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  • CLASSES

    Antineoplastic Monoclonal Antibodies

    BOXED WARNING

    Hepatitis, hepatitis B exacerbation

    Hepatitis B virus (HBV) reactivation resulting in hepatitis B exacerbation, fulminant hepatitis, hepatic failure, and death may occur during or following treatment with an anti-CD20 antibody, such as obinutuzumab. Screen all patients for HBV (e.g., HBsAg and anti-HBc titers) prior to starting obinutuzumab therapy. In patients who have evidence of HBV, consult with an expert in hepatitis management for monitoring and treatment recommendations. Additionally, monitor all patients with a history of prior hepatitis B during and for several months after obinutuzumab therapy for signs and symptoms of HBV reactivation. Discontinue therapy in patients who develop HBV reactivation and initiate treatment. The safety of resuming obinutuzumab therapy following HBV reactivation is not known.

    Progressive multifocal leukoencephalopathy

    Progressive multifocal leukoencephalopathy (PML) has been observed in patients treated with obinutuzumab. As PML can be fatal, instruct patients to notify their health care provider immediately if they notice any new or worsening neurological signs and symptoms such as ataxia, visual changes, or confusion. Similarly, suspect PML in any patient presenting with new onset or changes to pre-existing neurological symptoms. Discontinue obinutuzumab in patients who develop PML.

    DEA CLASS

    Rx

    DESCRIPTION

    CD20-directed monoclonal antibody
    Approved for use in previously untreated chronic lymphocytic leukemia, in combination with chlorambucil and for the treatment of follicular lymphoma in patients who relapsed after or are refractory to a rituximab-containing regimen, in combination with bendamustine followed by obinutuzumab monotherapy
    Black box warning for hepatitis B virus reactivation and progressive multifocal leukoencephalopathy

    COMMON BRAND NAMES

    GAZYVA

    HOW SUPPLIED

    GAZYVA Intravenous Inj Sol: 1mL, 25mg

    DOSAGE & INDICATIONS

    For the treatment of chronic lymphocytic leukemia (CLL).
    NOTE: The FDA has designated obinutuzumab as an orphan drug for the treatment of CLL.
    For the treatment of previously untreated CLL, in combination with chlorambucil.
    Intravenous dosage
    Adults

    100 mg IV on day 1, 900 mg IV on day 2, then 1,000 mg IV on days 8 and 15 in cycle 1; begin the next cycle of therapy on day 29. For cycles 2 to 6, give obinutuzumab 1,000 mg IV on day 1 repeated every 28 days. Administer obinutuzumab in combination with chlorambucil (0.5 mg/kg orally on day 1 and 15) in cycles 1 to 6. Premedicate all patients on days 1 and 2 of cycle 1 with acetaminophen 650 to 1,000 mg PO and an antihistamine (e.g., diphenhydramine 50 mg) 30 minutes prior to obinutuzumab and an IV glucocorticoid (i.e., dexamethasone 20 mg or methylprednisolone 80 mg) at least 1 hour prior to obinutuzumab. Premedication for subsequent obinutuzumab doses is as follows: acetaminophen 650 to 1,000 mg PO (all patients), an antihistamine (only in patients who had a grade 1 or higher infusion reaction with the previous infusion), and an IV glucocorticoid (only in patients who had a grade 3 infusion reaction with the previous dose or who have a lymphocyte count of greater than 25 X 109/L prior to the next treatment). Therapy interruption, discontinuation, or an infusion rate reduction may be necessary in patients who develop an infusion reaction. Take precautionary measures prior to the first infusion and prior to each subsequent infusion as needed in patients at high risk for developing tumor lysis syndrome. The median investigator-reported progression-free survival (PFS) time (primary endpoint) was significantly improved with obinutuzumab plus chlorambucil (26.7 months) compared with chlorambucil alone (11.1 months; hazard ratio (HR) = 0.18; 95% CI, 0.13 to 0.24; p < 0.001) and compared with rituximab plus chlorambucil (15.2 months; HR = 0.39; 95% CI, 0.31 to 0.49; p < 0.001) in patients with previously untreated CD20-positive chronic lymphocytic leukemia and coexisting conditions (median age, 73 years; median creatinine clearance, 62 mL/minute; median cumulative illness rating scale score, 8) in a multicenter, randomized, open-label, 3-arm, phase III trial (n = 781). The median overall survival (OS) time had not been reached in any of the treatment arms at the time of analysis; however, OS was significantly improved with obinutuzumab plus chlorambucil compared to chlorambucil alone (HR = 0.41; 95% CI, 0.23 to 0.74; p = 0.002) but not compared with rituximab plus chlorambucil (HR = 0.66; 95% CI, 0.41 to 1.06; p = 0.08).

