Obinutuzumab

Patients with an IRR (Grade 1-2) with the previous infusion 650–1,000 mg acetaminophen At least 30 minutes before GAZYVA infusion. anti-histamine (e.g., 50 mg diphenhydramine) Patients with a Grade 3 IRR with the previous infusion OR with a lymphocyte count > 25 × 10 9 /L prior to next treatment Intravenous glucocorticoid: 20 mg dexamethasone or 80 mg methylprednisolone Completed at least 1 hour prior to GAZYVA infusion. 650–1,000 mg acetaminophen At least 30 minutes before GAZYVA infusion. anti-histamine (e.g., 50 mg diphenhydramine) LN All patients Intravenous glucocorticoid (80 mg methylprednisolone) Completed between 30 and 60 minutes prior to GAZYVA infusion Starting from Dose 6, intravenous corticosteroid should only be administered to patients who have experienced an IRR in the prior infusion 650–1,000 mg acetaminophen anti-histamine (e.g., 50 mg diphenhydramine) Tumor Lysis Syndrome Prophylaxis Patients with high tumor burden, high circulating absolute lymphocyte counts (greater than 25 × 10 9 /L) or renal impairment are considered at risk of tumor lysis syndrome and should receive prophylaxis.

Important Dosing Information Premedicate before each infusion [see Dosage and Administration ] . Provide prophylactic hydration and anti-hyperuricemics to patients at high risk of tumor lysis syndrome [see Dosage and Administration and Warnings and Precautions ]. Administer only as an intravenous infusion through a dedicated line [see Dosage and Administration ] .

Do not administer as an intravenous push or bolus. Monitor blood counts at regular intervals. GAZYVA should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur [see Warnings and Precautions ].

Recommended Premedication and Prophylactic Medications Infusion-Related Reactions Premedication to reduce the risk of IRRs is outlined in Table 6 [see Warnings and Precautions ] . Hypotension may occur during GAZYVA intravenous infusions. Consider withholding antihypertensive treatments for 12 hours prior to and throughout each GAZYVA infusion and for the first hour after administration [see Warnings and Precautions ] . [See table below.] CLL or FL All subsequent infusions All patients 650–1,000 mg acetaminophen At least 30 minutes before GAZYVA infusion.

Patients with an IRR (Grade 1-2) with the previous infusion 650–1,000 mg acetaminophen At least 30 minutes before GAZYVA infusion. anti-histamine (e.g., 50 mg diphenhydramine) Patients with a Grade 3 IRR with the previous infusion OR with a lymphocyte count > 25 × 10 9 /L prior to next treatment Intravenous glucocorticoid: 20 mg dexamethasone or 80 mg methylprednisolone Completed at least 1 hour prior to GAZYVA infusion. 650–1,000 mg acetaminophen At least 30 minutes before GAZYVA infusion. anti-histamine (e.g., 50 mg diphenhydramine) LN All patients Intravenous glucocorticoid (80 mg methylprednisolone) Completed between 30 and 60 minutes prior to GAZYVA infusion Starting from Dose 6, intravenous corticosteroid should only be administered to patients who have experienced an IRR in the prior infusion 650–1,000 mg acetaminophen anti-histamine (e.g., 50 mg diphenhydramine) Tumor Lysis Syndrome Prophylaxis Patients with high tumor burden, high circulating absolute lymphocyte counts (greater than 25 × 10 9 /L) or renal impairment are considered at risk of tumor lysis syndrome and should receive prophylaxis.

Premedicate with anti-hyperuricemics (e.g., allopurinol or rasburicase) and ensure adequate hydration prior to start of GAZYVA therapy. Continue prophylaxis prior to each subsequent GAZYVA infusion, as needed [see Warnings and Precautions ] . Antimicrobial Prophylaxis Patients with Grade 3 to 4 neutropenia lasting more than one week are strongly recommended to receive antimicrobial prophylaxis until resolution of neutropenia to Grade 1 or 2.

Consider antiviral and antifungal prophylaxis for patients with severe and long lasting (> 1 week) neutropenia.

