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    Antineoplastic Monoclonal Antibodies Targeting CD20

    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 as part of combination therapy for the treatment of chronic lymphocytic leukemia and follicular lymphoma (FL); responding patients with FL may also receive up to 2 years of monotherapy
    Hepatitis B virus reactivation resulting in fulminant hepatitis, hepatic failure, and death has been reported.

    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. On days 1 and 2 of cycle 1, premedicate all patients 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) completed at least 1 hour prior to obinutuzumab. If a glucocorticoid-containing chemotherapy regimen is administered on the same day, the IV glucocorticoid can be replaced with an oral medication if given 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 to 3 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 cells/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 CLL or small lymphocytic lymphoma (SLL),† in combination with ibrutinib.
    NOTE: Ibrutinib is FDA approved in combination with obinutuzumab for the treatment of CLL/SLL.
    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 in combination with ibrutinib 420 mg orally once daily until disease progression; give obinutuzumab 1,000 mg IV on day 1 repeated every 28 days on cycles 2 to 6. Consider administering ibrutinib before obinutuzumab on days these agents are given on the same day.[56410] Premedicate patients with acetaminophen, an antihistamine, and a glucocorticoid prior to obinutuzumab infusions as recommended. Administer prophylactic hydration and anti-hyperuricemic agents to patients at high risk for tumor lysis syndrome. Therapy interruption, discontinuation, or an infusion rate reduction may be necessary in patients who develop an infusion reaction.[56353] At a median follow-up time of 31.3 months, the median progression-free survival (PFS) time was significantly improved with ibrutinib plus obinutuzumab compared with chlorambucil plus obinutuzumab (median time not reached vs. 19 months; hazard ratio (HR) = 0.23; 95% CI, 0.15 to 0.37; p less than 0.0001) in patients with previously untreated CLL or SLL (n = 15; 7%) in a multinational, randomized, phase 3 trial (the iLLUMINATE trial; n = 229). The estimated 30-month PFS rates were 79% and 31% in the ibrutinib plus obinutuzumab and chlorambucil plus obinutuzumab arms, respectively. There was no statistically significant difference in overall survival between treatment arms at the time of analysis. In the ibrutinib-containing arm, the median duration of therapy was 29.3 months. Eligible patients were either 65 years or older or had certain coexisting conditions that made them unsuitable for fludarabine-based chemoimmunotherapy.[63904]

    For the treatment of CLL or SLL, in combination with venetoclax†.
    NOTE: Venetoclax is FDA approved in combination with obinutuzumab for the treatment of CLL/SLL.
    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. Premedicate patients with acetaminophen, an antihistamine, and a glucocorticoid prior to obinutuzumab infusions as recommended. Administer prophylactic hydration and anti-hyperuricemic agents to patients at high risk for tumor lysis syndrome. Therapy interruption, discontinuation, or an infusion rate reduction may be necessary in patients who develop an infusion reaction. At a median follow-up of 39.6 months, the progression-free survival time (assessed by an independent review committee) was significantly improved with venetoclax plus obinutuzumab compared with obinutuzumab plus chlorambucil therapy (median time not reached vs. 35.6 months; hazard ratio (HR) = 0.31; 95% CI, 0.22 to 0.44; p less than 0.0001) in patients with previously untreated CLL in a randomized, open-label, phase 3 trial (the CLL14 trial; n = 432). Patients (median age, 72 years) in this study had coexisting medical conditions (defined as a total Cumulative Illness Rating Scale (CIRS) score of greater than 6 or a creatinine clearance of less than 70 mL/min). Additionally, undetectable minimal residual disease (MRD) rates were significantly improved in the peripheral blood (76% vs. 35%; p less than 0.0001) in patients who received venetoclax plus obinutuzumab therapy. At the time of analysis, the median overall survival time was not reached in either treatment arm (HR = 1.03; 95% CI, 0.6 to 1.75).

    For the treatment of previously untreated CLL or SLL, in combination with acalabrutinib†.
    NOTE: Acalabrutinib is FDA approved in combination with obinutuzumab for the treatment of previously untreated CLL/SLL.
    Intravenous dosage
    Adults

