Acellbia - instructions for use, dose, side effects, contraindications

auxiliary substances: sodium citrate dihydrate - 7.35 mg, polysorbate-80 - 0.70 mg, sodium chloride 9.00 mg, hydrochloric acid - up to pH 6.5, water for injection - up to 1 ml.

Description:Transparent, from colorless to light yellow liquid.

Pharmacotherapeutic group:Antitumor agent - antibodies monoclonal.

ATX: & nbsp

L.01.X.C Monoclonal antibodies

L.01.X.C.02 Rituximab

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 lower than 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 may be longer.

Anti-chimeric antibodies were detected in 1.1% of the examined patients with non-Hodgkin's lymphoma.Antimony antibodies in the examined patients were not identified.

Pharmacokinetics:

Non-Hodgkin's Lymphoma

According to population pharmacokinetic analysis in patients with non-Hodgkin's

lymphoma with single or multiple administration of rituximab in the form of monotherapy

or in combination with chemotherapy according to the scheme CHOP (cyclophosphamide, doxorubicin,

vincristine, prednisolone) nonspecific ground clearance (CL_I), specific ground clearance (CL₂)

(probably associated with B cells or tumor load) and the volume of distribution in the

plasma (V_I) are 0.14 l / day,

0.59 l / day and 2.7 l, respectively. Median of terminal half-life (T_1/2) is 22 days. Baseline Cd 19-positive cells and the size of the tumor focuses on CL2 rituximab administered intravenously at a dose of 375 mg / m² Once a week, for 4 weeks. Index CL₂ higher in patients with higher levels Cd 19-positive cells or a large tumor tumor size. Individual variability CL₂ remains after the correction of the size of the tumor focus and level Cd 19-positive cells. Relatively small changes in the indicator V_I depend on the surface area of the body (1.53-2.32 m²) and from chemotherapy according to the scheme CHOP and account for 27.1% and 19.0%, respectively. Age, sex, race, general condition on the WHO scale (World Health Organization) do not affect the pharmacokinetics of rituximab. Thus, dose adjustment of rituximab, depending on the above factors, does not significantly affect the pharmacokinetic variability.

The mean maximum concentration (Cmah) increases after each infusion: after the first infusion is 243 μg / ml, after the fourth infusion - 486 μg / ml, and after the eighth - 550 μg / ml. The minimum and maximum concentrations of the drug are inversely correlated with the original number Cd 19-positive B cells and the magnitude of the tumor burden. With effective treatment, the median equilibrium concentration of the drug is higher. The median of the equilibrium concentration of the drug is higher in patients with histological subtypes of tumor B, C and D (classification IWF), 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 chemotherapy CHOP was almost the same as with monotherapy. According to their own comparative study of the pharmacokinetics of rituximab in patients with low-grade non-Hodgkin's lymphoma, the area under the concentration-time curve in the Accembia® group was 16170.57 (μg / ml) hch, with MabThera® 17608.42 μg / ml) hch, rituximab clearance was 43.87 ml / (hxkg) and 43.17 ml / (hxkg), respectively. The maximum concentration CmAcellbia® was 172.19 μg / ml, and the time to reach Tmah - 31.17 h, in the MabThera group, similar indicators were 190.68 mcg / ml and 37.47 h respectively. The half-life (T_1/2) was in the group of the drug Acellbia® 49.60 h, in the MabThera® group 48.95 h. The ratio of the geometric mean AUC0-168 of the drug Acellbia® and the preparation MabThera was 80.13 - 118.18%, the ratio of the geometric mean CmAcellbia® preparation and MabThera® preparation - 81.82 -115.82%, which demonstrates the equivalence of the pharmacokinetic properties of Accebbium® and MabThera® when administered intravenously to patients.

Chronic lymphatic leukemia

The mean maximum concentration (Cmah) after the fifth infusion of rituximab in a dose of 500 mg / m² is 408 μg / ml.

Pharmacokinetics in selected patient groups

Floor: the volume of distribution and clearance of rituximab, adjusted for the body surface area in men is slightly larger than that of 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:

Non-Hodgkin's Lymphoma

- Recurrent or chemically resistant B-cell, C020-positive non-Hodgkin's lymphoma of low grade or follicular.

- Follicular lymphoma III-IV stages in combination with chemotherapy in previously untreated patients.

- Follicular lymphoma as maintenance therapy after responding to induction therapy.

- C020-positive diffuse B-large-cell non-Hodgkin's lymphoma in combination with chemotherapy according to the scheme CHOP.

Chronic lymphatic leukemia

- Chronic lymphocytic leukemia in combination with chemotherapy in patients who have not previously received standard therapy.

Recurrent or chemostatic chronic lymphocytic leukemia in combination with chemotherapy.