Dosage Modifications for Adverse Reactions Infusion-Related Reactions If a patient experiences an IRR, adjust the infusion as follows [see Warnings and Precautions ] : Grade 4 (life-threatening): Stop infusion immediately and permanently discontinue GAZYVA. Grade 3 (severe): Interrupt infusion and manage symptoms. For patients who experience Grade 3 IRRs during standard infusion, upon resolution of symptoms, consider restarting GAZYVA infusion at no more than half the previous rate (the rate being used at the time that the IRR reaction occurred), and if patient does not experience any further IRR symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose.

Permanently discontinue treatment if patients experience a Grade 3 or higher IRR at rechallenge. For patients with FL who experience Grade 3 IRRs during the approximately 90-minute infusion, upon resolution of symptoms, the infusion can be restarted at no more than half the previous rate (the rate being used at the time that the IRR occurred) and not greater than 400 mg/hr.

Administer subsequent infusions at the standard rate. Permanently discontinue treatment if patients experience a Grade 3 or higher IRR at rechallenge. For patients with CLL only, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour but not increased further. Grade 1–2 (mild to moderate): Reduce infusion rate or interrupt infusion and manage symptoms.

Upon resolution of symptoms, continue or resume GAZYVA infusion, and if patient does not experience any further IRR symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose. For patients with CLL only, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour but not increased further.

For patients with LN, reduce infusion rate to half the rate that was used at the time of the reaction and treat symptoms. Upon resolution of symptoms, the infusion should be kept at the reduced rate for an additional 30 minutes. If no further symptoms of IRR, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment dose.

Other Adverse Reactions Consider treatment interruption if patients experience an infection, Grade 3 or 4 cytopenia, or Grade 2 or higher non-hematologic toxicity.

Preparation and Administration Preparation Prepare the solution for infusion, using aseptic technique, as follows: Inspect visually for any particulate matter and discoloration prior to administration. Use a sterile needle and syringe to prepare GAZYVA. Dilute into a 0.9% Sodium Chloride Injection, USP PVC or non-PVC polyolefin infusion bag.

Chronic Lymphocytic Leukemia Preparation of solution for infusion on day 1 (100 mg) and day 2 (900 mg) of Cycle 1: Prepare day 1 (100 mg) and day 2 (900 mg) infusion bags at the same time using one vial (1,000 mg/40 mL) on day 1. Withdraw 40 mL of GAZYVA solution from the vial. Dilute 4 mL (100 mg) of GAZYVA into a 100 mL 0.9% Sodium Chloride Injection, USP infusion bag for immediate administration.

Dilute the remaining 36 mL (900 mg) into a 250 mL 0.9% Sodium Chloride Injection, USP infusion bag at the same time for use on day 2 and store in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours. After allowing the diluted bag to come to room temperature, use immediately. Clearly label each infusion bag. Preparation of solution for infusion on day 8 and 15 of Cycle 1 and day 1 of Cycles 2–6: Withdraw 40 mL of GAZYVA solution from the vial.

Dilute 40 mL (1,000 mg) into a 250 mL 0.9% Sodium Chloride Injection, USP infusion bag. Follicular Lymphoma and Active Lupus Nephritis Preparation of solution for infusion: Withdraw 40 mL of GAZYVA solution from the vial. Dilute 40 mL (1,000 mg) into a 250 mL 0.9% Sodium Chloride Injection, USP infusion bag. Mix diluted solution by gentle inversion.

Do not shake or freeze. For microbiological stability, immediately use diluted GAZYVA infusion solution. If not used immediately, store in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours prior to use. The product can be administered at a final concentration of 0.4 mg/mL to 4 mg/mL. Storage Use the diluted solution immediately.

If not used immediately, store for up to 24 hours at 2°C to 8°C. Discard after 24 hours. Administration Administer as an intravenous infusion only. Do not administer as an intravenous push or bolus. Do not mix GAZYVA with other drugs. No incompatibilities between GAZYVA and polyvinylchloride (PVC) or non-PVC polyolefin bags and administration sets have been observed.