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Gazyva® [Obinutuzumab]

Brand Hoffmann la roch

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Available since: 2019-09-19

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Clinical Pharmacology

Pharmacological.

Obinutuzumab is a humanized monoclonal anti-CD20 antibody of type II of the IgG1 subclass, obtained by humanizing the parent mouse antibody B-Ly1 and produced in a Chinese hamster ovary cell line using recombinant DNA technology.

Mechanism of action

Obinutuzumab is a recombinant humanized monoclonal anti-CD20 antibody of type II of the IgG1 isotype, obtained using glycoengineering. It specifically attacks the extracellular loop of the transmembrane CD20 antigen on the surface of non-cancerous and malignant pre-B and mature B lymphocytes, but not on the surface of hematopoietic stem cells, pro-B lymphocytes, normal plasma cells or other normal tissues. Glycoengineering of the Fc region of obinutuzumab results in higher affinity of Fc? RIII receptors for immune effector cells, such as natural killer cells (NK), macrophages and monocytes, compared with antibodies that were not subjected to glycoengineering.

In preclinical studies, obinutuzumab induces direct cell death and mediates antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cell phagocytosis (ADCP) by attracting Fc? RIII positive immune effector cells. In addition, in vivo, obinutuzumab mediates low complement complementary cytotoxicity (CDC). Compared with type I antibodies, obinutuzumab, a Type II antibody, is characterized by an increased ability to induce direct cell death with a concomitant decrease in CDC levels at equivalent doses. Obinutuzumab, as an antibody, was subjected to glyco-engineering, characterized by increased antibody-dependent cellular cytotoxicity (ADCC) compared with antibodies that were not subjected to glyco-engineering, at equivalent doses. In animal models, obinutuzumab mediates potent B-lymphocyte depletion and antitumor efficacy.

In a baseline clinical trial of BO21004 / CLL11, 91% (40 out of 44) of patients (who could be assessed) treated with the Gazyva ® preparation, observed depletion of B-lymphocytes (which was defined as a decrease in the number of B-lymphocytes CD19 +

Pharmacokinetics.

To analyze the pharmacokinetic (PK) data in 678 patients with non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) who participated in phase I, II and III studies, where they received obinutuzumab, a population-based PK model was constructed. This population PK model was used to describe the PK characteristics of obinutuzumab in patients with CLL.

Absorption

Obinutuzumab is injected intravenously, so the concept of absorption is not applicable. Studies in which obinutuzumab would be administered in other ways were not conducted. According to the population-based PK model, after infusion on day 1 of cycle 6, the median of C max in patients with CLL was 473.2 mcg / ml, and the AUC (τ) was at the level of 9516 mcg d / ml.

Distribution

After administration, the volume of distribution of the central compartment (2.76 L) approximately corresponds to the volume of serum, indicating that the division is largely limited to plasma and interstitial fluid.

Metabolism

Obinutuzumab metabolism was not directly studied. Antibodies are derived primarily by catabolism.

Removal

The clearance of obinutuzumab in patients with CLL in cycle 6 of treatment is approximately 0.083 l / day with a median elimination t½ of 30.3 days. Pulling obinutuzumab consists of a time-variable clearance model with two parallel paths that describe clearance, with a linear clearance path and a non-linear clearance path, which varies as a function of time. At the time of the start of treatment, the time-varying non-linear path of clearance is dominant, which accounts for the main path of clearance. With continued treatment, the effect of this path decreases, and the linear path of clearance begins to dominate.This indicates a target-mediated drug distribution (TMDD), when the initial excess of CD20 cells causes rapid depletion of obinutuzumab. However, once most CD20 cells are bound to obinutuzumab, the effect of the TMDD phenomenon on pharmacokinetics is reduced.

Pharmacokinetic-pharmacodynamic relationship

In a population pharmacokinetic analysis, it was found that sex is covariant, which explains some variability of results in different patients, since men have an equilibrium clearance (CLss) of 22% and a distribution volume (V) of 18%. However, the results of a population-based analysis showed that the differences in exposure are not significant (with cycle 6 of treatment, the calculated median AUC and C Max were respectively 11282 μg d / ml and 578.9 μg / ml in women and 8451 μg d / ml and 432 , 5 μg / ml in men), indicating that there is no need for dose adjustment through the floor.