Contraindications:- Hypersensitivity to rituximab, to any component of the drug Acellbia® or to mouse proteins.

- Acute infectious diseases, pronounced primary or secondary immunodeficiency.

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

- Pregnancy and the period of breastfeeding.

Carefully:Respiratory failure in history or tumor pulmonary infiltration; number of circulating malignant cells> 25 x 109 / l or high tumor burden; neutropenia (less than 1.5 x 109 / l), thrombocytopenia (less than 75 x 109 / L); chronic infections.

Pregnancy and lactation:

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

The level of B cells in newborns with the appointment of Acellbia® to women in

the time of pregnancy has not been studied.

Some newborns whose mothers received rituximab during pregnancy, there was a temporary depletion of the B-cell pool and lymphocytopenia. The effectiveness and safety of the drug in pregnant women is not proven. 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.Given that immunoglobulins of IgG class circulating in the mother's blood are excreted in breast milk, Acellbia® should not be used during lactation.

Dosing and Administration:

Rules for the 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 an 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 prepared solution prior to 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 not more than 24 hours at a temperature of 2 to 8 ° C. The prepared solution of the preparation Acellbia® is administered only intravenously, drip, through a separate catheter! Enter the drug intravenously struyno or bolusno not!

Recommended initial speed first infusion 50 mg / h, in the future it can be increased by 50 mg / h every 30 minutes, bringing to a maximum speed of 400 mg / h. Subsequent infusions you can start with a speed of 100 mg / h and increase it by 100 mg / h every 30 minutes to a maximum speed 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 every infusion of the drug Acellbia®, premedication should be performed (analgesic / antipyretic, for example, paracetamol; antihistamine, for example, diphenhydramine). If Acellbia® is not used in combination with chemotherapy containing glucocorticosteroids, glucocorticosteroids also enter into the composition of the premedication. Initial therapy:

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

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

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

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

- 8 cycles (cycle: 21 days) under the scheme R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone); If complete remission is achieved after 4 cycles, it is possible to limit to 6 cycles;

- 6 cycles (cycle: 21 days) under the scheme R-CHVP-Interferon (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 1 time in 2 months, no more than 2 years (12 infusions). If signs of disease progression appear, rituximab therapy should be discontinued;

- With relapsing or chemo-resistant lymphoma: 375 mg / m² 1 time in 3 months, not 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 chemotherapy according to the scheme CHOP: 375 mg / m² on the first day of each cycle of chemotherapy after intravenous glucocorticosteroid, 8 cycles. Other components of the circuit CHOP (cyclophosphamide, doxorubicin and vincristine) is administered after the administration of the drug Acellbia®.

Chronic lymphatic leukemia

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

In combination with chemotherapy (in patients who have 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 lymphocyte count> 25 x 10⁹/ l, intravenous prednisone / prednisolone at a dose of 100 mg 1 hour prior to infusion of rituximab is recommended to reduce the incidence and severity of acute infusion reactions and / or cytokine release syndrome.

Dosirovanie in special cases

Elderly age

Patients over 65 years of age doses not required.

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 have been 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.

Disorders from the blood and lymphatic system: very often - Lakopenia, neutropenia; often - thrombocytopenia, anemia; infrequently - lymphadenopathy, bleeding disorders, transient partial aplastic anemia, hemolytic anemia.

Disturbances from 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.

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

Disorders from the metabolism and nutrition: often - hyperglycemia, weight loss, peripheral edema, facial swelling, 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.

Disorders from the gastrointestinal tract: very often - nausea; often - vomiting, diarrhea, indigestion, lack of appetite, dysphagia, stomatitis, constipation, abdominal pain, swelling in the throat; infrequently - an increase in the abdomen.

Disorders from the cardiovascular system: 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 *.

Disturbances from the nervous system: often - dizziness, paresthesia, hypoesthesia, sleep disturbance, anxiety, agitation, vasodilation; infrequently - perversion of taste.

Disorders of the psyche: infrequently - nervousness, depression.

Disorders from the musculoskeletal and connective tissue ": often - myalgia, arthralgia, muscular hypertonia, back pain, neck pain, pain. Disorders from the skin and subcoid tissue: very often - itching, rash; often - urticaria, increased sweating at night, sweating, alopecia *. Disorders from the side of the organ of vision: often - disturbed tearing, conjunctivitis. Hearing disorders and labyrinthine disorders: often - pain and noise in the ears. Laboratory and instrumental data: very often - decrease in the level of immunoglobulins class G (IgG).

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

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).

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

Disturbances from the skin and subcutaneous tissues: very often - alopecia; often - skin diseases.

General disorders and disorders at the site of administration: often - fatigue, chills. * - frequency is indicated on the basis of observations in the therapy of recurrent / chemo-resistant chronic lymphocytic leukemia according to scheme R-FC.