    100 mg IV on day 1, 900 mg IV on day 2, and then 1,000 mg IV on days 8 and 15 beginning on cycle 2 of therapy followed by obinutuzumab 1,000 mg IV on day 1 repeated every 28 days for up to 6 cycles of therapy (cycles 3, 4, 5, 6, and 7) in combination with acalabrutinib 100 mg orally twice daily (approximately 12 hours apart) starting on day 1 of cycle 1 and continuing until disease progression. Premedicate patients with acetaminophen, an antihistamine, and a glucocorticoid prior to obinutuzumab infusions as recommended. Administer prophylactic hydration and anti-hyperuricemic agents to patients at high risk for tumor lysis syndrome. Therapy interruption, discontinuation, or an infusion rate reduction may be necessary in patients who develop an infusion reaction. The median progression-free survival time was significantly improved in patients with previously untreated CLL/SLL who received acalabrutinib plus obinutuzumab compared with obinutuzumab plus chlorambucil (median time not reached vs. 22.6 months; HR = 0.1; 95% CI, 0.06 to 0.17; p less than 0.0001) in a multicenter, open-label, randomized, 3-arm, phase 3 trial (n = 535; the ELEVATE-TN trial). At a median follow-up time of 28.3 months, the median overall survival time had not been reached in any treatment arm. Eligible patients (median age, 70 years; range, 41 to 91 years) in this trial were 65 years of age or older or had coexisting conditions (i.e., a total Cumulative Illness Rating Scale (CIRS) score of greater than 6 or a creatinine clearance of 30 to 69 mL/min).

    For the treatment of non-Hodgkin's lymphoma (NHL).
    NOTE: The FDA has designated obinutuzumab as an orphan drug for the treatment of follicular lymphoma.
    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, partial response , or stable disease after 6 cycles of obinutuzumab plus bendamustine; start monotherapy at approximately 2 months after the last dose administered during the induction phase. On day 1 of cycle 1, premedicate all patients 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) completed at least 1 hour prior to obinutuzumab. If a glucocorticoid-containing chemotherapy regimen is administered on day 1 of cycle 1, the IV glucocorticoid can be replaced with an oral medication if given 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 to 3 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 cells/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. At a median follow-up time of 31.8 months, the median progression-free survival time (primary endpoint assessed by an independent review committee) was significantly improved with obinutuzumab plus bendamustine compared with bendamustine alone (25.8 months vs. 14.1 months; hazard ratio (HR) = 0.57; 95% CI, 0.44 to 0.73; p less than 0.001) in patients with CD20-positive, indolent non-Hodgkin lymphoma that was refractory to rituximab-containing therapy in a multinational, randomized, phase 3 trial (the GADOLIN trial; n = 413). The overall survival time was also significantly improved in the obinutuzumab plus bendamustine arm (HR = 0.67; 95% CI, 0.47 to 0.96; p = .0269). Most patients in this study had received 1 or 2 prior therapies; 81% of patients (n = 335) had follicular lymphoma.

    For the treatment of previously untreated bulky stage II, stage III, or stage IV follicular lymphoma, in combination with chemotherapy followed by monotherapy in patients who achieve at least a partial remission.
    Intravenous dosage
    Adults

    1,000 mg IV on days 1, 8, and 15 on cycle 1, then 1,000 mg IV on day 1 for subsequent cycles. Administer obinutuzumab in combination with one of the following: 1) bendamustine 90 mg/m2 IV on days 1 and 2 repeated every 28 days for 6 cycles (plus prednisone 100 mg PO or equivalent on day 1 of cycle 1 only); 2) cyclophosphamide 750 mg/m2 IV, doxorubicin 50 mg/m2 IV, and vincristine 1.4 mg/m2 (maximum dose, 2 mg) IV on day 1 and prednisone 100 mg PO on days 1, 2, 3, 4, and 5 (CHOP) repeated every 21 days for 6 cycles (followed by 2 additional cycles of obinutuzumab alone for a total of 8 obinutuzumab cycles); or 3) cyclophosphamide 750 mg/m2 IV and vincristine 1.4 mg/m2 (maximum dose, 2 mg) IV on day 1 and prednisone 100 mg PO daily on days 1, 2, 3, 4, and 5 (CVP) repeated every 21 days for 8 cycles. Continue single-agent obinutuzumab 1,000 mg IV every 2 months for up to 2 years in patients who achieve a complete response or partial response after treatment with 6 to 8 cycles of obinutuzumab plus chemotherapy; start monotherapy at approximately 2 months after the last dose administered during the induction phase. On day 1 of cycle 1, premedicate all patients 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) completed at least 1 hour prior to obinutuzumab. If a glucocorticoid-containing chemotherapy regimen is administered on day 1 of cycle 1, the IV glucocorticoid can be replaced with an oral medication if given 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 to 3 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 cells/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. At a median follow-up time of 34.5 months (range, 0 to 54.5 months), the investigator-assessed 3-year progression-free survival rate (primary endpoint) was significantly improved in patients with previously untreated, CD20-positive advanced stage, grade 1 to 3a follicular lymphoma who received obinutuzumab compared with rituximab (80% vs. 73.3%; hazard ratio = 0.66; 95% CI, 0.51 to 0.85) in combination with chemotherapy (bendamustine, CHOP, or CVP) in a planned interim analysis of a randomized, phase III trial (n = 1,202; the GALLIUM trial).