    For the treatment of non-Hodgkin's lymphoma (NHL).
    NOTE: The FDA has designated obinutuzumab as an orphan drug for the treatment of FL.
    For the treatment of follicular lymphoma (FL) in patients who relapsed after or are refractory to a rituximab-containing regimen, in combination with bendamustine followed by monotherapy.
    Intravenous dosage
    Adults

    1,000 mg IV on days 1, 8, and 15 on cycle 1; begin the next cycle of therapy on day 29. For cycles 2 to 6, give obinutuzumab 1,000 mg IV on day 1 repeated every 28 days. Administer obinutuzumab in combination with bendamustine (90 mg/m2/day IV on days 1 and 2) in cycles 1 to 6. Continue single-agent obinutuzumab 1,000 mg IV every 2 months for 2 years in patients who achieve a complete response (CR), partial response (PR), or stable disease (SD) after 6 cycles of obinutuzumab plus bendamustine. Premedicate all patients on day 1 of cycle 1 with acetaminophen 650 to 1,000 mg PO and an antihistamine (e.g., diphenhydramine 50 mg) 30 minutes prior to obinutuzumab and an IV glucocorticoid (i.e., dexamethasone 20 mg or methylprednisolone 80 mg) at least 1 hour prior to obinutuzumab. Premedication for subsequent obinutuzumab doses is as follows: acetaminophen 650 to 1,000 mg PO (all patients), an antihistamine (only in patients who had a grade 1 or higher infusion reaction with the previous infusion), and an IV glucocorticoid (only in patients who had a grade 3 infusion reaction with the previous dose or who have a lymphocyte count of greater than 25 X 109/L prior to the next treatment). Therapy interruption, discontinuation, or an infusion rate reduction may be necessary in patients who develop an infusion reaction. Take precautionary measures prior to the first infusion and prior to each subsequent infusion as needed in patients at high risk for developing tumor lysis syndrome. A multinational, randomized, phase III trial (the GADOLIN trial; n = 396) was stopped early after results from a prespecified interim analysis demonstrated that the primary endpoint of median progression-free survival time (assessed by an independent review committee) was significantly improved with obinutuzumab plus bendamustine compared with bendamustine alone (median time not reached vs. 14.9 months; hazard ratio (HR) = 0.55; 95% CI, 0.4 to 0.74; p = 0.0001) in patients with CD20-positive, indolent non-Hodgkin lymphoma that was refractory to rituximab-containing therapy. The median follow-up time was 21.9 months in the obinutuzumab plus bendamustine arm and 20.3 months in the bendamustine alone arm. There was no difference in overall survival between treatment arms at the time of analysis. Patients in this study had received a median of 2 prior therapies (interquartile range, 1 to 2 therapies); 81% of patients (n = 321) had follicular lymphoma.

    MAXIMUM DOSAGE

    Adults

    1000 mg/dose IV.

    Geriatric

    1000 mg/dose IV.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Obinutuzumab has not been studied in patients with hepatic impairment. Specific guidelines for dosage adjustments in hepatic impairment are not available.

    Renal Impairment

    Obinutuzumab pharmacokinetics were not affected in patients with a baseline creatinine clearance (CrCl) as low as 30 mL/min; it appears that no dosage adjustments are needed. Obinutuzumab has not been studied in patients with a baseline CrCl less than 30 mL/min. Specific guidelines for dosage adjustments in renal impairment are not available.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Administer as an IV infusion only; do not administer as an intravenous push or bolus.
    Premedicate patients with acetaminophen 650 to 1,000 mg PO, an antihistamine (e.g., diphenhydramine 50 mg), and a glucocorticoid (i.e., dexamethasone 20 mg or methylprednisolone 80 mg) prior to obinutuzumab infusions as recommended.
    Administer prophylactic hydration and anti-hyperuricemic agents to patients at high risk for tumor lysis syndrome.
    If a planned dose is missed, administer the missed dose as soon as possible and adjust the dosing schedule accordingly. Chronic lymphocytic leukemia (CLL) patients who do not complete the day 1 cycle 1 dose may proceed to the day 2 cycle 1 dose if appropriate. In patients with follicular lymphoma (FL) receiving obinutuzumab monotherapy, maintain the original dosing schedule for subsequent doses if a dose is missed or delayed.
     
