Obinutuzumab is a monoclonal antibody that binds to the CD20 molecule found on pre B- and mature B-lymphocytes. It is indicated for the treatment of previously untreated chronic lymphocytic leukemia in combination with chlorambucil; relapsed or refractory follicular lymphoma (FL) in combination with bendamustine; and previously untreated bulky stage II, stage III, or IV FL in combination with chemotherapy. Patients with FL who respond to combination therapy may receive up to 2 years of obinutuzumab monotherapy. Hepatitis B virus reactivation resulting in fulminant hepatitis, hepatic failure, and death has been reported.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Emetic Risk
-Minimal
Route-Specific 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 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.
Elevated hepatic enzymes (27% to 50%; grade 3 or higher, 1% to 3%) and hypoalbuminemia (33% or less; grade 3 or higher, 1% or less) have been reported in patients who received obinutuzumab-containing therapy in clinical trials. Most cases of elevated hepatic enzymes occurred within 24 to 48 hours of the first infusion. Monitor liver function tests during obinutuzumab therapy, particularly during the first cycle. Therapy interruption or discontinuation may be necessary in patients who develop hepatotoxicity. Hepatotoxicity occurred in 4% of patients with previously untreated chronic lymphocytic leukemia who received obinutuzumab plus chlorambucil (n = 336) in a randomized, phase 3 trial; increased alkaline phosphatase level was reported in 18% of patients (n = 238) in the stage 1 of this trial. Hyperbilirubinemia (21%; grade 3 or higher, 2%) and increased alkaline phosphatase level (27%) occurred in patients with relapsed or refractory indolent non-Hodgkin lymphoma (including follicular lymphoma) who received obinutuzumab plus bendamustine (n = 204) for 6 cycles followed by obinutuzumab monotherapy in a randomized, phase 3 trial. Hypoproteinemia was reported in 32% of patients with newly diagnosed follicular lymphoma or marginal zone lymphoma who received obinutuzumab plus chemotherapy (n = 691) for 6 to 8 cycles followed by obinutuzumab monotherapy in a randomized, phase 3 trial.
Progressive multifocal leukoencephalopathy (PML) caused by the JC virus has occurred in patients who received obinutuzumab therapy. Evaluate patients who develop new onset or changes to preexisting neurologic manifestations for evidence of PML (e.g., brain MRI, lumbar puncture) and consult with a neurologist. In patients who develop PML, discontinue obinutuzumab and consider discontinuing or a dosage reduction of concomitant chemotherapy or immunosuppressive therapy (if applicable).
Grade 3 or 4 tumor lysis syndrome (TLS) has been reported in 0.5% to 2% of patients who received obinutuzumab-containing therapy in clinical trials; some cases were fatal. The highest incidence of TLS (2%) was observed in patients with chronic lymphocytic leukemia who received obinutuzumab plus chlorambucil (n = 336) in a randomized trial. Administer TLS prophylaxis with antihyperuricemics (e.g., allopurinol or rasburicase) and hydration prior to therapy initiation; continue prophylaxis prior to each subsequent 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. New or worsening grade 3 or 4 hyperuricemia was reported in 28% of patients with newly diagnosed follicular lymphoma or marginal zone lymphoma who received obinutuzumab plus chemotherapy (n = 691) for 6 to 8 cycles followed by obinutuzumab monotherapy in a randomized, phase 3 trial.
Neutropenia/agranulocytosis (10% to 53%; grade 3 or 4, 33% to 49%) including prolonged (3% or less) or late onset (16% or less) neutropenia, thrombocytopenia (14% or less; grade 3 or 4, 10% or less), and febrile neutropenia (5% or more) were reported in patients who received obinutuzumab-containing therapy in clinical trials. Monitor blood counts (e.g., CBC panel) and increase the frequency of monitoring in patients who develop grade 3 or 4 neutropenia or thrombocytopenia 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. Anemia (12%; grade 3 or 4, 5%) was reported in patients with previously untreated chronic lymphocytic leukemia who received obinutuzumab plus chlorambucil (n = 238) in a clinical study. New or worsening anemia (39% or less; grade 3 or 4, 10% or less), leukopenia (84% to 92%; grade 3 or 4, 35% to 49%), lymphopenia (80% to 97%; grade 3 or 4, 23% to 92%), neutropenia (76% to 84%; grade 3 or 4, 21% to 59%), and thrombocytopenia (68% or less; grade 3 or 4, 13% or less) occurred in patients who received obinutuzumab-containing therapy in clinical trials. One death due to neutropenia was reported with obinutuzumab therapy.