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

Below are the undesirable events encountered with rituximab therapy at the same frequency (or less frequently), as compared with the control group: hematotoxicity, neutropenic infections, urinary tract infections, septic shock, superinfections of the lungs, infection of implants, staphylococcal septicemia, nasal mucus, edema lung, heart failure, sensitivity disorders, venous thrombosis, incl. deep vein thrombosis of the extremities, mucositis, edema of the lower limbs, lowering the fraction of the left ventricle ejection, fever, deterioration in overall well-being, bacteremia, multiple organ failure, decompensation of diabetes mellitus.

The safety profile of rituximab in combination with chemotherapy according to MCP regimens, CHVP-IFN does not differ from that in combination with the drug with CVP, CHOP or FC in the corresponding 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, shaking, weakness, shortness of breath, nausea, rash, flushing, reduction of blood pressure, fever, itching, hives, feeling tongue irritation or swelling of the throat (angioneurotic edema), rhinitis, vomiting, pain in the foci of the tumor, headache, bronchospasm. It was reported on the development of signs of tumor lysis syndrome.

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

Infusion reactions 3 and 4 severity during infusion or within 24 hours after the Rituximab infusion occurred during the first cycle of chemotherapy in 12% of patients.

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

Infections

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 the cause) develop in 30.3% of patients. Severe infections (grade 3 and 4), including sepsis, were noted in 3.9% of patients.

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

With rituximab, an increase in the overall incidence of infections, including infections of 3-4 degrees of severity, was observed. 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 in patients with non-Hodgkin's lymphoma after progressiondisease and re-treatment.

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

In therapy with rituximab according to the scheme R-CVP there was no increase in the incidence of infections or invasions. The most frequent were upper respiratory tract infections (12.3% in the group R-CVP). Serious infections were observed in 4.3% of patients who received chemotherapy according to the scheme R-CVP; life-threatening infections are not registered. The proportion of patients with infections of 2-4 degrees of severity and / or febrile neutropenia in the group R- CHOP was 55.4%. The incidence of infections of 2-4 degrees of severity in the group R-CHOP was 45.5%. The incidence of fungal infections is 2-4 degrees of severity in the group R-CHOP was higher than in the group CHOP, due to a higher incidence of local candidiasis and was 4.5%. The frequency of herpetic infection 2-4 degrees of severity was higher in the group R-CHOP, than in the group CHOP and amounted to 4.5%.

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

On the part of the blood system

Monotherapy with pituximab (within 4 weeks)

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

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

Leukopenia (grade 3 and 4) was observed in 5% of patients, and neutropenia (3 and 4 degrees of severity) in 10% of patients who received rituximab. The incidence of thrombocytopenia (3-4 degrees of severity) was low and was <1%.

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

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

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

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

From the side of the cardiovascular system

Monotherapy with rituximab (within 4 weeks)

Side effects from the cardiovascular system were noted in 18.8%.The most common are arterial hypertension and lowering of blood pressure. In rare cases, there was a disturbance of cardiac rhythm of 3 and 4 degrees 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 3 and 4 severity was similar in patients receiving rituximab, and not receiving 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 <1%).

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

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

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

Nervous system

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

In patients (2%) of the group R-CHOP with cardiovascular risk factors, thromboembolic disorders of cerebral circulation developed during the first cycle of therapy, in contrast to patients in the group CHOP, whose cerebral circulation disorders developed during the period of observation 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, as in the first line of therapy for chronic lymphocytic leukemia (4% in the group R-FC), and in the treatment of recurrent / chemo-resistant chronic lymphocytic leukemia (3% in the group R-FC).

Concentration IgG

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

After induction therapy, concentration IgG was below the lower limit of the norm (<7 g / l) in the group receiving rituximab, and in the group not receiving the drug. In the group that did not receive rituximab, median level IgG consistently increased and exceeded the lower limit of the norm, while the median level IgG has not changed in the group receiving rituximab. In 60% of patients who received rituximab within 2 years, the level IgG remained below the lower limit. In the group without rituximab therapy, after 2 years, the level IgG 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 adverse reactions and

undesired reactions of 3 and 4 degrees 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 3 and 4 degrees of severity on the part of the blood and lymphatic system was higher than in younger patients.

High tumor load (diameter of single foci more than 10 cm): the frequency of undesired reactions of 3 and 4 severity was increased.

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

On the part of the respiratory system: respiratory insufficiency 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 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 lesions of the brain (P11E8) / reversible leukoencephalopathy syndrome with posterior brain lesions (PRLS). Symptoms included visual impairment, headache, convulsions and mental disorders, accompanied by an increase in blood pressure. Confirm diagnosis PRES/PRLS it is possible with the help of methods of visualization of the brain. In the described cases, patients had risk factors for development PRES/PRLS, such as underlying disease, increased blood pressure, 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 due to cytomegalovirus, Varicella zoster, Herpes simplex, polyomavirus JC (PML), hepatitis C virus.