Elderly patients

Population pharmacokinetic analysis of obinutuzumab showed that age does not affect obinutuzumab pharmacokinetics. Observations did not reveal a significant difference between obinutuzumab pharmacokinetics among patients aged 75 years (n = 128).

Children

Studies to study the pharmacokinetics of obinutuzumab in children have not been conducted.

Renal dysfunction

Population pharmacokinetic analysis of obinutuzumab showed that creatinine clearance does not affect obinutuzumab pharmacokinetics. The pharmacokinetics of obinutuzumab in patients with mild (CK 50–89 ml / min, n = 306) and moderate (CK from 30 to 49 ml / min, n = 72) impaired renal function was similar to those in patients with normal renal function (CK ³ 90 ml / min, n = 207). Data on pharmacokinetic parameters in patients with severe impaired renal function (CC 15-29 ml / min) are limited (n = 5), therefore, recommendations for dose adjustment cannot be given.

Liver dysfunction

In patients with impaired liver function, official pharmacokinetic studies have not been conducted.

Indications

Chronic lymphocytic leukemia:

- in combination with chlorambucil in patients with previously untreated chronic lymphocytic leukemia (CLL).

Composition

active ingredient: obinutuzumab;

1 bottle contains 1000 mg of Obinutuzumab, which corresponds to a concentration before dilution of 25 mg / ml;

Auxiliary substances: L-histidine; L-histidine hydrochloride, trehalose monohydrate dihydrate; poloxamer 188; water for injections.

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Dosage and Administration

The preparation of Gazyva ® should be administered under the supervision of an experienced physician and in conditions where it is possible to immediately carry out all emergency measures.

Dosage

Prevention of tumor lysis syndrome (SLS)

In order to reduce the risk of tumor lysis syndrome (see the section “Peculiarities of Use”), it is recommended that patients with high levels of lymphocytes in peripheral blood (> 25 × 10 9 / l) be treated with adequate hydration and administration of uricostatics (for example, allopurinol) for 12 -24 hours before the start of therapy.

Prevention and premedication for the prevention of infusion reactions (IR)

During the infusion of the Gazyva ®, hypotension may develop as a symptom of the infusion reaction. Because of this, it may be advisable to refrain from using antihypertensive drugs from 12:00 before the start of treatment, during the whole time of the infusion of the Gazyva ® preparation, as well as during the first hour after the introduction of the drug (see section "Features of use").

Table 1. Premedication, which must be carried out before the infusion of Gazyva ® with the aim of reducing the risk of developing infusion reactions

Day of the treatment cycle

Adverse reactions

Below are the undesirable reactions observed in clinical studies with a greater frequency (difference ≥2%) during therapy with the drug Gazyva®^® in combination with chlorambucil, compared with that on the background of therapy with chlorambucil alone or against the background of combination therapy with chlorambucil and rituximab. Adverse reactions are grouped according to MedDRA organ system classes.

Determination of the frequency of adverse reactions: very often (≥1 / 10), often (≥1 / 100 and

Injuries, poisoning and complications of manipulation: very often - infusion reactions.

On the part of the hematopoietic system: very often - neutropenia, thrombocytopenia, anemia; often - leukopenia.

Since the cardiovascular system: often - increased blood pressure, atrial fibrillation.

Infectious and parasitic diseases: often - urinary tract infections, herpes of the oral mucosa, rhinitis *, nasopharyngitis, pharyngitis.

On the part of the respiratory system: often - cough.

Metabolism: often - tumor lysis syndrome, hyperuricemia.

On the part of the musculoskeletal system: often - arthralgia, back pain, musculoskeletal pain in the chest.

Benign, malignant and unspecified neoplasms (including cysts and polyps): often - squamous cell carcinoma of the skin.

On the part of the digestive system: very often - diarrhea *; often - constipation.

On the part of the skin and subcutaneous tissues: often - alopecia.

From the laboratory indicators: often - a decrease in the number of leukocytes, a decrease in the number of neutrophils, an increase in body weight.

General reactions: very often - an increase in body temperature.

* The frequency of reports of these adverse reactions differed by less than 2% in patients receiving treatment with Gazyva®^® and chlorambucil, compared with patients receiving only chlorambucil or chlorambucil in combination with rituximab.

Fatal adverse reactions were not detected, the incidence of which would be higher by ≥2% in patients receiving treatment with Gazyva®^® and chlorambucil, compared with patients receiving only chlorambucil or chlorambucil in combination with rituximab.