New or worsening hyperkalemia (20% to 33%; grade 3 or 4, 3% or less), hypernatremia (16% or less; grade 3 or 4, less than 1%), hypocalcemia (32% to 39%; grade 3 or 4, 3% or less), hypokalemia (14% or less; grade 3 or 4, 1% or less), hyponatremia (26% or less; grade 3 or 4, 7% or less), and hypophosphatemia (41% or less; grade 3 or 4, 8% or less) occurred in patients who received obinutuzumab-containing therapy in clinical trials.
Musculoskeletal disorders including pain occurred in 18% to 54% of patients who received obinutuzumab-containing therapy in clinical trials. Arthralgia was reported in 16% of patients with newly diagnosed follicular lymphoma or marginal zone lymphoma who received obinutuzumab plus chemotherapy (n = 691) for 6 to 8 cycles followed by obinutuzumab monotherapy in a randomized, phase 3 trial. Musculoskeletal pain was reported in 20% of patients (n = 624) during obinutuzumab monotherapy. Back pain (5%; grade 3 or 4, less than 1%) was reported in patients with previously untreated chronic lymphocytic leukemia who received obinutuzumab plus chlorambucil (n = 238) in a clinical study. Arthralgia (12%; grade 3 or higher, less than 1%) and musculoskeletal pain (28%; grade 3 or higher, 1%) occurred in patients with relapsed or refractory indolent non-Hodgkin lymphoma (including follicular lymphoma) who received obinutuzumab plus bendamustine (n = 204) for 6 cycles in a randomized, phase 3 trial. Additionally, musculoskeletal pain was reported in 10% or more of patients (n = 158) during obinutuzumab monotherapy. The term musculoskeletal pain in this study included non-cardiac chest pain, bone pain, spinal pain, myalgia, back pain, neck pain, musculoskeletal discomfort, and extremity pain.
Worsening of pre-existing cardiotoxicity, including fatal cardiac events have been reported in patients treated with obinutuzumab.
Infection has been reported in 38% to 82% (grade 3 or 4, 11% to 21%) of patients who received obinutuzumab-containing therapy in clinical trials. 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. Naso-pharyngitis (6% or less; grade 3 or 4, less than 1%), urinary tract infection (13% or more; grade 3 or 4, 3% or less), lower respiratory tract infections (10% or more), upper respiratory tract infection (50% or less; grade 3 or 4, 3% or less), unspecified respiratory tract infection (14% or less; grade 3 or 4, 1% or less), sepsis (7% or less), herpes virus (18% or less; grade 3 or 4, 3% or less), and pneumonia (14% or less; grade 3 or 4, 7% or less) occurred in 38% to 82% (grade 3 or 4, 11% to 21%) of patients who received obinutuzumab-containing therapy in clinical trials. In 2 randomized trials, grade 3 to 5 infections occurred in 29% of follicular lymphoma patients who received obinutuzumab plus bendamustine (n = 204) and 15% of patients who received obinutuzumab plus a multi-agent chemotherapy regimen (n = 691); fatal infections were reported in 3% and less than 1% of patients, respectively. The grade 3 or 4 infection rates were less in obinutuzumab-treated patients who received GCSF prophylaxis compared with no prophylaxis (14% vs. 24%) in these 2 studies. Additionally, grade 3 to 5 infections were reported in up to 13% of patients during treatment with obinutuzumab monotherapy. The term respiratory tract infection included rhinovirus infection, laryngitis, nasopharyngitis, pharyngitis, rhinitis, tonsillitis, and sinusitis.
