Obinutuzumab

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)

Pharmacology

Mechanism of Action

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).

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: ~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 (CLL) 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 and (in patients achieving at least a partial remission) followed by obinutuzumab monotherapy.

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.

Dosage and Administration

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.

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 schedule 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 2019]): 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.

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 therapy; 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): 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 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 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 infusion. In addition, an IV glucocorticoid (dexamethasone 20 mg or methylprednisolone 80 mg) should be administered at least 1 hour prior to 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 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 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 infusion, in addition to acetaminophen and an antihistamine at least 30 minutes prior to 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: 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) followed by 48 hours (including infusion time) at room temperature of ≤30°C (≤86°F).

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

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

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. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. 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. 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

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. 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 reported in combination with chlorambucil or bendamustine in addition to reaction incidence during the monotherapy phase.

>10%:

Endocrine & metabolic: Hypophosphatemia (25% to 41%), hypocalcemia (37% to 38%;), hyperkalemia (33%), hyponatremia (26%), hypoalbuminemia (23%), hypokalemia (14%)

Gastrointestinal: Constipation (8% to 19%), vomiting

Hematologic & oncologic: Lymphocytopenia (80% to 99%; grades 3/4: 39% to 93%), leukopenia (6% to 86%; grades 3/4: 4% to 47%), neutropenia (11% to 76%; grades 3/4: 10% to 52%; onset ≥28 days after completion of treatment: 16%; lasting ≥28 days: 3%), decreased hemoglobin (50%), thrombocytopenia (11% to 48%; grades 3/4: 1% to 13% onset within 24 hours of infusion: 4%), anemia (12% to 39%; grades 3/4: 1% to 10%), hemorrhage (11%; grades 3/4: 5%)

Hepatic: Increased serum AST (24% to 27%), increased serum ALT (21% to 35%), increased serum alkaline phosphatase (18%)

Infection: Infection (38% to 66%)

Neuromuscular & skeletal: Musculoskeletal signs and symptoms (18% to 41%; including pain), back pain (5%), arthralgia (7% to 12%), weakness (11%)

Renal: Decreased creatinine clearance (43% to 58%), increased serum creatinine (30%)

Respiratory: Cough (10% to 26%), upper respiratory tract infection (12% to 13%), sinusitis (10% to 12%)

1% to 10%:

Central nervous system: Fatigue (8%)

Dermatologic: Pruritus (9%)

Gastrointestinal: Diarrhea (8% to 10%), nausea (8%), dyspepsia (5%)

Genitourinary: Urinary tract infection (5% to 10%)

Hematologic & oncologic: Tumor lysis syndrome, febrile neutropenia

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

Immunologic: Antibody development (1% to 7%)

Infection: Sepsis

Neuromuscular & skeletal: Limb pain (9%), back pain (5%)

Respiratory: Nasopharyngitis (6% to 9%), bronchitis (7%), nasal congestion (7%)

Miscellaneous: Infusion related reaction (initial infusion: 53% to 69%; grades 3/4: 9% to 20%; second infusion: 3% to 25%; subsequent infusions: ≤8%), fever (6% to 18%)

Frequency not defined:

Cardiovascular: Exacerbation of cardiac disease

Central nervous system: Progressive multifocal leukoencephalopathy

Infection: JCV (John Cunningham virus) infection, reactivation of HBV, viral infection (new or reactivation)

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 chemotherapy) 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 physicians 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 in patients who have received 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. Do not retreat with obinutuzumab in patients with known hypersensitivity reactions, including serum sickness.
• Infection: Bacterial, fungal, and new or reactivated viral infections may occur during and/or following 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 CHOP or 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. Delayed reactions (up to 24 hours later) and reactions with subsequent infusions have occurred. Premedicate with acetaminophen, an antihistamine, and an IV glucocorticoid (dexamethasone or methylprednisolone) prior to infusion. Hydrocortisone has not been effective in reducing the rate of infusion reactions and is not recommended. Infusion reactions may require rate reduction, interruption of therapy, or treatment discontinuation. Monitor during the entire infusion; monitor patients with preexisting cardiac or pulmonary conditions closely. Consider temporarily withholding antihypertensive therapies for 12 hours prior to, during, and for 1 hour after administration. Administer in a facility with immediate access to resuscitative measures (eg, glucocorticoids, epinephrine, bronchodilators, and/or oxygen).
• Progressive multifocal leukoencephalopathy: [US Boxed Warning]: Progressive multifocal leukoencephalopathy (PML) resulting in death may occur with treatment. PML is due to JC 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). Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia may occur. Administer prophylaxis (antihyperuricemic therapy [eg, allopurinol or rasburicase] and adequate hydration) in patients at high risk (high circulating lymphocyte counts [>25,000/mm³], high tumor burden, or renal impairment) prior to initiating obinutuzumab therapy (administer prior to each subsequent cycle 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:

• Antihypertensives: Due to the risk for hypotension, consider temporarily withholding antihypertensive therapies for 12 hours prior to, during, and for 1 hour after administration.
• Antiplatelet/anticoagulant medications: Due to the risk for thrombocytopenia and hemorrhagic events (particularly during the first cycle), consider withholding anticoagulants, platelet inhibitors, or other medications which may increase bleeding risk.
• 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.

Pregnancy

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. It has been recommended that females of reproductive potential use effective contraception during therapy and for 18 months after the last treatment (Gazyva Canadian product labeling).

Patient Education

What is this drug used for?

• It is used to treat a type of leukemia.
• It is used to treat a type of lymphoma.

Frequently reported side effects of this drug

• Constipation
• Lack of appetite
• Stuffy nose
• Sore throat
• Sinus pain
• Common cold symptoms

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• 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.
• 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.
• Fast heartbeat
• Severe headache
• Severe loss of strength and energy
• Chills
• Joint pain
• Muscle pain
• Facial flushing
• Facial swelling
• Nausea
• Vomiting
• Shortness of breath
• Severe dizziness
• Passing out
• Diarrhea
• Chest pain
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of 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 brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.