Description of individual unwanted reactions

Infusion reactions: the frequency of IR is 65% with the first dose (1000 mg). In 20% of patients, an IR of 3-4 severity was observed; there were no reports of death. In 7% of IR patients, they caused cessation of treatment with Ghaziv drug.^®. The frequency of IR in subsequent injections was 3%, respectively, after the second dose of the Gazyva® preparation^®(1000 mg) and 1% after administration of subsequent doses. RV of 3-4 severity was observed only with the introduction of the first 1000 mg of the drug Ghiva^®. The complex of measures for the prevention of IR can reduce the frequency of IR, with the exception of IR 3-4 severity. The following symptoms of infusion reactions were most frequently observed: nausea, chills, low blood pressure, fever, vomiting, shortness of breath, hot flashes, high blood pressure, headache, tachycardia and diarrhea. In addition, respiratory system and heart symptoms of IR were reported, such as: bronchospasm, throat and larynx irritation, wheezing, laryngeal edema, and atrial fibrillation.

Neutropenia and infections: the incidence of neutropenia during therapy with the drug Ghiva^® in combination with chlorambucil it is 40.7%, while the incidence of infection is 38%. Neutropenia was resolved spontaneously or after therapy with G-CSF. Infectious complications of grade 3–5 were observed in 12% of patients, and the incidence of death was

Thrombocytopenia: the overall incidence of thrombocytopenia during therapy with the drug Ghaziv^® in combination with chlorambucil it was 15.4%, while acute thrombocytopenia, which develops within 24 hours after the infusion, was observed in 4% of patients. The bleeding rate was 8%. Fatal bleeding cases were reported only in the first cycle of therapy in 1% of patients. The causal relationship between thrombocytopenia and the development of bleeding has not been established.

Progressive multifocal leukoencephalopathy (PML): 1 case of PML was reported in a patient who received the Gazyva® drug^® for the treatment of non-Hodgkin's lymphoma.

Reactivation of the hepatitis B virus: cases of reactivation of the hepatitis B virus have been reported during therapy with the Ghaziv drug.^®_.

The progression of concomitant heart disease: against the background of therapy with the drug Gazyva®^® there were cases of dysfunction of the heart, incl. fatal.

Changes in laboratory parameters: a transient increase in liver enzymes (AST, ALT, alkaline phosphatase) in the serum was observed shortly after the first infusion of the Gaziv drug^®.

Contraindications

- hypersensitivity (mediated by lgE) to obinutuzumab and to other components of the drug;

- age up to 18 years (efficacy and safety of use in children have not been established);

- pregnancy;

- breastfeeding period;

- active hepatitis B and / or other infections in the active phase;

- renal failure with CK≤30 ml / min.

With care: abnormal liver function; chronic and recurrent infections in history.

Drug interactions

Special studies of interaction with other drugs have not been conducted.

The risk of interaction with concurrently used drugs cannot be completely excluded.

Pregnancy and Lactation

The drug is contraindicated during pregnancy and lactation (breastfeeding).

Women of childbearing age should use effective methods of contraception during the period of treatment with Gazyva®^® and for 18 months after the end of therapy. Newborns whose mothers received the drug Ghaza^®during pregnancy, vaccination with live vaccines should not be given until their B-cell number has returned to normal.

Obinutuzumab is excreted in breast milk in animals. Breastfeeding is not recommended during treatment and for at least 18 months after the last dose of the Ghaziv preparation.^®.

Special instructions

The medical name of the drug should be indicated in the patient's medical documentation (Gazyva®^®) and batch number. Replacing the drug with any other biological drug requires coordination with your doctor. The information provided in this description applies only to the preparation Gaziv^®.

Infusion reactions

The most frequently observed adverse reactions in patients receiving the drug Ghiva^®, were IR, developed mainly during the introduction of the first 1000 mg of the drug.The complex of measures for the prevention of IR (use of a suitable GCS, oral administration of an analgesic / antihistamine drug, omission of an antihypertensive drug in the morning on the day of the first infusion, as well as a phased dose in cycle 1) reduces the frequency of IR, except for IR 3-4 degrees. It is recommended to take measures for the prevention of IR, as described above.

The frequency and severity of infusion reactions significantly decreased after the introduction of the first 1000 mg of the Gazyva® preparation^®, and with subsequent infusions, AI did not develop in most patients.

