Mabthera concentrate 100mg/10ml vial, 2pcs

Composition

>

1 ml (1 bottle) contains:  

Active ingredients:

rituximab 10 mg (100 mg).

Auxiliary substances:

sodium citrate dihydrate-7.35 mg,

polysorbate 80-0.7 mg,

sodium chloride-9 mg,

hydrochloric acid or sodium hydroxide (up to pH 6.5),

d/i water-up to 1 ml

Pharmacological action

Pharmacodynamics

Antitumor and immunomodulatory drug. Rituximab is a chimeric mouse/human monoclonal antibody that specifically binds to the CD20 transmembrane antigen. 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, and cells of other tissues and is expressed in more than 95% of cases in B-cell non-Hodgkin’s lymphomas. CD20 expressed on the cell after binding to the antibody is not internalized and ceases to enter the extracellular space from the cell membrane. 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 induction of apoptosis. Rituximab improves the sensitivity of the lines b-cell lymphoma of the person to the cytotoxic action of certain chemotherapeutic drugs in vitro.

The number of b-cells in peripheral blood after the first use of the drug is reduced below the norm and begins to recover in patients with haematological malignant disease after 6 months, reaching normal values after 12 months after completion of therapy, but in some cases, the duration of the recovery period the number of b-cells may be more.

In patients with rheumatoid arthritis, the duration of reduction in the number of B cells varies, and most patients are prescribed subsequent therapy until their number is fully restored. In a small number of patients, there is a long-term decrease in the number of B cells (for 2 years or more after the last dose of the drug).

In patients with granulomatosis with polyangiitis and microscopic polyangiitis, a decrease in the number of CD19-positive B cells to less than 10 cells/µl occurs after the first two infusions of rituximab and in most patients persists at this level for 6 months.

Antichymal antibodies were detected in 1.1% of the examined patients with non-Hodgkin’s lymphoma and 10% with rheumatoid arthritis. No antimuscular antibodies were detected in the examined patients.

Pharmacokinetics

Non-Hodgkin’s lymphoma

According to a population pharmacokinetic analysis in patients with non-Hodgkin’s lymphoma with a single or multiple use of Mabthera® as monotherapy or in combination with CHOP chemotherapy (cyclosporine, doxorubicin, vincristine, prednisone), the non-specific clearance (CL1), specific clearance (CL2), (probably related to B cells or tumor load), and the volume of distribution in plasma (V1) are 0.14 l/day,0.59 l/day and 2.7 l, respectively. The median terminal T1 / 2 is 22 days. Baseline CD19-positive cell count and tumor focus size affected by rituximab CL2 375 mg / m2 IV once a week, for 4 weeks. The CL2 score is higher in patients with a higher level of CD19-positive cells or a larger tumor focus. Individual CL2 variability persists even after correction of the size of the tumor focus and the level of CD19-positive cells. Relatively small changes in the V1 index depend on the size of the body surface area (1.53-2.32 m2) and on chemotherapy according to the CHOP scheme and amount to 27.1% and 19%, respectively. Age, gender, race, and general health on the WHO scale do not affect the pharmacokinetics of rituximab. Thus, dose adjustment of rituximab depending on the factors listed above does not significantly affect the pharmacokinetic variability.

The average Cmax increases after each infusion: after the first infusion – 243 mcg / ml, after the fourth infusion – 486 mcg/ml, after the eighth-550 mcg/ml. Cmin and Cmax of the drug are inversely correlated with the initial number of CD19-positive B cells and the amount of tumor load. With effective treatment, the median Css of the drug is higher. The median Css of the drug is higher in patients with histological subtypes of the tumor B, C and D (classification IWF – International Working Formula) than with subtype A. Traces of rituximab can be detected in the body within 3-6 months after the last infusion.

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

Chronic lymphocytic leukemia

The average Cmax after the fifth rituximab 500 mg/m2 infusion is 408 mcg / ml.

Rheumatoid arthritis

After two intravenous infusions of 1000 mg with a 2-week break, the average Cmax of rituximab was 369 mcg / ml, average T 1/2 – 19,2-20,8 The average systemic clearance was 0.23 l/day and the steady – state Vd was 4.6 l. After the second infusion, the average Cmax was 16-19% higher compared to the first infusion. After repeated treatment, the pharmacokinetic parameters of rituximab are comparable to the first course of treatment.

Granulomatosis with polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis

According to a population pharmacokinetic analysis, after four infusions of rituximab at a dose of 375 mg/m2 once a week, the median T 1/2 was 23 days, the average clearance was 0.313 l / day, and the Vd was 4.5 l. The pharmacokinetic parameters of rituximab in granulomatosis with polyangiitis and microscopic polyangiitis were almost the same as in rheumatoid arthritis.

Pharmacokinetics in certain groups of patients

with Vd and the clearance of rituximab adjusted for body surface area in men is slightly larger than in women, no dose adjustment of rituximab is required. Pharmacokinetic data are not available in patients with renal or hepatic insufficiency.

Indications

Non-Hodgkin’s lymphoma:

• recurrent or hemostasia b-cell, CD20-positive non-Hodgkin’s lymphoma, low-grade or follicular;
• follicular lymphoma stage III-IV in combination with chemotherapy in previously untreated patients,
• follicular lymphoma as a maintenance therapy after response to induction therapy;
• CD20-positive diffuse large b-cell non-Hodgkin’s lymphoma in combination with chemotherapy scheme CHOP.

Chronic lymphocytic leukemia:

• chronic lymphocytic leukemia in combination with chemotherapy in patients who have not previously received standard therapy;
• recurrent or chemo-resistant chronic lymphocytic leukemia in combination with chemotherapy.

Rheumatoid arthritis:

• moderate to severe rheumatoid arthritis (active form) in adults in combination with methotrexate in case of intolerance or inadequate response to current therapy regimens including one or more TNFa inhibitors, including for inhibition of radiologically proven joint destruction.

