obinutuzumab

oh-bi-nue-TOOZ-ue mab

Therapeutic Classification: antineoplastics

Pharmacologic Classification: monoclonal antibodies

High Alert

Previously untreated chronic lymphocytic leukemia (in combination with chlorambucil).
Follicular lymphoma in patients who have relapsed after, or are refractory to, a rituximab-containing regimen (in combination with bendamustine, followed by obinutuzumab monotherapy).
Previously untreated stage II bulky, III, or IV follicular lymphoma (in combination with chemotherapy, followed by obinutuzumab monotherapy in patients achieving at least a partial remission).

Humanized anti-CD20 monoclonal IgG1 antibody, targeting an antigen found on the surface of pre and mature B- lymphocytes. Result is B-cell lysis and depletion.

Therapeutic effects:

Improved progression-free survival.

Absorption: IV administration results in complete bioavailability.

Distribution: Unknown.

Metabolism/Excretion: Unknown.

Half-Life: 28.4 days.

(improvement progression-free survival)

ROUTE	ONSET	PEAK	DURATION
IV	within 3 mo	12 mo	unknown

Contraindicated in:

Hypersensitivity;
Active infection;
Lactation: Lactation.

Use Cautiously in:

Hepatitis B virus (HBV) infection (may reactivate);
OB: Use during pregnancy only if potential maternal benefit justifies potential fetal risk;
Rep: Women of reproductive potential;
Pedi: Safety and effectiveness not established in children.

CV: hypotension

GI: HBV reactivation, hypocalcemia, hypokalemia, hyponatremia

Hemat: anemia, BLEEDING, DISSEMINATED INTRAVASCULAR COAGULATION (DIC), NEUTROPENIA, THROMBOCYTOPENIA

Neuro: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)

Resp: cough

Misc: infusion reactions, fever, HYPERSENSITIVITY REACTIONS (INCLUDING BRONCHOSPASM, URTICARIA, AND SERUM SICKNESS), INFECTION (INCLUDING BACTERIAL, FUNGAL, AND VIRAL), TUMOR LYSIS SYNDROME

Drug-drug:

↑risk of immunosuppression/neutropenia with other antineoplastics, immunosuppressants or radiation therapy.
May ↓ antibody response to and ↑ risk of adverse reactions from live-virus vaccines (do not administer prior to or during treatment).
Concurrent use of anticoagulants or antiplatelet agents, especially during the first cycle, may ↑ risk of bleeding.

Chronic Lymphocytic Leukemia

Cycles 1–6 (each cycle = 28 days) should also include chlorambucil.
IV (Adults ): Day 1 of Cycle 1: 100 mg; Day 2 of Cycle 1: 900 mg; Days 8 and 15 of Cycle 1: 1000 mg; Day 1 of Cycles 2–61000 mg.

Relapsed or Refractory Follicular Lymphoma

Cycles 1–6 should also include bendamustine.
IV (Adults ): Days 1, 8, and 15 of Cycle 1: 1000 mg, Day 1 of Cycles 2–6: 1000 mg. If patient achieves disease stability, complete response, or partial response after 6 cycles, continue obinutuzumab as monotherapy as 1000 mg every 2 mo for up to 2 yr.

Previously Untreated Follicular Lymphoma

May be administered for cycles 1–6 (each cycle = 28 days) with bendamustine; cycles 1–6 (each cycle = 21 days) with CHOP, followed by 2 additional cycles (each cycle = 21 days) of obinutuzumab monotherapy; or cycles 1–8 (each cycle = 21 days) with CVP).
IV (Adults ): Days 1, 8, and 15 of Cycle 1: 1000 mg, Day 1 of Cycles 2–6 or Cycles 2–8: 1000 mg. If patient achieves disease stability, complete response, or partial response after 6–8 cycles, continue obinutuzumab as monotherapy as 1000 mg every 2 mo for up to 2 yr.

