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Obinutuzumab

Medically reviewed by Drugs.com. Last updated on Mar 28, 2020.

Pronunciation

(oh bi nue TOOZ ue mab)

Index Terms

  • GA101
  • R05072759
  • R7159

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Gazyva: 1000 mg/40 mL (40 mL)

Brand Names: U.S.

  • Gazyva

Pharmacologic Category

  • Antineoplastic Agent, Anti-CD20
  • Antineoplastic Agent, Monoclonal Antibody

Pharmacology

Obinutuzumab is a glycoengineered type II anti-CD20 monoclonal antibody. The CD20 antigen is expressed on the surface of pre B- and mature B-lymphocytes; upon binding to CD20, obinutuzumab activates complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis, resulting in cell death (Sehn 2012).

Distribution

Vd: ~4.1 to 4.3 L

Half-Life Elimination

25.5 to 35.3 days

Use: Labeled Indications

Chronic lymphocytic leukemia: Treatment of previously untreated chronic lymphocytic leukemia in combination with chlorambucil.

Follicular lymphoma:

Previously untreated: Treatment of previously untreated stage II bulky, stage III, or stage IV follicular lymphoma in combination with chemotherapy (followed by obinutuzumab monotherapy) in patients achieving at least a partial remission.

Relapsed/refractory: Treatment of follicular lymphoma (in combination with bendamustine followed by obinutuzumab monotherapy) in patients who relapsed after, or are refractory to, a rituximab-containing regimen.

Contraindications

Known hypersensitivity reactions (eg, anaphylaxis) to obinutuzumab or any component of the formulation; serum sickness with prior obinutuzumab use.

Dosing: Adult

Note: Premedication with acetaminophen, an antihistamine, and a glucocorticoid (dexamethasone or methylprednisolone) 30 to 60 minutes prior to treatment may be necessary (see Administration). Antihyperuricemic prophylaxis and adequate hydration are recommended for patients at high risk for tumor lysis syndrome. Antimicrobial, antiviral, and antifungal prophylaxis may be considered in certain patients. Consider temporarily withholding antihypertensive therapies for 12 hours prior to, during, and for 1 hour after obinutuzumab administration (due to the risk for hypotension).

Chronic lymphocytic leukemia (previously untreated; in combination with chlorambucil [Goede 2014]): IV:

Cycle 1: 100 mg on day 1, followed by 900 mg on day 2, followed by 1,000 mg weekly for 2 doses (days 8 and 15); treatment cycle is 28 days.

Cycles 2 through 6: 1,000 mg on day 1 every 28 days for 5 doses.

Missed doses: Administer the missed dose as soon as possible; adjust dosing schedule to maintain the time interval between doses. In some cases, patients who do not complete the day 1 cycle 1 dose may proceed to the day 2 cycle 1 treatment (if appropriate).

Chronic lymphocytic leukemia (previously untreated, as a single agent [off label; Byrd 2016]): IV:

Cycle 1: 100 mg on day 1, followed by 900 mg on day 2, followed by 1,000 mg weekly for 2 doses (days 8 and 15); treatment cycle is 21 days.

Cycles 2 through 8: 1,000 mg on day 1 every 21 days for 7 doses.

Chronic lymphocytic leukemia (previously untreated, in combination with acalabrutinib [off-label combination; Sharman 2020]): IV:

Cycle 2: 100 mg on day 1, followed by 900 mg on day 2, followed by 1,000 mg weekly for 2 doses (days 8 and 15); treatment cycle is 28 days (cycle 1 is acalabrutinib only; obinutuzumab begins with cycle 2).

Cycles 3 through 7: 1,000 mg on day 1 every 28 days for 5 doses (continue acalabrutinib until disease progression or unacceptable toxicity).

Chronic lymphocytic leukemia (previously untreated, in combination with ibrutinib [off-label combination; Moreno 2019]): IV:

Cycle 1: 100 mg on day 1, followed by 900 mg on day 2, followed by 1,000 mg weekly for 2 doses (days 8 and 15); treatment cycle is 28 days.

Cycles 2 through 6: 1,000 mg on day 1 every 28 days for 5 doses (continue ibrutinib until disease progression or unacceptable toxicity).

