Obinutuzumab, a recombinant humanized anti-CD20 monoclonal antibody, is an antineoplastic agent;1, 4 the drug also is referred to as a type II anti-CD20 monoclonal antibody.13, 15, 16
Obinutuzumab is used in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia (CLL);1, 2 obinutuzumab is designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this cancer.3
The current indication for obinutuzumab is based principally on results of an open-label, randomized, active-controlled, multicenter study in 781 patients with previously untreated CD20-positive CLL.1, 2 Patients were randomized in a 2:2:1 ratio to receive obinutuzumab in combination with chlorambucil, rituximab in combination with chlorambucil, or chlorambucil alone.1, 2 After 118 patients had been assigned to the chlorambucil monotherapy group, randomization to this group was closed and randomization to the 2 combination regimens continued in a 1:1 ratio.2 The primary measure of efficacy was progression-free survival as assessed by the investigator; secondary end points included overall survival, progression-free survival as assessed by an independent review facility (IRF), and overall response rate.2 The median age of patients was 73 years; 22, 42, or 36% of the patients had Binet stage A, B, or C disease, respectively.1, 2 Most patients had more than 3 coexisting medical conditions (82%) or a creatinine clearance of less than 70 mL/minute (65%).1, 2 Therapy was administered in 4-week cycles for a total of 6 cycles.1, 2 Dosages of the drugs were obinutuzumab 1 g by IV infusion once weekly for 3 doses during cycle 1, followed by 1 g by IV infusion every 4 weeks for an additional 5 cycles; chlorambucil 0.5 mg/kg on days 1 and 15 of each cycle; and rituximab 375 mg/m2 on day 1 of cycle 1, followed by 500 mg/m2 every 4 weeks for an additional 5 cycles.1, 2 Because of a high rate of infusion-related reactions in patients receiving obinutuzumab 1 g once weekly for 3 doses during cycle 1, the study protocol was amended to divide the initial 1-g dose of obinutuzumab on day 1 of cycle 1 into 2 infusions (100 mg on day 1 and 900 mg on day 2 of cycle 1).1, 2 (See Infusion-related Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
In patients receiving obinutuzumab in combination with chlorambucil, median IRF-assessed progression-free survival was prolonged compared with that in patients receiving chlorambucil alone (23 versus 11.1 months, respectively).1 Effects of obinutuzumab on investigator-assessed progression-free survival and IRF-assessed progression-free survival were comparable.1, 2 Patients receiving obinutuzumab in combination with chlorambucil appeared to have a higher overall response rate (75.9 versus 32.1%, respectively) and a longer median duration of response (15.2 versus 3.5 months, respectively) compared with those receiving chlorambucil alone; 27.8% of patients receiving obinutuzumab in combination with chlorambucil achieved a complete response compared with 0.9% of those receiving chlorambucil alone.1 At the time of the primary analysis for comparison of obinutuzumab in combination with chlorambucil versus rituximab in combination with chlorambucil, obinutuzumab-treated patients appeared to have a higher overall response rate (78.4 versus 65.1%) and longer progression-free survival (26.7 versus 15.2 months) than rituximab-treated patients.2 Effects on overall survival remain to be established; however, a planned interim analysis suggested a trend toward a survival benefit in patients receiving obinutuzumab in combination with chlorambucil compared with those receiving chlorambucil alone, but no difference in overall survival between obinutuzumab- or rituximab-treated patients.2 Infusion-related reactions and grade 3 or 4 neutropenia occurred more frequently in patients receiving obinutuzumab.2
Patients at high risk of tumor lysis syndrome (i.e., patients with a high number of circulating malignant cells [lymphocyte count of 25,000/mm3 or greater] or a large tumor burden) should receive adequate hydration and prophylaxis with an antihyperuricemic agent (e.g., allopurinol) beginning 12-24 hours prior to the first dose of obinutuzumab.1 (See Tumor Lysis Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Obinutuzumab should be administered only in settings where adequate monitoring can be performed and appropriate medical support is available for management of potential infusion-related reactions.1 (See Infusion-related Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
To minimize the risk of infusion-related events associated with obinutuzumab, the manufacturer recommends a premedication regimen (e.g., a corticosteroid, an antihistamine, and acetaminophen) prior to obinutuzumab infusions.1 Hydrocortisone has not been effective in reducing the rate of infusion-related events associated with obinutuzumab and is not recommended as premedication.1 Acetaminophen 650 mg to 1 g should be administered at least 30 minutes prior to each obinutuzumab infusion.1 On days 1 and 2 of cycle 1, an antihistamine (e.g., diphenhydramine hydrochloride 50 mg) and IV corticosteroid (dexamethasone 20 mg or methylprednisolone 80 mg) also should be administered at least 30 minutes and 1 hour, respectively, prior to infusion of obinutuzumab.1 Recommendations for antihistamine and/or corticosteroid premedication prior to subsequent doses of obinutuzumab (days 8 and 15 of cycle 1 and day 1 of cycles 2-6) are based on the patient's tolerance of the previous infusion.1 Patients who have experienced a grade 1 or 2 infusion-related reaction should receive an antihistamine prior to subsequent doses, while those who have experienced a grade 3 infusion-related reaction should receive both an antihistamine and a corticosteroid prior to subsequent doses.1 In addition, corticosteroid premedication is recommended for patients with a high