Instruction for use: Acellbia

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Dosage form: Concentrate for solution for infusion

Active substance: Rituximabum

ATX

L01XC02 Rituximab

Pharmacological group:

Antitumor agent - monoclonal antibodies [Antitumor agents - monoclonal antibodies]

The nosological classification (ICD-10)

C82 Follicular [nodular] non-Hodgkin's lymphoma: Brill-Simmers disease; Malignant lymphoma; Hepatic Lymphoma; Recurrent non-Hodgkin's lymphoma; Follicular B-cell non-Hodgkin's lymphoma; Follicular lymphoma; Lymphoma of the liver

C83 Diffuse non-Hodgkin's lymphoma: Diffuse B-large-cell non-Hodgkin's lymphoma; Malignant lymphoma; Malignant lymphoma, especially of the histiocytic type; Lymphoblastic non-Hodgkin's lymphoma; Lymphoma non-Hodgkin's diffuse; Hepatic Lymphoma; Recurrence of lymphoma; Recurrent non-Hodgkin's lymphoma; Lymphoma of the liver

C85.1 B-cell lymphoma, unspecified: Chemically resistant B-cell non-Hodgkin's lymphoma; B-cell non-Hodgkin's lymphoma; Follicular B-cell lymphoma; Diffuse B-Large-Cell Non-Hodgkin's Lymphoma

C85.9 Non-Hodgkin lymphoma of unspecified type: Non-Hodgkin's lymphoma; Non-Hodgkin's Lymphomas; Non-Hodgkin's Malignant Lymphoma

C91 Lymphoid leukemia [lymphatic leukemia]: Lymphatic leukemia; Lymphoproliferative diseases; Neuroleukemia; Refractory acute lymphoblastic leukemia; Refractory lymphoblastic leukemia; Transformation of preleukemias; Chronic lymphocytic leukemia; Lymphoproliferative disorders

Composition

Concentrate for solution for infusion 1 ml

active substance: Rituximab 10 mg

Auxiliary substances: sodium citrate dihydrate - 7.35 mg; Polysorbate 80 - 0.7 mg; Sodium chloride - 9 mg; Hydrochloric acid - up to pH 6.5; Water for injection - up to 1 ml

Description of dosage form

Transparent, from colorless to light yellow liquid.

Pharmachologic effect

Mode of action - Antitumor.

Pharmacodynamics

The active component of the drug Acellbia® is rituximab, a chimeric mouse / human monoclonal antibody that specifically binds to the transmembrane CD20 antigen. This antigen is located on pre-B lymphocytes and mature B lymphocytes, but is absent on stem hemopoietic cells, pro-B cells, normal plasma cells, cells of other tissues and is expressed in more than 95% of cases with B-cell non-Hodgkin's lymphomas. The CD20 expressed on the cell after binding to the antibody is not internalized and ceases to flow from the cell membrane to the extracellular space. CD20 does not circulate in the plasma as a free antigen and therefore does not compete for binding to the antibody.

Rituximab binds to CD20 antigen on B lymphocytes and initiates immunological reactions mediating lysis of B cells. Possible mechanisms of cell lysis include complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and induction of apoptosis.

Rituximab increases the sensitivity of human B-cell lymphoma lines to the cytotoxic effect of certain chemotherapeutic drugs in vitro.

The number of B cells in the peripheral blood after the first administration of the drug is below normal and begins to recover in patients with hematologic malignancies after 6 months, reaching normal values 12 months after completion of therapy, however, the duration of the recovery period of the number of B cells can be longer.

Anti-chimeric antibodies were detected in 1.1% of the examined patients with non-Hodgkin's lymphoma.

Anti-mouse antibodies in the examined patients were not detected.

Pharmacokinetics

Non-Hodgkin's Lymphoma

According to the population pharmacokinetic analysis, in patients with non-Hodgkin's lymphoma with single or multiple administration of rituximab in monotherapy or in combination with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone), non-specific clearance (Cl1), specific clearance (Cl2) B-cells or tumor load) and Vd in plasma (Vd1) are 0.14 l / day, 0.59 l / day and 2.7 l, respectively.

The median of the terminal T1 / 2 is 22 days. The baseline level of CD19-positive cells and the size of the tumor focuses on Cl2 rituximab administered IV at a dose of 375 mg / m2 once a week for 4 weeks.