Gastrointestinal adverse events including diarrhea (10% to 30%; grade 3 or 4, 3% or less), constipation (8% to 32%; grade 3 or 4, less than 1%), and decreased appetite/anorexia (14% or less; grade 3 or 4, less than 1%) were reported in patients who received obinutuzumab-containing therapy in clinical trials. In 1 study, the term diarrhea included gastroenteritis. GI perforation has been reported in patients (mainly non-Hodgkin lymphoma patients) who received obinutuzumab therapy.
Antibody formation has occurred with obinutuzumab therapy. Anti-obinutuzumab antibodies were found in 7% of patients with previously untreated chronic lymphocytic leukemia who received obinutuzumab (n = 271) in a clinical trial. No anti-obinutuzumab antibodies were observed in patients with indolent non-Hodgkin lymphoma who received obinutuzumab plus bendamustine (n = 194) in another clinical trial. Additionally, 1 patient (0.2%) with newly diagnosed follicular lymphoma developed anti-obinutuzumab antibodies following treatment with obinutuzumab plus chemotherapy (n = 564) in a randomized, phase 3 trial. The neutralizing activity of anti-obinutuzumab antibodies has not been assessed.
Cough was reported in 10% to 35% (grade 3 or 4, less than 1%) of patients who received obinutuzumab-containing therapy in clinical trials.
Rash (17%; grade 3 or 4, less than 1%) and pruritus (11%) occurred in patients with relapsed or refractory indolent non-Hodgkin lymphoma (including follicular lymphoma) who received obinutuzumab plus bendamustine (n = 204) for 6 cycles followed by obinutuzumab monotherapy in a randomized, phase 3 trial. Additionally, rash was reported in 10% or more of patients (n = 158) during obinutuzumab monotherapy. The term rash included urticaria, skin reaction, and dermatitis. Pruritus occurred in 11% (grade 3 or 4, less than 1%) of patients with newly diagnosed follicular lymphoma or marginal zone lymphoma who received obinutuzumab plus chemotherapy (n = 691) for 6 to 8 cycles followed by obinutuzumab monotherapy in a randomized, phase 3 trial.
Fever was reported in 19% or less (grade 3 or 4, less than 1%) of patients who received obinutuzumab-containing therapy in clinical trials. In 1 study, the term fever included hyperthermia.
Fatigue (40%; grade 3 or higher, 3%) occurred in patients with relapsed or refractory indolent non-Hodgkin lymphoma (including follicular lymphoma) who received obinutuzumab plus bendamustine (n = 204) for 6 cycles followed by obinutuzumab monotherapy in a randomized, phase 3 trial. Additionally, fatigue was reported in 10% or more patients (n = 158) during obinutuzumab monotherapy. The term fatigue included asthenia and lethargy.
Headache including migraine (18%; grade 3 or higher, less than 1%) occurred in patients with newly diagnosed follicular lymphoma or marginal zone lymphoma who received obinutuzumab plus chemotherapy (n = 691) for 6 to 8 cycles followed by obinutuzumab monotherapy in a randomized, phase 3 trial.
Infusion-related reactions were reported in 58% to 72% (grade 3 or higher, 5% to 20%) of patients who received obinutuzumab-containing therapy at the standard infusion rate in clinical trials; most reactions occurred with the first obinutuzumab infusion. The safety of a shortened infusion duration of obinutuzumab (approximately 90 minutes) was evaluated in patients with previously untreated FL in a single-arm study. An infusion reaction developed in 58% (grade 3 or higher, 5%) of patients who received the standard infusion rate during the first cycle; infusion reactions occurred in 10% of patients who received the shorter infusion in cycle 2, and in only one patient (grade 3, 1%) who received the shorter infusion following cycle 2. The most frequently reported symptoms include nausea, fatigue, chest discomfort, dyspnea, dizziness, vomiting, diarrhea, rash, hypertension, hypotension, flushing, headache, pyrexia, and chills. Other infusion-related symptoms include sinus tachycardia, bronchospasm, larynx and throat irritation, wheezing, and laryngeal edema. Premedicate patients with acetaminophen, antihistamine, and a glucocorticoid prior to the obinutuzumab infusion. Monitor patients for signs and symptoms of infusion-related reactions during the entire infusion. An infusion rate reduction, infusion interruption, or therapy discontinuation may be necessary depending on the severity of the infusion-related reaction; institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) as indicated. In patients on antihypertensive medications, consider holding the antihypertensive therapy for 12 hours prior to, during, and for an hour after the obinutuzumab infusion. Consider the benefits versus the risks of withholding antihypertensive therapy in patients at risk for hypertensive crisis.
