Dosage & Administration
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Gazyva Prescribing Information
- 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, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV-positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation [see Warnings and Precautions (5.1)].
- Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA [see Warnings and Precautions (5.2)].
Chronic Lymphocytic Leukemia (CLL)
GAZYVA, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia.
Follicular Lymphoma (FL)
GAZYVA, in combination with bendamustine followed by GAZYVA monotherapy, is indicated for the treatment of patients with follicular lymphoma who relapsed after, or are refractory to, a rituximab-containing regimen.
GAZYVA, in combination with chemotherapy followed by GAZYVA monotherapy in patients achieving at least a partial remission, is indicated for the treatment of adult patients with previously untreated stage II bulky, III or IV follicular lymphoma.
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)].
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.
| Day of treatment cycle | Dose of GAZYVA | Rate of infusion | |
|---|---|---|---|
| Cycle 1 (loading doses) | Day 1 | 100 mg | Administer at 25 mg/hr over 4 hours. Do not increase the infusion rate. |
| Day 2 | 900 mg | If no infusion-related reaction (IRR) occurred during the previous infusion, administer at 50 mg/hr. The rate of the infusion can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr. If an IRR occurred during the previous infusion, administer at 25 mg/hr. The rate of infusion can be escalated in increments of up to 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr. | |
| Day 8 | 1,000 mg | If no IRR occurred during the previous infusion and the final infusion rate was 100 mg/hr or faster, infusions can be started at a rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. If an infusion-related reaction occurred during the previous infusion, administer at 50 mg/hr. The rate of infusion can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr. | |
| Day 15 | 1,000 mg | ||
| Cycles 2–6 | Day 1 | 1,000 mg | |
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.
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.
GAZYVA should be administered at the standard infusion rate in Cycle 1 (see Table 2). In patients with FL who do not experience a Grade 3 or higher IRR during Cycle 1, GAZYVA may be administered as a shorter, approximately 90-minute infusion from Cycle 2 onwards (see Table 3) with continued premedication.
| Day of treatment cycle | Dose of GAZYVA | Rate of infusion | |
|---|---|---|---|
| Cycle 1 (loading doses) | Day 1 | 1,000 mg | Administer at 50 mg/hr. The rate of the infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. |
| Day 8 | 1,000 mg | If no infusion-related reaction or an infusion-related reaction of Grade 1 occurred during the previous infusion and the final infusion rate was 100 mg/hr or faster, infusions can be started at a rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. If an infusion-related reaction of Grade 2 or higher occurred during the previous infusion, administer at 50 mg/hr. The rate of infusion can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr. | |
| Day 15 | 1,000 mg | ||
| Cycles 2–6 or 2–8 | Day 1 | 1,000 mg | |
| Monotherapy | Every two months for up to two years | 1,000 mg | |
| Day of treatment cycle | Dose of GAZYVA | Rate of infusion | |
|---|---|---|---|
| |||
| Cycle 1 | Days 1, 8, 15 | 1,000 mg | See Table 2 |
| Cycles 2–6 * or 2-8 * | Day 1 | 1,000 mg | If no Grade 3 or higher IRR occurred during Cycle 1: 100 mg/hr for 30 minutes, then 900 mg/hr for approximately 60 minutes. If an IRR of Grade 1-2 with ongoing symptoms or a Grade 3 or higher IRR occurred during the previous approximately 90-minute infusion, administer all subsequent GAZYVA infusions at the standard infusion rate (see Table 2). |
| Monotherapy * | Every two months for up to two years | 1,000 mg | |
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.
Recommended Premedication and Prophylactic Medications
Infusion-Related Reactions
Premedication to reduce the risk of IRRs is outlined in Table 4 [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)].
| Day of Treatment Cycle | Patients requiring premedication | Premedication | Administration |
|---|---|---|---|
| Premedication applies to both standard and approximately 90-minute infusions. | |||
| |||
| Cycle 1: CLL Day 1, Day 2 FL Day 1 | All patients | 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) | |||
| All subsequent infusions, CLL or FL | 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 × 109/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) | |||
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.
Dosage Modifications for Adverse Reactions
Infusion-Related Reactions
If a patient experiences an 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.
- 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 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 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 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.
- 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.
