Composition, form of production and packaging
Concentrate for the preparation of a solution for infusions in the form of a transparent or opalescent liquid from a colorless to slightly brownish color.
1 ml of 1 fl.
epinutuzumab 25 mg 1000 mg
Excipients: L-histidine - 57.6 mg, L-histidine hydrochloride monohydrate - 89.6 mg,?,? - trehalose dihydrate - 3632 mg, poloxamer 188 - 8 mg, water d / and - up to 40 ml.
40 ml - vials of colorless glass (1) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2017.
PHARMACHOLOGIC EFFECT
Antitumor drug.
Mechanism of action
Obinutuzumab is a recombinant, humanized, type II monoclonal antibody with a modified glycosylation scheme belonging to the IgG1 class and having a specificity for the CD20 antigen. Obinutuzumab selectively interacts with the extracellular region of the transmembrane CD20 antigen located on the surface of normal and malignant mature B lymphocytes and their precursors, but does not bind to stem hemopoietic cells, pro-B lymphocytes, plasma cells, or other normal tissues.
Due to the modification of the glycosylation scheme of the Fc fragment, prenutuzumab has an increased affinity for the Fc? RIII receptors on the surface of the effector cells of the immune system, in particular natural killers, macrophages and monocytes, compared to antibodies that did not undergo such a modification.
Obinutuzumab directly induces cell death, mediates antibody-dependent cellular cytotoxicity (AZPC), and antibody-dependent cellular phagocytosis (AZKF) by attracting FcО±RIII-positive effector cells of the immune system. In addition, prenutuzumab in low degree induces complement-dependent cytotoxicity (CCC).Compared to anti-CD20 antibodies of type I, ponotusumab (type II antibody) has an increased ability to directly induce cell death in the background of a decreased ability to cause CCD. Due to the modification of the glycosylation regimen, ponutunuzumab more effectively induces AZKTS and AZKF compared to anti-CD20 antibodies that did not undergo such a modification, which is manifested in more severe depletion of the B-cell pool and increased antitumor activity.
Depletion of the CD19 + B-cell pool (up to <0.07? 10 9 / L) was observed in 91% of patients with chronic lymphocytic leukemia (CLL) after completion of therapy with ponutunumumab in combination with chlorambucil and persisted for 6 months.
Recovery of the number of B-cells occurred within 12-18 months in 35% of patients in the absence of progression and in 13% of patients with progression of the disease.
Immunogenicity
Testing for the presence of antibodies to the drug (ATA) was carried out at various time points. In 10 out of 146 patients who received the Gaziva В® drug, antibodies to the drug were detected 12 months after the completion of the last cycle of therapy. Patients showed no cases of anaphylaxis or hypersensitivity reactions associated with ATA, or a negative impact on the clinical response.
In 2 patients with indolent non-Hodgkin's lymphoma from the group of therapy with the drug GazivaВ® in combination with bendamustine and having positive results in the initial determination of human antibodies to human antibodies (ANAS - HumanAnti-HumanAntibodies), infusion reactions developed. Education ANAS to the preparation Gaziva В® during or after its use was not observed.
The results of the immunogenicity assay largely depend on various factors, the methodology of the assay, the concentration of the Gaziva В® / antibodies in serum, the concomitant medications and the nature of the underlying disease. Thus, comparing the frequency of detection of antibodies to the Gaziva В® preparation and the frequency of detection of antibodies to other biological preparations may not be informative.
PHARMACOKINETICS
Suction
Obinutuzumab is administered iv. Other ways of drug administration have not been studied. The calculated value of the median C max after infusion in cycle 6, day 1 in patients with chronic lymphocytic leukemia was 465.7 Ојg / ml, and the AUC value for the period of AUC (t) was 8961 Ојg / ml and in patients with indolent non-Hodgkin's lymphoma (INHL ) - 539.3 Ојg / ml and 10,956 Ојg / dl, respectively.
Distribution
After IV introduction, the volume of distribution in the central chamber (V c ) is 2.72 liters and is approximately equal to the volume of serum. The values ​​of Vc and Vd of ponutunuzumab in the equilibrium state (V ss ) indicate that the distribution occurs only in plasma and extracellular fluid.
Metabolism
There have not been any separate studies of the metabolism of pontumatusum. Like other antibodies, ponutuzumab is mainly exposed to catabolism.
