is based on observations during therapy of relapsed/chemo-resistant chronic lympholeukemia with 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 lympholeukemia.

The adverse events that occurred with rituximab therapy at the same rate (or less frequently) compared to the control group are listed below: Hematotoxicity, neutropenic infections, urinary tract infections, septic shock, pulmonary superinfections, implant infection, staphylococcal septicemia, nasal mucous discharge, pulmonary edema, heart failure, sensory disorders, venous thrombosis, includingincluding deep vein thrombosis of extremities, mucositis, edema of lower extremities, decreased left ventricular ejection fraction, fever, worsening of general well-being, bacteremia, multiple organ failure, decompensation of diabetes mellitus.

The safety profile of rituximab in combination with chemotherapy with MSR, CHVP-IFN regimens does not differ from that of combining the drug with CVP, SNR or FC in the respective populations.

Infusion reactions

Monotherapy with rituximab (for 4 weeks)

More than 50% of patients experienced phenomena resembling infusion reactions, most commonly in the first infusions. Infusion reactions include chills, shivering, weakness, shortness of breath, nausea, rash, hot flashes, decreased blood pressure, fever, itching, urticaria, sensation of tongue irritation or laryngeal edema (angioedema), rhinitis, vomiting, pain in tumor foci, headache, bronchospasm. The development of signs of tumor lysis syndrome has been reported.

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

Infusion reactions of grade 3 and 4 severity during infusion or within 24 hours of rituximab infusion were noted during the first cycle of chemotherapy in 12% of patients.

The rate of infusion reactions decreased with each subsequent cycle and by the 8th cycle of chemotherapy, the rate of infusion reactions had decreased to less than 1%. In addition to those mentioned above (with rituximab monotherapy), infusion reactions 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

Monotherapy with rituximab (for 4 weeks)

Rituximab causes depletion of the B-cell pool in 70-80% of patients and decreased serum immunoglobulin concentrations in a small number of patients. Bacterial, viral, fungal infections and infections without a definite etiology (weight, regardless of the cause) develop in 30.3% of patients. Severe infections (grade 3 and 4), including sepsis, were reported in 3.9% of patients.

Supported therapy (non-Hodgkin’s lymphoma) up to 2 years

With rituximab therapy, there was an increase in the overall frequency of infections, including grade 3-4 infections. No increase in infectious complications was observed with 2-year maintenance therapy.

Cases of progressive multifocal leukoencephalopathy (PML) with fatal outcome in patients with non-Hodgkin’s lymphoma after disease progression and retreatment have been reported.

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; and R-FC for chronic lymph leukemia

There was no increase in the frequency of infections or invasions with rituximab therapy with the R-CVP regimen. The most common were upper respiratory tract infections (12.3% in the R-CVP group). Serious infections were observed in 4.3% of patients treated with R-CVP; no life-threatening infections were reported. The percentage of patients with grade 2-4 infections and/or febrile neutropenia in the R-CVP group was 55.4%. The cumulative incidence of grade 2-4 infections in the R-CNR group was 45.5%. The incidence of grade 2-4 fungal infections in the R-SNOR group was higher than in the CHOP group due to a higher incidence of local candidiasis and was 4.5%. The incidence of herpes infections of grade 2-4 severity was higher in the R-CHOP group than in the CHOP group and was 4.5%.

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

Blood system side

Monotherapy with rituximab (for 4 weeks)

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

Supportive therapy (non-Hodgkin’s lymphoma) up to 2 years

Leukopenia (grade 3 and 4 severity) was seen in 5% of patients and neutropenia (grade 3 and 4 severity) in 10% of patients receiving rituximab. The incidence of thrombocytopenia (grade 3-4 severity) was low at < 1%.

About 50% of patients for whom there was evidence of B-cell count recovery required 12 months or more after completion of rituximab induction therapy to restore B-cell count to normal levels.

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

Severe neutropenia and leukopenia: Grade 3 and 4 leukopenia were more frequent in patients who received rituximab in combination with chemotherapy compared with patients who received chemotherapy alone. The incidence of severe leukopenia was 88% in patients receiving R-CNR 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 for previously untreated chronic lymph leukemia. The higher rate of neutropenia in patients who received rituximab and chemotherapy was not associated with an increased rate of infections and invasions compared with patients who received chemotherapy alone. In patients with relapsed or chemoresistant chronic lymph leukemia after R-FC therapy, in some cases, leytropenia was characterized by a longer course and later manifestation.

Severe anemia and thrombocytopenia (grade 3 and 4): there was no significant difference in the frequency of grade 3 and 4 anemia between the groups. In the R-FC group of first-line therapy for chronic lymph leukemia, grade 3 and 4 anemia occurred in 4% of patients, and grade 3 and 4 thrombocytopenia in 7% of patients. In the R-FC group for relapsed or chronic lympholeukemia, grade 3 and 4 anemia occurred in 12% of patients and grade 3 and 4 thrombocytopenia occurred in 11% of patients.