Chronic lymphocytic leukemia (previously untreated patients with coexisting conditions, in combination with venetoclax [off-label combination; Fischer 2019]): IV:

Cycle 1: 100 mg on day 1, followed by 900 mg on day 2 (or 1,000 mg on day 1), followed by 1,000 mg weekly for 2 doses (days 8 and 15); treatment cycle is 28 days (venetoclax is initiated on day 22 of cycle 1).

Cycles 2 through 6: 1,000 mg on day 1 every 28 days for 5 doses (continue venetoclax until the end of cycle 12).

Follicular lymphoma (previously untreated; Marcus 2017): IV:

Note: Patients with complete response or partial response to the initial 6 or 8 cycles of combination therapy (with either bendamustine or cyclophosphamide, doxorubicin, vincristine, prednisone [CHOP] or cyclophosphamide, vincristine, and prednisone [CVP]) should continue on obinutuzumab as monotherapy for up to 2 years.

Cycle 1 (either in combination with bendamustine or with CHOP or CVP chemotherapy): 1,000 mg weekly for 3 doses on day 1, day 8, and day 15; treatment cycle is either 21 or 28 days (depending on combination therapy).

Cycles 2 through 6 (in combination with bendamustine): 1,000 mg on day 1 every 28 days for 5 doses.

Cycles 2 through 8 (in combination with CHOP): 1,000 mg on day 1 every 21 days for 5 combination therapy doses (in combination with CHOP in cycles 2 through 6), followed by 1,000 mg on day 1 every 21 days for 2 doses (as monotherapy) in cycles 7 and 8.

Cycles 2 through 8 (in combination with CVP): 1,000 mg on day 1 every 21 days for 7 doses.

Obinutuzumab monotherapy: 1,000 mg once every 2 months for up to 2 years beginning ~2 months after the last induction phase obinutuzumab dose.

Missed doses: Administer the missed dose as soon as possible; adjust dosing schedule accordingly to maintain the time interval between chemotherapy cycles. During obinutuzumab monotherapy, maintain the original dosing schedule for subsequent doses.

Follicular lymphoma (relapsed/refractory; Cheson 2018; Sehn 2016): IV:

Note: Patients with stable disease, complete response, or partial response after 6 cycles of combination therapy (with bendamustine) should continue on obinutuzumab as monotherapy for up to 2 years.

Cycle 1 (in combination with bendamustine): 1,000 mg weekly for 3 doses on day 1, day 8, and day 15; treatment cycle is 28 days.

Cycles 2 through 6 (in combination with bendamustine): 1,000 mg on day 1 every 28 days for 5 doses.

Obinutuzumab monotherapy: 1,000 mg once every 2 months for up to 2 years beginning ~2 months after the last induction phase obinutuzumab dose.

Missed doses: Administer the missed dose as soon as possible; adjust dosing schedule accordingly to maintain the time interval between chemotherapy cycles. During obinutuzumab monotherapy, maintain the original dosing schedule for subsequent doses.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Hematologic:

Grade 3 or 4 neutropenia: Consider treatment interruption and use of granulocyte colony-stimulating factors. In patients with severe and long-lasting (>1 week) neutropenia, antimicrobial prophylaxis is recommended until neutropenia improves to grade 1 or 2. Consider antiviral and antifungal prophylaxis in patients with severe and long-lasting (>1 week) neutropenia.

Grade 3 or 4 thrombocytopenia: Consider treatment interruption.

Infusion reactions:

Mild to moderate (Grades 1 and 2): Reduce infusion rate or interrupt infusion and manage symptoms as appropriate. Upon symptom resolution, continue or resume infusion. If no further infusion reaction symptoms occur, may resume infusion rate escalation as appropriate for the treatment cycle dose. For CLL only, day 1 (cycle 1) infusion rate may be increased back up to a maximum of 25 mg/hour after 1 hour.

Severe (Grade 3): Interrupt infusion; manage symptoms as appropriate. Upon symptom resolution, may reinitiate infusion at no more than 50% of the rate at which the reaction occurred. If no further infusion reaction symptoms occur, may resume infusion rate escalation as appropriate for the treatment cycle dose. For CLL only, day 1 (cycle 1) infusion rate may be increased back up to a maximum of 25 mg/hour after 1 hour. Permanently discontinue if ≥ grade 3 infusion-related symptoms occur upon rechallenge.

Life-threatening (Grade 4): Discontinue infusion immediately; permanently discontinue therapy.