Granulomatosis with polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis:

• severe forms of active granulomatosis with polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis in combination with corticosteroids.

Use during pregnancy and lactation

Immunoglobulins G (IgG) are able to cross the placental barrier.

The level of B-cells in newborns when prescribing Mabthera® to women during pregnancy has not been studied.

Some newborns whose mothers received rituximab during pregnancy experienced temporary depletion of the B-cell pool and lymphocytopenia. Therefore, Mabthera should not be given to pregnant women unless the potential benefits of therapy outweigh the potential risks.

Women of childbearing age should use effective methods of contraception during treatment and for 12 months after the end of treatment with Mabthera®.

It is not known whether rituximab is excreted in breast milk. Given that IgG class immunoglobulins circulating in the mother’s blood are excreted in breast milk, Mabthera® should not be used during breastfeeding.

Contraindications

• Hypersensitivity to rituximab, any component of the drug, or mouse proteins;
• acute infectious diseases;
• severe primary or secondary immunodeficiency;
• severe heart failure (NYHA class IV) in rheumatoid arthritis;
• children and adolescents under 18 years of age (efficacy and safety have not been established);
• pregnancy;
• breastfeeding.

With caution: use in patients with a history of respiratory failure or lung tumor infiltration; with the number of circulating malignant cells >25,000/µl or a high tumor load; neutropenia (less than 1,500/µl), thrombocytopenia (less than 75,000/µl); with chronic infections.

Side effects

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

• very often (≥10%);
• often (≥1%- < 10%);
• infrequently (≥0.1%-

Experience of using the drug in oncohematological diseases

Mabthera® in the treatment of low-grade or follicular non-Hodgkin’s lymphoma-monotherapy/maintenance therapy

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

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; infrequently-lymphadenopathy, blood clotting disorders, 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; infrequently – hypoxia, impaired lung function, obliterating bronchiolitis, bronchial asthma.

From the immune system: very often – angioedema; often-hypersensitivity reactions.

From the side 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.

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 cardiovascular system: often-low blood pressure, increased blood pressure, orthostatic hypotension, tachycardia, arrhythmia, atrial fibrillation*, myocardial infarction*, cardiac pathology*; infrequently-left ventricular heart failure*, ventricular and supraventricular tachycardia*, bradycardia, myocardial ischemia*, angina pectoris*.

From the nervous system: often – dizziness, paresthesia, hypesthesia, sleep disturbance, anxiety, agitation, vasodilation; infrequently-perversion of taste.

From the side of the psyche: infrequently-nervousness, depression.

Musculoskeletal and connective tissue disorders: often – myalgia, arthralgia, muscle hypertonus, back pain, neck pain, pain.

From 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-violations of lacrimation, conjunctivitis.

From the side of the organ of hearing and labyrinth disorders: often-pain and tinnitus.

Laboratory and instrumental data: very often – a decrease in the concentration of immunoglobulins G(IgG). * The frequency is indicated only for adverse reactions ≥3 degrees of severity in accordance with the toxicity criteria of the National Cancer Institute (NCI-CTC).

Mabthera 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 with a higher frequency.

Infectious and parasitic diseases: very often – bronchitis; often-acute bronchitis, sinusitis, hepatitis B* (reactivation of the hepatitis B virus and primary infection).

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

From the skin and subcutaneous tissues: very often – alopecia; often-skin diseases.

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

* – the frequency is indicated based on observations in the treatment of recurrent / chemo-resistant chronic lymphocytic leukemia according to the R-FC scheme.

** – long-term and/or delayed neutropenia was observed after completion of therapy according to the R-FC scheme in previously untreated patients or in patients with recurrent / chemo-resistant chronic lymphocytic leukemia.

The following adverse reactions occurred with the same frequency (or less frequently) during treatment with Mabthera® compared to the control group: hematotoxicity, neutropenic infections, urinary tract infections, septic shock, lung superinfections, implant infection, staphylococcal septicemia, nasal mucosa, pulmonary edema, heart failure, sensitivity disorders, venous thrombosis, including deep vein thrombosis of the extremities, mucositis, edema lower extremities, decreased left ventricular ejection fraction, increased body temperature, deterioration of general well-being, falling, multiple organ failure, bacteremia, decompensation of diabetes mellitus.

The safety profile of Mabthera in combination with chemotherapy according to the MCP, CHVP-IFN regimens does not differ from that in combination with CVP, CHOP or FC in the corresponding populations.

Infusion reactions

Monotherapy with Mabthera® (for 4 weeks)

More than 50% of patients experienced events resembling infusion reactions, most often during the first infusions. Infusion reactions include chills, shivering, weakness, shortness of breath, nausea, rash, hot flashes, low blood pressure, fever, pruritus, urticaria, irritation of the tongue or laryngeal edema (angioedema), rhinitis, vomiting, pain in the tumor foci, headache, bronchospasm. Signs of tumor lysis syndrome have been reported.

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

Grade 3 and 4 infusion reactions during the infusion or within 24 hours after the infusion of Mabthera® were observed during the first cycle of chemotherapy in 12% of patients. The frequency of infusion reactions decreased with each subsequent cycle, and by the 8th cycle of chemotherapy, the frequency of infusion reactions reached less than 1%. Infusion reactions in addition to those indicated above (with Mabthera 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

Monotherapy with Mabthera® (for 4 weeks)

Mabthera 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 without a specified etiology (all, 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.

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

When treated with Mabthera®, there was an increase in the overall frequency of infections, including 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 fatal outcome have been reported in patients with non-Hodgkin’s lymphoma after disease progression and repeated treatment.