The Cl2 score is higher in patients with a higher CD19-positive cell count or larger tumor cell size. Individual variability of Cl2 persists after correction of the size of the tumor and the level of CD19-positive cells. Relatively small changes in the Vd1 index depend on the body surface area (1.53-2.32 m2) and CHOP chemotherapy and are 27.1% and 19%, respectively.

Age, sex, race, general condition on the WHO scale do not affect the pharmacokinetics of rituximab. Thus, correction of the dose of rituximab depending on the above factors does not significantly affect the pharmacokinetic variability.

The average Cmax increases after each infusion: after the first infusion is 243 μg / ml, after the fourth infusion - 486 μg / ml, after the eighth - 550 μg / ml. Cmin and Cmax of the preparation are inversely correlated with the initial number of CD19-positive B cells and the tumor burden.

With an effective treatment, the median Css of the drug is higher. Median Css of the drug is higher in patients with histological subtypes of tumor B, C and D (classification of IWF) 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 almost the same as with monotherapy.

Chronic lymphocytic leukemia

The average Cmax after the 5th infusion of rituximab at a dose of 500 mg / m2 is 408 μg / ml.

Pharmacokinetics in selected patient groups

Floor. Vd and clearance of rituximab, corrected for body surface area in men, are slightly higher than in women, dose adjustment of rituximab is not required.

Patients with renal and hepatic insufficiency. Pharmacokinetic data in patients with renal and hepatic insufficiency are absent.

Indications of the preparation Acellbia

Non-Hodgkin's lymphoma:

- relapsing or chemically resistant B-cell, CD20-positive, low-grade or follicular;

- follicular lymphoma of III-IV stage in combination with chemotherapy in previously untreated patients;

- follicular lymphoma as maintenance therapy after responding to induction therapy;

- CD20-positive diffuse large B-cell, in combination with chemotherapy according to CHOP;

Chronic lymphocytic leukemia:

- in combination with chemotherapy in patients who have not previously received standard therapy;

- relapsing or chemo-resistant, in combination with chemotherapy.

Contraindications

Hypersensitivity to rituximab, any component of the drug Acellbia® or mouse proteins;

Acute infectious diseases, severe primary or secondary immunodeficiency;

pregnancy;

The period of breastfeeding;

Children under 18 years of age (efficacy and safety not established).

With caution: respiratory failure in history or tumor pulmonary infiltration; Number of circulating malignant cells> 25000 / μL or high tumor burden; Neutropenia (<1500 / μl), thrombocytopenia (<75,000 / μl); Chronic infections.

Application in pregnancy and breastfeeding

The level of B cells in newborns with the appointment of the drug Acellbia® to women during pregnancy has not been studied.

Some newborns whose mothers received rituximab during pregnancy experienced a temporary depletion of the B-cell pool and lymphocytopenia. In this regard, rituximab should not be given to pregnant women, unless the possible benefits of therapy do not exceed the potential risk.

During the treatment period and within 12 months after the end of treatment with the drug Acellbia®, women of childbearing age should use effective methods of contraception.

It is not known whether Acellbia® is excreted in breast milk. The drug Acellbia® should not be used during lactation.

Side effects

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

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

Reports of adverse reactions were reported for 12 months after monotherapy and up to 1 month after maintenance therapy with rituximab.

Infectious and parasitic diseases: very often - bacterial and viral infections; Often - respiratory 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, clotting of blood, transient partial aplastic anemia, hemolytic anemia.

On the part of the respiratory system, chest and mediastinal organs: often - rhinitis, bronchospasm, cough, respiratory diseases, dyspnea, chest pain; Infrequently - hypoxia, impaired lung function, bronchiolitis obliterans, bronchial asthma.

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

On the part of metabolism and nutrition: often - hyperglycemia, weight loss, peripheral edema, edema of the face, increased LDH activity, hypocalcemia.

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

From the digestive tract: very often - nausea; Often - vomiting, diarrhea, indigestion, lack of appetite, dysphagia, stomatitis, constipation, abdominal pain, swelling in the throat; Infrequent - an increase in the abdomen.

On the part of the CAS: often - lowering blood pressure, increasing blood pressure, orthostatic hypotension, tachycardia, arrhythmia, atrial fibrillation *, cardiac pathology *; Infrequently - left ventricular heart failure *, ventricular and supraventricular tachycardia *, bradycardia, myocardial ischemia *, angina *.