Infection: Consider treatment interruption.

Other toxicity: Consider treatment interruption for ≥ grade 2 nonhematologic toxicity.

Reconstitution

Chronic lymphocytic leukemia:

Cycle 1, day 1 and 2 doses (100 mg and 900 mg, respectively [on day 1, use 1 vial to prepare day 1 and day 2 infusion bags]): Withdraw 40 mL of obinutuzumab solution from vial. Dilute 4 mL into a 100 mL infusion bag of NS (100 mg dose; use immediately). Dilute remaining 36 mL into a 250 mL NS infusion bag (900 mg dose, for use on day 2); store at 2°C to 8°C (36°F to 46°F) for up to 24 hours; use immediately after reaching room temperature. Gently invert to mix; do not shake or freeze.

Cycle 1 (day 8 and 15 doses) and day 1 of cycles 2 through 6 (1,000 mg): Withdraw 40 mL of obinutuzumab solution from vial. Dilute into a 250 mL NS infusion bag. Gently invert to mix; do not shake or freeze.

Do not use other diluents (eg, dextrose) to prepare the infusion. Final concentration for administration should be 0.4 to 4 mg/mL. May use PVC or non-PVC infusion bags.

Follicular lymphoma (1,000 mg): Withdraw 40 mL of obinutuzumab solution from vial. Dilute into a 250 mL NS infusion bag. Gently invert to mix; do not shake or freeze.

Do not use other diluents (eg, dextrose) to prepare the infusion. Final concentration for administration should be 0.4 to 4 mg/mL. May use PVC or non-PVC polyolefin infusion bags.

Administration

IV: For IV infusion only. Do not administer IV push or as a bolus. Administer through a dedicated IV line; do not mix with or infuse with other medications. May use PVC or non-PVC administration sets. Premedication with acetaminophen, an antihistamine, and a glucocorticoid (dexamethasone or methylprednisolone) may be required to prevent infusion reactions (see below). In patients with severe (grade 3 or 4) neutropenia lasting more than 1 week, antimicrobial prophylaxis is strongly recommended (continue until neutropenia resolves to grade 1 or 2); antiviral and antifungal prophylaxis should be considered.

Premedication to prevent infusion reactions:

Chronic lymphocytic leukemia (CLL) (cycle 1 [days 1 and 2]) and follicular lymphoma (FL) (day 1): All patients should receive acetaminophen (650 to 1,000 mg) and an antihistamine (eg, diphenhydramine 50 mg) at least 30 minutes prior to obinutuzumab infusion. In addition, an IV glucocorticoid (dexamethasone 20 mg or methylprednisolone 80 mg) should be administered at least 1 hour prior to obinutuzumab infusion. If a glucocorticoid-containing chemotherapy regimen is administered on the same day as obinutuzumab, the glucocorticoid may be administered as an oral medication if administered at least 1 hour prior to obinutuzumab (an IV glucocorticoid is therefore not required).

All subsequent infusions: All patients should receive acetaminophen 650 to 1,000 mg at least 30 minutes prior to obinutuzumab infusion.

If patients experienced grade 1 or 2 infusion-related reaction with previous infusion: Administer an antihistamine (eg, diphenhydramine 50 mg) in addition to acetaminophen at least 30 minutes prior to obinutuzumab infusion.

If patients experienced a grade 3 infusion-related reaction with previous infusion or have a lymphocyte count >25,000 cells/mm3 prior to next treatment: Administer an IV glucocorticoid (dexamethasone 20 mg or methylprednisolone 80 mg) at least 1 hour prior to obinutuzumab infusion, in addition to acetaminophen and an antihistamine at least 30 minutes prior to obinutuzumab infusion.

Infusion rate:

CLL:

Cycle 1 (day 1): Infuse at 25 mg/hour over 4 hours; do not increase the infusion rate.

Cycle 1 (day 2): If no reaction to previous infusion, initiate infusion at 50 mg/hour for 30 minutes; if tolerated, may escalate rate in increments of 50 mg/hour every 30 minutes to a maximum rate of 400 mg/hour. If an infusion reaction occurred during the previous infusion, initiate infusion at 25 mg/hour for 30 minutes; if tolerated, may escalate rate in increments of up to 50 mg/hour every 30 minutes to a maximum rate of 400 mg/hour.

