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Obinutuzumab (Monograph)

Brand name: Gazyva
Drug class: Antineoplastic Agents
Chemical name: Disulfide with human-mouse monoclonal GA101 κ-chain anti-(human CD20 (antigen)) (human-mouse monoclonal GA101 heavy chain) immunoglobulin G1 dimer
Molecular formula: C6512H10060N1712O2020S44
CAS number: 949142-50-1

Warning

    HBV Reactivation
  • Reactivation of HBV infection (including fulminant hepatitis and hepatic failure), sometimes fatal, reported.

  • Screen all patients for HBV infection prior to initiation of therapy.

  • Discontinue obinutuzumab and concomitant chemotherapy if HBV reactivation occurs. (See HBV Reactivation under Cautions.)

    Progressive Multifocal Leukoencephalopathy (PML)
  • PML, sometimes fatal, can occur. (See Progressive Multifocal Leukoencephalopathy under Cautions.)

Introduction

Antineoplastic agent; a recombinant humanized anti-CD20 monoclonal antibody.

Uses for Obinutuzumab

Chronic Lymphocytic Leukemia (CLL)

Treatment of previously untreated CLL.

Designated an orphan drug by FDA for the treatment of CLL.

Obinutuzumab Dosage and Administration

General

Tumor Lysis Syndrome Prophylaxis

Premedication for Infusion-related Reactions

Anti-infective Prophylaxis

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion. Do not administer by rapid IV injection (e.g., IV push or bolus).

Do not admix with any other drug.

Dilution

Must be diluted to final concentration of 0.4–4 mg/mL prior to IV infusion.

Immediate administration recommended. (See Storage under Stability.)

Do not shake vial.

Vials are for single use only.

To simultaneously prepare doses of 100 and 900 mg (days 1 and 2 in cycle 1): Withdraw 40 mL of obinutuzumab injection concentrate from a vial containing 1 g in 40 mL. Add 4 mL of drug concentrate to an infusion bag containing 100 mL of 0.9% sodium chloride injection and add the remaining 36 mL of drug concentrate to an infusion bag containing 250 mL of 0.9% sodium chloride injection to yield final concentrations of approximately 1 and 3.1 mg/mL, respectively; gently invert bag to mix solution. Store diluted solution for day 2 of cycle 1 at 2–8°C for up to 24 hours.

To prepare a 1-g dose: Withdraw 40 mL of obinutuzumab injection concentrate from a vial containing 1 g in 40 mL and add to an infusion bag containing 250 mL of 0.9% sodium chloride injection to yield a final concentration of approximately 3.4 mg/mL; gently invert bag to mix solution.

If the diluted solution was previously refrigerated, bring to room temperature and use immediately.

Rate of Administration

Day 1 of cycle 1 (100 mg): Infuse at a rate of 25 mg/hour over 4 hours.

Day 2 of cycle 1 (900 mg): Infuse at an initial rate of 50 mg/hour; if infusion-related events do not occur, the infusion rate may be increased in increments of 50 mg/hour every 30 minutes to a maximum rate of 400 mg/hour.

Subsequent doses (1 g each; days 8 and 15 of cycle 1 and day 1 of cycles 2–6): Infuse at an initial rate of 100 mg/hour; if infusion-related events do not occur, the infusion rate may be increased in increments of 100 mg/hour every 30 minutes to a maximum rate of 400 mg/hour.

For grade 4 infusion-related reaction, permanently discontinue obinutuzumab.

For grade 3 infusion-related reaction, interrupt the infusion until the reaction has resolved. Upon resumption, reduce the rate by at least 50%; if no further infusion-related events occur, increase the infusion rate as tolerated in increments and intervals appropriate for the treatment cycle dose (as described above). If a grade 3 infusion-related reaction recurs, permanently discontinue obinutuzumab.

For grade 1 or 2 infusion-related reaction, reduce the infusion rate or interrupt the infusion; the infusion may be restarted at a reduced rate once the reaction has resolved. If no further infusion-related events occur, increase the infusion rate as tolerated in increments and intervals appropriate for the treatment cycle dose (as described above).

Dosage

Adults

CLL
IV

Cycle 1: 100 mg on day 1, 900 mg on day 2, then 1 g once weekly for 2 doses (days 8 and 15); administer in combination with chlorambucil. If dose on day 1 of cycle 1 is not completed, subsequent dose on day 2 of cycle 1 may be administered if continued therapy is appropriate.