Excretion
The prevalence of prenutuzumab in patients with CLL was approximately 0.11 l / day and in patients with INHL approximately 0.08 l / day with a median T 1/2 of26.4 days with CLL and 36.8 days for INHL.
The removal of ponunutuzumab is characterized by both linear clearance and nonlinear clearance. In the initial period of treatment, the time-dependent nonlinear clearance is the main, but with the continuation of therapy, its contribution gradually decreases, and the linear path becomes dominant. This indicates a target-mediated distribution of the drug (OMPR), in which an excess of CD20 + B cells determines a drastic decrease in the concentration of prenutuzumab in serum. When most of the CD20 + B cells are associated with ponubutuzumab, OMRP has minimal effect on the pharmacokinetics of the drug.
Pharmacokinetics in specific patient groups
According to the population analysis, the clearance in the equilibrium state and V d in men are higher by 18% and 19%, respectively. However, differences in the exposure of exogenous tonsillum in men and women are insignificant (for CLL medians AUC and C max in the 6 cycle were 11 282 Ојg / d and 578.9 Ојg / ml in women and 8451 Ојg / dl and 432.5 Ојg / ml for men, respectively, with median AUC and C max , 1372 Ојg / ml and 635.7 Ојg / ml for women and 9769 Ојg / ml for mice and 481.3 Ојg / ml for men, respectively), dose adjustment depending on sex is not required.
There were no significant differences in the pharmacokinetics of pontinumusumab in patients <65 years of age, 65 to 75 years of age, and in patients> 75 years of age.
The values ​​of the pharmacokinetic parameters of profinutuzumab in patients with mild (KK 50-89 ml / min) and mean (KK 30-49 ml / min) degree of renal failure are similar to those in patients with normal renal function (KK-90 ml / min). Data on pharmacokinetics in patients with severe renal insufficiency (QC 15-29 ml / min) are limited, so it is not possible to give special instructions for dosing.
Special studies of pharmacokinetics in patients with impaired liver function were not performed.
INDICATIONS
Chronic lymphocytic leukemia:
- in combination with chlorambucil in patients with previously untreated chronic lymphocytic leukemia (CLL).
Follicular lymphoma:
- in combination with bendamustine and subsequent maintenance monotherapy with Gaziv В® in patients with follicular lymphoma who did not respond to rituximab treatment or treatment with rituximab-containing regimens, or who developed disease progression during or after such treatment.
DOSING MODE
Infusion of the Gaziva В® drug should be performed under close supervision of a medical specialist with experience in the treatment of anaphylaxis, with access to emergency medicine.
The drug Gaziva В® is administered only IV / in a drip, through a separate catheter. You can not inject the drug intravenously in a bolus or bolus.
Preparation of the drug for administration should be carried out in aseptic conditions, The preparation Gaziva В® does not contain antimicrobial preservatives.
The dilution of the drug Gaziva В® should be carried out by highly qualified medical personnel.
For the administration of Gaziva В® , only 0.9% sodium chloride solution should be used. Do not use other solvents, in particular a solution of dextrose (5%).
The drug Gaziva В® in the form of a solution with a concentration of 0.4 mg / ml - 20 mg / ml is compatible with infusion bags of polyvinylchloride, polyethylene, polypropylene or polyolefin, with infusion systems of polyvinyl chloride, polyurethane or polyethylene, with embedded filters of polyethersulfone, 3-way stop crane of polycarbonate, with catheters made of polyesterurethane.
The solution of Gaziva В® preparation should not be frozen and shaken.
Premedication and prevention of tumor lysis syndrome (SLO)
Patients with high tumor burden and / or high lymphocyte count in peripheral blood (> 25 Г— 10 9 / L) and / or renal insufficiency (CC <70 mL / min) require the prophylaxis of OA because they are at risk of developing VL.
Prevention includes adequate hydration and the administration of hypo-uricemic drugs (eg, allopurinol or other alternative drugs) prior to infusion of the Gaziva В®preparation in accordance with standard practice. In the event that the patient's condition still meets the criteria of the OA, before each subsequent infusion it is also necessary to carry out prophylaxis of the OA.
Premedication and prevention of infusion reactions
Information on conducting premedication to reduce the risk of developing infusion reactions is given in Table 1. Premedication of GCS is recommended for patients with follicular lymphoma (PL) and is mandatory for patients with chronic lymphocytic leukemia (CLL) with the first infusion. Premedication with subsequent infusions and other types of premedication should be carried out as described below.
