GAZYVA Solution for injection Ref.[10820] Active ingredients: Obinutuzumab

2.1 Important Dosing Information

• Premedicate before each infusion [see Dosage and Administration (2.4)].
• Provide prophylactic hydration and anti-hyperuricemics to patients at high risk of tumor lysis syndrome [see Dosage and Administration (2.4) and Warnings and Precautions (5.4)].
• Administer only as an intravenous infusion through a dedicated line [see Dosage and Administration (2.6)].
• 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 (5.3)].

2.2 Recommended Dosage for Chronic Lymphocytic Leukemia

Each dose of GAZYVA is 1,000 mg administered intravenously with the exception of the first infusions in Cycle 1, which are administered on day 1 (100 mg) and day 2 (900 mg) according to Table 1.

Table 1. Dose of GAZYVA to be Administered During Six 28-Day Treatment Cycles for Patients with CLL:

If a planned dose of GAZYVA is missed, administer the missed dose as soon as possible and adjust dosing schedule to maintain the time interval between doses. If appropriate, patients who do not complete the Day 1 Cycle 1 dose may proceed to the Day 2 Cycle 1 dose.

2.3 Recommended Dosage for Follicular Lymphoma

Each dose of GAZYVA is 1,000 mg administered intravenously according to Table 2.

For patients with relapsed or refractory FL, administer GAZYVA in combination with bendamustine in six 28-day cycles. Patients who achieve stable disease, complete response, or partial response to the initial 6 cycles should continue on GAZYVA 1,000 mg as monotherapy for up to two years.

For patients with previously untreated FL, administer GAZYVA with one of the following chemotherapy regimens:

• Six 28-day cycles in combination with bendamustine
• Six 21-day cycles in combination with CHOP, followed by 2 additional 21-day cycles of GAZYVA alone
• Eight 21-day cycles in combination with CVP

Patients with previously untreated FL who achieve a complete response or partial response to the initial 6 or 8 cycles should continue on GAZYVA 1,000 mg as monotherapy for up to two years.

Table 2. Dose of GAZYVA to be Administered During 6–8 Treatment Cycles, Followed by GAZYVA Monotherapy for Patients with FL:

If a planned dose of GAZYVA is missed, administer the missed dose as soon as possible. During GAZYVA and chemotherapy treatment, adjust the dosing schedule accordingly to maintain the time interval between chemotherapy cycles. During monotherapy, maintain the original dosing schedule for subsequent doses. Initiate monotherapy approximately two months after the last dose of GAZYVA administered during the induction phase.

2.4 Recommended Premedication and Prophylactic Medications

Infusion-Related Reactions

Premedication to reduce the risk of infusion-related reactions is outlined in Table 3 [see Warnings and Precautions (5.3)].

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 (5.3)].

Table 3. Premedication for GAZYVA Infusion to Reduce Infusion-Related Reactions (IRR):

^* Hydrocortisone is not recommended as it has not been effective in reducing the rate of infusion-related reactions.
^† If a glucocorticoid-containing chemotherapy regimen is administered on the same day as GAZYVA, the glucocorticoid can be administered as an oral medication if given at least 1 hour prior to GAZYVA, in which case additional intravenous glucocorticoid as premedication is not required.

Tumor Lysis Syndrome Prophylaxis

Patients with high tumor burden, high circulating absolute lymphocyte counts (greater than 25 × 10⁹/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 (5.4)].

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.

2.5 Dosage Modifications for Adverse Reactions

Infusion-Related Reactions

If a patient experiences an infusion-related reaction (IRR), adjust the infusion as follows [see Warnings and Precautions (5.3)]:

• Grade 4 (life-threatening): Stop infusion immediately and permanently discontinue GAZYVA.
• Grade 3 (severe): Interrupt infusion and manage symptoms. 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 IRR at rechallenge.
  • For CLL patients 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 CLL patients only, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour but not increased further.

Other Adverse Reactions

Consider treatment interruption if patients experience an infection, Grade 3 or 4 cytopenia, or a ≥ Grade 2 non-hematologic toxicity.

2.6 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 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 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
  • 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.

There has been no experience with overdose in human clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy.

Store at 2°C to 8°C (36°F to 46°F). Do not use beyond expiration date stamped on carton. Protect from light. DO NOT FREEZE. DO NOT SHAKE.