Cycles 2–6: 1 g every 4 weeks in combination with chlorambucil.

If a dose is missed, administer the missed dose as soon as possible and adjust the schedule to maintain the recommended 4-week interval between doses.

Therapy Interruption for Toxicity
Infusion-related Effects

Reduce the infusion rate or interrupt the infusion depending on the severity. (See Rate of Administration under Dosage and Administration.) If the reaction is grade 4, permanently discontinue obinutuzumab.

Hematologic Toxicity

If grade 3 or 4 cytopenia occurs, consider temporary interruption.

Infectious Complications

If infection occurs, consider temporary interruption.

Other Nonhematologic Toxicity

If grade 2 or greater nonhematologic toxicity occurs, consider temporary interruption.

Special Populations

Hepatic Impairment

No specific dosage recommendations; not specifically studied in hepatic impairment.

Renal Impairment

No specific dosage recommendations; not specifically studied in renal impairment with baseline Clcr <30 mL/minute.

Geriatric Patients

Recommended adult dosage for treatment of CLL is based on clinical trial experience mainly in geriatric patients.

Cautions for Obinutuzumab

Contraindications

Warnings/Precautions

Warnings

HBV Reactivation

Reactivation of HBV infection (including fulminant hepatitis, hepatic failure, and death) reported in patients receiving anti-CD20 monoclonal antibodies, such as obinutuzumab.

Reactivation reported in patients with the following serologic markers: hepatitis B surface antigen-positive [HBsAg-positive]; HBsAg-negative and hepatitis B core antibody-positive [anti-HBc-positive]; or HBsAg-negative, anti-HBc-positive, and hepatitis B surface antibody-positive [anti-HBs-positive].

FDA's review of 109 reports of fatal HBV-related acute liver injury in patients receiving ofatumumab or rituximab revealed highly variable onset of HBV reactivation (from 63 days after initiation of therapy to 12 months after last dose) and recent or concomitant use of other immunosuppressive agents in all 32 patients with documented (by seroconversion or serum HBV DNA) HBV reactivation. Longer intervals to HBV reactivation (up to 24 months after completion of rituximab therapy) also reported.

Screen all patients for HBV infection prior to initiation of obinutuzumab therapy. Consult hepatitis expert regarding monitoring and antiviral prophylaxis for patients with evidence of HBV infection (HBsAg-positive with any antibody status or HBsAg-negative and anti-HBc-positive). Monitor patients with evidence of current or prior HBV infection for clinical or laboratory manifestations of hepatitis or HBV reactivation during therapy and for several months thereafter.

If HBV reactivation occurs, discontinue obinutuzumab and any concomitant chemotherapy immediately and initiate appropriate treatment (e.g., antiviral therapy). Consult expert in managing HBV infections regarding resumption of obinutuzumab once control of HBV reactivation has been achieved. Safety of resuming obinutuzumab not known.

Progressive Multifocal Leukoencephalopathy

JC virus infection causing PML (which may be fatal) reported. Consider PML in any patient with new or worsening neurologic manifestations. If PML is suspected, withhold obinutuzumab and consider diagnostic evaluation (e.g., consultation with neurologist, brain MRI scan, lumbar puncture). If PML is confirmed, permanently discontinue the drug; consider dosage reduction or discontinuance of concomitant immunosuppressive therapy.

Other Warnings and Precautions

Infusion-related Effects

Risk of severe or life-threatening infusion-related reactions (e.g., bronchospasm, larynx and throat irritation, wheezing, dyspnea, laryngeal edema, flushing, hypertension, hypotension, tachycardia, nausea, vomiting, diarrhea, pyrexia, headache, chills). Generally more frequent during the first 2 infusions (total dose of 1 g) than during subsequent infusions of obinutuzumab; reactions have occurred within 24 hours of administration.

Premedication (acetaminophen, antihistamine, and corticosteroid) recommended prior to obinutuzumab infusions. (See Premedication for Infusion-related Reactions under Dosage and Administration.)

Monitor patients closely during infusions of the drug for manifestations of infusion-related reactions.

Preexisting cardiac or pulmonary conditions may increase the risk of severe infusion-related reactions; more frequent monitoring during and following infusions is indicated in such patients. Because hypotension may occur, consider withholding antihypertensive therapy. (See General under Dosage and Administration.)

Reduce the infusion rate or interrupt the infusion depending on the severity. (See Rate of Administration under Dosage and Administration.)