Given that one of the manifestations of infusion reactions may be a decrease in blood pressure, consideration should be given to the possibility of suspending treatment with antihypertensive agents for 12 hours before each infusion during the infusion and within 1 hour after its termination.
Table 1. Premedication before the introduction of the drug Gaziva В® , necessary to reduce the risk of developing infusion reactions (IR)
Day of the medication cycle Patients requiring premedication Drug application
Cycle 1 CLL Day 1, 2 FL Day1 All patients with GCS, iv *: prednisone / prednisolone 100 mg or dexamethasone 20 mg or methylprednisolone 80 mg The administration should be completed at least 1 hour prior to the onset of infusion of Gaziva В®
Analgesic / antipyretics for oral administration, for example, acetaminophen / paracetamol 1000 mg At least 30 minutes before the infusion of the drug Gaziva В®
An antihistamine, for example, diphenhydramine 50 mg
All subsequent infusions of CLL and FL Patients without IR with previous infusion Analgetic / antipyretic for oral administration, eg acetaminophen / paracetamol 1000 mg At least 30 minutes prior to the onset of infusion of Gaziva В®
Patients with MI (1 or 2 degrees) with a previous infusion Analgesic / antipyretics for oral administration, for example, acetaminophen / paracetamol 1000 mg At least 30 minutes prior to the onset of infusion of the drug Gaziva В®
An antihistamine, for example, diphenhydramine 50 mg
Patients with grade 3 infarction with prior infusion or patients with a lymphocyte count> 25 Г— 10 9 / L prior to infusion of GCS, iv *: prednisone / prednisolone 100 mg or dexamethasone 20 mg or methylprednisolone 80 mg The introduction must be completed no less than 1 h before the infusion of the drug Gaziva В®
Analgesic / antipyretics for oral administration, for example, acetaminophen / paracetamol 1000 mg At least 30 minutes before the infusion of the drug Gaziva В®
An antihistamine, for example, diphenhydramine 50 mg
* Do not use hydrocortisone, t. it is not effective for preventing IR.
Standard dosing regimen
Chronic lymphocytic leukemia (in combination with chlorambucil)
Cycle 1
The recommended dose of Gaziva В® is 1000 mg IV during the day 1 and 2, then on day 8 and day 15 of the 1st 28-day cycle as indicated in Table 2.
Table 2. Introduction of Gaziva В® in CLL
Day of the therapy cycle Dose of the drug Gaziva В® Infusion rate (if an infusion reaction occurs, the rate of infusion should be changed as indicated in Table 4)
Cycle 1 Day 1 100 mg 25 mg / h for 4 hours. Do not increase the infusion rate.
Day 2 or Day 1 (continued) 900 mg If no infusion reactions occurred during the previous infusion, the infusion rate is 50 mg / h. The infusion rate can be gradually increased in steps of 50 mg / h every 30 minutes to a maximum rate of 400 mg / h.
Day 8 1000 mg If no infusion reactions occurred during the previous infusion (the final infusion rate is 100 mg / h), the initial infusion rate is 100 mg / h and then gradually it is necessary to increase the rate in steps of 100 mg / h every 30 minutes to the maximum speed 400 mg / h.
Day 15 1000 mg
Cycles 2-6 Day 1 1000 mg
Dosing regimen of chlorambucil
The use of Gaziva В® in combination with chlorambucil has been studied for the use of chlorambucil orally at a dose of 0.5 mg / kg / day on day 1 and day 15 of each cycle of therapy (cycles 1-6).
Dose skip
If a planned dose of Gaziv В® is missed, the drug should be administered as soon as possible; Do not wait for the next scheduled introduction. Between the administrations should maintain the recommended interval.
Follicular lymphoma
Induction therapy (in combination with bendamustine)
The recommended dose of Gaziva В® is 1000 mg with administration on days 1, 8 and 15 of the first 28-day treatment cycle, followed by administration of 1000 mg on day 1 of each subsequent 28-day treatment cycle (cycles 2-6) as indicated in Table 3.
Supportive therapy
Patients who responded to induction therapy (ie, in the first 6 treatment cycles) or patients with stable disease should continue supporting therapy with Gaziv В® as a monotherapy dose of 1,000 mg once in 2 months for no more than 2 years. With the progression of the disease, therapy with GazivВ® should be discontinued.
