Dosing and uses of Gazyva (obinutuzumab)
Adult dosage forms and strengths
IV solution
- 25mg/mL (1000mg/40mL single-use vial)
Chronic Lymphocytic Leukemia
Indicated for previously untreated chronic lymphocytic leukemia in combination with chlorambuciL
Administer for 6 treatment cycles (28-day cycles)
Cycle 1
- Day 1: 100 mg IV infused at 25 mg/hr over 4 hr; do not increase infusion rate
- Day 2: 900 mg IV infused at 50 mg/hr; if tolerated, may increase infusion rate by increments of 50 mg/hr q30min to maximum of 400 mg/hr
- Days 8 and 15: 1000 mg IV infused at 100 mg/hr; may increase infusion rate by increments of 100 mg/hr q30min to a maximum of 400 mg/hr
Cycles 2-6
- Day 1: 1000 mg IV infused at 100 mg/hr; may increase infusion rate by increments of 100 mg/hr q30min to a maximum of 400 mg/hr
Follicular Lymphoma
For patients with follicular lymphoma who relapsed after, or are refractory to, rituximab-containing regimen
Administer in combination with bendamustine followed by obinutuzumab monotherapy
Cycle 1
- Day 1: 1000 mg IV infused at 50 mg/hr; escalate the rate of infusion in 50 mg/hr increments every 30 min to a maximum 400 mg/hr
- Day 8: 1000 mg IV; if no infusion reaction occurred during previous infusion and final infusion rate was 100 mg/hr or faster, may initiate infusions at 100 mg/hr with increments of 100 mg/hr every 30 min to maximum 400 mg/hr
- Day 15: 1000 mg IV; if no infusion reaction occurred during previous infusion and final infusion rate was 100 mg/hr or faster, may initiate infusions at 100 mg/hr with increments of 100 mg/hr every 30 min to maximum 400 mg/hr
Cycles 2-6
- Day 1: 1000 mg IV; if no infusion reaction occurred during previous infusion and final infusion rate was 100 mg/hr or faster, may initiate infusions at 100 mg/hr with increments of 100 mg/hr every 30 min to maximum 400 mg/hr
Monotherapy
- Every 2 months for 2 years: 1000 mg IV; if no infusion reaction occurred during previous infusion and final infusion rate was 100 mg/hr or faster, may initiate infusions at 100 mg/hr with increments of 100 mg/hr every 30 min to maximum 400 mg/hr
Missed dose
- If dose missed, administer missed dose as soon as possible
- During obinutuzumab and bendamustine treatment, adjust dosing schedule accordingly
- During monotherapy, maintain the original dosing schedule for subsequent doses
Premedication
Premedicate to reduce risk of infusion reactions
When glucocorticoids are indicated, use dexamethasone or methylprednisolone; hydrocortisone is not recommended as it has not been effective in reducing the rate of infusion reactions
Hypotension may occur during IV infusions; consider withholding antihypertensive agents for 12 hr prior to and throughout each obinutuzumab infusion and for the first hr after administration
For patients with high tumor burden and/or high circulating absolute lymphocyte counts, premedicate with anti-hyperuricemics (eg, allopurinol) beginning 12-24 hr before initiating therapy and ensure adequate hydration for prophylaxis of tumor lysis syndrome
Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period; antiviral and antifungal prophylaxis should be considered
Cycle 1
- CLL Days 1 and 2 or FL Day 1
- Dexamethasone 20 mg IV or methylprednisolone 80 mg IV; complete administration at least 1 hr prior to obinutuzumab infusion
- Acetaminophen 650-1000 mg PO; complete administration at least 30 min prior to obinutuzumab infusion
- Diphenhydramine 50 mg IV/PO; complete administration at least 30 min prior to obinutuzumab infusion
All subsequent infusions
- All patients: Acetaminophen 650-1000 mg PO; complete administration at least 30 min prior to obinutuzumab infusion
- Infusion-related reaction (≥Grade 1) with previous infusion: Add diphenhydramine 50 mg IV/PO; complete administration at least 30 min prior to obinutuzumab infusion
- Infusion-related reaction (Grade 3) with previous infusion OR with a lymphocyte count >25 x 10^9/L prior to next treatment: Dexamethasone 20 mg IV or methylprednisolone 80 mg IV; complete administration at least 1 hr prior to obinutuzumab infusion
Dosage modifications
Consider treatment interruption, if patients experience an infection, Grade 3 or 4 cytopenia, or a ≥Grade 2 nonhematologic toxicity
Infusion-related reactions
- Adjust infusion as follows:
- Grade 4 (life threatening): Stop infusion immediately and permanently discontinue
- Grade 3 (severe): Interrupt infusion and manage symptoms; upon resolution of symptoms, consider restarting infusion at ≤50% of the previous rate 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
- For CLL patients only
- Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hr, but not increased further
- Permanently discontinue treatment if patients experience a Grade 3 infusion related symptom upon rechallenge
- Grade 1-2 (mild-to-moderate): Reduce infusion rate or interrupt infusion and treat symptoms; upon resolution, continue/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
- For CLL patients only
- Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hr, but not increased further
Marginal Zone Lymphoma (Orphan)
Orphan designation for treatment of splenic marginal zone lymphoma
Sponsor
- Genentech, Inc; 1 DNA Way, MS# 214A; South San Francisco, CA 94080-4990
Pediatric dosage forms and strengths
Safety and efficacy not established