Insomnia (15%; grade 3 or higher, less than 1%) occurred in patients with newly diagnosed follicular lymphoma or marginal zone lymphoma who received obinutuzumab plus chemotherapy (n = 691) for 6 to 8 cycles followed by obinutuzumab monotherapy in a randomized, phase 3 trial.
Hypersensitivity reactions (e.g., dyspnea, bronchospasm, hypotension, urticaria, and tachycardia) have been reported in patients who received obinutuzumab therapy. Late-onset hypersensitivity diagnosed as serum sickness has been reported in post-marketing surveillance. Symptoms of serum sickness may include chest pain (unspecified), diffuse arthralgia, and fever. It may be difficult to clinically distinguish hypersensitivity reactions from infusion-related reactions; hypersensitivity often occurs after previous obinutuzumab exposure and rarely occurs with the firs infusion. If a hypersensitivity reaction is suspected, hold the infusion; do not retreat patients who have a hypersensitivity reaction including serum sickness with obinutuzumab therapy.
Hepatitis B virus (HBV) reactivation/hepatitis B exacerbation resulting in fulminant hepatitis, hepatic failure, and death may occur during or following treatment with an anti-CD20 antibody, such as obinutuzumab. Monitor patients who have had HBV for signs and symptoms of HBV reactivation during and for several months after obinutuzumab therapy. Discontinue obinutuzumab therapy (and concomitant chemotherapy if applicable) in patients who develop HBV reactivation and start appropriate treatment. There is insufficient data regarding the safety of resuming obinutuzumab in patients who had a reactivation of HBV during therapy.
Severe and sometimes fatal disseminated intravascular coagulation (DIC) was reported in 0.3% of patients with previously untreated follicular lymphoma or marginal zone lymphoma in a randomized, open-label clinical trial (GALLIUM); all events occurred within 1 to 2 days after the first infusion. The majority of cases involved changes in platelet counts and coagulation parameters following the first infusion, with spontaneous resolution by day 8. In some cases, DIC was associated with infusion-related reactions, tumor lysis syndrome, or both. Evaluate potential causes in patients with suspected DIC and monitor coagulation parameters, platelet counts, and for signs and symptoms of bleeding or thrombosis. Manage according to standard guidelines for DIC; supportive care including transfusion of blood products and other medical management may be necessary.
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 (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.
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) 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.
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;if clinically indicated, evaluate laboratory coagulation parameters. Fatal bleeding, sometimes during the first therapy cycle, has been reported in patients who received obinutuzumab in combination with chemotherapy. Severe and sometimes fatal disseminated intravascular coagulation (DIC) has also been reported; the majority of cases involved changes in platelets and laboratory coagulation parameters following the first infusion. Evaluate potential causes in patients with suspected DIC and monitor coagulation parameters, platelet counts, and for signs and symptoms of bleeding or thrombosis. Manage according to standard DIC guidelines. 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.
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, 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.
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.
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.
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.
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.
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. 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 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.
-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: Obinutuzumab is designated as an orphan drug by the FDA for the treatment of follicular lymphoma.
-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 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).
-for the treatment of relapsed or refractory follicular lymphoma following 2 or more lines of systemic therapy, in combination with zanubrutinib:
NOTE: Zanubrutinib is FDA approved in combination with obinutuzumab for this indication.
