Gazyva^® (Concentrate) Instructions for Use

Marketing Authorization Holder

F. Hoffmann-La Roche, Ltd (Switzerland)

Manufactured By

Roche Diagnostics GmbH (Germany)

Or

Pharmstandard-UfaVITA OJSC (Russia)

Packaging and Quality Control Release

F.Hoffmann-La Roche, Ltd (Switzerland)

Or

PHARMSTANDARD-UfaVITA, OJSC (Russia)

ATC Code

L01FA03 (Obinutuzumab)

Active Substance

Obinutuzumab (Rec.INN registered by WHO)

Dosage Form

Gazyva®

Concentrate for solution for infusion 1000 mg/40 ml: vial 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion as a clear or opalescent liquid from colorless to slightly brownish.

Excipients: L-histidine, L-histidine hydrochloride monohydrate, α,α-trehalose dihydrate, poloxamer 188, water for injections.

40 ml – colorless glass vials (1) – cardboard boxes^×.

^× A protective holographic sticker is applied to the package to control the first opening.
To control the first opening, self-adhesive round stickers with the inscription “control of opening” are affixed to the package (in the case of packaging at OJSC “Pharmstandard-UfaVITA”).

Clinical-Pharmacological Group

Antitumor drug. Monoclonal antibodies

Pharmacotherapeutic Group

Antineoplastic agents, monoclonal antibodies

Pharmacological Action

Antitumor agent. Obinutuzumab is a recombinant, humanized type II monoclonal antibody with a modified glycosylation pattern, belonging to the IgG1 class and having specificity for the CD20 antigen. Obinutuzumab selectively interacts with the extracellular domain of the transmembrane CD20 antigen located on the surface of normal and malignant mature B-lymphocytes and their precursors, while it does not bind to hematopoietic stem cells, pro-B-lymphocytes, plasma cells, or other normal tissues.

Due to the modification of the glycosylation pattern of the Fc fragment, Obinutuzumab has an increased affinity for FcγRIII receptors on the surface of effector cells of the immune system, in particular natural killer cells, macrophages, and monocytes, compared to antibodies that have not undergone such modification.

Obinutuzumab directly induces cell death, mediates antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) by recruiting FcγRIII-positive effector cells of the immune system. In addition, Obinutuzumab induces complement-dependent cytotoxicity (CDC) to a low degree. Compared to type I anti-CD20 antibodies, Obinutuzumab (a type II antibody) has an increased ability to directly induce cell death against a background of a reduced ability to cause CDC. Due to the modification of the glycosylation pattern, Obinutuzumab induces ADCC and ADCP more effectively compared to anti-CD20 antibodies that have not undergone such modification, which is manifested in a more pronounced depletion of the B-cell pool and increased antitumor activity.

Depletion of the CD19+ B-cell pool (to values <0.07×10⁹/L) was observed in 91% of patients with chronic lymphocytic leukemia (CLL) after completion of therapy with obinutuzumab in combination with chlorambucil and persisted for 6 months.

Recovery of B-cell counts occurred within 12-18 months in 35% of patients without disease progression and in 13% of patients with disease progression.

Pharmacokinetics

After IV infusion, the calculated median C_max in cycle 6, day 1 in patients with chronic lymphocytic leukemia was 465.7 µg/ml, and the AUC value for the period of application AUC_(t) was 8961 µg×day/ml, and in patients with indolent non-Hodgkin’s lymphoma (iNHL) – 539.3 µg/ml and 10,956 µg×day/ml, respectively.

After IV administration, V_d in the central chamber is 2.72 L and is approximately equal to the serum volume. The V_ss values indicate that distribution occurs only in the blood plasma and extracellular fluid.

Like other antibodies, Obinutuzumab is predominantly catabolized.

The clearance of obinutuzumab 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 of 26.4 days for CLL and 36.8 days for iNHL.

The elimination of obinutuzumab is characterized by both linear clearance and non-linear clearance.

Indications

Chronic lymphocytic leukemia: in combination with chlorambucil in patients with previously untreated chronic lymphocytic leukemia.

Follicular lymphoma: in combination with bendamustine and subsequent maintenance monotherapy with obinutuzumab in patients with follicular lymphoma who have not responded to rituximab treatment or to a treatment regimen containing rituximab, or who have disease progression during or after such treatment.

Lupus nephritis class III or IV (in combination with or without class V): in combination with immunosuppressive therapy.

ICD codes

Dosage Regimen

Administer by IV infusion only. Do not administer as an intravenous push or bolus.

The standard single dose is 1000 mg administered on day 1 of each cycle, with the exception of the first cycle which utilizes a split dose.

For the first cycle, administer a split dose: 100 mg on day 1 and 900 mg on day 2.

For cycles 2-6 (or as per the specific treatment protocol), administer the full 1000 mg dose on day 1.

Premedicate prior to each infusion to reduce the risk and severity of infusion-related reactions. Administer a glucocorticoid, an antihistamine, and an antipyretic.

Initiate the infusion at a rate of 50 mg/hour. In the absence of infusion reactions, the rate may be increased in increments of 50 mg/hour every 30 minutes, up to a maximum rate of 400 mg/hour.

For the first 1000 mg dose (i.e., the 900 mg dose on day 2 of cycle 1), if the previous infusion was well tolerated, initiate at a rate of 100 mg/hour and increase by 100 mg/hour every 30 minutes to a maximum of 400 mg/hour.

For all subsequent 1000 mg infusions, if the previous infusion was well tolerated, initiate at a rate of 100 mg/hour and increase by 100 mg/hour every 30 minutes to a maximum of 400 mg/hour.