Table 3. Introduction of the drug Gaziva В® in FL
Day of the therapy cycle Dose of the drug Gaziva В® Infusion rate (if an infusion reaction occurs, the rate of infusion should be changed as indicated in Table 4)
Cycle 1 Day 1 1000 mg 50 mg / h. The infusion rate can be gradually increased in steps of 50 mg / h every 30 minutes to a maximum rate of 400 mg / h.
Day 8 1000 mg If no infusion reactions occurred during the previous infusion (the final infusion rate is 100 mg / h), the initial infusion rate is 100 mg / h and then gradually it is necessary to increase the rate in steps of 100 mg / h every 30 minutes to the maximum speed 400 mg / h.
Day 15 1000 mg
Cycles 2-6 Day 1 1000 mg
Maintenance therapy every 2 months, no more than 2 years or until the disease progresses 1000 mg
Dosing regimen of bendamustine
The use of Gaziva В® in combination with bendamustine was studied for the dosing regimen of bendamustine 90 mg / m 2 / day IV on days 1 and 2 of all cycles of therapy (cycles 1-6).
Dose skip
If a planned dose of Gaziv В® is missed, the drug should be administered as soon as possible; Do not wait for the next scheduled introduction. During induction therapy between administrations, the planned interval should be maintained. During the maintenance therapy for the introduction of subsequent doses should adhere to the initial schedule of drug administration.
Correction of dose (all indications)
Changing the dose of Gaziva В® is not recommended.
Recommendations for changing the dosage regimen in the event of symptomatic adverse events (including infusion reactions) are presented in Table 4 and in the section "Special instructions".
4 degree (life-threatening IR) Stop the infusion and completely stop therapy.
3 degree (severe IR) - Temporarily stop the infusion and conduct symptomatic therapy. - After resolving the symptoms, resume the infusion at a rate of 2 times lower than the rate at which the infusion reactions developed. - In the future, in the absence of any symptoms of infarction, the infusion rate can be increased with the step and interval recommended in Tables 2 and 3. • In the first cycle of therapy for patients with CLL receiving the first dose of Gaziva ® , divided into 2 days, per day 1, the infusion rate can be increased one hour after the resolution of the symptoms of MI, but no more than 25 mg / h. - With the re-development of IR of the 3rd degree, the infusion should be stopped and the therapy completely discontinued.
1-2 degree (IR of light and medium degree) - Reduce the rate of infusion and conduct symptomatic therapy. - After resolving the symptoms, continue the infusion. - If the patient does not have symptoms of ID, the infusion rate can be increased in increments and intervals recommended in Tables 2 and 3. • In the first cycle of therapy for patients with CLL receiving the first dose of Gaziva ® , divided by 2 days, on day 1, the rate Infusion can be increased one hour after resolving the symptoms of TS, but not more than 25 mg / h.
Special patient groups
In elderly and senile patients, dose adjustment is not required
The effectiveness and safety of Gaziva В® in children and adolescents under the age of 18 years is not established.
Correction dose of the drug Gaziva В® in patients with impaired renal function of mild and moderate severity (CK> 30 ml / min) is not required. The effectiveness and safety of Gaziva В® in patients with QC <30 ml / min is not established.
The effectiveness and safety of Gaziva В® in patients with impaired liver function are not established.
Instructions for preparing a solution for infusions
For the first dose (1000 mg) drug Gaziva В® in the first cycle CLL it is recommended to use 2 infusion package of different sizes, which will distinguish between the dose of 100 mg, intended for administration in cycle 1 day 1 and dose 900 mg for administration in cycle 1 day 1 or day 2 (see. Table 5).
Should be selected from the vial 40 mL drug concentrate Gaziva В® .
Enter 4 ml of concentrate infusion bag with a volume of 100 ml and 36 ml of concentrate remained - in an infusion bag with a volume of 250 ml containing sterile pyrogen-free 0.9% sodium chloride solution. Label each infusion bag.
Table 5.