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

No increase in the incidence of infections or infestations was observed during R-CVP therapy with Mabthera. Upper respiratory tract infections were the most common (12.3% in the R-CVP group). Serious infections were reported in 4.3% of patients treated with 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 fungal infections of 2-4 degrees of severity 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 compared to the CHOP group and amounted to 4.5%.

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

From the hematopoietic system

Monotherapy with Mabthera® (for 4 weeks)

1.7% – severe thrombocytopenia (grade 3 and 4); 4.2% – severe neutropenia; 1.1% – severe anemia (grade 3 and 4).

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

Leukopenia (3 and 4 degrees of severity) was observed in 5% of patients, neutropenia (3 and 4 degrees of severity) – in 10% of patients receiving Mabthera®. The incidence of thrombocytopenia (3-4 degrees of severity) during Mabthera therapy was low and amounted to < 1%.

Approximately 50% of patients who had data on B cell count recovery required 12 months or more to restore B cell count to normal levels after completing Mabthera induction therapy.

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

Severe neutropenia and leukopenia (grade 3 and 4): Grade 3 and 4 leukopenia were more common in patients treated with Mabthera in combination with chemotherapy compared to patients treated with chemotherapy alone. The incidence of severe leukopenia was 88% in patients treated with R-CHOP and 23% in patients treated with 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 lymphocytic leukemia.A higher incidence of neutropenia in patients treated with Mabthera and chemotherapy was not associated with an increased incidence of infections and infestations compared to patients treated with chemotherapy alone. In patients with recurrent or chemo-resistant chronic lymphocytic leukemia after R-FC therapy, in some cases neutropenia was characterized by a long course or later manifestation periods.

Severe anemia and thrombocytopenia (grade 3 and 4): There was no significant difference in the incidence of grade 3 and grade 4 anemia in the groups. In the R-FC group, first-line treatment for chronic lymphocytic leukemia was associated with grade 3 and 4 anemia in 4% of patients, and grade 3 and 4 thrombocytopenia in 7% of patients. In the R-FC group, with recurrent or chemo-resistant chronic lymphocytic leukemia, anemia of 3 and 4 degrees of severity occurred in 12% of patients, thrombocytopenia of 3 and 4 degrees of severity – in 11% of patients.

Nervous system disorders

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

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

The overall incidence of grade 3 and 4 neurological disorders was low in both first-line treatment for chronic lymphocytic leukemia (4% in the R-FC group) and recurrent/chemo-resistant chronic lymphocytic leukemia (3% in the R-FC group).

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 ( In the non-Mabthera group, the median IgG concentration consistently increased and exceeded the lower limit of normal, while the median IgG concentration did not change in the Mabthera group. In 60% of patients treated with Mabthera® for 2 years, the IgG concentration remained below the lower limit. In the group without Mabthera® therapy, after 2 years, the IgG concentration remained below the lower limit in 36% of patients.

Special categories of patients

Monotherapy with Mabthera® (for 4 weeks)

In elderly patients (65 years and older), the frequency and severity of all grade 3 and 4 adverse reactions and side effects does not differ from those in younger patients.

Combination therapy

In elderly patients (65 years and older) with first-line therapy, as well as in the treatment of recurrent/chemo-resistant chronic lymphocytic leukemia, the frequency of grade 3 and 4 adverse reactions from the blood and lymphatic system was higher compared to younger patients.

With a high tumor load (the diameter of single foci is more than 10 cm), the frequency of grade 3 and 4 adverse reactions is increased.

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

Experience of using the drug in rheumatoid arthritis

The following are the adverse reactions that occurred during Mabthera therapy with a frequency of at least 2% and at least 2% difference compared to the control group.

From the immune system, general disorders and disorders at the injection site: very often – infusion reactions* (often – increased and decreased blood pressure, hot flashes, rash, urticaria, itching, chills, fever, nausea, rhinitis, sore throat, tachycardia, weakness, pain in the mouth and throat, peripheral edema, erythema).

* – the following clinically significant infusion reactions were also infrequently observed: generalized edema, bronchospasm, wheezing, laryngeal edema, angioedema, generalized pruritus, anaphylaxis, anaphylactoid reaction. Infectious and parasitic diseases: very often-urinary tract infections, upper respiratory tract infections; often-bronchitis, sinusitis, gastroenteritis, foot dermatophytosis.

From the digestive system: often-dyspepsia, diarrhea, gastroesophageal reflux, ulceration of the oral mucosa, pain in the upper right quadrant of the abdomen.

From the nervous system: very often – headache; often-migraine, paresthesia, dizziness, sciatica.

Mental disorders: often – depression, anxiety.

Musculoskeletal and connective tissue disorders: often-arthralgia, musculoskeletal pain, osteoarthritis, bursitis.

From the skin and subcutaneous tissues: often-alopecia.

Laboratory and instrumental data: often-hypercholesterolemia.

Repeat therapy: the profile of adverse reactions during repeated use does not differ from that during the initial therapy. The safety profile improved with each subsequent course of therapy and was characterized by a decrease in the frequency of infusion reactions, infections and exacerbations of the disease, which were most common in the first 6 months of therapy.

Infusion-related reactions: Infusion-related reactions were the most common adverse reaction when using Mabthera®.35% of patients experienced at least one infusion reaction, with serious infusion reactions occurring in less than 1% of patients, regardless of dose. In most cases, infusion reactions were 1 and 2 degrees of severity. The proportion of grade 3 infusion reactions and infusion reactions leading to discontinuation of therapy decreased with each subsequent course of treatment, and such reactions were rarely observed starting from course 3. There were no infusion reactions of 4 degrees of severity or deaths due to their development.

23% of patients experienced the following symptoms of infusion reactions after the first use of Mabthera: nausea, pruritus, fever, urticaria/rash, chills, trembling, sneezing, angioedema, pharyngeal irritation, cough, and bronchospasm with or without an increase or decrease in blood pressure. Premedication with intravenous corticosteroids significantly reduces the frequency and severity of such events.