From the nervous system: often - dizziness, paresthesia, hypoesthesia, sleep disturbance, anxiety, agitation, vasodilation; Infrequently - a perversion of taste.

Disorders of the psyche: infrequently - nervousness, depression.

On the part of the musculoskeletal system: often - myalgia, arthralgia, muscle hypertonia, back pain, neck pain, pain.

From the skin and subcutaneous tissues: very often - itching, rash; Often - hives, increased sweating at night, sweating, alopecia *.

From the side of the organ of vision: often - disturbance of lacrimation, conjunctivitis.

From the side of the hearing organ and labyrinthine disturbances: often - pain and noise in the ears.

Laboratory and instrumental data: very often - decrease in IgG level.

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

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

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

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

On the part of 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.

* Frequency is indicated on the basis of observations in the therapy of recurrent / chemostable chronic lymphocytic leukemia according to the R-FC scheme.

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

Below are the undesirable events encountered with rituximab therapy at the same frequency (or less frequently) than in the control group: hematotoxicity, neutropenic infections, urinary tract infections, septic shock, superinfections of the lung, implant infection, staphylococcal septicemia, nasal mucus, pulmonary edema , Heart failure, sensitivity disorders, venous thrombosis, incl. Deep vein thrombosis of the extremities, mucositis, edema of the lower extremities, lowering of the left ventricular ejection fraction, increased temperature, deterioration in overall well-being, bacteremia, multiple organ failure, decompensation of diabetes mellitus.

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

Infusion reactions

Monotherapy with rituximab (within 4 weeks)

More than 50% of the patients had symptoms resembling infusion reactions, most often with the first infusions. Infusion reactions include chills, shivering, weakness, dyspnoea, nausea, rash, hot flashes, fever, fever, itching, urticaria, irritation of the tongue or laryngeal edema (angioedema), rhinitis, vomiting, pain in the tumor, headache, bronchospasm . The development of signs of tumor lysis syndrome has been reported.

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

Infusion reactions of the 3rd and 4th degree of severity during infusion or within 24 hours after infusion of rituximab were observed during the first cycle of chemotherapy in 12% of patients. The frequency of infusion reactions decreased with each subsequent cycle and the frequency of infusion reactions decreased to less than 1% by the 8th cycle of chemotherapy. Infusion reactions in addition to those indicated above (with monotherapy with rituximab) 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 (within 4 weeks)

Rituximab causes depletion of the B-cell pool in 70-80% of patients and a decrease in serum immunoglobulin concentrations in a small number of patients. Bacterial, viral, fungal infections and infections without specified etiology (all, regardless of cause) develop in 30.3% of patients. Severe infections (3rd and 4th degree of severity), including sepsis, were noted in 3.9% of patients.

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

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

Cases of progressive multifocal leukoencephalopathy (PML) with fatal outcome in patients with non-Hodgkin's lymphoma after progression of the disease and re-treatment are reported.

In the treatment of rituximab according to the R-CVP scheme, there was no increase in the incidence of infections or invasions.

The most frequent 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; Life-threatening infections are not registered. The proportion of patients with infections of grade 2-4 and / or febrile neutropenia in the R-CHOP group was 55.4%. The total incidence of infections of grade 2-4 in the R-CHOP group was 45.5%. The incidence of fungal infections of grade 2-4 in the R-CHOP group was higher than in the CHOP group, due to a higher incidence of local candidiasis and was 4.5%. The frequency of herpetic infection of 2-4 degree was higher in the R-CHOP group than in the CHOP group and was 4.5%.

In patients with chronic lymphatic leukemia, the incidence of hepatitis B (exacerbation and primary infection) of the 3rd to 4th degree in the R-FC group was 2%.

On the part of the blood system

Monotherapy with rituximab (within 4 weeks)

Severe thrombocytopenia (grade 3 and 4) was noted in 1.7% of patients, severe neutropenia - in 4.2% of patients and anemia of severe severity (3rd and 4th degree of severity) in 1, 1% of patients.

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

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

Approximately 50% of patients for whom there was data on the recovery of the number of B cells, after the completion of induction therapy with rituximab, took 12 months or more to restore the number of B cells to normal levels.