Dose Gaziva В® , intended for administration The required amount of concentrate formulation Gaziva В® volume infusion package
100 mg of 4 ml 100 ml
900 mg 36 ml 250 ml
1000 ml 250 mg 40 ml
Introduction Gaziva preparation В® on day 8 and day 15 and at cycle 1 day 1 of therapy cycles 2-6 CLL and during all cycles of therapy PL
from 40 ml vial away Gaziva concentrate formulation В® and put in an infusion bag made of PVC or polyolefin (non-PVC) containing a sterile, pyrogen-free 0.9% sodium chloride solution.
The package should be carefully turn the stirring solution, avoiding excess foaming.
It visually check the prepared solution for infusion for mechanical inclusions and discoloration.
From the point of view of the microbiological purity of the prepared solution for infusion should be used immediately. In exceptional cases, the prepared solution can be stored for more than 24 hours at a temperature of from 2 В° to 8 В° C, if the preparation for infusion occurred in a controlled and validated aseptic conditions. At the same time due to storage conditions (storage rules and duration) responsible professionals ready solution.
Cooked Gaziva drug solution В® physically and chemically stable for 24 hours at a temperature of from 2 В° to 8 В° C, then for 24 hours at room temperature (? 30 В° C) and then for no longer than 24 hours, during which should be completed infusion.
SIDE EFFECT
Chronic lymphocytic leukemia
following are unwanted reactions observed in clinical trials with a higher frequency (difference? 2%) on drug therapy Gaziva В® in combination with chlorambucil, compared with that during therapy with chlorambucil alone or in combination therapy with rituximab and chlorambucil. Adverse reactions are grouped into classes according to MedDRA organ systems.
The following classification is used to describe the frequency of adverse reactions: very common (1/10?), Often, infrequently, rarely (1/10 (1/100 and <1/10?) (1/1000 and <1/100?)? 000 and <1/1000) and very rare (<1/10 000), including isolated cases.
Injury, poisoning and complications of manipulation: very often - infusion reactions.
From hemopoiesis system: very often - neutropenia, thrombocytopenia, and anemia; often - leukopenia.
Cardio-vascular system: often - increased blood pressure, atrial fibrillation.
Infectious and parasitic diseases: often - urinary tract infection, mucosa of oral herpes, rhinitis *, nasopharyngitis, pharyngitis.
From the respiratory system: often - cough.
From a metabolism: often - tumor lysis syndrome, hyperuricemia.
On the part of the musculoskeletal system: often - arthralgia, back pain, musculoskeletal chest pain.
Benign, malignant and unspecified tumors (including cysts and polyps): often - squamous cell carcinoma of the skin.
From the digestive system: very often - diarrhea *; often - constipation.
Skin and subcutaneous tissue disorders: often - alopecia.
On the part of performance of laboratory and instrumental studies: often - reduced number of white blood cells, decreased number of neutrophils, the increase in body weight.
General reactions: very often - fever.
* The frequency of adverse reactions data messages differ by less than 2% of patients receiving drug treatment Gaziva В® and chlorambucil, compared with patients receiving only chlorambucil or chlorambucil in combination with rituximab.
There were no fatal adverse reactions, frequency of which would be higher by? 2% of patients receiving drug treatment Gaziva В® and chlorambucil, compared with patients receiving only chlorambucil or chlorambucil in combination with rituximab.
Non-Hodgkin's lymphoma
in a subgroup of patients with follicular lymphoma (FL), the profile of adverse reactions was consistent with that of the general population of patients with indolent non-Hodgkin's lymphoma (iNHL).
Adverse reactions described in this section (based on the safety population, which consisted of 392 patients with iNHL, 81% of which had the PL) were identified during induction therapy with Gaziva В® in combination with bendamustine supporting monotherapy Gaziva В® and during follow-up. 79.4% of patients receiving drug Gaziva В® in combination with bendamustine received all 6 cycles of therapy with Gaziva В® and 75.6% of patients received all 6 bendamustine therapy cycles as compared with 66.7% of patients in group bendamustine.
The following are adverse reactions observed in clinical trials with greater frequency (difference? 2%) during therapy with the drug GazivaВ® in combination with bendamustine during induction therapy followed by maintenance monotherapy Gaziva В® , as compared with induction therapy only bendamustine. Adverse reactions are grouped into classes according to the organ systems MedDRA a .
The following classification is used to describe the frequency of adverse reactions: very common (1/10?), Often, infrequently, rarely (1/10 (1/100 and <1/10?) (1/1000 and <1/100?)? 000 and <1/1000) and very rare (<1/10 000), including isolated cases.