    Dilution:
    Add the calculated dose to a PVC or non-PVC polyolefin infusion bag containing 0.9% sodium chloride for a final concentration between 0.4 mg/mL to 4 mg/mL; do not mix with dextrose 5% in water or other diluents.
    Mix diluted solution by gentle inversion;do not shake or freeze.
    100-mg dose (CLL only): Withdraw 4 mL from the obinutuzumab 25 mg/mL vial and dilute in 100 mL of 0.9% sodium chloride.
    900-mg dose (CLL only): Withdraw 36 mL from the obinutuzumab 25 mg/mL vial and dilute in 250 mL of 0.9% sodium chloride.
    1,000-mg dose: Withdraw 40 mL from the obinutuzumab 25 mg/mL vial and dilute in 250 mL of 0.9% sodium chloride.
    Storage following dilution: Store at 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours. Allow the diluted solution to warm to room temperature before administration.
     
     
    Intermittent Infusion:
    Administer only as an intravenous infusion through a dedicated line; do not mix with other drugs.
    Closely monitor patients during the infusion for signs or symptoms of an infusion-related reaction; stop the infusion if a patient develops a reaction and institute medical management as needed.
    CLL
    100-mg dose: Administer at an initial rate of 25 mg/hr over 4 hours. Do not increase the infusion rate.
    900-mg dose: Administer at an initial rate of 50 mg/hr for 30 minutes (0 to 30 minutes). If no hypersensitivity or infusion-related events occur, increase the infusion rate by 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr.
    1000-mg dose: Administer at an initial rate of 100 mg/hr for 30 minutes (0 to 30 minutes). If no hypersensitivity or infusion-related events occur, increase the infusion rate by 100 mg/hr every 30 minutes to a maximum rate of 400 mg/hr.
    FL
    First 1,000-mg dose: Administer at an initial rate of 50 mg/hr for 30 minutes. If no hypersensitivity or infusion-related events occur, increase the infusion rate by 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr.
    Subsequent 1,000-mg doses: Administer at an initial rate of 100 mg/hr for 30 minutes if no infusion reaction occurred during the previous infusion and the final infusion rate was 100 mg/hr or faster. If no hypersensitivity or infusion-related events occur, increase the infusion rate by 100 mg/hr every 30 minutes to a maximum rate of 400 mg/hr.

    STORAGE

    GAZYVA:
    - Diluted product if not used immediately can be stored at 36 to 46 degrees F for up to 24 hours
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Store between 36 to 46 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Hepatitis, hepatitis B exacerbation

    Hepatitis B virus (HBV) reactivation resulting in hepatitis B exacerbation, fulminant hepatitis, hepatic failure, and death may occur during or following treatment with an anti-CD20 antibody, such as obinutuzumab. Screen all patients for HBV (e.g., HBsAg and anti-HBc titers) prior to starting obinutuzumab therapy. In patients who have evidence of HBV, consult with an expert in hepatitis management for monitoring and treatment recommendations. Additionally, monitor all patients with a history of prior hepatitis B during and for several months after obinutuzumab therapy for signs and symptoms of HBV reactivation. Discontinue therapy in patients who develop HBV reactivation and initiate treatment. The safety of resuming obinutuzumab therapy following HBV reactivation is not known.

    Progressive multifocal leukoencephalopathy

    Progressive multifocal leukoencephalopathy (PML) has been observed in patients treated with obinutuzumab. As PML can be fatal, instruct patients to notify their health care provider immediately if they notice any new or worsening neurological signs and symptoms such as ataxia, visual changes, or confusion. Similarly, suspect PML in any patient presenting with new onset or changes to pre-existing neurological symptoms. Discontinue obinutuzumab in patients who develop PML.