Infections: When treated with Mabthera, the overall incidence of infections, which were mostly mild to moderate in severity (most often upper respiratory tract infections and urinary tract infections), was 97 per 100 patient-years. The incidence of severe infections, some of which were fatal, was 4 per 100 patient-years. Among the clinically significant serious adverse events, pneumonia was also observed (1.9%).

Malignancies: The incidence of malignancies after use of Mabthera® does not exceed that in the age-and gender-appropriate population and is 0.8 per 100 patient-years.

On the part of laboratory parameters: hypogammaglobulinemia (a decrease in the concentration of IgG and IgM immunoglobulins below the lower limit of normal), not accompanied by an increase in the overall frequency of infections or the frequency of serious infections. During the first course of Mabthera therapy, including several months after the end of therapy, cases of neutropenia, mainly transient and mild to moderate severity, have been reported. The incidence of severe neutropenia (grade 3 and 4) was 0.94%, compared to 0.27% in the non-treated group.

Given that after the first course of Mabthera therapy, the incidence of severe neutropenia was 1.06 per 100 patient-years compared to 0.53 per 100 patient-years in the absence of such therapy, and after repeated use, the incidence of severe neutropenia was 0.97 per 100 patient-years compared to 0.88 per 100 patient-years in the absence of such therapy, severe neutropenia can only be considered an adverse reaction in relation to the first course of Mabthera therapy. The time of neutropenia manifestation was different. Neutropenia was not associated with an increased incidence of serious infections, and in most cases, patients received repeated courses of Mabthera after episodes of neutropenia.

Experience of using the drug in granulomatosis with polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis

The following are the adverse events that were observed with the use of Mabthera® with a frequency of ≥10% (very common) compared to the frequency of adverse reactions with cyclophosphamide (cross-replacement of the drug or replacement with another therapy based on an informed clinical decision was allowed).

Infectious and parasitic diseases: infections, including the most common upper respiratory tract infections, urinary tract infections, herpes zoster – 61.6% (in the comparison group-46.9%).

From the gastrointestinal tract: nausea-18.2% (in the comparison group-20.4%), diarrhea-17.2% (in the comparison group-12.2%).

From the nervous system: headache – 17.2% (in the comparison group -19.4%).

Musculoskeletal and connective tissue disorders: muscle spasms – 17.2% (in the comparison group-15.3%), arthralgia-13.1% (in the comparison group-9.2%).

From the blood and lymphatic system: anemia-16.2% (in the comparison group-20.4%), leukopenia-10.1% (in the comparison group-26.5%).

General disorders and disorders at the injection site: peripheral edema – 16.2% (in the comparison group-6.1%), weakness-13.1% (in the comparison group-21.4%).

Immune system disorders: infusion reactions, including the most common ones, cytokine release syndrome, redness, throat irritation, tremor-12.1% (in the comparison group-11.2%).

Mental disorders: insomnia – 14.1% (in the comparison group-12.2%).

Laboratory and instrumental data: increased ALT activity – 13.1% (in the comparison group-15.3%).

Respiratory, thoracic and mediastinal disorders: cough-13.1% (in the comparison group-11.2%), nosebleeds – 11.1% (in the comparison group – 6.1%), dyspnoea – 10.1% (in the comparison group-11.2%).

From the cardiovascular system: increased blood pressure-12.1% (in the comparison group-5.1%).

Skin and subcutaneous tissue disorders: rash – 10.1% (in the comparison group-17.3%).

Infusion-related reactions: All infusion-related reactions observed during or within 24 hours of Mabthera infusion were grade 1 and grade 2. Cytokine release syndrome, redness, throat irritation, and tremor were the most common symptoms. The use of Mabthera in combination with intravenous corticosteroids may have reduced the frequency and severity of these adverse reactions.

Infections: The overall incidence of infections with Mabthera was 210 per 100 patient-years. Infections were mostly mild to moderate in severity and most often included upper respiratory tract infections, urinary tract infections, and herpes zoster. The incidence of serious infections with Mabthera was 25 per 100 patient-years. Among serious infections with Mabthera, pneumonia was most frequently reported (4%).

Malignant diseases: the incidence of new cases of malignant diseases with the use of Mabthera ® corresponds to the indicators in the population and is 2.05 per 100 patient-years.

On the part of laboratory parameters: hypogammaglobulinemia (decrease in the concentration of immunoglobulins below the lower limit of normal) IgA, IgG and IgM at 6 months of therapy in the Mabthera group was 27%,58% and 51%, respectively, compared with 25%,50% and 46% in the comparison group. In patients with low concentrations of IgA, IgG, and IgM, there was no increase in the overall incidence of infections or the incidence of serious infections.

Grade 3 and 4 neutropenia was observed in 24% of patients in the Mabthera group and in 23% of patients in the comparison group. Patients treated with rituximab did not experience an increase in the incidence of serious neutropenia-related infections. The effect of rituximab on the development of neuropenia with repeated use has not been studied.

Post-marketing use of Mabthera 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 diseases and/or receiving cytotoxic chemotherapy; very rarely-vasculitis, mainly cutaneous (leukocytoclastic).

From the respiratory system: respiratory failure and pulmonary infiltrates due to infusion reactions; in addition to adverse reactions from the lungs due to infusion reactions, interstitial lung disease was observed, in some cases with a fatal outcome.

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

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

From the nervous system: rarely-craniocerebral nerve neuropathy in combination with or without peripheral neuropathy (marked decrease in visual acuity, hearing, damage to other sensory organs, facial nerve paresis) during various periods of therapy up to several months after the end of treatment with Mabthera®. Patients treated with Mabthera have been reported to develop posterior reversible encephalopathy syndrome (PRES)/posterior reversible leukoencephalopathy syndrome (PRLS). Symptoms included visual impairment, headache, seizures, and mental disorders, whether or not accompanied by an increase in blood pressure. The diagnosis of PRES/PRLS can be confirmed using brain imaging techniques. In these cases, 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 and reactions at the injection site: rarely – serum sickness.