In case of an infusion reaction, interrupt the infusion immediately and manage symptoms appropriately. Upon resolution, the infusion may be resumed at a reduced rate, as per clinical judgment.

Monitor patients closely during and for several hours after the infusion for signs of infusion reactions, tumor lysis syndrome, and other adverse events.

Adverse Reactions

Infections and infestations: very common – upper respiratory tract infections, sinusitis; common – urinary tract infections, nasopharyngitis, pharyngitis, lung infection, influenza, oral mucosal herpes.

Blood and lymphatic system disorders: very common – neutropenia, thrombocytopenia, anemia; common – leukopenia, lymph node pain.

Cardiac disorders: common – increased blood pressure, atrial fibrillation; common – heart failure.

Gastrointestinal disorders: very common – constipation, diarrhea; common – dyspepsia, colitis, hemorrhoids.

Musculoskeletal and connective tissue disorders: very common – arthralgia; common – back pain, musculoskeletal chest pain, limb pain, bone pain.

Respiratory, thoracic and mediastinal disorders: common – cough.

Eye disorders: common – eye hyperemia.

Metabolism and nutrition disorders: common – tumor lysis syndrome, hyperuricemia, weight increased.

Skin and subcutaneous tissue disorders: common – pruritus, night sweats, eczema, alopecia.

Benign, malignant and unspecified neoplasms (including cysts and polyps): common – squamous cell carcinoma of skin.

General disorders and administration site conditions: very common – pyrexia, asthenia, infusion reactions.

Contraindications

Active hepatitis B and/or other active infections; renal failure with CrCl <30 ml/min; pregnancy; lactation (breastfeeding) period; age under 18 years; hypersensitivity (IgE-mediated) to obinutuzumab.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Women of childbearing potential should use effective methods of contraception during treatment and for 18 months after the end of therapy.

Obinutuzumab is excreted in breast milk in animals. Breastfeeding is contraindicated during treatment and for at least 18 months after the last dose of obinutuzumab.

Use in Hepatic Impairment

Use with caution in patients with impaired liver function.

Use in Renal Impairment

Contraindicated in patients with renal failure with CrCl <30 ml/min.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

In patients with CLL aged ≥75 years receiving obinutuzumab therapy in combination with chlorambucil, the frequency of serious adverse events and fatal adverse events may be higher compared to patients younger than 75 years.

Special Precautions

Use with caution in patients with impaired liver function; history of chronic and recurrent infections.

A set of measures to prevent infusion reactions (use of appropriate glucocorticosteroids, oral administration of an analgesic/antihistamine, skipping an antihypertensive drug) in patients with CLL can reduce the frequency of infusion reactions, with the exception of grade 3-4 infusion reactions.

If infusion reactions develop, the infusion rate should be adjusted depending on the severity of the observed reaction; if necessary, the infusion should be interrupted and therapy completely discontinued.

Therapy with obinutuzumab should be completely discontinued in case of development of life-threatening acute respiratory symptoms; grade 4 (life-threatening) infusion reactions; recurrent (ongoing/recurrent) grade 3 infusion reaction.

Patients with concomitant cardiac or pulmonary diseases should be closely monitored during and after the infusion.

If tumor lysis syndrome develops, careful monitoring of renal function and fluid-electrolyte balance is necessary, followed by correction of electrolyte disturbances, and supportive care measures, including dialysis if required.

Cases of late-onset neutropenia (occurring no earlier than 28 days after the end of treatment) and prolonged neutropenia lasting more than 28 days after the end or discontinuation of therapy have been reported.

If thrombocytopenia is detected, regular laboratory testing should be performed until the reaction resolves. In serious or life-threatening cases, the possibility of delaying the administration of obinutuzumab should be considered. The decision to perform hemotransfusion (platelet transfusion) is made by the attending physician in accordance with the practice established in the medical institution. Concomitant use of drugs that can exacerbate thrombocytopenia, such as platelet aggregation inhibitors and anticoagulants, especially in the 1st cycle of therapy, should be taken into account.

In patients with concomitant cardiac diseases, arrhythmias (in particular, atrial fibrillation and tachyarrhythmias), angina pectoris, acute coronary syndrome, myocardial infarction, and heart failure may develop. These events can occur during infusion reactions and have a fatal outcome. Patients with a history of heart disease require careful monitoring. In addition, caution should be exercised when performing hydration in such patients, avoiding fluid overload.

Before using obinutuzumab, all patients should be screened for hepatitis B virus, including determination of HBsAg status, HBcAb status, and additional markers according to established local practice. Patients with positive serological markers of hepatitis B require consultation with a hepatologist. Such patients should be appropriately monitored and measures should be taken to prevent reactivation of hepatitis B virus in accordance with local standards.

If new neurological symptoms develop or existing ones change, diagnostics should be performed to rule out progressive multifocal leukoencephalopathy (PML).

In patients with CLL aged ≥75 years receiving obinutuzumab therapy in combination with chlorambucil, the frequency of serious adverse events and fatal adverse events may be higher compared to patients younger than 75 years.

Drug Interactions

Limited drug interaction studies of obinutuzumab with bendamustine, CHOP regimen drugs (cyclophosphamide, doxorubicin, vincristine, prednisolone), FC regimen drugs (fludarabine, cyclophosphamide) and chlorambucil have been conducted. Concomitant administration of obinutuzumab did not affect the pharmacokinetics of bendamustine, FC or individual components of the CHOP regimen; furthermore, there was no noticeable effect of bendamustine, FC, chlorambucil or CHOP on the pharmacokinetics of obinutuzumab. The risk of interaction with other drugs cannot be completely excluded.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.