    Cardiac disease, hypertension, infusion-related reactions, pulmonary disease

    Infusion-related reactions including severe and life-threatening reactions (e.g., hypotension, tachycardia, dyspnea, bronchospasm, larynx and throat irritation, wheezing, and laryngeal edema) have been reported with obinutuzumab therapy. Other more commonly reported infusion-related symptoms include nausea, fatigue, dizziness, vomiting, diarrhea, hypertension, flushing, headache, fever, and chills. Infusion reactions may occur during or up to 24 hours following the first obinutuzumab infusion or with subsequent infusions. Premedicate patients with acetaminophen, antihistamine, and a glucocorticoid as recommended. Closely monitor patients during each infusion. Therapy interruption, an infusion rate reduction, or permanent therapy discontinuation may be necessary in patients who develop an infusion reaction. Manage symptoms as appropriate with supportive care measures (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen). Patients with pre-existing cardiac disease or pulmonary disease may be at greater risk of more severe reactions; monitor these patients more frequently during and after the infusion. In patients with pre-existing hypertension, consider withholding antihypertensive medications for 12 hours prior to, during, and for the first hour after each infusion until blood pressure is stable; weigh the risk versus benefit of withholding antihypertensive medications in patients at high risk for hypertensive crisis.

    Tumor lysis syndrome (TLS)

    Tumor lysis syndrome (TLS) has been reported with obinutuzumab therapy; some cases were fatal. Patients with high tumor burden, a lymphocyte count greater than 25 X 109cells/L, or renal impairment have an increased risk of developing TLS. These patients should receive TLS prophylaxis with a uric acid lowering agent (e.g., allopurinol or rasburicase) and hydration prior to the first infusion and prior to each subsequent obinutuzumab infusion as needed. Monitor serum electrolytes, uric acid, and renal function in patients at risk for TLS. If TLS occurs, correct electrolyte abnormalities, maintain fluid balance, and administer supportive care; start dialysis if indicated.

    Anticoagulant therapy, bleeding, neutropenia, thrombocytopenia

    Severe hematologic toxicity including grade 3 and 4 neutropenia and thrombocytopenia has been reported with obinutuzumab therapy; late onset (i.e., after 28 days of therapy) and/or prolonged (i.e., lasting more than 28 days) neutropenia has occurred. Obtain blood counts (e.g., CBC panel) and monitor patients for signs of bleeding, particularly in the first cycle of therapy; bleeding resulting in death during the first therapy cycle has been reported in patients with chronic lymphocytic leukemia. In patients who develop grade 3 or 4 neutropenia or thrombocytopenia, increase the frequency of monitoring until toxicity resolution. Dose delay or reductions and/or supportive care such as granulocyte colony-stimulating factors or platelet transfusions may be necessary in these patients. Patients who develop grade 3 or 4 neutropenia lasting more than 1 week should receive antimicrobial prophylaxis until the neutropenia resolves to grade 2 or less. Antiviral and antifungal prophylaxis may also be considered with obinutuzumab therapy. Patients receiving concomitant medications that can cause bleeding such as platelet inhibitors (e.g., aspirin, NSAIDs) and anticoagulant therapy may be at increased of developing a serious bleeding event; consider holding these types of medications, particularly during the first cycle of obinutuzumab therapy.

    Fungal infection, infection, viral infection

    Do not administer obinutuzumab to patients with active infection. Bacterial infection, fungal infection, and viral infection have been reported during and after treatment with obinutuzumab; some cases have resulted in death. Monitor patients for signs and symptoms of infection; consider interrupting treatment in patients who develop an infection. Patients who experience grade 3 or 4 neutropenia lasting more than 1 week should receive antimicrobial prophylaxis until the neutropenia resolves to grade 2 or less. Antiviral and antifungal prophylaxis may also be considered with obinutuzumab therapy. Patients with a history of recurring or chronic infections may be at increased risk for developing a serious infection.

    Neonates, vaccination

    Vaccination with live or attenuated viral vaccines during or following treatment with obinutuzumab has not been studied and is not recommended until recovery of B-cells. Additionally, avoid giving live vaccines to neonates and infants exposed to obinutuzumab in utero until B-cell function returns.

