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Obinutuzumab

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
Brands: Gazyva

Warning(s)

  • HBV Reactivation
  • Reactivation of HBV infection (including fulminant hepatitis and hepatic failure), sometimes fatal, reported.1 5 6 7 8

  • Screen all patients for HBV infection prior to initiation of therapy.1

  • Discontinue obinutuzumab and concomitant chemotherapy if HBV reactivation occurs.1 (See HBV Reactivation under Cautions.)

  • Progressive Multifocal Leukoencephalopathy (PML)
  • PML, sometimes fatal, can occur.1 (See Progressive Multifocal Leukoencephalopathy under Cautions.)

Introduction

Antineoplastic agent; a recombinant humanized anti-CD20 monoclonal antibody.1 4

Uses for Obinutuzumab

Chronic Lymphocytic Leukemia (CLL)

Treatment of previously untreated CLL.1 2

Designated an orphan drug by FDA for the treatment of CLL.3

Obinutuzumab Dosage and Administration

General

  • Administer in setting where adequate monitoring can be performed and appropriate medical support for treating infusion-related reactions is available.1

  • Consider withholding antihypertensive therapy for 12 hours prior to, during, and for 1 hour following each obinutuzumab infusion until BP has stabilized; however, consider potential risks and benefits of withholding antihypertensive therapy in patients at risk of hypertensive crisis.1

Tumor Lysis Syndrome Prophylaxis

  • In patients at high risk of tumor lysis syndrome, hydrate and administer an antihyperuricemic agent (e.g., allopurinol) beginning 12–24 hours prior to the first obinutuzumab infusion.1 (See Tumor Lysis Syndrome under Cautions.)

Premedication for Infusion-related Reactions

  • Administer acetaminophen 650 mg to 1 g at least 30 minutes prior to each obinutuzumab infusion.1

  • Also administer an antihistamine (e.g., diphenhydramine hydrochloride 50 mg) and an IV corticosteroid (dexamethasone 20 mg or methylprednisolone 80 mg) at least 30 minutes and 1 hour, respectively, prior to obinutuzumab infusions on days 1 and 2 of cycle 1.1

  • Recommendations for antihistamine and/or corticosteroid premedication prior to subsequent obinutuzumab infusions (days 8 and 15 of cycle 1 and day 1 of cycles 2–6) are based on prior tolerance of the drug.1

  • If grade 1 or 2 infusion-related reaction occurred during a previous infusion, administer an antihistamine (e.g., diphenhydramine hydrochloride 50 mg) at least 30 minutes prior to subsequent infusions.1

  • If grade 3 infusion-related reaction occurred during a previous infusion, administer an antihistamine (e.g., diphenhydramine hydrochloride 50 mg) and an IV corticosteroid (dexamethasone 20 mg or methylprednisolone 80 mg) at least 30 minutes and 1 hour, respectively, prior to subsequent infusions.1

  • If circulating lymphocyte count prior to the next cycle is >25,000/mm3, administer an IV corticosteroid (dexamethasone 20 mg or methylprednisolone 80 mg) at least 1 hour prior to the obinutuzumab infusion.1

  • Hydrocortisone has not been effective in reducing the rate of infusion-related events.1

Anti-infective Prophylaxis

  • Anti-infective prophylaxis strongly recommended in neutropenic patients; consider antiviral and antifungal prophylaxis.1 (See Infectious Complications under Cautions.)

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1 Do not administer by rapid IV injection (e.g., IV push or bolus).1

Do not admix with any other drug.1

Dilution

Must be diluted to final concentration of 0.4–4 mg/mL prior to IV infusion.1

Immediate administration recommended.1 (See Storage under Stability.)