Mostly mild to moderately severe MIs were observed, which were resolved after slowing down or temporary cessation of the first infusion, however, it is also known about severe and life-threatening MIs that require symptomatic therapy. ILs may not clinically differ from IgE-mediated allergic reactions (for example, anaphylaxis). In patients with a high tumor load (for example, with a high content of lymphocytes in the peripheral blood in CLL (> 25 × 10⁹/ l)) the risk of developing severe RI is increased. Measures for the prevention of IR are described above.

If the patient develops IR, the infusion rate should be adjusted depending on the severity of the observed reaction.

With the development of grade 4 IL, infusion should be interrupted and therapy should be completely stopped.

With the development of grade 3 IR, you should temporarily stop the infusion and carry out drug therapy necessary to eliminate the symptoms.

With the development of IR 1-2 degrees, you should slow down the infusion and conduct the necessary symptomatic therapy.

After resolving the symptoms of IR, the infusion can be resumed (except for cases of IV grade 4) at a rate 2 times lower than the rate at which the AI developed. If the patient does not experience a recurrence of the same adverse event of the same degree of severity, you can increase the infusion rate with the same step and interval as recommended in Table 2. If the rate of renewed infusion is not well tolerated, follow the infusion rate recommendations for cycle 1 , day 1 and day 2.

Therapy with Ghaziv^® should be completely stopped, in case of development:

- life-threatening acute respiratory symptoms;

- IR 4 degrees (life-threatening);

- repeated (ongoing / recurrent) TI 3 degrees.

Patients with concomitant heart or lung diseases should be closely monitored during and after the infusion. During the infusion of the drug Gaziv^® possible lowering of blood pressure. In this regard, it is necessary to consider the possibility of stopping the treatment with antihypertensive drugs for 12 hours before each infusion, during each infusion and for 1 hour after drug administration. It is necessary to evaluate the benefits and the possible risk of stopping antihypertensive drugs in patients at high risk of developing a hypertensive crisis.

Hypersensitivity reactions, incl. anaphylaxis

Against the background of therapy with Ghaziv^® possible development of anaphylaxis. Difficulties in the differential diagnosis of hypersensitivity reactions or infusion reactions.

If a hypersensitivity reaction is suspected during the infusion (symptoms develop, as a rule, in subsequent administrations, very rarely symptoms develop during the first infusion), the administration should be stopped and the therapy with Gazyva®^® should cancel.

Patients with an established IgE-mediated hypersensitivity to the drug Gazyva®^® therapy with this drug is contraindicated.

Tumor lysis syndrome

There have been cases of SLO. Patients at risk of developing SLO (patients with a high tumor load and / or high content of lymphocytes in the peripheral blood and / or kidney failure (CC

Neutropenia

Cases of severe and life-threatening neutropenia, including febrile neutropenia, have been observed. With the development of neutropenia, patients need careful observation and regular laboratory examination until the symptoms are completely resolved. If necessary, therapy should be carried out in accordance with locally accepted practice and the need for G-CSF should be considered. For any manifestation of concomitant infection, it is necessary to prescribe the appropriate treatment. It was reported about cases of neutropenia with late manifestation (occurrence no earlier than 28 days after the end of treatment) and prolonged neutropenia lasting more than 28 days after termination or cancellation of therapy.

Thrombocytopenia

There have been cases of severe and life-threatening thrombocytopenia, incl. cases of acute thrombocytopenia that developed within 24 hours after the infusion. In the 1st cycle of treatment, there were cases of bleeding with a fatal outcome. The relationship between the development of bleeding and thrombocytopenia has not been established. During treatment, patients need to be carefully monitored for the development of thrombocytopenia, especially in the 1st cycle. If thrombocytopenia is detected, regular laboratory testing is necessary until the reaction is resolved. In serious or life-threatening cases, consideration should be given to postpone the administration of the drug Gaziv^®_.The decision to conduct blood transfusion (platelet transfusion) is made by the attending physician in accordance with the practice established in the hospital. It is necessary to take into account the use of concomitant drugs that can aggravate thrombocytopenia, such as platelet aggregation inhibitors and anticoagulants, especially in cycle 1 of therapy.