Cycle 1 (days 8 and 15), and cycles 2 through 6 (day 1): If no reaction to previous infusion and the final infusion rate was 100 mg/hour or faster, initiate infusion at 100 mg/hour for 30 minutes; if tolerated, may escalate infusion rate in increments of 100 mg/hour every 30 minutes to a maximum rate of 400 mg/hour. If an infusion reaction occurred during the previous infusion, initiate infusion at 50 mg/hour for 30 minutes; if tolerated, may escalate rate in increments of 50 mg/hour every 30 minutes to a maximum rate of 400 mg/hour.

FL (previously untreated or relapsed/refractory):

Cycle 1 (day 1): Initiate infusion at 50 mg/hour for 30 minutes; if tolerated, may escalate rate in increments of 50 mg/hour every 30 minutes to a maximum rate of 400 mg/hour.

All subsequent infusions: If no reaction or grade 1 reaction to previous infusion and the final infusion rate was 100 mg/hour or faster, initiate infusion at 100 mg/hour for 30 minutes; if tolerated, may escalate rate in increments of 100 mg/hour every 30 minutes to a maximum rate of 400 mg/hour. If a grade 2 or higher infusion reaction occurred during the previous infusion, initiate infusion at 50 mg/hour for 30 minutes; if tolerated, may escalate rate in increments of 50 mg/hour every 30 minutes to a maximum rate of 400 mg/hour.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze or shake. Protect from light. Solutions diluted in NS for infusion should be used immediately. If not used immediately, the diluted solutions may be stored up to 24 hours at 2°C to 8°C (36°F to 46°F); discard after 24 hours.

Drug Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amisulpride (Oral): May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Anticoagulants: May enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: Obinutuzumab may enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Management: Consider avoiding Echinacea in patients receiving therapeutic immunosuppressants. If coadministered, monitor for reduced efficacy of the immunosuppressant during concomitant use. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Inebilizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Management: Avoid use of immunosuppressants (including systemic corticosteroids) prior to initiation of nivolumab. Use of immunosuppressants after administration of nivolumab (eg, for immune-related toxicity) is unlikely to affect nivolumab efficacy. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Ozanimod: Immunosuppressants may enhance the immunosuppressive effect of Ozanimod. Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Management: Consider avoiding concomitant use of roflumilast and immunosuppressants as recommended by the Canadian product monograph. Inhaled or short-term corticosteroids are unlikely to be problematic. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Management: Concomitant use of upadacitinib with potent immunosuppressants is not recommended. Drugs listed as exceptions to this monograph are discussed in separate drug interaction monographs. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

Adverse reactions are reported in combination with chlorambucil or bendamustine unless incidence is identified as having occurred during the monotherapy phase.

>10%:

Dermatologic: Pruritus (11%), skin rash (monotherapy: ≥10%; combination therapy: 17%)

Endocrine & metabolic: Hyperkalemia (20% to 33%), hypernatremia (16%), hyperuricemia (28%), hypoalbuminemia (23% to 33%), hypocalcemia (32% to 39%), hypokalemia (14%), hyponatremia (26%), hypophosphatemia (36% to 41%)

Gastrointestinal: Constipation (8% to 32%) decreased appetite (14%), diarrhea (monotherapy: ≥10%; combination therapy: 10% to 30%)

Genitourinary: Urinary tract infection (monotherapy: ≥10%; combination therapy: 5% to 13%)

Hematologic & oncologic: Anemia (12% to 39%; grades 3/4: 5% to 10%), hemorrhage (12%; grades 3/4: 4%), hypoproteinemia (32%), leukopenia (84% to 92%; grades 3/4: 35% to 49%, grade 4: 17%), lymphocytopenia (monotherapy: grades 3/4: 23%, grade 4: 5%; combination therapy: 80% to 97%; grades 3/4: 39% to 92%; grade 4: 33%), neutropenia (monotherapy: 13% to 20%; grades 3/4: 21% to 25%, grade 4: 10%; combination therapy: 37% to 84%; grades 3/4: 33% to 59%; onset ≥28 days after completion of treatment: 4% to 16%; lasting ≥28 days: 1% to 3%), thrombocytopenia (14% to 68%; grades 3/4: 10% to 13%; onset within 24 hours of infusion: 4%)

Hepatic: Hyperbilirubinemia (21%), increased serum alanine aminotransferase (28% to 50%), increased serum alkaline phosphatase (18% to 27%), increased serum aspartate aminotransferase (27% to 44%)