Do not shake vial.1

Vials are for single use only.1

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.1 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.1 Store diluted solution for day 2 of cycle 1 at 2–8°C for up to 24 hours.1

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.1

If the diluted solution was previously refrigerated, bring to room temperature and use immediately.1

Rate of Administration

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

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.1

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.1

For grade 4 infusion-related reaction, permanently discontinue obinutuzumab.1

For grade 3 infusion-related reaction, interrupt the infusion until the reaction has resolved.1 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).1 If a grade 3 infusion-related reaction recurs, permanently discontinue obinutuzumab.1

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.1 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).1

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.1 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.1

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

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.1

Therapy Interruption for Toxicity
Infusion-related Effects

Reduce the infusion rate or interrupt the infusion depending on the severity.1 (See Rate of Administration under Dosage and Administration.)1 If the reaction is grade 4, permanently discontinue obinutuzumab.1

Hematologic Toxicity

If grade 3 or 4 cytopenia occurs, consider temporary interruption.1

Infectious Complications

If infection occurs, consider temporary interruption.1

Other Nonhematologic Toxicity

If grade 2 or greater nonhematologic toxicity occurs, consider temporary interruption.1

Special Populations

Hepatic Impairment

No specific dosage recommendations; not specifically studied in hepatic impairment.1

Renal Impairment

No specific dosage recommendations; not specifically studied in renal impairment with baseline Clcr <30 mL/minute.1

Geriatric Patients

Recommended adult dosage for treatment of CLL is based on clinical trial experience mainly in geriatric patients.1

Cautions for Obinutuzumab

Contraindications

  • No known contraindications.1

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.1 5 6 7 8

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].1 5

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.5 Longer intervals to HBV reactivation (up to 24 months after completion of rituximab therapy) also reported.6 12

Screen all patients for HBV infection prior to initiation of obinutuzumab therapy.1 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).1 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.1

If HBV reactivation occurs, discontinue obinutuzumab and any concomitant chemotherapy immediately and initiate appropriate treatment (e.g., antiviral therapy).1 Consult expert in managing HBV infections regarding resumption of obinutuzumab once control of HBV reactivation has been achieved.1 Safety of resuming obinutuzumab not known.1

Progressive Multifocal Leukoencephalopathy

JC virus infection causing PML (which may be fatal) reported.1 Consider PML in any patient with new or worsening neurologic manifestations.1 If PML is suspected, withhold obinutuzumab and consider diagnostic evaluation (e.g., consultation with neurologist, brain MRI scan, lumbar puncture).1 If PML is confirmed, permanently discontinue the drug; consider dosage reduction or discontinuance of concomitant immunosuppressive therapy.1

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). 1 2 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.1

Premedication (acetaminophen, antihistamine, and corticosteroid) recommended prior to obinutuzumab infusions.1 (See Premedication for Infusion-related Reactions under Dosage and Administration.)

Monitor patients closely during infusions of the drug for manifestations of infusion-related reactions.1

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.1 Because hypotension may occur, consider withholding antihypertensive therapy.1 (See General under Dosage and Administration.)

Reduce the infusion rate or interrupt the infusion depending on the severity.1 (See Rate of Administration under Dosage and Administration.)

Provide appropriate treatment and supportive care (e.g., corticosteroid, epinephrine, bronchodilator, oxygen) as clinically indicated.1

Tumor Lysis Syndrome

Tumor lysis syndrome may occur within 12–24 hours following initial infusion.1 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.1 (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.1

Infectious Complications

Serious bacterial, new or reactivated viral, or fungal infections reported during and following completion of obinutuzumab therapy.1 Manufacturer states that the drug should not be used in patients with active infections.1 Risk of infection may be increased in patients with history of recurring or chronic infections.1

Hematologic Effects

Risk of severe, prolonged (lasting >28 days), or delayed-onset (≥28 days following completion of therapy) neutropenia.1

Risk of severe or acute-onset (≤24 hours after completion of therapy) thrombocytopenia.1

Monitor CBCs and platelet counts at regular intervals; more frequent monitoring recommended in patients with grade 3 or 4 cytopenia.1 Transfusion of blood products (i.e., platelets) may be necessary.1

If neutropenia occurs, anti-infective, antiviral, or antifungal prophylaxis may be necessary.1 (See Anti-infective Prophylaxis under Dosage and Administration.)