Infections: reactivation of viral hepatitis B (in most cases with a combination of Mabthera® 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 Mabthera was prescribed for indications not prescribed in the medical instructions, patients with previously diagnosed Kaposi’s sarcoma experienced sarcoma progression (most of the patients were HIV-positive).

From the gastrointestinal tract: perforation of the stomach and / or intestines (possibly fatal) in combination with Mabthera® with chemotherapy for non-Hodgkin’s lymphoma.

From the blood and lymphatic system: rarely-neutropenia, which occurred 4 weeks after the last use of rituximab; transient increase in IgM concentration in patients with Waldenstrom’s macroglobulinemia, followed by a return to its original value after 4 months.

Post-marketing use of Mabthera for rheumatoid arthritis, granulomatosis with polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis

The following are adverse reactions that have been observed in patients with rheumatoid arthritis with post-marketing use of Mabthera®, and are also expected, or have been observed in patients with granulomatosis with polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis.

Infections: PML, hepatitis B virus reactivation.

On the part of the body as a whole, reactions at the injection site: reactions resembling serum sickness; severe infusion reactions, in some cases with a fatal outcome.

From the skin and its appendages: very rarely – toxic epidermal necrolysis and Stevens-Johnson syndrome, in some cases with a fatal outcome.

From the blood and lymphatic system: rarely-neutropenia (including severe cases with late manifestation and cases of prolonged neutropenia), some of which have been associated with fatal infections.

Nervous system disorders: cases of PRES/PRLS have been reported in patients treated with Mabthera. Symptoms included visual impairment, headache, seizures, and mental disorders, whether or not accompanied by an increase in blood pressure. The diagnosis of PRES/PRLS can be confirmed using brain imaging techniques. In these cases, patients had risk factors for developing PRES/PRLS, such as elevated blood pressure, immunosuppressive therapy, and/or other concomitant therapy.

Interaction

Data on drug interactions with Mabthera are limited.

In patients with chronic lymphocytic leukemia, concomitant use of Mabthera®, fludarabine and cyclophosphamide did not change the pharmacokinetic parameters.

Concomitant use of methotrexate does not affect the pharmacokinetics of rituximab in patients with rheumatoid arthritis.

When prescribed with other monoclonal antibodies for diagnostic or therapeutic purposes, patients with antibodies against mouse proteins or anti-chimeric antibodies have an increased risk of allergic reactions.

In patients with rheumatoid arthritis, the incidence of serious infections during therapy with Mabthera® (before therapy with other biologic-based anti-inflammatory drugs (DMARDs)) It is 6.1 per 100 patient-years, while during subsequent therapy with other DMARDs-4.9 per 100 patient-years.

When Mabthera® is administered, polyvinyl chloride or polyethylene infusion systems or bags can be used due to the compatibility of the material with the drug.

How to take, course of use and dosage

Rules for preparation and storage of the solution

The required amount of the drug is collected 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 infusions or 5% dextrose solution (solutions should be sterile and non-pyrogenic). For mixing, carefully turn the bottle (bag)over to avoid foaming. Before use, it is necessary to inspect the solution for the absence of foreign impurities or discoloration.

The doctor is responsible for the preparation, conditions, and storage time of the finished solution prior to use.

Since Mabthera® does not contain preservatives, the prepared solution should be used immediately.

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

Mabthera® is administered only by intravenous drip, through a separate catheter! It is impossible to administer the drug intravenously in a jet or bolus!

The recommended initial rate of the first infusion is 50 mg / h, then it can be increased by 50 mg/h every 30 minutes, bringing up to a maximum rate of 400 mg / h.

Subsequent infusions can be started at a rate of 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 reduce the dose of rituximab. If Mabthera is administered in combination with chemotherapy, the dose reduction of chemotherapeutic agents is carried out in accordance with standard recommendations.

Standard dosage regimen

Low-grade non-Hodgkin’s lymphoma or follicular

Before each infusion of Mabthera®, premedication should be performed (analgesic/antipyretic, for example, paracetamol; antihistamine, for example, diphenhydramine). If Mabthera® is not used in combination with chemotherapy containing corticosteroids, then the premedication also includes CORTICOSTEROIDS.

Initial therapy

Monotherapy of adult patients: 375 mg / m2 once a week, for 4 weeks.

In combination with chemotherapy according to any regimen: 375 mg / m2 on the first day of the chemotherapy cycle after intravenous use of corticosteroids as a component of therapy, during:

• 8 cycles (cycle: 21 days) in the scheme of R-CVP (rituximab, cyclophosphamide, vincristine, prednisone);
• 8 cycles (cycle: 28 days) in the scheme of R-MCP (rituximab, mitoxantrone, chlorambucil, prednisolone);
• 8 cycles (cycle: 21 days) in the scheme of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone); in the case of complete remission after 4 cycles may be limited to 6 cycles;
• 6 cycles (cycle: 21 days) in the scheme of R-CHVP-Interferon (rituximab, cyclophosphamide, doxorubicin, teniposide, prednisone+interferon).

Repeated use in case of relapse (in patients who responded to the first course of therapy): 375 mg / m2 once a week, for 4 weeks.

Maintenance therapy (after response to induction therapy):

• in previously untreated patients: 375 mg / m2 once every 2 months, no more than 2 years (12 infusions). If signs of disease progression appear, Mabthera therapy should be discontinued;for recurrent or chemo-resistant lymphoma: 375 mg / m2 once every 3 months, no more than 2 years.
• If signs of disease progression appear, Mabthera therapy should be discontinued.