Infection: Herpes virus infection (monotherapy: 13%; combination therapy: 18%), infection (38% to 82%)

Nervous system: Fatigue (monotherapy: ≥10%; combination therapy: 40%), headache (18%), insomnia (15%)

Neuromuscular & skeletal: Arthralgia (12% to 16%), musculoskeletal signs and symptoms (18% to 54%; including musculoskeletal pain: monotherapy: 20%; combination therapy: 28%)

Renal: Increased serum creatinine (30%)

Respiratory: Cough (monotherapy: 23%; combination therapy: 10% to 35%), pneumonia (14%), respiratory tract infection (monotherapy: ≥10%; combination therapy: 14%), upper respiratory tract infection (monotherapy: 40%; combination therapy: 36% to 50%)

Miscellaneous: Fever (19%), infusion related reaction (monotherapy: 8% to 9%; combination therapy: 66% to 72%, initial infusion: 37% to 65%, subsequent infusions and cycles: ≤23% [dependent on dose, cycle, and use of premeditations]; can be severe infusion related reaction)

1% to 10%:

Hematologic & oncologic: Febrile neutropenia (6%), tumor lysis syndrome (grades 3/4: ≤2%)

Hepatic: Increased liver enzymes (4%; may be secondary or exacerbated by premedications)

Immunologic: Antibody development (≤7%)

Infection: Sepsis (7%)

Neuromuscular & skeletal: Back pain (5%)

Respiratory: Nasopharyngitis (6%)

Frequency not defined:

Cardiovascular: Exacerbation of cardiac disease

Hepatic: Fulminant hepatitis, hepatic failure

Infection: JC virus infection, reactivation of HBV

Nervous system: Progressive multifocal leukoencephalopathy

Postmarketing:

Gastrointestinal: Gastrointestinal perforation

Hypersensitivity: Hypersensitivity reactions, serum sickness

ALERT: U.S. Boxed Warning

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, including obinutuzumab. Screen all patients for HBV infection before treatment initiation. Monitor HBV-positive patients during and after treatment with obinutuzumab. Discontinue obinutuzumab and concomitant medications in the event of HBV reactivation.

Progressive multifocal leukoencephalopathy:

Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur in patients receiving obinutuzumab.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Severe and life-threatening (grade 3 and 4) neutropenia (including neutropenic fever) has been observed in clinical trials. Neutropenia may have a late onset (>28 days after therapy completion) and/or be prolonged (duration >28 days). Consider administration of granulocyte colony-stimulating factors in patients who develop grade 3 or 4 neutropenia. Monitor for signs/symptoms of infection; antimicrobial prophylaxis is recommended in neutropenic patients with severe neutropenia that lasts more than 1 week (continue prophylaxis until neutropenia improves to ≤ grade 2). Antiviral and/or antifungal prophylaxis should also be considered. Severe and life-threatening thrombocytopenia has also been reported when used in combination with chemotherapy. In a small percentage of patients, thrombocytopenia occurred acutely (within 24 hours) after obinutuzumab administration; platelet transfusions may be necessary. Fatal hemorrhagic events have been reported; monitor frequently for thrombocytopenia and bleeding episodes, particularly during the initial cycle. Thrombocytopenia may require dose delays of obinutuzumab and chemotherapy and/or dose reductions of chemotherapy. Consider withholding platelet inhibitors, anticoagulants, or other medications which may increase bleeding risk (especially during the first cycle). Leukopenia, lymphopenia, and anemia commonly occur. Monitor blood counts frequently throughout therapy.

• Hepatitis B virus reactivation: [US Boxed Warning]: Hepatitis B virus (HBV) reactivation may occur with use of CD20-directed cytolytic antibodies (including obinutuzumab) and may result in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) prior to therapy initiation; monitor patients for clinical and laboratory signs of hepatitis or HBV during and for several months after treatment. Discontinue obinutuzumab (and concomitant medications) if viral hepatitis develops and initiate appropriate antiviral therapy. Reactivation has occurred in patients who are HBsAg positive as well as in those who are HBsAg negative but are anti-HBc positive; HBV reactivation has also been observed in patients who had previously resolved HBV infection. HBV reactivation has been reported for other CD20-directed antibodies after therapy discontinuation. Reactivation of HBV replication is often followed by hepatitis. Use cautiously in patients who show evidence of prior HBV infection (eg, HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive); consult with appropriate clinicians regarding monitoring and consideration of antiviral therapy before and/or during obinutuzumab treatment. The safety of resuming obinutuzumab treatment following HBV reactivation is not known; discuss reinitiation of therapy in patients with resolved HBV reactivation with health care providers experienced in HBV management.