Severe neutropenia and leukopenia: patients receiving rituximab in combination with chemotherapy, leukopenia of 3rd and 4th degree of severity were more often compared with patients receiving chemotherapy alone. The incidence of severe leukopenia was 88% in patients receiving R-CHOP and 23% in patients receiving R-FC. The incidence of severe neutropenia was 24% in the R-CVP group, 97% in the R-CHOP group, and 30% in the R-FC group with previously untreated chronic lymphocytic leukemia. A higher incidence of neutropenia in patients receiving rituximab and chemotherapy was not associated with an increased incidence of infections and invasions compared with patients receiving chemotherapy alone. In patients with relapsing or chemically resistant chronic lymphocytic leukemia after R-FC therapy, in some cases neutropenia was characterized by a prolonged course and later manifestation periods.

Severe anemia and thrombocytopenia (3rd and 4th degree of severity): there was no significant difference in the frequency of anemia of the 3rd and 4th degree of severity in the groups. In the R-FC group, in the first line of therapy for chronic lymphocytic leukemia, anemia of the 3rd and 4th degree of severity was found in 4% of patients, thrombocytopenia of the 3rd and 4th degree of severity in 7% of patients. In the R-FC group with recurrent or chronic lymphocytic leukemia, grade 3 and 4 anemia occurred in 12% of patients, thrombocytopenia of the 3rd and 4th degree of severity in 11% of patients.

On the part of the CAS

Monotherapy with rituximab (within 4 weeks)

Side effects from the CVS were noted in 18.8%. The most frequent increase and decrease in blood pressure. In a few cases there was a disturbance of the heart rhythm of the 3rd and 4th degree of severity (including, ventricular and supraventricular tachycardia) and angina.

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

The incidence of cardiovascular disorders of the 3rd and 4th degree was similar in patients who received rituximab and did not receive it. Serious cardiovascular disorders occurred in less than 1% of patients who did not receive rituximab, and 3% of patients who received the drug (atrial fibrillation in 1%, myocardial infarction in 1%, left ventricular failure <1%, myocardial ischemia - Y <1%).

The frequency of cardiac rhythm disorders of the 3rd and 4th degree of severity, mainly supraventricular arrhythmias (tachycardia, flutter and atrial fibrillation) in the R-CHOP group was higher and amounted to 6.9%. All arrhythmias developed either due to infusion of rituximab, or were associated with predisposing conditions such as fever, infection, acute myocardial infarction, or concomitant diseases of the respiratory system and CCC. R-CHOP and CHOP groups did not differ in the frequency of other cardiological adverse events of the 3rd and 4th degree of severity, including heart failure, myocardial disease, and IHD manifestations

The overall incidence of cardiovascular disorders of the 3rd and 4th degree was low in both the first line of therapy for chronic lymphocytic leukemia (4% in the R-FC group) and in the treatment of recurrent / chemostatic chronic lymphocytic leukemia (4% in the R- FC).

Nervous system

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

Patients (2%) of the R-CHOP group with cardiovascular risk factors developed thromboembolic disorders of the cerebral circulation during the first cycle of therapy, in contrast to patients in the CHOP group who developed circulatory disorders during the observation period without treatment. The difference between groups in the frequency of other thromboembolism was absent.

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

Concentration of IgG

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

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

Special categories of patients

Monotherapy with rituximab (within 4 weeks)

Elderly age (≥65 years): the frequency and severity of all unwanted reactions and adverse reactions of the 3rd and 4th degree of severity does not differ from that of younger patients.

Combination Therapy

Elderly age (65 years and older): with the first line of therapy, as well as in the treatment of recurrent / chemo-resistant chronic lymphocytic leukemia, the incidence of side effects of the 3rd and 4th degree of severity on the part of the blood and lymphatic system was higher compared to younger Patients.

High tumor load (diameter of single foci more than 10 cm): increased frequency of adverse reactions of the 3rd and 4th degree of severity.

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

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

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

On the part of the respiratory organs: respiratory failure and pulmonary infiltrates, caused by infusion reactions; In addition to undesirable phenomena from the lungs caused by infusion reactions, interstitial lung disease was observed, in some cases with a fatal outcome.

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

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

From the side of the nervous system: rarely neuropathy of the cranial nerves in combination with or without peripheral neuropathy (marked reduction in visual acuity, hearing loss, other sensory organs, facial nerve paresis) at various periods of therapy up to several months after completion of the rituximab treatment course . In patients treated with rituximab, reversible encephalopathy with posterior brain damage (PRES) / reversible leukoencephalopathy syndrome with posterior brain damage (PRLS) was observed. Symptoms included visual impairment, headache, convulsions, and mental disorders, accompanied by an increase in blood pressure.