Diffuse B-large cell non-Hodgkin’s lymphoma

Before each infusion of Mabthera®, premedication should be performed (analgesic/antipyretic, for example, paracetamol; antihistamine, for example, diphenhydramine). If Mabthera® is not used in combination with chemotherapy containing corticosteroids, then the premedication also includes CORTICOSTEROIDS.

In combination with chemotherapy according to the CHOP scheme: 375 mg / m2 on the first day of each chemotherapy cycle after intravenous use of corticosteroids,8 cycles. Other components of the CHOP regimen (cyclophosphamide, doxorubicin, and vincristine) are administered after Mabthera is prescribed.

Chronic lymphocytic leukemia

Before each infusion of Mabthera®, premedication should be performed (analgesic/antipyretic, for example, paracetamol; antihistamine, for example, diphenhydramine). If Mabthera® is not used in combination with chemotherapy containing corticosteroids, then the premedication also includes CORTICOSTEROIDS.

In combination with chemotherapy (in patients who have not previously received standard therapy and with recurrent / chemo-resistant lymphocytic leukemia): 375 mg / m2 on the first day of the first cycle, then 500 mg / m2 on the first day of each subsequent cycle,6 cycles. Chemotherapy is performed after use of Mabthera®.

To reduce the risk of tumor lysis syndrome, prophylactic provision of adequate hydration and use of uricostatics 48 hours before the start of therapy is recommended. In patients with chronic lymphocytic leukemia and a lymphocyte count >25,000/µl, intravenous use of prednisone/prednisolone at a dose of 100 mg 1 hour before the infusion of Mabthera® is recommended to reduce the frequency and severity of acute infusion reactions and/or cytokine release syndrome.

Rheumatoid arthritis

Before each infusion of Mabthera®, premedication should be performed (analgesic/antipyretic, for example, paracetamol; antihistamine, for example, diphenhydramine). In addition, corticosteroids should be premedicated to reduce the frequency and severity of infusion reactions. Patients should receive 100 mg of methylprednisolone IV 30 minutes before the start of each Mabthera infusion.

Initial therapy: 1000 mg IV drip, slowly,1 time in 2 weeks, course – 2 infusions.

Repeated use: the need for repeated courses of therapy is recommended to be evaluated 24 weeks after the previous course. Repeated use is performed if there is residual disease activity or if the disease activity increases by more than 2.6 according to DAS28-ESR (disease activity index for 28 joints and erythrocyte sedimentation rate). Repeat courses can be scheduled no earlier than 16 weeks after the previous course.

Recommended dosage regimen for repeated use: 1000 mg 1 time in 2 weeks, course – 2 infusions.

Granulomatosis with polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis

Before each infusion of Mabthera®, premedication should be performed (analgesic/antipyretic, for example, paracetamol; antihistamine, for example, diphenhydramine).

Recommended dosage regimen:

• therapy with corticosteroids is recommended to start within 2 weeks prior to the first infusion of MabThera® or on the day of the first infusion of MabThera® methylprednisolone (V/V) at a dose of 1000 mg/day with a duration from 1 to 3 days, then oral prednisolone at a dose of 1 mg/kg/day (not to exceed 80 mg/day) with gradual reduction in the dose of the latter to the complete abolition (the rate of dose reduction is determined by the particular clinical situation). Oral corticosteroid therapy can be continued during and after the end of Mabthera ® use;
• Mabthera® – 375 mg / m2 once a week, for 4 weeks.

Prevention of pneumocystic pneumonia (caused by Pneumocystis jiroveci) is recommended during and after completion of therapy with Mabthera® in patients with granulomatosis with polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis.

Dosage in special cases

No dose adjustment is required in patients over 65 years of age.

Overdose

No cases of overdose in humans have been observed.

Single doses of rituximab greater than 1000 mg have not been studied.

The maximum dose of 5000 mg was given to patients with chronic lymphocytic leukemia; no additional safety data were obtained.

Due to the increased risk of infectious complications due to depletion of the B-lymphocyte pool, the infusion of Mabthera® should be discontinued, the patient’s condition should be monitored, and a detailed general blood test should be prescribed.

Special instructions

In the patient’s medical documentation, the trade name of the drug (Mabthera®) should be indicated. Replacement of the drug with any other biological drug requires approval from the attending physician. The information provided in these instructions applies only to Mabthera®.

The drug Mabthera® is administered under the close supervision of an oncologist, hematologist or rheumatologist in the presence of the necessary conditions for resuscitation.

Non-Hodgkin’s lymphoma and chronic lymphocytic leukemia

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. Fatal infusion reactions have been reported during post-marketing use of the drug. Most patients develop fever with chills or tremors within 0.5-2 hours after the first infusion of Mabthera. Severe reactions include symptoms from the lungs, low blood pressure, urticaria, angioedema, nausea, vomiting, weakness, headache, itching, irritation of the tongue or pharyngeal edema (vascular edema), rhinitis, hot flashes, pain in the foci of the disease and, in some cases, signs of rapid tumor lysis syndrome. Infusion reactions disappear after interrupting the use of Mabthera® and drug therapy (including intravenous use of 0.9% sodium chloride solution, diphenhydramine and acetaminophen, bronchodilators, corticosteroids, etc. ). In most cases, after the complete disappearance of symptoms, the infusion can be resumed at a rate of 50% of the previous one (for example,50 mg/h instead of 100 mg/h). In most patients with non-life-threatening infusion reactions, rituximab treatment was fully completed. Continuation of therapy after complete disappearance of symptoms is rarely accompanied by repeated development of severe infusion reactions.

Due to the potential development of anaphylactic reactions and other hypersensitivity reactions with intravenous use of protein preparations, it is necessary to have means for their relief: epinephrine, antihistamines and corticosteroids.