Cardiovascular side

Monotherapy with rituximab (for 4 weeks)

Cardiovascular side effects were reported in 18.8%. The most common were arterial hypertension and decreased blood pressure. In isolated cases, heart rhythm disturbances of severity 3 and 4 (including ventricular and supraventricular tachycardia) and angina pectoris were observed.

Supported therapy (non-Hodgkin’s lymphoma) for up to 2 years

The incidence of grade 3 and 4 cardiovascular events was similar in patients who received rituximab and those who did not. Severe 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 and combinations with chemotherapy on the following regimens: R-CVP for non-Hodgkin’s lymphoma; R-CNOR for diffuse B-cell non-Hodgkin’s lymphoma; R-FC for chronic lympholeukemia

The incidence of heart rhythm disturbances of severity 3 and 4, mainly supraventricular arrhythmias (tachycardia, atrial flutter, and fibrillation), was higher in the R-CHOP group and was 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 respiratory and cardiovascular diseases. The R-CHOP and CHOP groups did not differ in the frequency of other grade 3 and 4 cardiac adverse events, including heart failure, myocardial disease, and manifestation of coronary heart disease.

The overall incidence of grade 3 and 4 cardiovascular adverse events was low in both first-line therapy for chronic lymph leukemia (4% in the R-FC group) and therapy for relapsed/chemoresistant chronic lymph 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-CNOR for diffuse B-cell non-Hodgkin’s lymphoma; R-FC for chronic lympholeukemia

Patients (2%) in the R-CHOP group with cardiovascular risk factors developed cerebral thromboembolic circulatory disorders during the first cycle of therapy, in contrast to patients in the CHOP group, who developed cerebral circulatory disorders during follow-up without treatment. There was no difference between the groups in the incidence of other thromboembolism.

The overall incidence of neurologic disorders of grade 3 and 4 severity was low in both first-line therapy for chronic lymph leukemia (4% in the R-FC group) and in therapy for relapsed/chemo-resistant chronic lymph leukemia (3% in the R-FC group).

IgG concentrations

Supportive 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 group receiving rituximab and in the group not receiving the drug. In the group not receiving rituximab, median IgG levels consistently increased and exceeded the lower limit of normal, whereas median IgG levels were unchanged in the group receiving rituximab. IgG levels remained below the lower limit in 60% of patients treated with rituximab for 2 years. In the group without rituximab therapy, the IgG level remained below the lower limit in 36% of patients after 2 years.

Special patient categories

Monotherapy with rituximab (for 4 weeks)

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

Combination therapy

Elderly age (65 years and older): the incidence of Grade 3 and 4 adverse reactions from the blood and lymphatic system was higher in first-line therapy as well as in therapy with relapsed/chemoresistant chronic lympholysaccharide compared to younger patients.

High tumor burden (single lesions greater than 10 cm in diameter): incidence of Grade 3 and 4 adverse reactions was increased.

Retreatment: The incidence and severity of adverse reactions did not differ from that with initial therapy.

Information on post-registration use of rituximab in non-Hodgkin’s lymphoma and chronic lymphatic leukemia

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, mostly cutaneous (leukocytoclastic).

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

Hematological and lymphatic system: reversible acute thrombocytopenia associated with infusion reactions.

Skin and its appendages: rare – severe bullous reactions, toxic epidermal necrolysis and Stevens-Johnson syndrome, in some cases with fatal outcome.

Nervous system disorders: rare – cranial nerve neuropathy in combination with peripheral neuropathy or without it (marked decrease of visual acuity, hearing, other sensory organs affection, facial nerve paresis) during various periods of therapy up to several months after treatment with rituximab. Reversible encephalopathy with posterior brain injury (PRES)/reversible leukoencephalopathy with posterior brain injury (PRLS) syndrome were observed in patients treated with rituximab. Symptomatology included visual impairment, headache, seizures, and psychiatric disorders, with or without elevated blood pressure. The diagnosis of PRES/PRLS could be confirmed by brain imaging techniques. In the cases described, patients had risk factors for PRES/PRLS, such as underlying disease, increased blood pressure, immunosuppressive therapy and/or chemotherapy.

In general, site of administration reactions: rarely, serum sickness.

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

In patients with previously diagnosed Kaposi’s sarcoma, progression of sarcoma was observed (most patients were HIV-positive) when rituximab was administered for indications not included in the medical instructions.

Gastrointestinal tract: gastric and/or intestinal perforation (possibly fatal) when combining rituximab with chemotherapy for non-Hodgkin’s lymphoma.

Blood and lymphatic system disorders: rare neutropenia occurring 4 weeks after the last administration of rituximab; transient increase in IgM levels in patients with Waldenstrom macroglobulinemia with subsequent return to baseline values after 4 months.

Overdose

There have been no cases of overdose in humans. Single doses of rituximab above 1000 mg have not been studied. A maximum dose of 5000 mg has been administered to patients with chronic lymph leukemia; no additional safety data have been obtained. Due to an increased risk of infectious complications if the B-lymphocyte pool is depleted, the infusion rate should be withdrawn or reduced, and the need for a detailed general blood count should be considered.