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

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

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

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

On the part of the blood system and lymphatic system: rarely - neutropenia, which occurred 4 weeks after the last introduction of rituximab; Transient increase in IgM level in patients with Waldenstrom macroglobulinemia with subsequent return to its initial value after 4 months.

Interaction

Data on drug interactions of rituximab are limited.

In patients with chronic lymphocytic leukemia with simultaneous application of rituximab, fludarabine and cyclophosphamide, pharmacokinetic parameters do not change.

There are no clinical studies data on the presence of a synergistic effect with the use of the drug Acellbia® in combination with chemotherapy.

When administered with other monoclonal antibodies for diagnostic or therapeutic purposes, patients with antibodies against mouse proteins or anti-chimera antibodies increase the risk of allergic reactions.

With the introduction of the drug Acellbia®, PVC or PE infusion systems or bags can be used due to the compatibility of the material with the preparation.

Dosing and Administration

Rules of preparation and storage of a solution

The necessary amount of Acellbia® is taken under aseptic conditions and diluted to the calculated concentration (1-4 mg / ml) in the infusion bottle (package) with 0.9% sodium chloride solution for infusions or 5% dextrose solution (the solutions must be sterile and pyrogen-free ). For mixing, gently invert the vial (packet) to avoid foaming. Before administration, it is necessary to inspect the solution for any foreign matter or discoloration.

The doctor is responsible for the preparation, conditions and time of storage of the finished solution before its use. Since the preparation Acellbia® does not contain preservatives, the prepared solution must be used immediately. The prepared infusion solution is physically and chemically stable for 12 hours at room temperature or for a maximum of 24 hours at a temperature of 2 to 8 ° C.

A prepared solution of the drug Acellbia® is administered only IV, drip, through a separate catheter! Enter the drug in / in a stream or bolusno it is impossible!

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

Correction of dose during therapy

Reduce the dose of Acellbia® is not recommended. If Acellbia® is administered in combination with chemotherapy, a reduction in the dose of chemotherapeutic drugs is carried out in accordance with standard recommendations.

Standard dosing regimen

Non-Hodgkin's lymphoma of low grade or follicular

Before each infusion of the drug Acellbia®, premedication should be performed (analgesic / antipyretic, for example, paracetamol; antihistamine, eg diphenhydramine). If Acellbia® is not used in combination with chemotherapy containing glucocorticosteroids, then SCS is also part of the premedication.

Initial therapy:

- monotherapy in adult patients: 375 mg / m2 once a week, for 4 weeks;

- in combination with chemotherapy under any scheme: 375 mg / m2 on the first day of the chemotherapy cycle after intravenous administration of GCS as a component of therapy, during:

A) 8 cycles (cycle 21 days) with the R-CVP scheme (rituximab, cyclophosphamide, vincristine, prednisolone);

B) 8 cycles (cycle 28 days) with the R-MCP scheme (rituximab, mitoxantrone, chlorambucil, prednisolone);

C) 8 cycles (21 day cycle) with the R-CHOP scheme (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone); In case of achieving complete remission after the 4th cycle, it is possible to limit to 6 cycles;

D) 6 cycles (21 day cycle) with the R-CHVP-Interferon scheme (rituximab, cyclophosphamide, doxorubicin, teniposide, prednisolone + 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.

Supportive therapy (after responding to induction therapy):

- in previously untreated patients: 375 mg / m2 every 2 months, no more than 2 years (12 infusions). If signs of disease progression appear, rituximab should be discontinued;

- with relapsing or chemo-resistant lymphoma: 375 mg / m2 every 3 months, no more than 2 years. If signs of disease progression appear, therapy with Acellbia® should be discontinued.

Diffuse B-Large-Cell Non-Hodgkin's Lymphoma

In combination with CHOP chemotherapy: 375 mg / m2 on the first day of each cycle of chemotherapy after intravenous administration of GCS, 8 cycles. Other components of the CHOP scheme (cyclophosphamide, doxorubicin and vincristine) are administered after the administration of the drug Acellbia®.