    Pregnancy

    Obinutuzumab should only be used during pregnancy if the potential benefit to the mother justifies the potential risk to the fetus. There are no adequate or well-controlled studies of obinutuzumab in pregnant women; however, monoclonal antibodies are transferred across the placenta. Fetal B-cell depletion likely occurs if obinutuzumab is administered during pregnancy; therefore, avoid giving live vaccines to neonates and infants exposed to obinutuzumab in utero until B-cell function returns. Opportunistic infections and immune responses against obinutuzumab were reported in the off-spring of pregnant cynomolgus monkeys who received weekly obinutuzumab doses that resulted in exposures of up to 2.4 times the exposure produced by the recommended human dose of 1000 mg given monthly. Obinutuzumab was detected in the offspring and B cells were completely depleted at 28 days postpartum; within 6 months after birth, immune function was restored. No embryotoxic or teratogenic effects were observed in this study.

    Breast-feeding

    It is not known if obinutuzumab is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Human IgG is secreted into human milk but antibodies in breast milk typically are not found in significant amounts in neonates or infants. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    Hepatotoxicity

    Hepatotoxicity, including elevated hepatic enzymes (e.g., increased AST/ALT levels) has occurred with obinutuzumab therapy in chronic lymphocytic leukemia patients who had normal baseline hepatic function. Typically, elevated hepatic enzymes occurred within 24 to 48 hours of the first infusion; some cases occurred concurrently with infusion reactions or tumor lysis syndrome. Monitor liver function tests during obinutuzumab therapy, particularly during the first cycle. Therapy interruption or discontinuation may be necessary in patients who develop hepatotoxicity.

    ADVERSE REACTIONS

    Severe

    lymphopenia / Delayed / 35.0-93.0
    neutropenia / Delayed / 27.0-52.0
    leukopenia / Delayed / 20.0-47.0
    infusion-related reactions / Rapid / 11.0-20.0
    infection / Delayed / 11.0-16.0
    thrombocytopenia / Delayed / 0-13.0
    anemia / Delayed / 0-10.0
    hyponatremia / Delayed / 3.0-7.0
    hypophosphatemia / Delayed / 5.0-7.0
    bleeding / Early / 0-5.0
    hypocalcemia / Delayed / 2.0-3.0
    elevated hepatic enzymes / Delayed / 0-2.0
    tumor lysis syndrome (TLS) / Delayed / 0.5-2.0
    diarrhea / Early / 0-2.0
    hypoalbuminemia / Delayed / 0-1.0
    hypokalemia / Delayed / 0-1.0
    back pain / Delayed / 0-1.0
    sinusitis / Delayed / 0-1.0
    pharyngitis / Delayed / 0-1.0
    fever / Early / 0-1.0
    asthenia / Delayed / 0-1.0
    hepatic failure / Delayed / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    GI perforation / Delayed / Incidence not known
    laryngeal edema / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known

    Moderate

    constipation / Delayed / 8.0-19.0
    antibody formation / Delayed / 1.0-7.0
    hepatitis / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    wheezing / Rapid / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    dyspnea / Early / Incidence not known

    Mild

    musculoskeletal pain / Early / 18.0-41.0
    cough / Delayed / 10.0-26.0
    arthralgia / Delayed / 7.0-12.0
    pruritus / Rapid / 0-9.0
    nasal congestion / Early / 0-7.0
    vomiting / Early / 10.0
    nausea / Early / 8.0
    fatigue / Early / 8.0
    dyspepsia / Early / Incidence not known
    flushing / Rapid / Incidence not known
    headache / Early / Incidence not known
    throat irritation / Early / Incidence not known
    chills / Rapid / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Anagrelide: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Anticoagulants: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Antithrombin III: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Apixaban: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Argatroban: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Aspirin, ASA; Dipyridamole: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Betrixaban: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Bivalirudin: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Cilostazol: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Clopidogrel: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Dabigatran: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Dalteparin: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Danaparoid: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Desirudin: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Dipyridamole: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Edoxaban: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Enoxaparin: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Eptifibatide: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Fondaparinux: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Heparin: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Lepirudin: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Pentosan: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Platelet Inhibitors: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Prasugrel: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Rivaroxaban: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Ticagrelor: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Ticlopidine: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Tinzaparin: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Tirofiban: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Vorapaxar: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Warfarin: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.