American Society of Clinical Oncology (ASCO) provisional clinical opinion update on hepatitis B virus screening recommendations (Hwang 2015): Patients receiving anti-CD20 antibodies are at high risk for HBV reactivation. Screen for HBV infection with HBsAg and anti-HBc tests prior to treatment initiation; either a total anti-HBc (with both immunoglobulin G [IgG] and immunoglobulin M [IgM]) or anti-HBc IgG test should be used to screen for chronic or resolved HBV infection (do not use anti-HBc IgM, as it may only confirm acute HBV infection). In addition, patients who have risk factors for HBV infection (eg, birthplace in a country with ≥2% HBV prevalence, household or sexual contact with HBV-infected patients, high-risk behaviors [eg, intravenous drug use], and HIV infection) should also be screened prior to beginning therapy. Initiate prophylactic antiviral therapy (utilizing antivirals with low rates of viral resistance) for HBsAg-positive/anti-HBc-positive patients (without delaying cancer therapy) and continue the antivirals during and for ~6 to 12 months after completing treatment. HBsAg-negative/anti-HBc-positive patients should be monitored for HBV reactivation with HBV DNA and ALT testing approximately every 3 months during treatment; antiviral therapy may be initiated prophylactically or begun promptly at the first sign of HBV reactivation.

• Hypersensitivity/serum sickness: Hypersensitivity reactions have been reported with obinutuzumab. Signs of immediate-onset hypersensitivity included dyspnea, bronchospasm, hypotension, urticaria, and tachycardia. Late-onset hypersensitivity (diagnosed as serum sickness) has also been reported with obinutuzumab; symptoms included chest pain, diffuse arthralgia, and fever. Hypersensitivity reactions may be difficult to clinically differentiate from infusion-related reactions. However, hypersensitivity very rarely occurs with the initial infusion and generally occurs after a prior exposure. If a hypersensitivity reaction is suspected during or after an infusion, stop the infusion and permanently discontinue treatment. Obinutuzumab is contraindicated in patients with known hypersensitivity reactions (including serum sickness) with prior obinutuzumab use.

• Infection: Bacterial, fungal, and new or reactivated viral infections may occur during and/or following obinutuzumab therapy; serious and/or fatal infections have been reported. Grade 3 and higher infections have been observed (during and after treatment) when obinutuzumab was administered in combination with chemotherapy followed by obinutuzumab monotherapy. A higher incidence of grade 3 to 5 infections (including during monotherapy and after treatment) have been observed when obinutuzumab was administered in combination with bendamustine (compared to cyclophosphamide, doxorubicin, vincristine, prednisone [CHOP] or cyclophosphamide, vincristine, and prednisone [CVP]). Do not administer to patients with an active infection. Patients with a history of recurrent or chronic infections may be at increased risk; monitor closely for signs/symptoms of infection.

• Infusion reaction: May cause severe and life-threatening infusion reactions; reactions may include bronchospasm, dyspnea, chest discomfort, tachycardia, larynx and throat irritation, wheezing, laryngeal edema, flushing, rash, hypertension, hypotension, fever, dizziness, nausea, vomiting, diarrhea, headache, fatigue, and/or chills. Infusion reactions occur more frequently with the first 1,000 mg infused or on day 1 of the infusion. Infusion reactions have occurred within 24 hours of receiving obinutuzumab; reactions with subsequent infusions have also occurred. Premedicate with acetaminophen, an antihistamine, and a glucocorticoid (dexamethasone or methylprednisolone) prior to infusion. Hydrocortisone has not been effective in reducing the rate of infusion reactions and is not recommended. Based on the severity, infusion reactions may require interruption of therapy, rate reduction, and/or treatment discontinuation; appropriate medical management (eg, glucocorticoids, epinephrine, bronchodilators, and/or oxygen) may also be necessary. Monitor closely during the entire infusion; patients with preexisting cardiac or pulmonary conditions may be at higher risk for infusion reactions and should be monitored more frequently during infusion and in the postinfusion period. Because infusion reaction may include hypotension, consider temporarily withholding antihypertensive therapies for 12 hours prior to, during, and for 1 hour after administration (consider risks/benefits of withholding antihypertensive therapy in patients at risk for hypertensive crisis).