Chronic lymphocytic leukemia

Before each infusion of the drug Acellbia®, premedication should be performed (analgesic / antipyretic, for example, paracetamol; antihistamine, eg diphenhydramine). If rituximab is not used in combination with chemotherapy containing GCS, then SCS is also included in the premedication.

In combination with chemotherapy (in patients who had not previously received standard therapy and with relapsing / 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 the administration of the drug Acellbia®.

To reduce the risk of developing tumor lysis syndrome, preventive maintenance of adequate hydration and the introduction of uricostatics 48 hours before the start of therapy are recommended. In patients with chronic lymphocytic leukemia and a lymphocyte count> 25000 / μL, the administration of prednisone / prednisolone 100 mg / hour prior to infusion of rituximab is recommended to reduce the incidence and severity of acute infusion reactions and / or cytokine release syndrome.

Dosing in special case

Elderly age. In patients older than 65 years, dose adjustment is not required.

Overdose

Cases of overdose in humans were not observed.

Single doses of rituximab above 1000 mg have not been studied. The maximum dose of 5000 mg was given to patients with chronic lymphocytic leukemia, no additional safety data was obtained. In connection with the increased risk of infectious complications when the B-lymphocyte pool is depleted, it is necessary to cancel or reduce the infusion rate, to consider the need for a detailed general blood test.

Special instructions

The drug Acellbia® is administered under the supervision of an oncologist or hematologist, provided that the necessary conditions for resuscitation are available.

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. There are reports of lethal infusion reactions described during the post-marketing use of the drug. In most patients within 30 minutes - 2 hours after the onset of the first infusion of rituximab, a fever with chills or tremors occurs. Severe reactions include symptoms on the part of the lungs, lowering blood pressure, urticaria, angioedema, nausea, vomiting, weakness, headache, itching, tongue irritation or swelling of the pharynx (vascular edema), rhinitis, hot flashes, pain in the foci of the disease and in some cases - Signs of fast tumor lysis syndrome. Infusion reactions disappear after the interruption of rituximab administration and drug therapy (intravenous infusion of 0.9% sodium chloride solution, diphenhydramine and acetaminophen, bronchodilators, GCS, etc.). In most cases, after complete disappearance of the symptoms, the infusion can be resumed at a rate of 50% of the preceding (for example, 50 instead of 100 mg / h). In most patients with life-threatening infusion reactions, the course of treatment with rituximab was completely completed.

Continuation of therapy after complete disappearance of symptoms is rarely accompanied by repeated development of severe infusion reactions.

In connection with the potential for the development of anaphylactic reactions and other hypersensitivity reactions with / in the administration of protein preparations, it is necessary to have the means for their reduction: adrenaline, antihistamines and GCS.

Side effect of the lungs. Hypoxia, pulmonary infiltrates and acute respiratory failure. Some of these phenomena were preceded by severe bronchospasm and shortness of breath. Perhaps the increase in symptoms over time or clinical deterioration after initial improvement. Patients with pulmonary symptoms or other severe infusion reactions should be carefully observed until the symptoms are completely resolved. Acute respiratory failure may be accompanied by the formation of interstitial infiltrates in the lungs or pulmonary edema, often manifested in the first 1-2 hours after the start of the first infusion. With the development of severe reactions from the lungs, infusion of rituximab should be stopped immediately and intensive symptomatic therapy should be prescribed. Since the initial improvement in clinical symptoms may be replaced by worsening, patients should be carefully monitored before resolution of pulmonary symptoms.

Syndrome of rapid lysis of the tumor. Rituximab mediates the rapid lysis of benign or malignant CD20-positive cells. Tumor lysis syndrome is possible after the first infusion of rituximab in patients with a large number of circulating malignant lymphocytes. Tumor lysis syndrome includes: hyperuricemia, hyperkalemia, hypocalcemia, hyperphosphatemia, acute renal failure, increased LDH level. Patients at risk (patients with high tumor burden or a large number of circulating malignant cells (> 25000 / μl), such as chronic lymphocytic leukemia or lymphoma from the cells of the mantle zone) need careful medical supervision and regular laboratory testing. When developing symptoms of rapid lysis of the tumor, appropriate therapy is carried out.

After complete relief of symptoms in a limited number of cases, rituximab therapy was continued in conjunction with the prevention of rapid tumor lysis syndrome.