    PREGNANCY AND LACTATION

    Pregnancy

    Obinutuzumab should only be used during pregnancy if the potential benefit to the mother justifies the potential risk to the fetus. There are no adequate or well-controlled studies of obinutuzumab in pregnant women; however, monoclonal antibodies are transferred across the placenta. Fetal B-cell depletion likely occurs if obinutuzumab is administered during pregnancy; therefore, avoid giving live vaccines to neonates and infants exposed to obinutuzumab in utero until B-cell function returns. Opportunistic infections and immune responses against obinutuzumab were reported in the off-spring of pregnant cynomolgus monkeys who received weekly obinutuzumab doses that resulted in exposures of up to 2.4 times the exposure produced by the recommended human dose of 1000 mg given monthly. Obinutuzumab was detected in the offspring and B cells were completely depleted at 28 days postpartum; within 6 months after birth, immune function was restored. No embryotoxic or teratogenic effects were observed in this study.

    It is not known if obinutuzumab is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Human IgG is secreted into human milk but antibodies in breast milk typically are not found in significant amounts in neonates or infants. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Obinutuzumab is a humanized monoclonal antibody derived from the murine Bly—1 antibody that binds specifically to the CD20 antigen on pre B- and mature B-lymphocytes. Obinutuzumab is glycoengineered, which increases CD16A binding by 7 to 10 fold, improving antibody dependent cellular cytotoxicity (ADCC). Anti-CD20 monoclonal antibodies have two subtypes: type I and type II agents. Type I agents (rituximab-like) redistribute CD20 into membrane lipid rafts and have high complement dependent cytotoxicity, while type II agents (tositumomab-like) do not activate complement and cause direct, programmed cell death. Obinutuzumab is a type II anti-CD20 antibody, indicating that cell death is nonapoptotic, independent of caspase activity, and correlated with homotypic adhesion. After binding to CD20, obinutuzumab causes redistribution of the actin cytoskeleton which triggers enlargement of the lysosomal compartment. This results in lysosomal membrane permeabilization (LMP), causing cathepsin B release into the cytosol and nonapoptotic cell death. This mechanism is independent of BCL-2 and caspase activation, which potentially circumvents resistance to chemotherapy-induced apoptosis. In summary, obinutuzumab causes lysis of B cells by engaging immune effector cell mechanisms (antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis), activating intracellular death signaling pathways, and to a lesser extent, activation of the complement cascade.

    PHARMACOKINETICS

    Obinutuzumab is given as an intravenous infusion. It has both linear and non-linear (time-dependent) clearance pathways; the impact of non-linear clearance becomes less significant as treatment continues. Following obinutuzumab therapy, the geometric mean volume of distribution (Vd) at steady state was 4.1 L (coefficient of variance (CV), 20%), clearance was 0.11 L/day (CV, 53%), and terminal half-life was 26.4 days (CV, 48%) in patients with chronic lymphocytic leukemia in a population pharmacokinetic (PK) analysis. Following obinutuzumab therapy in patients with indolent non-Hodgkin lymphoma, the geometric mean Vd at steady state, clearance, and terminal half-life values were 4.3 L (CV, 22%) , 0.08 L/day (CV, 45%), and 36.8 days (CV, 40%), respectively. Obinutuzumab causes CD19 B-cell depletion (CD19 B-cell counts < 0.07 X 109 cells/L). Initial recovery occurred at approximately 9 months after the last obinutuzumab dose in some patients; at 18 months of follow-up, B-cell depletion persists in some patients. B-cell depletion in the peripheral blood is not directly correlated with B-cell depletion in solid organs or malignancies, and has not been directly correlated to clinical response.

    Intravenous Route

    The pharmacokinetic parameters of obinutuzumab were evaluated in 678 patients with chronic lymphocytic leukemia (CLL) (50.4%) or non-Hodgkin lymphoma (B-cell lymphoma (BCL), 42.2%; diffuse large B-cell lymphoma (DLBCL), 4.4%; mantle cell lymphoma (MCL), 2.9%) from 4 clinical studies. Following obinutuzumab 1,000 mg IV on days 1, 8, and 15 of cycle 1 and 1,000 mg IV on day 1 of cycles 2 to 6, the steady-state mean AUC values were 9,943 microgram (mcg)/mL X hr (+/-4,908), 12,574 mcg/mL X hr (+/- 5,648), 12,626 mcg/mL X hr (+/-5,865), and 6,038 mcg/mL X hr (+/-3,028) in patients with CLL, BCL, DLBCL, and MCL, respectively, in an adjusted analysis.