Acellbia 10 mg/ml 10 ml, 2 pcs.

The active ingredient in Acellbia® 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 patients examined.

Indications

Non-Hodgkin’s lymphoma

Chronic lympholeukemia

Active ingredient

Composition

1 ml of the concentrate contains:

The active ingredient: rituximab 10 mg.

How to take, the dosage

Regulations for solution preparation and storage

The required amount of Acellbia® preparation 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 its use.

Because Acellbia® contains no preservatives, the prepared solution should be used immediately.

The prepared infusion solution is physically and chemically stable for 12 h at room temperature or for no more than 24 h at 2° to 8°C.

The prepared Acellbia® solution is administered only intravenously, by drip, through a separate catheter! The drug must not be administered intravenously by trickle or bolus!

The recommended initial infusion rate for 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 can be started at 100 mg/h and increased by 100 mg/h every 30 min to a maximum rate of 400 mg/h.

Dose adjustment during therapy

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

The standard dosing regimen

Non-Hodgkin’s lymphoma of low-grade malignancy or follicularity

. A premedication (an analgesic/antipyretic such as paracetamol; an 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.

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:

Renewed use 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

Premedication (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 the administration of Acellbia®.

Dosage in special cases

Elderly age

Dose adjustment is not necessary in patients over 65 years of age.

Interaction

There are limited data on drug interactions of rituximab. Pharmacokinetic parameters do not change in patients with chronic lympholeukemia when concomitant use of rituximab, fludarabine and cyclophosphamide. There are no data from clinical studies on the presence of synergistic effects when using Acellbia® 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 the means for their management: adrenaline, antihistamines and glucocorticosteroids.

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 symptoms 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 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., chronic lympholeukemia or mantle cell lymphoma) in whom the risk of extremely severe infusion reactions may be particularly high should be treated with extreme caution, under close supervision. The first infusion of the drug should be given at a lower 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 stopped at least 12 hours before rituximab infusion.

Control of blood cells. Although rituximab monotherapy has no myelosuppressive effects, caution should be exercised when the drug is prescribed 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. Routine peripheral blood counts, including platelet counts, should be determined routinely during treatment.

Infections. The drug Acellbia® should not be administered to patients with severe acute infection.

Hepatitis B. All patients should be screened for hepatitis B before prescribing rituximab. A minimum set of tests should include HbsAg and HbcAb; 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 monitored appropriately and measures taken to prevent hepatitis B virus reactivation in accordance with local guidelines.

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 these patients, a differential diagnosis to rule out PML and consultation with a neurologist should be made.

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

Immunization. The safety and efficacy of immunization with live viral vaccines after rituximab treatment have 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 Acellbia® affects the ability to drive and operate vehicles and mechanisms is unknown, although pharmacological activity and adverse events described do not suggest such an effect.

Contraindications

With caution: History of respiratory failure or tumor infiltration of the lungs; number of circulating malignant cells >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 evaluate the frequency 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, blood clotting disorder, transient partial aplastic anemia, hemolytic anemia.

Respiratory system, thoracic and mediastinal disorders: frequently – rhinitis, bronchospasm, cough, respiratory disorders, dyspnea, chest pain; infrequently – hypoxia, lung function disorders, bronchiolitis obliterans, bronchial asthma.

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

Mechanism and nutrition disorders: frequently – 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; infrequently – perversion of taste.

Mental disorders: infrequent – nervousness, depression.

Muscular and connective tissue disorders: often – 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*.

Visual disorders: often – tear production disorders, conjunctivitis.

Hearing and labyrinth disorders: often – pain and tinnitus.

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

* – The frequency is only for adverse reactions of ≥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

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

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 diseases.

General disorders and disorders at the site of administration: often – 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 following are the adverse events that occurred with rituximab therapy at the same frequency (or less frequently) compared to the control group: Hematotoxicity, neutropenic infections, urinary tract infections, septic shock, pulmonary superinfections, implant infection, staphylococcal septicemia, nasal mucous discharge, pulmonary edema, heart failure, sensory disturbances, 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, CNR or FC in the respective populations.

Infusion reactions

Rituximab monotherapy (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 incidence of infusion reactions decreased with each subsequent cycle and by the 8th cycle of chemotherapy, the incidence 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 (3 and 4 degrees of severity), including sepsis, are noted in 3.9% of patients.

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

There was an increase in the overall incidence of infections, including grade 3 to 4 infections, with rituximab therapy. There was no increase in the incidence of infectious complications with 2-year maintenance therapy.

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

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 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 frequent ones were upper respiratory tract infections (12.3% in the R-CVP group). Serious infections were observed in 4.3% of patients receiving R-CVP chemotherapy; 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 herpetic 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 lymph leukemia, the incidence of hepatitis B (exacerbation and primary infection) of grade 3-4 severity in the R-FC group was 2%.

Blood system disorders

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

Approximately 50% of patients for whom there was evidence of B-cell count recovery took 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 regimen therapy, in some cases the leitropenia was characterized by a longer course and later manifestation time.

Severe anemia and thrombocytopenia (grade 3 and 4 severity): there was no significant difference in the incidence 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 system disorders

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.

Supportive 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. 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 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 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

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 thromboembolisms.

The overall incidence of grade 3 and 4 neurologic impairment 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 (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 of relapsed/chemoresistant chronic lymphocytosis compared to younger patients.

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

Retreatment: incidence and severity of adverse reactions are the same as with initial therapy.

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

Cardiovascular system effects: 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).

Respiratory system disorders: 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, with fatal outcome in some cases.

Blood and lymphatic system disorders: 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, high blood pressure, immunosuppressive therapy and/or chemotherapy.

Body-wide, 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.

When rituximab was administered for an indication not included in the medical instructions, progression of sarcoma was observed in patients with previously diagnosed Kaposi sarcoma (most patients were HIV-positive).

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