    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

    Emetic Risk
    Minimal

    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 IV push or bolus.
    Premedicate patients with acetaminophen, an antihistamine, and a glucocorticoid 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. Adjust the dosing schedule accordingly to maintain the time interval between cycles when obinutuzumab in used in combination with chemotherapy. If appropriate, patients with chronic lymphocytic leukemia (CLL) who do not complete the day 1 cycle 1 dose may proceed to the day 2 cycle 1 dose. 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 Injection for a final concentration between 0.4 mg/mL and 4 mg/mL.
    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.
    Prepare day 1 (100 mg) and day 2 (900 mg) infusion bags (for CLL only) at the same time using 1 vial (1,000 mg/40 mL) on day 1.
    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: Use immediately if possible; however, diluted solutions may be stored at 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours prior to use. 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/hour over 4 hours. Do not increase the infusion rate.
    900-mg dose: Administer at an initial rate of 50 mg/hour for 30 minutes. If no infusion-related reaction occurred during the 100-mg infusion; increase the infusion rate by 50 mg/hour every 30 minutes to a maximum rate of 400 mg/hour. If an infusion-related reaction occurred during the previous infusion, start at 25 mg/hour; increase the infusion rate by 50 mg/hour every 30 minutes to a maximum rate of 400 mg/hour.
    1000-mg dose: Administer at an initial rate of 100 mg/hour for 30 minutes if no infusion-related reaction occurred and the final rate of infusion was at least 100 mg/hour during the previous infusions. Increase the infusion rate by 100 mg/hour every 30 minutes to a maximum rate of 400 mg/hour. If an infusion-related reaction occurred during the previous infusion, start at 50 mg/hour; increase the infusion rate by 50 mg/hour every 30 minutes to a maximum rate of 400 mg/hour.
    FL
    Cycle 1, day 1: Administer at an initial rate of 50 mg/hour for 30 minutes. If no infusion-related reaction occurs, increase the infusion rate by 50 mg/hour every 30 minutes to a maximum rate of 400 mg/hour.
    Cycle 1, days 8 and 15 (standard infusion rate): If a grade 1 infusion-related reaction or no infusion-related reaction occurred during the previous infusion AND the final infusion rate was 100 mg/hour or faster, administer at an initial rate of 100 mg/hour; increase the infusion rate by 100 mg/hour every 30 minutes to a maximum rate of 400 mg/hour. If a grade 2 or higher infusion-related reaction occurred during the previous infusion, start at 50 mg/hour; increase the infusion rate by 50 mg/hour every 30 minutes to a maximum rate of 400 mg/hour.
    Subsequent cycles: If a grade 3 or higher infusion-related reaction does not occur in cycle 1, consider a 90-minute infusion for subsequent doses: administer at an initial rate of 100 mg/hour for 30 minutes and then increase the rate to 900 mg/hour for approximately 60 minutes. If an infusion-related reaction of grade 1 or 2 with ongoing symptoms or a grade 3 or higher infusion-related reaction occurred during the previous approximately 90-minute infusion, resume the standard infusion rate.

    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

    Severe and life-threatening infusion-related reactions and hypersensitivity reactions have been reported with obinutuzumab therapy; late-onset hypersensitivity diagnosed as serum sickness has also occurred. Use is contraindicated in patients with a history of serum sickness or hypersensitivity to obinutuzumab (or to any of the excipients) with prior obinutuzumab use. If a hypersensitivity reaction is suspected, hold the infusion; do not resume treatment in patients who have a hypersensitivity reactions including serum sickness with obinutuzumab therapy. Infusion reactions may occur during or up to 24 hours following the obinutuzumab infusion. 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; fatal bleeding, sometimes during the first therapy cycle, has been reported in patients who received obinutuzumab in combination with chemotherapy. 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. Consider antiviral and antifungal prophylaxis in patients with severe and prolonged (longer than 1 week) neutropenia. Patients with a history of recurring or chronic infections may be at increased risk for developing a serious infection.

    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.

    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

    Based on its mechanism of action and data from animal studies, fetal B-cell depletion may occur if obinutuzumab is administered during pregnancy. Advise pregnant women of the fetal risk associated with obinutuzumab treatment.There are no adequate or well-controlled studies of obinutuzumab in pregnant women; however, monoclonal antibodies are transferred across the placenta. Due to the potential for B-cell depletion, 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 1,000 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.

    Contraception requirements, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during obinutuzumab treatment. Female patients of reproductive potential should use effective contraception during and for 6 months after the last obinutuzumab dose. Women who become pregnant while receiving obinutuzumab should be apprised of the potential hazard to the fetus.