Gazyva (obinutuzumab) adverse (side) effects
>10%
Infusion related reactions (69%)
Neutropenia (33%)
Hypocalcemia (32%)
Hyperkalemia (31%)
Hyponatremia (29%)
Creatinine increased (28%)
AST increased (28%)
ALT increased (25%)
Hypoalbuminemia (16%)
Alkaline phosphatase increased (16%)
Thrombocytopenia (15%)
Hypokalemia (13%)
Anemia (12%)
1-10%
Pyrexia (10%)
Cough (10%)
Leukopenia (7%)
Tumor lysis syndrome (2%)
Warnings
Black box warnings
Progressive multifocal leukoencephalopathy (PML) including fatal PML, can occur in patients receiving obinutuzumaB
Hepatitis B virus reactivation
- Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies
- Screen all patients for HBV infection before treatment initiation
- Monitor HBV positive patients during and after treatment
- Discontinue obinutuzumab and concomitant medications in the event of HBV reactivation
Contraindications
None
Cautions
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
May reactivate hepatitis B virus (see Black box warnings)
Progressive multifocal leukoencephalopathy (PML) reported (see Black box warnings)
Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia from tumor lysis syndrome (TLS) can occur within 12-24 hr after the first infusion (see Premedication)
Serious bacterial, fungal, and new or reactivated viral infections can occur; do not give obinutuzumab with an active infection
Neutropenia may occur (in combination with chlorambucil, Grade 3 or 4 neutropenia reported in 34% of patients); patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period; antiviral and antifungal prophylaxis should be considered
Thrombocytopenia may occur (in combination with chlorambucil, Grade 3 or 4 neutropenia reported in 12% of patients); monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle; management of hemorrhage may require blood product support
Safety and efficacy of immunization with live or attenuated viral vaccines during or following obinutuzumab therapy has not been studied; immunization with live virus vaccines is not recommended during treatment and until B-cell recovery
Infusion-related reactions
- May cause severe and life-threatening infusion reactions (see Dosage modification and Premedication sections)
- Patients with pre-existing cardiac or pulmonary conditions are at greater risk of severe reactions
- Monitor closely throughout the infusion and the post-infusion period; interrupt or discontinue infusion for reactions
- Due to the risk of infusion induced hypotension, consider withholding antihypertensive treatments for 12 hr prior to, during , and for the first hour after administration until blood pressure is stable
- Consider the benefits versus the risks of withholding their antihypertensive medication in patients who are at increased of hypertensive crisis
Pregnancy and lactation
Pregnancy: Obinutuzumab is likely to cause fetal B-cell depletion; avoid administering live vaccines to neonates and infants exposed to obinutuzumab in utero until B-cell recovery occurs
Lactation: Unknown if distributed in human breast milk; excreted in the milk of lactating cynomolgus monkeys and human IgG is known to be excreted in human milk; consider developmental and health benefits along with the mother’s clinical need for therapy and any potential adverse effects on breastfed infant
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Gazyva (obinutuzumab)
Mechanism of action
CD20-directed cytolytic antibody; upon binding to CD20, obinutuzumab mediates B-cell lysis through 1) engagement of immune effector cells, 2) by directly activating intracellular death signaling pathways and/or, 3) activation of the complement cascade
CD20 antigen is expressed on the surface of pre B- and mature B-lymphocytes; the immune effector cell mechanisms include antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis
Distribution
Vd: 3.8 L
Elimination
Half-life: 28.4 days
Clearance: 0.09 L/day
Administration
IV Preparation
Inspect visually for any particulate matter and discoloration prior to administration
Dilute into 0.9% NaCl PVC or non-PVC polyolefin infusion bag
Do not use other diluents (eg, dextrose 5%)
Dilute under appropriate aseptic conditions
100 mg and 900 mg doses
- Withdraw 40 mL of solution from the via
- Dilute 4 mL (100 mg) into 100 mL 0.9% NaCl 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
- After allowing the diluted bag to come to room temperature, use immediately
- Clearly label each infusion bag
1000 mg dose
- Withdraw 40 mL of solution from the vial
- Dilute 40 mL (1000 mg) into a 250 mL 0.9% NaCl infusion bag
- Mix diluted solution by gentle inversion; do not shake
- For microbiological stability, the diluted infusion solution should be used immediately
- The product can be administered at a final concentration of 0.4 mg/mL to 4 mg/mL
IV Administration
Administer as IV infusion only
Do not administer as IV push or bolus
Do not mix with other drugs
Missed dose
- If a planned dose 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
Storage
Do not freeze or shake either unopened vials or diluted solution
Unopened vials: Store between 2-8°C [36-46°F]) in original carton and protect from light
Reconstituted vials: If not used immediately, the solution may be stored in a refrigerator at 2-8°C (36-46°F) for up to 24 hr prior to use