Patients with a large number of circulating malignant cells (> 25,000 / mm3) or a high tumor burden (eg with chronic lymphocytic leukemia or mantle cell lymphoma) who are at risk of extremely severe infusion reactions may be particularly high, Acellbia® should be administered with extreme caution , Under close supervision. The first infusion of the drug in such patients should be administered at a lower rate or divided the dose of the drug for two days during the first cycle of therapy and every subsequent cycle if the number of circulating malignant cells remains> 25000 / μL.

Side effect from the CVS. During the infusion, careful monitoring of patients with a history of cardiovascular disease is required in connection with the possibility of developing angina pectoris, arrhythmia (flutter and atrial fibrillation), heart failure or myocardial infarction. Because of the possibility of developing hypotension at least 12 hours before the infusion of rituximab, antihypertensive drugs should be discontinued.

Control of blood elements. Although rituximab monotherapy does not have a mielosuppressive effect, caution should be taken to prescribe the drug for neutropenia of less than 1500 / μL and / or thrombocytopenia of less than 75,000 / μL, as the experience of its clinical use in such patients is limited. Rituximab was used in patients after autologous bone marrow transplantation and in other risk groups with possible disruption of bone marrow function without causing the effects of myelotoxicity. During the 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. The drug Acellbia® should not be administered to patients with severe acute infection.

Hepatitis B. In the appointment of a combination of rituximab with chemotherapy, exacerbation of hepatitis B or fulminant hepatitis (including fatal outcome) was noted. Predisposing factors included both the stage of the underlying disease and cytotoxic chemotherapy.

Before prescribing Acellbia®, all patients should be screened for hepatitis B according to local guidelines. Acellbia® should not be used in patients with active hepatitis B. Patients with positive serological markers of hepatitis B should consult a hepatologist before using rituximab; In respect of such patients, it is necessary to conduct appropriate monitoring and take measures to prevent the reactivation of the hepatitis B virus in accordance with local standards.

Progressive multifocal leukoencephalopathy (PML). The use of rituximab in patients with non-Hodgkin's lymphoma and chronic lymphocytic leukemia was observed in cases of PML. Most patients received rituximab in combination with chemotherapy or in combination with hematopoietic stem cell transplantation. If neurologic symptoms occur in these patients, differential diagnosis should be performed to exclude PML and consult a neurologist.

Skin reactions. The cases of development of such severe skin reactions as toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported, in some cases with fatal outcome. When identifying such reactions, Acellbia® should be discontinued. The issue of the resumption of rituximab should be addressed individually, taking into account the benefit-risk relationship for each individual patient.

Immunization. The safety and effectiveness of immunization with live viral vaccines after treatment with rituximab has not been studied. Vaccination with live viral vaccines is not recommended. Vaccination with inactivated vaccines is possible, but the frequency of response may be reduced. In patients with recurrent non-Hodgkin's lymphoma of low grade, there was a decrease in the response rate for tetanus toxoid and KNL-neoantigen (KHL-hemocyanin fisurelia) compared with patients who did not receive rituximab (16 vs. 81% and 4 vs 69% More than 2-fold increase in the antibody titer), respectively). However, the average antibody titre to the antigen set (Streptococcus pneumonia, Influenza A, parotitis, rubella, chickenpox) did not change for at least 6 months after rituximab therapy (when compared with antibody titers prior to treatment).

Influence on the ability to drive vehicles and mechanisms. Does the drug Acellbia® affect the ability to drive vehicles and work with machines and mechanisms - is unknown.

Release Form

Concentrate for solution for infusion, 10 mg / ml.

For 10 ml, 30 ml or 50 ml of the drug in the bottles of colorless neutral glass I hydrolytic class, sealed with rubber stoppers with the rolling of aluminum caps.

On 2 fl. (10 ml of the preparation) in a contour cell box made of PVC film. 1 contour squamut package is placed in a pack of cardboard.

On 1 fl. (30 ml or 50 ml of the drug) is placed in a pack of cardboard.

Manufacturer

CJSC BIOCAD, Russia

Conditions of supply of pharmacies

On prescription.

Storage conditions of the drug Acellbia

In the dark place at a temperature of 2-8 ° C (do not freeze).

Keep out of the reach of children.

Shelf life of the drug Acellbia

2,5 years.

Do not use after the expiry date printed on the package.

Instructions

Instruction for use: Acellbia

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