    Breast-feeding

    It is not known if obinutuzumab is secreted in human milk or if the drug has effects on the breastfed child or on milk production. Human IgG is secreted into human milk. Because of the potential of serious adverse reactions in the breastfed child, advise women to avoid breast-feeding during treatment and for 6 months after the last obinutuzumab dose.

    ADVERSE REACTIONS

    Severe

    lymphopenia / Delayed / 0-92.0
    neutropenia / Delayed / 0-59.0
    leukopenia / Delayed / 0-49.0
    hyperuricemia / Delayed / 0-28.0
    infection / Delayed / 11.0-21.0
    infusion-related reactions / Rapid / 11.0-20.0
    thrombocytopenia / Delayed / 0-13.0
    anemia / Delayed / 0-10.0
    hypophosphatemia / Delayed / 0-8.0
    hyponatremia / Delayed / 0-7.0
    elevated hepatic enzymes / Delayed / 1.0-3.0
    hyperkalemia / Delayed / 0-3.0
    hypocalcemia / Delayed / 0-3.0
    diarrhea / Early / 0-3.0
    fatigue / Early / 0-3.0
    hyperbilirubinemia / Delayed / 0-2.0
    tumor lysis syndrome (TLS) / Delayed / 0.5-2.0
    hypoalbuminemia / Delayed / 0-1.0
    hypokalemia / Delayed / 0-1.0
    hypernatremia / Delayed / 0-1.0
    back pain / Delayed / 0-1.0
    arthralgia / Delayed / 0-1.0
    musculoskeletal pain / Early / 0-1.0
    pharyngitis / Delayed / 0-1.0
    anorexia / Delayed / 0-1.0
    cough / Delayed / 0-1.0
    rash / Early / 0-1.0
    pruritus / Rapid / 0-1.0
    fever / Early / 0-1.0
    insomnia / Early / 0-1.0
    progressive multifocal leukoencephalopathy / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    cardiotoxicity / Delayed / Incidence not known
    GI perforation / Delayed / Incidence not known
    laryngeal edema / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    serum sickness / Delayed / Incidence not known
    hepatitis B exacerbation / Delayed / Incidence not known

    Moderate

    headache / Early / 0-18.0
    antibody formation / Delayed / 0.2-7.0
    constipation / Delayed / 0-1.0
    bone pain / Delayed / Incidence not known
    hyperthermia / Delayed / Incidence not known
    migraine / Early / Incidence not known
    hypertension / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    dyspnea / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    wheezing / Rapid / Incidence not known
    chest pain (unspecified) / Early / Incidence not known

    Mild

    rhinitis / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    lethargy / Early / Incidence not known
    dizziness / Early / Incidence not known
    flushing / Rapid / Incidence not known
    chills / Rapid / Incidence not known
    vomiting / Early / Incidence not known
    throat irritation / Early / Incidence not known
    nausea / Early / 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.
    Anifrolumab: (Major) Coadministration is not recommended. Anifrolumab has not been studied in combination with other biologic therapies including B-cell targeted therapies such as obinutuzumab. Potential concerns with use of these drugs together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.
    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.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    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.
    Live Vaccines: (Contraindicated) Do not administer live vaccines to obinutuzumab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving obinutuzumab. Before initiation of obinutuzumab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Obinutuzumab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    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.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    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.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    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

    Based on its mechanism of action and data from animal studies, fetal B-cell depletion may occur if obinutuzumab is administered during pregnancy. Advise pregnant women of the fetal risk associated with obinutuzumab treatment.There are no adequate or well-controlled studies of obinutuzumab in pregnant women; however, monoclonal antibodies are transferred across the placenta. Due to the potential for B-cell depletion, 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 1,000 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 the drug has effects on the breastfed child or on milk production. Human IgG is secreted into human milk. Because of the potential of serious adverse reactions in the breastfed child, advise women to avoid breast-feeding during treatment and for 6 months after the last obinutuzumab dose.

    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 25.5 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, 21%) , 0.08 L/day (CV, 41%), and 35.3 days (CV, 35%), respectively. Obinutuzumab causes CD19 B-cell depletion (CD19 B-cell counts less than 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. In another analysis that evaluated PK parameters in patients who received standard obinutuzumab dosing, the geometric mean Cmax was 466.3 mcg/mL (CV, 35%) in patients with CLL and the geometric mean Cmax values ranged from 513.4 to 676.4 in patients with follicular lymphoma (FL). Additionally, the geometric mean AUC was 8,701 mcg/mL X hr (CV, 51%) in patients with CLL and the geometric mean AUC values ranged from 10,088 to 11,362 mcg/mL X hr in patients with FL.