Injury, poisoning and complications of manipulation: very often - infusion reactions *.
From hemopoiesis system: very often - neutropenia; often - painful lymph nodes.
Cardio-vascular system: often - heart failure.
From a sight organ: often - bloodshot eyes.
From the digestive system: very often - constipation; often - indigestion, colitis, hemorrhoids.
Infectious and parasitic diseases: very often - upper respiratory tract infection, sinusitis; often - urinary tract infection, nasopharyngitis, pharyngitis, pulmonary infection, influenza.
On the part of the musculoskeletal system: very often - arthralgia; often - pain in the limbs, bone pain.
Mental disorders: often - depression.
From the urinary system: often - dysuria, urinary incontinence.
The respiratory system:very often - cough; often - nasal congestion, rhinorrhea.
Skin and subcutaneous tissue disorders: often - itching, night sweats, eczema.
General reactions: very often - fever, asthenia; often - pain in the chest.
and coded using MedDRA adverse reactions reported by researchers (with the exception of infusion reactions).
* Defined as any related adverse event occurring during or within 24 hours after the infusion.
Not found fatal adverse reactions, the incidence of which would have been higher by ≥2% in patients receiving induction therapy with Gaziva ® and bendamustine, and then maintain monotherapy Gaziva ®Compared with patients receiving only bendamustine.
During maintenance monotherapy Gaziva В® most common adverse events were cough (14.7%) upper respiratory infection (11.9%), neutropenia (10.5%), sinusitis (9.8%), diarrhea (8.4%), infusion reactions (8.4% ), nausea (7.7%), fatigue (7.7%), bronchitis (7%), arthralgia (7%), nasopharyngitis (6.3%), urinary tract infection (6.3%) and fever (5.6%). The most common adverse reactions 3-5 severity were neutropenia (9.8%) and anemia, febrile neutropenia, thrombocytopenia, sepsis, infection of the upper respiratory tract and urinary tract infection (all with frequency 1.4%).
Description of the individual undesirable reactions
Infusion reactions
Most of the following symptoms of infusion reactions (IR) were frequently observed: nausea, vomiting, decreased blood pressure, increased blood pressure, increased body temperature, vomiting, shortness of breath, "tides", headache, tachycardia and diarrhea.
In addition, the reported symptoms of MI from the respiratory system and heart, such as bronchospasm, irritation of the throat and larynx, wheezing, laryngeal edema and atrial fibrillation.
Chronic lymphocytic leukemia
incidence of infusion reactions is 65% when administering the first dose (1000 mg). About 20% of patients experienced MI Grade 3-4, reports of deaths were absent. In 7% of patients IR caused the cessation of treatment Gaziva drug В® . IR frequency for subsequent introductions were respectively 3% after the second dose of the drug Gaziva В®(1000 mg) and 1% after administration of subsequent doses. IR Grade 3-4 only observed upon administration of the first formulation 1000 mg GazivaВ® . The complex of measures for the prevention of MI can reduce the frequency of MI except IR Grade 3-4.
Non-Hodgkin's lymphoma
In cycle 1, the overall frequency of occurrence of TS was greater in patients receiving the drug Gaziva В® and bendamustine (55%) compared with patients receiving only bendamustine (42%) (MI 3.5 severity were observed in 9% and 2 % respectively, reports of deaths were absent). In patients receiving the drug Gaziva В® and bendamustine, incidence of the IR was highest on day 1 (38%) and decreased progressively on days 2, 8 and 15 (25%, 7% and 4%, respectively).
During cycle 2 the incidence of IR was lower in patients treated Gaziva В® and bendamustine (24%) compared with patients receiving only bendamustine (32%). The incidence of MI during subsequent introductions were comparable in both groups and decreased as of each cycle. TS also observed in 8% of patients during the period of maintenance therapy with Gaziva В® . In general, 3% of patients developed TS, leading to cessation of drug treatment Gaziva В® .
Neutropenia and infection
Chronic lymphocytic leukemia
The incidence of neutropenia in the background of therapy with Gaziva В®in combination with chlorambucil is 40.7%, the rate of infection was 38%. Neutropenia resolved spontaneously or after treatment with granulocyte colony-stimulating factor. Infectious complications 3-5 severity was observed in 12% of patients, and the incidence of fatalities was <1%. Also reported cases of prolonged neutropenia (2%) and a late manifestation of neutropenia (16%).
