GAZYVA™

GAZYVA is produced by mammalian cell (CHO) suspension culture. GAZYVA is a sterile, clear, colorless to slightly brown, preservative free liquid concentrate for intravenous administration. GAZYVA is supplied at a concentration of 25 mg/mL in 1000 mg single use vials. The product is formulated in 20 mM L-histidine/L-histidine hydrochloride, 240 mM trehalose, 0.02% poloxamer 188. The pH is 6.0.

1. Infusion reactions: Premedicate patients with glucocorticoid, acetaminophen and anti-histamine. Monitor patients closely during infusions. Interrupt or discontinue infusion for reactions.
2. Tumor Lysis Syndrome: Anticipate tumor lysis syndrome; premedicate with anti-hyperuricemics and adequate hydration especially for patients with high tumor burden and/or high circulating lymphocyte count. Correct electrolyte abnormalities, provide supportive care, and monitor renal function and fluid balance.
3. Neutropenia: Monitor for infection.
4. Thrombocytopenia: Monitor platelet counts and for bleeding. Management of hemorrhage may require blood product support.
5. Immunization: Do not administer live virus vaccines prior to or during GAZYVA.

To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See PACKAGE INSERT for PATIENT COUNSELING INFORMATION and Medication Guide.

• Premedicate before each infusion.
• Administer only as an intravenous infusion through a dedicated line.
• 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 reactions that can be fatal if they occur [see Warnings and Precautions].

Recommended Dose:
Each dose of GAZYVA is 1000 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).

Table 1 Dose of GAZYVA to be administered during 6 treatment cycles each of 28 days duration

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

If a patient experiences an infusion reaction of any grade during infusion, adjust the infusion as follows [see Warnings and Precautions]:

• Grade 4 (life threatening): Stop infusion immediately and permanently discontinue GAZYVA therapy.
• 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 infusion reaction occurred) and, if patient does not experience any further infusion reaction 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 infusion related symptom at re-challenge.
• Grade 1-2 (mild to moderate): Reduce infusion rate or interrupt infusion and treat symptoms. Upon resolution of symptoms, continue or resume infusion and, if patient does not experience any further infusion reaction symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose.

Recommended Premedication
Premedication is recommended to reduce the risk of infusion reactions as outlined in Table 2 [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].

For patients with high tumor burden and/or high circulating absolute lymphocyte counts (greater than 25 x 10⁹/L), premedicate with anti-hyperuricemics (e.g., allopurinol) beginning 12-24 hours prior to start of therapy and ensure adequate hydration for prophylaxis of tumor lysis syndrome [see Warnings and Precautions ].

Table 2 Premedication for GAZYVA Infusion to Reduce Infusion-Related Reactions

*Hydrocortisone is not recommended as it has not been effective in reducing the rate of infusion reactions.

Premedication for anti-microbial prophylaxis
Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered.

Treatment Interruption for Toxicity
Consider treatment interruption, if patients experience an infection, Grade 3 or 4 cytopenia, or a = Grade 2 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.
• Dilute into a 0.9% sodium chloride PVC or non-PVC polyolefin infusion bag. Do not use other diluents such as dextrose (5%).
• Preparation of solution for infusion on Day 1 (100 mg) and Day 2 (900 mg) of Cycle 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 infusion bag for immediate administration.
  • Dilute the remaining 36 mL (900 mg) into a 250 mL 0.9% sodium chloride 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 Cycles 2-6:
  • Withdraw 40 mL of GAZYVA solution from the vial.
  • Dilute 40 mL (1000 mg) into a 250 mL 0.9% sodium chloride infusion bag.
• Mix diluted solution by gentle inversion. Do not shake or freeze.
• For microbiological stability, the diluted GAZYVA infusion solution should be used immediately. Dilute under appropriate aseptic conditions. If not used immediately, the solution may be stored 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.

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 [see How Supplied/Storage and Handling].

GAZYVA 1000 mg/40 mL (25 mg/mL) single-use vials containing preservative-free solution (NDC 50242-070-01) are stable at 2°C to 8°C (36°F to 46°F). Do not use beyond expiration date stamped on carton. GAZYVA vials should be protected from light. DO NOT FREEZE. DO NOT SHAKE.

For the diluted product, chemical and physical stability have been demonstrated in 0.9% NaCl at concentrations of 0.4 mg/mL to 20 mg/mL for 24 hours at 2°C to 8°C (36°F to 46°F) followed by 48 hours (including infusion time) at room temperature (≤ 30°C/86°F). GAZYVA does not contain antimicrobial preservatives. Therefore care must be taken to ensure that the solution for infusion is not microbiologically compromised during preparation. The solution for infusion should be used immediately. If not used immediately, the prepared solution may be stored up to 24 hours at 2-8°C. No incompatibilities between GAZYVA and polyvinyl chloride or polyolefin infusion materials have been observed in concentration ranges from 0.4 mg/mL to 20.0 mg/mL after dilution of GAZYVA with 0.9% sodium chloride.