Provide appropriate treatment and supportive care (e.g., corticosteroid, epinephrine, bronchodilator, oxygen) as clinically indicated.

Tumor Lysis Syndrome

Tumor lysis syndrome may occur within 12–24 hours following initial infusion. Increased risk in patients with large tumor burden and/or high number of circulating malignant cells (lymphocyte count ≥25,000/mm3); take appropriate precautions in such patients. (See Tumor Lysis Syndrome Prophylaxis under Dosage and Administration.)

If tumor lysis syndrome develops, correct electrolyte abnormalities, monitor renal function and fluid balance, and employ supportive care (e.g., dialysis) as clinically indicated.

Infectious Complications

Serious bacterial, new or reactivated viral, or fungal infections reported during and following completion of obinutuzumab therapy. Manufacturer states that the drug should not be used in patients with active infections. Risk of infection may be increased in patients with history of recurring or chronic infections.

Hematologic Effects

Risk of severe, prolonged (lasting >28 days), or delayed-onset (≥28 days following completion of therapy) neutropenia.

Risk of severe or acute-onset (≤24 hours after completion of therapy) thrombocytopenia.

Monitor CBCs and platelet counts at regular intervals; more frequent monitoring recommended in patients with grade 3 or 4 cytopenia. Transfusion of blood products (i.e., platelets) may be necessary.

If neutropenia occurs, anti-infective, antiviral, or antifungal prophylaxis may be necessary. (See Anti-infective Prophylaxis under Dosage and Administration.)

Monitor for signs or symptoms of infection; if infection develops, institute appropriate treatment.

Immunization

Safety and efficacy of immunization with live or attenuated virus vaccines during or following obinutuzumab therapy not established.

Avoid immunization with live virus vaccines during obinutuzumab therapy and until recovery of B-cell counts.

Immunogenicity

Antibodies to obinutuzumab reported. Clinical relevance is not known. Neutralizing antibodies have not been assessed.

Specific Populations

Pregnancy

Category C.

Teratogenicity not demonstrated in animals; however, presence of obinutuzumab and depletion of B cells were observed in offspring on day 28 postpartum. B-cell count and immune function normalized within 6 months of birth.

Avoid pregnancy during and for 12 months after therapy.

Lactation

Not known whether obinutuzumab is distributed into milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Most (82%) patients in the phase 3 clinical trial in CLL were ≥65 years of age. No overall differences in efficacy relative to younger adults. Serious or fatal adverse events occurred at a higher incidence among patients ≥75 years of age.

Hepatic Impairment

Not studied in patients with hepatic impairment.

Renal Impairment

Pharmacokinetics not affected by baseline Clcr >30 mL/minute. Not studied in patients with baseline Clcr <30 mL/minute.

Common Adverse Effects

Infusion-related reactions, pyrexia, cough, musculoskeletal disorders, neutropenia, lymphopenia, leukopenia, thrombocytopenia, hypocalcemia, hyperkalemia, hyponatremia, elevated aminotransferase (i.e., AST, ALT) concentrations, elevated Scr, hypoalbuminemia, elevated serum alkaline phosphatase concentration, hypokalemia.

Drug Interactions

No formal drug interaction studies to date.

Obinutuzumab Pharmacokinetics

Absorption

Duration

Time required for B-cells to recover to normal levels following obinutuzumab therapy approximately 9 months in some patients; in other patients, B-cell depletion persisted at 18 months.

Distribution

Extent

Not known whether distributed into human milk.

Elimination

Half-life

Approximately 28–30 days in patients with CLL.

Exhibits linear and time-dependent nonlinear clearance; nonlinear clearance diminishes following repeated administration during a treatment course.

Special Populations

Body weight and age do not have meaningful effects on pharmacokinetics of obinutuzumab.

Clcr >30 mL/minute does not affect pharmacokinetics; not studied in patients with Clcr <30 mL/minute.

Stability

Storage

Parenteral

Injection Concentrate

2–8°C. Do not freeze. Protect vials from light.

Following dilution, use immediately or store at 2–8°C; discard after 24 hours.

Compatibility

Parenteral

No incompatibilities observed with PVC or polyolefin bags and administration sets.

Solution Compatibility

Compatible

Sodium chloride 0.9%

Incompatible

Dextrose 5% in water

Actions

Advice to Patients

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Obinutuzumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV infusion only

25 mg/mL (1 g)

Gazyva

Genentech

AHFS DI Essentials™. © Copyright 2024, Selected Revisions August 28, 2014. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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Frequently asked questions