Monitor for signs or symptoms of infection; if infection develops, institute appropriate treatment.1

Immunization

Safety and efficacy of immunization with live or attenuated virus vaccines during or following obinutuzumab therapy not established.1

Avoid immunization with live virus vaccines during obinutuzumab therapy and until recovery of B-cell counts.1

Immunogenicity

Antibodies to obinutuzumab reported.1 Clinical relevance is not known.1 Neutralizing antibodies have not been assessed.1

Specific Populations

Pregnancy

Category C.1

Teratogenicity not demonstrated in animals; however, presence of obinutuzumab and depletion of B cells were observed in offspring on day 28 postpartum.1 B-cell count and immune function normalized within 6 months of birth.1

Avoid pregnancy during and for 12 months after therapy.1

Lactation

Not known whether obinutuzumab is distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

Most (82%) patients in the phase 3 clinical trial in CLL were ≥65 years of age.1 No overall differences in efficacy relative to younger adults.1 Serious or fatal adverse events occurred at a higher incidence among patients ≥75 years of age.1

Hepatic Impairment

Not studied in patients with hepatic impairment.1

Renal Impairment

Pharmacokinetics not affected by baseline Clcr >30 mL/minute.1 Not studied in patients with baseline Clcr <30 mL/minute.1

Common Adverse Effects

Infusion-related reactions,1 pyrexia,1 cough,1 musculoskeletal disorders,1 neutropenia,1 lymphopenia,1 leukopenia,1 thrombocytopenia,1 hypocalcemia,1 hyperkalemia,1 hyponatremia,1 elevated aminotransferase (i.e., AST, ALT) concentrations,1 elevated Scr,1 hypoalbuminemia,1 elevated serum alkaline phosphatase concentration,1 hypokalemia.1

Interactions for Obinutuzumab

No formal drug interaction studies to date.1

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.1

Distribution

Extent

Not known whether distributed into human milk.1

Elimination

Half-life

Approximately 28–30 days in patients with CLL.1 19

Exhibits linear and time-dependent nonlinear clearance; nonlinear clearance diminishes following repeated administration during a treatment course.1

Special Populations

Body weight and age do not have meaningful effects on pharmacokinetics of obinutuzumab.1

Clcr >30 mL/minute does not affect pharmacokinetics; not studied in patients with Clcr <30 mL/minute.1

Stability

Storage

Parenteral

Injection Concentrate

2–8°C.1 Do not freeze.1 Protect vials from light.1

Following dilution, use immediately or store at 2–8°C; discard after 24 hours.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

No incompatibilities observed with PVC or polyolefin bags and administration sets.1

Solution Compatibility

Compatible

Sodium chloride 0.9%1

Incompatible

Dextrose 5% in water1

Actions

  • An IgG1 kappa immunoglobulin that binds specifically to antigen CD20 (expressed on the surface of normal and malignant B-cells, including B-CLL cells), triggering a host immune response causing B-cell lysis.1 4 13 14 15 17

  • Mechanism of cell lysis is thought to involve antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC).1 17

  • Contains a nonfucosylated Fc domain engineered to enhance binding affinity of obinutuzumab for receptors, resulting in enhanced ADCC against malignant B cells relative to rituximab.13 15 16 17 18

  • Modified elbow hinge sequences may enhance type II antibody properties of the drug, such as increased direct induction of programmed cell death.13 17

  • Compared with rituximab, obinutuzumab induces a lower level of CDC activity but elicits more potent homotypic adhesion and direct induction of programmed cell death.15 17 18

  • Obinutuzumab is tenfold to 25-fold more potent than rituximab at depleting B-cells in blood obtained from healthy individuals and also more effective than rituximab in depleting B cells in blood from an individual with CLL.15

Advice to Patients

  • Risk of infusion-related reactions; importance of reporting signs and symptoms of such reactions (e.g., dizziness, nausea, chills, fever, vomiting, diarrhea, breathing difficulty, chest pain).1