Intravenous dosage:
Adults: 1,000 mg IV on days 1, 8, and 15 of cycle 1; 1,000 mg IV on day 1 of cycles 2, 3, 4, 5, and 6; and 1,000 mg IV every 8 weeks for up to 20 doses in combination with zanubrutinib 160 mg orally twice daily OR 320 mg orally once daily until disease progression. The day 1, cycle 1 obinutuzumab dose may be given as 100 mg IV on day 1 and 900 mg IV on day 2. The treatment cycle length was 28 days in cycles 1 to 6. 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. The overall response rate (primary endpoint evaluated by independent central review) was significantly improved with zanubrutinib plus obinutuzumab compared with obinutuzumab alone (69% vs. 46%; p-value = 0.001) in 217 patients with relapsed or refractory grade 1, 2, or 3a follicular lymphoma in a randomized (2:1) phase 2 (ROSEWOOD) trial. The complete response rate was also significantly higher in the combination therapy arm compared with the obinutuzumab alone arm (39% and 19%; p-value = 0.004). At a median follow-up time of 20.2 months, the median duration of response was not reached in the combination therapy arm and 14 months in the obinutuzumab alone arm. The median progression-free survival (28 vs. 10.4 months; hazard ratio (HR) = 0.5; 95% CI, 0.33 to 0.75) and overall survival (OS; not estimable vs. 34.6 months; HR = 0.62; 95% CI, 0.35 to 1.07) times were longer in the combination therapy arm. Although the OS improvement was not significant in the combination therapy arm, 35 of 72 patients (48.6%) from the obinutuzumab only arm had crossed over. Patients (median age, 64 years; range, 31 to 88 years) in this study had received a median of 3 (range, 2 to 11) prior lines of therapy that included an anti-CD20 antibody and an alkylator-based combination therapy; 21% of patients had received a previous stem-cell transplantation.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Infusion-Related Reactions
Grade 1 or 2 (mild to moderate) reactions: Hold or reduce the infusion rate. Manage symptoms with supportive care measures (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) as appropriate. Resume or continue the infusion at a reduced rate upon symptom resolution. If the reaction does not recur, the infusion rate may be increased at the appropriate increments and intervals for the treatment cycle dose. In patients with chronic lymphocytic leukemia (CLL), the day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour but do not increase further.
Grade 3 (severe) reactions: Hold the infusion and manage symptoms with supportive care measures (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) as appropriate. Upon symptom resolution, resume the infusion at a rate half the previous rate or less (maximum for FL patients receiving a 90-minute infusion, 400 mg/hour). If the patient does not experience any further symptoms, those receiving the standard infusion rate may have their rate increased at the appropriate increments and intervals for the treatment cycle dose. In patients with CLL, the day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour but do not increase further. Subsequent infusions in patients with FL should be administered at the standard rate. Permanently discontinue therapy if a grade 3 infusion reaction occurs upon re-challenge.
Grade 4 (life-threatening) reactions: Stop the infusion immediately and permanently discontinue therapy. Manage symptoms with supportive care measures (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) as appropriate.
Other Toxicity
Infection, grade 3 or 4 cytopenias, or grade 2 or higher non-hematologic toxicity: Consider interrupting treatment.
Maximum Dosage Limits:
-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.
Patients with Hepatic Impairment Dosing
Obinutuzumab has not been studied in patients with hepatic impairment. Specific guidelines for dosage adjustments in hepatic impairment are not available.
Patients with Renal Impairment Dosing
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.
*non-FDA-approved indication
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.
Bacillus Calmette-Guerin Vaccine, BCG: (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.
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.
Chikungunya Vaccine, Live: (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.
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.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
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.
Intranasal Influenza Vaccine: (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.
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.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (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.
Measles/Mumps/Rubella Vaccines, MMR: (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.
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.
Rotavirus Vaccine: (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.
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.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (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.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (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.
Smallpox Vaccine, Vaccinia Vaccine: (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.
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.
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.
Typhoid Vaccine: (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.
Varicella-Zoster Virus Vaccine, Live: (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.
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.
Yellow Fever Vaccine, Live: (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.
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.
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.
-Route-Specific Pharmacokinetics
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.
-Special Populations
Renal Impairment
Baseline creatinine clearance (range, 22 to greater than 120 mL/min) did not affect the pharmacokinetic parameters of obinutuzumab in a population analysis.
Geriatric
Age (range, 22 to 89 years) does not affect the pharmacokinetics of obinutuzumab.
Obesity
Increased body weight is associated with an increase in obintuzumab volume of distribution and clearance; however, a dose adjustment is not necessary.