Solution for injection: 25 mg/mL

Monitor patient with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several mo following therapy.
Monitor for signs of PML (new onset or changes in pre-existing neurological signs and symptoms). Initiate evaluation for PML (neurological consultation, brain MRI, lumbar puncture) if signs occur. Discontinue obinutuzumab if PML is suspected.
Assess for infusion-related reactions (hypotension, tachycardia, dyspnea, bronchospasm, larynx and throat irritation, wheezing, laryngeal edema, nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, chills) closely, especially during first 24 hr. Premedicate and treat symptoms (glucocorticoids, epinephrine, bronchodilators, oxygen).
Monitor patient for tumor lysis syndrome due to rapid reduction in tumor volume (acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hypophosphatemia). Risks are higher in patients with greater tumor burden and rapidly proliferating tumors; may be fatal. Correct electrolyte abnormalities, hydrate patient, administer antihyperuricemic agents, monitor renal function and fluid balance, and administer supportive care, including dialysis, as indicated.

Lab Test Considerations:

Screen all patients for HBV infection. For patients with evidence of HBV infection (HBsAg positive or HBsAg negative but anti-HBc positive consult health care professional with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.
- Monitor CBC frequently during therapy. May cause neutropenia; monitor for infection. Neutropenia may occur late onset, more than 28 days after completion of therapy and may be prolonged, lasting longer than 28 days. Consider antimicrobial prophylaxis (antiviral, antifungal) for patients with Grade 3–4 neutropenia >1 wk until resolution to Grade 1–2.
- Monitor platelet count frequently during therapy, especially during first cycle. May cause thrombocytopenia. May occur within 24 hr of infusion. May require platelet transfusion. May also cause DIC (especially during first cycle), which is associated with changes in platelets and coagulation parameters. If DIC suspected, monitor platelets, coagulation parameters, and for signs/symptoms of clotting or bleeding. May require transfusion of blood products.

Administration should be limited to health care professionals and facilities able to manage severe infusion reactions.
Premedicate patients with a high tumor burden and/or high circulating absolute lymphocyte counts (>25 × 10⁹/L) with antihyperuricemics (allopurinol) beginning 12–24 hr before starting therapy. Ensure adequate hydration for prophylaxis of tumor lysis syndrome.
- May cause hypotension. May require withholding antihypertensives for 12 hr prior to and during each infusion and for first hr after infusion.
- Premedicate patients with neutropenia with antimicrobial prophylaxis and consider antiviral and antifungal prophylaxis. Consider interrupting therapy if infection, Grade 3 or 4 cytopenia, or a ≥Grade 2 nonhematologic toxicity occurs.
- Premedication Guidelines:Cycle 1: Day 1 and 2: Premedicate all patients with glucocorticoids IV: dexamethasone 20 mg or methylprednisolone 80 mg completed 1 hr prior to obinutuzumab infusion. Acetaminophen 650–1000 mg and antihistamine (diphenhydramine 50 mg) at least 30 min prior to infusion. Cycle 1: Day 8 and 15 and Cycle 2–6 Day 1: Premedicate all patients with acetaminophen 650–1000 mg at least 30 min before obinutuzumab infusion. Premedicate patients with ≥Grade 1 infusion reaction with previous infusion with antihistamine (diphenhydramine 50 mg) at least 30 min prior to infusion. Premedicate patients with a Grade 3 infusion-related reaction with previous infusion OR with a lymphocyte count >25 × 10⁹/L prior to next treatment with glucocorticoids IV: dexamethasone 20 mg or methylprednisolone 80 mg completed 1 hr prior to obinutuzumab infusion.

IV Administration:

Intermittent Infusion: Diluent: Dilute into 0.9% NaCl PVC or non-PVC polyolefin infusion bag. Do not use other diluents.
- Day 1 (100 mg) and Day 2 (900 mg) of Cycle 1:Withdraw 40 mL of obinutuzumab from vial. Dilute 4 mL (100 mg) into 100 mL of 0.9% NaCl infusion bag for immediate administration. Dilute remaining 36 mL (900 mg) into 250 mL of 0.9% NaCl infusion bag at same time for use on Day 2. Store in refrigerator for up to 24 hr. Infuse immediately after allowing bag to come to room temperature.
- Day 8 and 15 of Cycle 1 and Day 1 Cycles 2–6: Withdraw 40 mL of obinutuzumab from vial. Dilute 40 mL (1000 mg) into 250 mL of 0.9% NaCl. Gently invert to mix; do not shake or freeze. If not administered immediately, stable in refrigerator for up to 24 hr. Concentration: 0.4 mg/mL to 4 mg/mL.
Rate: Do not administer via IV push or bolus. Chronic lymphocytic leukemia: Day 1, Cycle 1: Infuse at 25 mg/hr over 4 hr. Do not increase infusion rate. Day 2, Cycle 1: Infuse at 50 mg/hr. Increase infusion rate in increments of 50 mg/hr every 30 min to a maximum of 400 mg/hr. Days 8 and 15, Cycle 1; and Day 1, Cycles 2–6: Infuse at 100 mg/hr and increase rate in 100 mg/hr increments every 30 min to a maximum of 400 mg/hr. Follicular lymphoma: Day 1, Cycle 1: Infuse at 50 mg/hr. Increase infusion rate in increments of 50 mg/hr every 30 min to a maximum of 400 mg/hr. Days 8 and 15, Cycle 1; and Day 1, Cycles 2–6 or Cycles 2–8: If no infusion reaction occurred with previous infusion or if Grade 1 infusion reaction occurred during previous infusion, infuse at 100 mg/hr and increase rate in 100 mg/hr increments every 30 min to a maximum of 400 mg/hr. Day 1, Cycles 2–6 or Cycles 2–8; or monotherapy (alternative 90-min infusion approach):If ≥Grade 3 infusion reaction did not occur during Cycle 1, start infusion at 100 mg/hr for 30 min, then increase to 900 mg/hr for 60 min.
- If infusion reaction occurs, adjust rate as follows: Chronic lymphocytic leukemia: Day 2, Cycle 1: If infusion reaction occurred during Day 1, start infusion at 25 mg/hr; infusion rate can then be increased in increments of 50 mg/hr every 30 min to a maximum of 400 mg/hr. Days 8 and 15, Cycle 1; and Day 1, Cycles 2–6:If infusion reaction occurred during any previous infusion, start infusion at 50 mg/hr; infusion rate can then be increased in increments of 50 mg/hr every 30 min to a maximum of 400 mg/hr. Follicular lymphoma: Days 8 and 15, Cycle 1; Day 1, Cycles 2–6 or Cycles 2–8; or monotherapy:If ≥Grade 2 infusion reaction occurred during any previous infusion, start infusion at 50 mg/hr; infusion rate can then be increased in increments of 50 mg/hr every 30 min to a maximum of 400 mg/hr. For Cycles 2–6 or 2–8 or during monotherapy, if Grade 1–2 infusion reaction with ongoing symptoms or ≥Grade 3 infusion reaction occurred with 90-min infusion, administer all subsequent infusions at standard infusion rate.
Y-Site Incompatibility: Infuse through a dedicated line.

Explain purpose of obinutuzumab to patient.
Advise patient to avoid live viral vaccines during therapy
Instruct patient to notify health care professional immediately if signs and symptoms of infusion reaction (dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, chest pain), tumor lysis syndrome (nausea, vomiting, diarrhea, lethargy), infection (fever, cough), hepatitis (worsening fatigue, yellow discoloration of skin or eyes) or new changes in neurological symptoms (confusion, dizziness, loss of balance, difficulty talking or walking, vision problems) occur.
Rep: May cause fetal harm. Caution females of reproductive potential to use effective contraception and avoid breastfeeding during and for 6 mo after last dose of therapy. Advise patient to notify health care professional immediately if pregnancy is suspected. May cause fetal B-cell depletion; avoid administering live vaccines to neonates and infants exposed to obinutuzumab in utero until B-cell recovery occurs.
Emphasize importance of regular lab test to monitor for adverse reactions.

Decrease in progression of chronic lymphocytic leukemia and follicular lymphoma.

Gazyva

NDC Code

50242- Genentech, Inc.
- 50242-070- Gazyva
  - 50242-070-01- 1 VIAL, SINGLE-USE in 1 CARTON (50242-070-01) / 40 mL in 1 VIAL, SINGLE-USE

50242- Genentech, Inc.
- 50242-070- Gazyva
  - 50242-070-86- 1 VIAL, SINGLE-USE in 1 CARTON (50242-070-86) / 40 mL in 1 VIAL, SINGLE-USE

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