Side effect from the lungs. Hypoxia, pulmonary infiltrates, and acute respiratory failure. Some of these events were preceded by severe bronchospasm and shortness of breath. Symptoms may increase over time or worsen clinically after initial improvement. Patients with pulmonary symptoms or other severe infusion reactions should be carefully monitored until symptoms resolve completely. Acute respiratory failure may be accompanied by the formation of interstitial infiltrates in the lungs or pulmonary edema, often manifests itself in the first 1-2 hours after the start of the first infusion. If severe lung reactions develop, rituximab infusion should be stopped immediately and intensive symptomatic therapy should be prescribed. Since the initial improvement in clinical symptoms may be followed by deterioration, patients should be carefully monitored until the resolution of pulmonary symptoms.

Rapid tumor lysis syndrome. Mabthera® mediates rapid lysis of benign or malignant CD20-positive cells. Tumor lysis syndrome is possible after the first infusion of Mabthera® in patients with a large number of circulating malignant lymphocytes.Tumor lysis syndrome includes: hyperuricemia, hyperkalemia, hypocalcemia, hyperphosphatemia, acute renal failure, increased LDH activity. Patients at risk (patients with a high tumor burden or with the number of circulating malignant cells >25,000 / µl, for example, with chronic lymphocytic leukemia or lymphoma from the mantle zone cells) need careful medical supervision and regular laboratory examination. If symptoms of rapid tumor lysis develop, appropriate therapy is performed. After complete relief of symptoms in a limited number of cases, therapy with Mabthera® was continued in combination with the prevention of rapid tumor lysis syndrome.

Patients with a large number of circulating malignant cells (>25,000 / µl) or a high tumor load (for example, with chronic lymphocytic leukemia or mantle cell lymphoma), in which the risk of extremely severe infusion reactions may be particularly high, Mabthera® should be prescribed with extreme caution, under close supervision. The first infusion of the drug in such patients should be administered at a lower rate or divided by 2 days during the first cycle of therapy and in each subsequent cycle, if the number of circulating malignant cells persists >25,000 / µl. >

Side effect from the cardiovascular system. During the infusion process, patients with a history of cardiovascular disease should be closely monitored for the possibility of angina, arrhythmia (flutter and atrial fibrillation), heart failure, or myocardial infarction. Due to the possibility of hypotension, antihypertensive medications should be discontinued at least 12 hours before the Mabthera infusion.

Control of shaped blood elements. Although monotherapy with Mabthera® does not have a myelosuppressive effect, caution should be exercised when prescribing the drug for neutropenia less than 1500/µl and/or thrombocytopenia less than 75,000 / µl, since the experience of its clinical use in such patients is limited. Mabthera® was used in patients after autologous bone marrow transplantation and in other risk groups with possible bone marrow dysfunction, without causing myelotoxicity phenomena. During treatment, it is necessary to regularly determine the detailed analysis of peripheral blood, including counting the number of platelets in accordance with routine practice.

Infections. Mabthera should not be used in patients with severe acute infection.

Hepatitis B. Reactivation of the hepatitis B virus or fulminant hepatitis (including fatal cases) have been reported when Mabthera was combined with chemotherapy. Predisposing factors included both the stage of the underlying disease and cytotoxic chemotherapy.

Before prescribing Mabthera®, all patients should be screened for hepatitis B. The minimum set of tests should include the determination of HBsAg and HBcAb, and the list of tests can be supplemented in accordance with local recommendations. Mabthera® should not be used in patients with active hepatitis B. Patients with positive serological markers of hepatitis B should consult a hepatologist before using Mabthera®; such patients should be appropriately monitored and measures taken to prevent reactivation of the hepatitis B virus in accordance with local standards.

Progressive multifocal leukoencephalopathy (PML). Cases of PML have been reported with Mabthera in patients with non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Most patients received Mabthera in combination with chemotherapy or in combination with hematopoietic stem cell transplantation. If neurological symptoms occur in such patients, it is necessary to conduct a differential diagnosis to exclude PML and consult a neurologist.

Skin reactions. Severe skin reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported, with some cases resulting in death. If these reactions occur, Mabthera should be discontinued.

Immunization. The safety and efficacy of immunization with live viral vaccines after treatment with Mabthera® has not been studied. Vaccination with live viral vaccines is not recommended. Vaccination with inactivated vaccines is possible, but the response rate may decrease. In patients with recurrent low-grade non-Hodgkin’s lymphoma, there was a decrease in the frequency of response to tetanus toxoid and KHL-neoantigen (KHL-hemocyanin of the fissurelian mollusk) compared with patients who did not receive Mabthera (16% vs. 81% and 4% vs. 76%, respectively; the evaluation criterion was a more than 2 – fold increase in antibody titer). However, the average antibody titer for the antigen set (Streptococcus pneumoniae, influenza A, mumps, rubella, chickenpox) did not change for at least 6 months after Mabthera therapy (when compared with the antibody titer before treatment).

Rheumatoid arthritis, granulomatosis with polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis

For other autoimmune diseases, the efficacy and safety of Mabthera have not been established.

Infusion reactions. The development of infusion reactions may be due to the release of cytokines and / or other mediators. Before each infusion of Mabthera, premedication with an analgesic/antipyretic and an antihistamine should be performed. In addition, patients with rheumatoid arthritis should receive premedication with corticosteroids before each infusion of Mabthera® to reduce the frequency and severity of infusion reactions.