The progression of concomitant heart disease

In patients with concomitant heart disease, the development of arrhythmias is possible (in particular, atrial fibrillation and tachyarrhythmia), angina pectoris, acute coronary syndrome, myocardial infarction and heart failure. These phenomena can develop during infusion reactions and be fatal. Patients with a history of heart disease need careful monitoring. In addition, in such patients, care should be taken when hydrating, avoiding the formation of excess fluid in the body.

Infections

Gaziv preparation^® should not be used if the patient has a vaktivny infection. Care should be taken when deciding on the appointment of the drug Gaziv^® in patients with recurrent and chronic infections in history. Possible development of serious bacterial and fungal infections, as well as the development or reactivation of viral infections during therapy and after its termination. Reported fatal cases of infectious diseases.

Reactivation of hepatitis B virus

Against the background of the use of anti-CD-20 drugs, it is possible to reactivate the hepatitis B virus. In some cases, it is accompanied by fulminant hepatitis, liver failure, and death is possible.

Before prescribing the drug Gaziv^® All patients should be screened for the hepatitis B virus, including the determination of HBsAg status, HBsAg status, and additional markers according to established local practice. Gaziv preparation^® should not be used in patients with active hepatitis B. Patients with positive serological markers of hepatitis B should consult a hepatologist before prescribing the drug Ghiva^®. For these patients, appropriate monitoring should be carried out and measures taken to prevent the reactivation of the hepatitis B virus in accordance with local standards.

Progressive multifocal leukoencephalopathy

With the development of new neurological symptoms or changes in existing ones, it is necessary to make a diagnosis in order to exclude PML. Symptoms of PML are not specific and may vary depending on the location of the damage. Motor symptoms associated with pyramidal disorders (in particular, muscle weakness, paralysis, sensitivity disorders), cerebellar disorders and visual field defects, and anomalies of sensitivity are often observed. Possible violations of higher cortical functions, such as aphasia or visual spatial disorientation. Diagnosis of PML may include consulting a neurologist, brain MRI, and lumbar puncture to analyze the spinal fluid for DNA of the JC virus. Therapy with Ghaziv^® it is necessary to stop at the time of the survey and completely stop it if the diagnosis of PML is confirmed. The possibility of suspending or reducing the intensity of concomitant immunosuppressive or chemotherapy should also be considered. For treatment of PML, the patient should be referred to a neurologist.

Immunization

Safety of immunization with live or attenuated antiviral vaccines after completion of therapy with Gazyva®^® has not been studied, vaccination with live antiviral vaccines during therapy and until the recovery of the B-cell pool is not recommended.

Patients with impaired renal function

In patients with CLL and moderate renal impairment (KK® in combination with chlorambucil, the incidence of serious adverse events and fatal adverse events may be higher compared with patients with QA ≥50 ml / min. Effectiveness differences between patients with QC

Elderly and senile patients

In patients with CLL aged ≥75 years, receiving therapy with Gazyva®^® in combination with chlorambucil, the incidence of serious adverse events and fatal adverse events may be higher compared with patients younger than 75 years. There are no differences in treatment efficacy between patients aged ≥75 years and patients younger than 75 years.

Instructions for the destruction of unused drug or drug expired

Contact with gaziv medicine^® into the environment should be kept to a minimum. Do not dispose of the product with waste water or with household waste. The destruction of an unused drug or a drug that has expired should be carried out in accordance with the requirements of the medical institution.

Influence on ability to drive vehicles and mechanisms

The influence of the drug Ghaziv^® The ability to drive and work with mechanisms has not been studied. With the development of infusion reactions and other adverse reactions, it is recommended to refrain from driving vehicles and mechanisms until the symptoms are completely resolved.

Overdosage

Experience exceeding the recommended dose of the drug Gazyva®^® missing. The use of doses from 50 mg to 2000 mg per single infusion has been studied. The severity and frequency of adverse reactions did not depend on the dose.

Treatment: in case of an accidental excess of the dose of the Gazyva®^® it is necessary to immediately stop the infusion or reduce the dose. In connection with the increased risk of infectious complications in case of depletion of the B-lymphocyte pool, the patient should be carefully monitored and the need for a complete general blood test should be considered.

Brand name: Gazyva®
Active ingredient: Obinutuzumab
Dosage form: Concentrate for preparing a solution for infusion in the form of a transparent or opalescent liquid from colorless to slightly brownish color.
Manufacturer: Hoffmann la roch
Country of Origin: Switzerland