  • Risk of tumor lysis syndrome; importance of reporting symptoms of tumor lysis syndrome (e.g., nausea, vomiting, diarrhea, lethargy).1

  • Risk of infection; importance of reporting signs or symptoms of infection (e.g., cough, fever).1

  • Risk of PML; importance of reporting new or worsening neurologic symptoms (e.g., confusion, dizziness or loss of balance, difficulty speaking or walking, changes in vision).1

  • Risk of HBV reactivation; importance of reporting symptoms of hepatitis (e.g., worsening fatigue, icteric changes).1 Importance of informing clinician of presence of HBV carrier state or of any history of HBV infection.5

  • Advise patients that they should not receive a live viral vaccine if they have recently received obinutuzumab.1

  • Importance of routine monitoring of blood cell counts.1

  • Necessity of advising women to avoid pregnancy and breast-feeding while receiving therapy.1 Advise women to use an effective method of contraception during therapy and for 12 months after the last dose of obinutuzumab.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

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, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Genentech Inc. Gazyva (obinutuzumab) injection for IV infusion prescribing information. South San Francisco, CA; 2013 Nov.

2. Goede V, Fischer K, Busch R et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014; 370:1101-10. [PubMed 24401022]

3. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2014 Apr 25.

4. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125486Orig1s000: Pharmacology review(s). From FDA website.

5. Food and Drug Administration. Drug safety communication: Boxed warning and new recommendations to decrease risk of hepatitis B reactivation with the immune-suppressing and anti-cancer drugs Arzerra (ofatumumab) and Rituxan (rituximab) [2013 Sep 25]. From FDA website.

6. Chew E, Thursky K, Seymour JF. Very late onset hepatitis-B virus reactivation following rituximab despite lamivudine prophylaxis: the need for continued vigilance. Leuk Lymphoma. 2013; :.

7. Oh MJ, Lee HJ. A study of hepatitis B virus reactivation associated with rituximab therapy in real-world clinical practice: a single-center experience. Clin Mol Hepatol. 2013; 19:51-9. [PubMed 23593610]

8. Yang JD, Girotra M, Vaid A et al. Hepatitis B reactivation in patient with non-Hodgkin's lymphoma receiving rituximab-based chemotherapy: need for education and attention. J Ark Med Soc. 2013; 110:110-2. [PubMed 24367885]

9. Artz AS, Somerfield MR, Feld JJ et al. American Society of Clinical Oncology provisional clinical opinion: chronic hepatitis B virus infection screening in patients receiving cytotoxic chemotherapy for treatment of malignant diseases. J Clin Oncol. 2010; 28:3199-202. [PubMed 20516452]

10. European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012; 57:167-85. [PubMed 22436845]

11. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009; 50:661-2. [PubMed 19714720]

12. Biogen Idec/Genentech. Rituxan (rituximab) injection for IV infusion prescribing information. South San Francisco, CA; 2013 Sep.

13. Patz M, Isaeva P, Forcob N et al. Comparison of the in vitro effects of the anti-CD20 antibodies rituximab and GA101 on chronic lymphocytic leukaemia cells. Br J Haematol. 2011; 152:295-306. [PubMed 21155758]

14. Teeling JL, Mackus WJ, Wiegman LJ et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol. 2006; 177:362-71. [PubMed 16785532]

15. Mössner E, Brünker P, Moser S et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 2010; 115:4393-402. [PubMed 20194898]

16. Rafiq S, Butchar JP, Cheney C et al. Comparative assessment of clinically utilized CD20-directed antibodies in chronic lymphocytic leukemia cells reveals divergent NK cell, monocyte, and macrophage properties. J Immunol. 2013; 190:2702-11. [PubMed 23418626]

17. Klein C, Lammens A, Schäfer W et al. Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties. MAbs. 2013 Jan-Feb; 5:22-33.

18. Alduaij W, Ivanov A, Honeychurch J et al. Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies. Blood. 2011; 117:4519-29. [PubMed 21378274]

19. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125486Orig1s000: Medical review(s). From FDA website.

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