When prescribing rituximab according to indications not provided for in the medical instruction, patients with previously diagnosed Kaposi's sarcoma experienced progression of the sarcoma (most patients were HIV positive).

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

On the part of the blood system and lymphatic system: rarely - neutropenia, occurring 4 weeks after the last administration of rituximab; transient rise in the level IgM in patients with Waldenstrom's macroglobulinemia followed by a return to baseline after 4 months.

Overdose:No cases of overdose were observed in humans. Single doses of rituximab above 1000 mg have not been studied. A 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 with the depletion of the B-lymphocyte pool, the speed of infusion should be abolished or reduced, and the need for a detailed general blood test should be considered.

Interaction:

Data on drug interactions of rituximab are limited. In patients with chronic lymphatic leukemia with the simultaneous use 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®, polyvinyl chloride or polyethylene infusion systems or bags can be used due to the compatibility of the material with the preparation.

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. Most patients within 30 min -2h After the onset of the first infusion of rituximab, a fever with chills or tremors appears.Severe reactions include symptoms from 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 administration of 0.9% sodium chloride solution, diphenhydramine and acetaminophen, bronchodilators, glucocorticosteroids, etc.). In most cases, after complete disappearance of the symptomatology, the infusion can be resumed at a rate of 50% of the preceding (eg 50 mg / h 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 intravenous administration of protein preparations, it is necessary to havemeans for their relief: adrenaline, antihistamine and glucocorticosteroid drugs.

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 C020-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 levels. Patients at risk (patients with high tumor burden or a large number of circulating malignant cells (> 25 x 10⁹/ l), for example, with chronic lymphocytic leukemia or lymphoma from the cells of the mantle zone) require careful medical supervision and regular laboratory testing. With the development of 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 x 10⁹/ l) or high tumor load (eg, chronic lymphocytic leukemia or mantle cell lymphoma), in which the 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 slower 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> 25 x 10⁹/ l.

Side effect of the cardiovascular system. 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 monotherapy with rituximab does not have a myelosuppressive effect, caution should be taken to prescribe the drug for neutropenia of less than 1.5 x 10⁹/ l and / or thrombocytopenia less than 75 x Ю⁹/ l, since 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 a possible violation of bone marrow function without causing the phenomena 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. Before prescribing rituximab, all patients should be screened for hepatitis B. A minimum set of tests should include a definition HbsAg and HbcAb; in accordance with local recommendations, the list of tests can be supplemented. Atsellbiya® The drug should not be used in patients with active hepatitis B. Patients with positive serological markers of hepatitis B should consult a hepatologist before 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). When rituximab was used in patients with non-Hodgkin's lymphoma and chronic lymphocytic leukemia, cases PML. Most patients received rituximab in combination with chemotherapy or in combination with transplantation of hematopoietic stem cells. If neurologic symptoms occur in these patients, differential diagnosis should be made to exclude PML and a neurologist's consultation.

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

Immunization. The safety and efficacy 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 to the administration of tetanus toxoid and KHL-neoantigen (KHL - Hemocyanin mollusc fissurelia) compared with patients who did not receive rituximab (16% vs. 81% and 4% vs. 69% (evaluation criterion - more than 2-fold increase in antibody titer), respectively). However, the average value of antibody titre to a set of antigens (Streptococcus pneumonia, Influenza A, mumps, rubella, varicella) did not change for at least 6 months after rituximab therapy (when compared with the antibody titre before treatment).

Effect on the ability to drive transp. cf. and fur:Whether the preparation of Acellbia® affects the ability to manage and work with machines and mechanisms is unknown, although the pharmacological activity and the described undesirable phenomena do not give grounds for assuming such an effect.

Form release / dosage:

Concentrate for the preparation of a solution for infusions of 10 mg / ml.

Packaging:

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

For 2 bottles (10 ml of the drug) in a contour mesh package made of PVC film. On 1 contour acheikova packing together with the instruction on application place in a pack from a cardboard.

For 1 bottle (30 ml or 50 ml of the drug), together with the instructions for use are placed in a pack of cardboard.

Storage conditions:

At a temperature of 2 to 8 ° C in a dark place. Do not freeze.

Keep out of the reach of children.

Shelf life:

2 years and 6 months.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-002420

Date of registration:04.04.2014/04.06.2014

Date of cancellation:2019-04-04

The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia

Manufacturer: & nbsp

BIOCAD, CJSC Russia

Information update date: & nbsp05.05.2016

Illustrated instructions

Instructions

Acellbia® (Acellbia®)