- Preparation of solution for infusion on day 1 (100 mg) and day 2 (900 mg) of Cycle 1:
- 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.
Injection: 1,000 mg/40 mL (25 mg/mL) clear, colorless to slightly brown solution in single-dose vial.
Pregnancy
Risk Summary
Based on findings from animal studies and its mechanism of action, GAZYVA can cause fetal B-cell depletion [see Clinical Pharmacology (12.1)]. There are no data with GAZYVA use in pregnant women to inform a drug-associated risk. Monoclonal antibodies are transferred across the placenta. In animal reproduction studies, weekly intravenous administration of obinutuzumab to pregnant cynomolgus monkeys from day 20 of pregnancy until parturition which includes the period of organogenesis at doses with exposures up to 2.4 times the exposure at the clinical dose of 1,000 mg monthly produced opportunistic infections and immune complex mediated hypersensitivity reactions. No embryo-toxic or teratogenic effects were observed in the monkeys (see Data). Advise pregnant women of the potential risk to the fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
GAZYVA is likely to cause fetal B-cell depletion (see Data). Avoid administering live vaccines to neonates and infants exposed to GAZYVA in utero until B-cell recovery occurs [see Warnings and Precautions (5.11) and Clinical Pharmacology (12.2)].
Data
Animal Data
In a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition, which includes the period of organogenesis. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. There were no embryo-toxic or teratogenic effects in animals. Secondary opportunistic infections, immune complex mediated hypersensitivity reactions, or a combination of both were observed in exposed dams. When first measured on day 28 postpartum, obinutuzumab was detected in offspring at levels in the range of maternal serum levels on the same day, and B-cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.
Obinutuzumab was measured in the milk of lactating cynomolgus monkeys on day 28 postpartum after weekly intravenous administration from day 20 of pregnancy until parturition. Concentrations in milk were approximately 0.04% and 0.13% of concentrations in maternal serum in the 25 and 50 mg/kg groups, respectively.
Lactation
Risk Summary
There is no information regarding the presence of GAZYVA in human milk, the effects on the breastfed child, or the effects on milk production. However, low levels of obinutuzumab were present in the milk of lactating cynomolgus monkeys [see Use in Specific Populations (8.1)]. Human IgG is known to be present in human milk. Because of the potential of serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with GAZYVA and for 6 months after the last dose.
Females and Males of Reproductive Potential
GAZYVA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with GAZYVA and for 6 months after the last dose.
Pediatric Use
The safety and effectiveness of GAZYVA in pediatric patients have not been established.
Geriatric Use
Chronic Lymphocytic Leukemia
Of 336 patients with previously untreated CLL who received GAZYVA in combination with chlorambucil, 81% were 65 years and older, while 46% were 75 and older. Of the patients 75 years and older, 46% experienced serious adverse reactions and 7% experienced adverse reactions leading to death. Of the patients younger than 75, 33% experienced a serious adverse reaction and 2% an adverse reaction leading to death. No significant differences in efficacy were observed between younger and older patients [see Clinical Studies (14.1)].
Non-Hodgkin Lymphoma
Of 204 patients in GADOLIN with relapsed or refractory NHL treated with GAZYVA plus bendamustine, 44% were 65 and over, while 14% were 75 and over. In patients 65 and over, 55% of patients experienced serious adverse reactions and 28% experienced adverse reactions leading to treatment withdrawal while in patients under 65, 37% and 14% experienced serious adverse reactions and adverse reactions leading to treatment withdrawal, respectively. No clinically meaningful differences in efficacy were observed between these patients and younger patients in GADOLIN.
Of the 691 patients in GALLIUM treated with GAZYVA plus chemotherapy as first-line therapy, 33% were 65 and over, while 7% were 75 and over. Of patients 65 and over, 63% experienced serious adverse reactions and 26% experienced adverse reactions leading to treatment withdrawal, while in patients under 65, 43% experienced serious adverse reactions and 13% had an adverse reaction leading to treatment withdrawal. No clinically meaningful differences in efficacy were observed between these patients and younger patients in GALLIUM.
GAZYVA is contraindicated in patients with known hypersensitivity reactions (e.g., anaphylaxis) to obinutuzumab or to any of the excipients, or serum sickness with prior obinutuzumab use [see Warnings and Precautions (5.4)].