Non-Hodgkin's Lymphoma
incidence of neutropenia in a group of drug therapy Gaziva В® and bendamustine was higher compared to the group treated only bendamustine. The incidence of infections was 66% in the drug therapy Gaziva В®and bendamustine and 57% in the group receiving only bendamustine (3-5 phenomenon severity were observed in 18% and 17%, respectively, deaths were recorded in 3% and 4%, respectively). Also reported cases of prolonged neutropenia (3% in a group of drug therapy GazivaВ® and bendamustine) and neutropenia, late-onset (7% in a group of drug therapy Gaziva В® and bendamustine).
Thrombocytopenia
Chronic lymphocytic leukemia
The overall incidence of thrombocytopenia during therapy with the drug Gaziva В®in combination with chlorambucil was 15.4%, while the acute thrombocytopenia that develops within 24 h after infusion, there was 4% of patients. Bleeding rate was 8%. About fatal cases of bleeding was reported only in the first cycle of therapy in 1% of patients. The causal relationship between the development of thrombocytopenia and bleeding has not been established.
Non-Hodgkin's Lymphoma
incidence of thrombocytopenia in a group of drug therapy Gaziva В® and bendamustine was lower (15%) compared to the group treated only bendamustine (24%). Frequency hemorrhagic events (11% in the drug therapy Gaziva В® and bendamustine, 10% in the group of bendamustine) and hemorrhagic phenomena 3-5 severity (5% in a group of drug therapy GazivaВ® and bendamustine, 3% in the bendamustine) was comparable in both treatment groups, of deaths have been reported.
Multiochagovaya progressive leukoencephalopathy (PML)
progressive leukoencephalopathy multiochagovaya registered in patients receiving the drug Gaziva В® .
Reactivation of hepatitis B
have been reported cases of reactivation of hepatitis B virus during therapy with the drug Gaziva В® .
The progression of heart disease associated
Against the background of therapy with Gaziva В® have been cases of cardiac function, including fatal.
Perforation of the digestive tract
Reported cases of perforation of the digestive tract in patients receiving the drug Gaziva В® , mostly about non-Hodgkin's lymphoma.
Changes in laboratory parameters
transient elevation of liver enzymes (AST, ALT, ALP) in the blood serum was observed shortly after the first infusion preparation Gaziva В® .
CONTRAINDICATIONS
- active hepatitis B and / or other infections in the active phase;
- Renal Failure CS 30 ml / min;?
- Pregnancy;
- the period of breastfeeding;
- the age of 18 years (effectiveness and safety of use in children has not been established);
- hypersensitivity (mediated lgE) to obinutuzumabu and to other components of the formulation.
With caution should be prescribed with abnormal liver function; chronic and recurrent infections in history.
PREGNANCY AND LACTATION
The drug is contraindicated during pregnancy and lactation (breastfeeding).
Women of childbearing potential must use effective contraception during treatment with Gaziva В® and for 18 months after completion of therapy.
It is necessary to consider the deferral of vaccination with live vaccines in infants whose mothers received the drug Gaziva В® during pregnancy, as long as the number of B cells in them will not be restored to normal.
Obinutuzumab Crafted with breast milk in animals. Breast-feeding is not recommended during treatment and, at least for 18 months after the last dose of the drug Gaziva В® .
APPLICATION FOR FUNCTIONS OF THE LIVER
Correction dose Gaziva В® in patients with impaired renal function (creatinine clearance> 30 ml / min) is required.
Efficacy and safety Gaziva drug В® patients with creatinine clearance <30 mL / min is not installed. Use of the drug in patients with renal insufficiency CS? 30 ml / min contraindicated.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Precautions should be prescribed to patients with impaired liver function.
The efficacy and safety of the drug Gaziva В® in patients with hepatic impairment have not been established.
APPLICATION FOR CHILDREN
Use of the drug in patients under 18 years is contraindicated (efficacy and safety in children has not been established).
APPLICATION IN ELDERLY PATIENTS
Dose adjustment in patients with middle and old age is not required.
SPECIAL INSTRUCTIONS
The patient's medical records should indicate the trade name of the drug (Gaziva В® ) and the batch number. Replacement of the drug to any other biological medicinal product requires agreement with the attending physician. informatio