• Progressive multifocal leukoencephalopathy: [US Boxed Warning]: Progressive multifocal leukoencephalopathy (PML) resulting in death may occur with treatment. PML is due to John Cunningham virus infection. Consider PML in any patient with new onset or worsening neurological symptoms and if PML is suspected, discontinue obinutuzumab (consider discontinuation or dose reduction of any concomitant chemotherapy or immunosuppressive therapy) and evaluate promptly.

• Tumor lysis syndrome: Tumor lysis syndrome (TLS) has been reported with obinutuzumab (some cases fatal). Patients with high tumor burden, high circulating lymphocyte counts (>25,000/mm3), or renal impairment are at higher risk for TLS. Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia may occur. Administer appropriate TLS prophylaxis with antihyperuricemic therapy (eg, allopurinol, rasburicase) and adequate hydration in patients at high risk prior to initiating obinutuzumab therapy (and prior to subsequent cycles if needed). Monitor lab parameters during initial treatment days in patients at risk for TLS. Correct electrolyte abnormalities; monitor renal function and hydration status, and administer supportive care, including dialysis as indicated.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Immunizations: Administration of live virus vaccines during treatment (and until B-cell recovery) is not recommended; the safety and efficacy of immunization with live or attenuated viral vaccines during or after obinutuzumab therapy has not been determined. If obinutuzumab exposure occurs during pregnancy, the safety and timing of live virus vaccinations for the infant should be evaluated.

Monitoring Parameters

CBC with differential (at regular intervals), renal function, electrolytes, uric acid (if at risk for tumor lysis syndrome); hepatitis B screening in all patients (HBsAg and anti-HBc measurements) prior to therapy initiation. Hepatitis B virus (HBV) screening recommendations (American Society of Clinical Oncology provisional clinical opinion update [Hwang 2015]): Screen for HBV infection with hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) tests prior to treatment initiation; either a total anti-HBc (with both immunoglobulin G [IgG] and immunoglobulin M [IgM]) or anti-HBc IgG test should be used to screen for chronic or resolved HBV infection (do not use anti-HBc IgM as it may only confirm acute HBV infection). HBsAg-negative/anti-HBc-positive patients should be monitored for HBV reactivation with HBV DNA and ALT testing approximately every 3 months during treatment.

Monitor for signs of active hepatitis B infection (during and for up to 12 months after therapy completion). Monitor for signs or symptoms of infusion reaction; signs of infection; fluid status; signs/symptoms of progressive multifocal leukoencephalopathy (PML; focal neurologic deficits, which may present as hemiparesis, visual field deficits, cognitive impairment, aphasia, ataxia, and/or cranial nerve deficits); evaluate for PML with brain MRI, lumbar puncture, and neurologist consultation.

Reproductive Considerations

Females of reproductive potential should use effective contraception during therapy and for 6 months after the last obinutuzumab dose.

Pregnancy Considerations

Obinutuzumab is a humanized monoclonal antibody (IgG1). Potential placental transfer of human IgG is dependent upon the IgG subclass and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).

Based on the mechanism of action and on animal data, if exposure occurs during pregnancy, B-cell counts may be depleted and immunologic function may be affected in the neonate after birth. Administration of live vaccines to neonates and infants exposed in utero should be avoided until after B-cell recovery.

Patient Education

What is this drug used for?

• It is used to treat types of leukemia and lymphoma.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Diarrhea

• Constipation

• Lack of appetite

• Nose irritation

• Throat irritation

• Common cold symptoms

• Loss of strength and energy

• Muscle pain

• Joint pain

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Progressive multifocal leukoencephalopathy like confusion, depression, trouble with memory, behavioral changes, change in strength on one side is greater than the other, trouble speaking, change in balance, or vision changes

• Infection

• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes

• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting

• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; unable to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish

• Infusion reaction like fast heartbeat, fever, chills, muscle pain, joint pain, flushing, swelling of face, nausea, vomiting, weakness, shortness of breath, dizziness, passing out, diarrhea, or chest pain

• Severe headache

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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