In most cases, infusion reactions in patients with rheumatoid arthritis were mild or moderate in severity. Severe infusion reactions with fatal outcomes were reported during the post-marketing period. It is necessary to carefully monitor patients with previously identified diseases of the cardiovascular system, as well as those who have previously had adverse reactions from the heart and lungs. The most common infusion reactions were headache, pruritus, sore throat, hot flashes, rash, urticaria, increased blood pressure, and fever. Infusion reactions were more common after the first infusion of any course of treatment than after the second infusion. Subsequent infusions of Mabthera were more easily tolerated than the first infusions. Serious infusion reactions were observed in less than 1% of patients, most often during the first infusion of the first cycle. Infusion reactions disappear after slowing down or interrupting the use of Mabthera® and drug therapy (antipyretics, antihistamines and sometimes oxygen, intravenous use of 0.9% sodium chloride solution, bronchodilators and, if necessary, corticosteroids). If infusion reactions develop, depending on their severity and the necessary treatment, the use of Mabthera® should be temporarily suspended or discontinued.

In most cases, after the complete disappearance of symptoms, the infusion can be resumed at a rate of 50% of the previous one (for example,50 mg / h instead of 100 mg / h).

Infusion reactions observed in granulomatosis with polyangiitis and microscopic polyangiitis were consistent with those already described in rheumatoid arthritis. The lower frequency and severity of infusion reactions in granulomatosis with polyangiitis and microscopic polyangiitis could be associated with the use of high doses of corticosteroids.

Due to the potential development of anaphylactic reactions and other immediate hypersensitivity reactions with intravenous use of protein preparations, it is necessary to have means for their relief: epinephrine, antihistamines and corticosteroids.

Side effect from the cardiovascular system. Due to the possibility of hypotension, antihypertensive medications should be discontinued at least 12 hours before the infusion of Mabthera®.

Patients with a history of cardiovascular disease should be closely monitored for possible angina or arrhythmia (flutter and atrial fibrillation), heart failure, or myocardial infarction.

Infections. Due to the possible increased risk of infectious complications, Mabthera should not be used in patients with acute infection or severe immunodeficiency (hypogammaglobulinemia or low CD4, CD8 levels). Caution should be exercised when prescribing Mabthera in patients with a chronic infection or in the presence of conditions predisposing to the development of serious infections. If an infectious complication occurs, appropriate therapy should be prescribed.

Hepatitis B. When using Mabthera® in patients with rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis, cases of hepatitis B virus reactivation (including fatal outcome) were observed. Before prescribing Mabthera®, all patients should be screened for hepatitis B. The minimum set of tests should include the determination of HBsAg and HBcAb, and the list of tests can be supplemented in accordance with local recommendations. Mabthera® should not be used in patients with active hepatitis B. Patients with positive serological markers of hepatitis B should consult a hepatologist before using Mabthera®; such patients should be appropriately monitored and measures taken to prevent reactivation of the hepatitis B virus in accordance with local standards.

Progressive multifocal leukoencephalopathy (PML). During the period of post-marketing use of Mabthera® to patients with autoimmune diseases, including:with rheumatoid arthritis, fatal cases of PML have been observed. Some patients had multiple risk factors for PML: comorbidities, long-term use of immunosuppressive therapy or chemotherapy. Cases of PML have also been reported in patients with autoimmune diseases who are not receiving Mabthera. If neurological symptoms occur in such patients, it is necessary to conduct a differential diagnosis to exclude PML and consult a neurologist.

Skin reactions. Cases of severe skin reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported, in some cases with a fatal outcome. If these reactions occur, Mabthera should be discontinued.

Immunization. The safety and efficacy of immunization with live viral vaccines after treatment with Mabthera® has not been studied. Vaccination with live viral vaccines is not recommended. Vaccination with inactivated vaccines is possible, but the response rate may decrease.

Before using Mabthera® in patients with rheumatoid arthritis, the patient’s vaccination status should be studied and the appropriate recommendations should be followed. Vaccination should be completed at least 4 weeks prior to rituximab use.

After 6 months of treatment with Mabthera® and methotrexate, there was a decrease in the response rate to the introduction of polysaccharide pneumococcal vaccine (43% vs. 82%, at least 2 serotypes of antibodies to pneumococcus), KHL-neoantigen (KHL-hemocyanin of shellfish fissurelia) (34% vs. 80%) compared with methotrexate monotherapy. After treatment with Mabthera® and methotrexate, the response rate to tetanus toxoid use was similar to that after methotrexate monotherapy (39% vs. 42%).

If necessary, vaccination with inactivated vaccines should be completed at least 4 weeks before the second course of therapy.

The number of patients with rheumatoid arthritis and positive titers of antibodies to Streptococcus pneumoniae, influenza A, mumps, rubella, chickenpox and tetanus toxin before and 1 year after starting therapy with Mabthera® did not change.

Antichymal antibodies. The appearance of antichymal antibodies in most patients with rheumatoid arthritis was not accompanied by clinical manifestations or an increased risk of reactions during subsequent infusions, but rarely their presence can be associated with more severe allergic or infusion reactions with repeated infusions during subsequent courses and insufficient effect on reducing the pool of B cells during subsequent courses of therapy.

Patients with rheumatoid arthritis who have not previously received methotrexate. Mabthera® is not recommended for the treatment of patients who have not previously received methotrexate, as a favorable benefit/risk ratio for this category of patients has not been confirmed.

Use in pediatrics

The safety and efficacy of the drug in children have not been established. Hypogammaglobulinemia was observed in children with Mabthera, in some cases in severe form, which required long-term immunoglobulin replacement therapy. The consequences of depletion of the B-cell pool in children are unknown. Disposal Mabthera® should be disposed of in accordance with local regulations.

Influence on the ability to drive vehicles and other mechanisms that require increased concentration of attention

Whether rituximab affects the ability to drive and work with machines and mechanisms is unknown, although the pharmacological activity and the described adverse events do not give reason to assume such an effect.

Form of production

Concentrate for preparation of solution for infusions.

Storage conditions

In a dark place, at a temperature of 2-8 °C

Shelf

life 2.5 years

Active ingredient

Rituximab

Conditions of release from pharmacies

By prescription

Dosage form

infusion solution