circulating lymphocyte count (exceeding 25,000/mm3) prior to the next dose of obinutuzumab.1 Recommended dosages of antihistamines and corticosteroids are the same as those used prior to the initial infusion.1 (See Infusion-related Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Because hypotension may occur during administration of obinutuzumab, consideration should be given to withholding antihypertensive therapy for 12 hours prior to, during, and for 1 hour following each obinutuzumab infusion until blood pressure has stabilized; however, the potential risks and benefits of withholding antihypertensive therapy should be considered in patients at increased risk of hypertensive crisis.1 (See Infusion-related Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Anti-infective prophylaxis is strongly recommended during therapy with obinutuzumab in patients with neutropenia; antiviral and antifungal prophylaxis should be considered.1 (See Infectious Complications under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Obinutuzumab is administered by IV infusion.1 The drug should not be administered by rapid IV injection, such as IV push or bolus .1
Unopened vials of obinutuzumab injection concentrate should be protected from light, stored at 2-8°C, and should not be frozen or shaken.1
Prior to administration, obinutuzumab injection concentrate must be diluted using proper aseptic technique.1 The manufacturer states that obinutuzumab may be administered following dilution to a final concentration of 0.4-4 mg/mL.1
Obinutuzumab injection concentrate should be inspected visually for particulate matter and discoloration.1 Solutions of the drug should be clear and colorless to slightly brown.1
Diluted solutions of obinutuzumab for administration on day 1 (100 mg) and day 2 (900 mg) of cycle 1 may be prepared on the same day.1 For simultaneous preparation of both doses, 40 mL of obinutuzumab injection concentrate should be withdrawn from a vial labeled as containing 1 g in 40 mL.1 For the 100-mg dose, 4 mL of the injection concentrate is added to a PVC or non-PVC polyolefin infusion bag containing 100 mL of 0.9% sodium chloride to yield a final concentration of approximately 1 mg/mL.1 The diluted solution of the drug for day 1 of cycle 1 should be administered immediately.1 For the 900-mg dose, the remaining 36 mL of obinutuzumab injection concentrate is added to a PVC or non-PVC polyolefin infusion bag containing 250 mL of 0.9% sodium chloride to yield a final concentration of approximately 3.1 mg/mL.1 The diluted solution of the drug for day 2 of cycle 1 should be stored at 2-8°C for up to 24 hours; the solution should be brought to room temperature and then administered immediately.1
For a 1-g dose of obinutuzumab, 40 mL of obinutuzumab injection concentrate should be withdrawn from a vial labeled as containing 1 g in 40 mL and added to an infusion bag containing 250 mL of 0.9% sodium chloride to yield a final concentration of approximately 3.4 mg/mL.1 The manufacturer recommends immediate administration of diluted solutions of the drug.1 If immediate administration is not possible, diluted solutions of the drug may be stored at 2-8°C for up to 24 hours; the solution should be brought to room temperature and then administered immediately.1
Diluted obinutuzumab solutions should be mixed by gentle inversion and should not be shaken.1 Obinutuzumab injection concentrate should not be diluted in 5% dextrose injection.1 Obinutuzumab should not be admixed with any other drug.1 Commercially available obinutuzumab injection concentrate contains no preservatives and is intended for single use; any partially used vials should be discarded.1
The initial obinutuzumab dose (100 mg; day 1 of cycle 1) should be infused IV at a rate of 25 mg/hour over 4 hours.1 The second dose of obinutuzumab (900 mg; day 2 of cycle 1) should be infused at an initial rate of 50 mg/hour; if infusion-related reactions do not occur, the infusion rate may be increased in increments of 50 mg/hour every 30 minutes to a maximum rate of 400 mg/hour.1 Subsequent doses of obinutuzumab (1 g each; days 8 and 15 of cycle 1 and day 1 of cycles 2-6) should be infused at an initial rate of 100 mg/hour; if infusion-related events do not occur, the infusion rate may be increased in increments of 100 mg/hour every 30 minutes to a maximum rate of 400 mg/hour.1
If infusion-related reactions occur, the infusion rate should be reduced or obinutuzumab therapy should be interrupted depending on the severity of the reaction.1 If the infusion-related reaction is grade 4 in severity, therapy with obinutuzumab should be permanently discontinued.1 If the infusion-related reaction is grade 3, the obinutuzumab infusion should be interrupted; once the reaction has resolved, the infusion may be resumed but the rate of infusion should be reduced by at least 50%.1 If no further infusion-related reactions occur, the infusion rate may be increased in increments and intervals appropriate for the treatment cycle dose.1 If a grade 3 infusion-related reaction recurs, treatment with obinutuzumab should be permanently discontinued.1 For grade 1 and 2 infusion-related reactions, the infusion rate should be reduced or the infusion should be interrupted until the reaction has resolved; if infusion-related reactions do not occur upon resumption or continuation at a reduced rate, the infusion rate may be increased in increments and intervals appropriate for the treatment cycle dose.1 (See Infusion-related Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
For the treatment of previously untreated chronic lymphocytic leukemia (CLL) in adults, obinutuzumab is administered in combination with chlorambucil in 4-week cycles for a maximum of 6 cycles.1 During cycle 1, the recommended dosage of obinutuzumab is 100 mg on day 1, followed by 900 mg on day 2, and then 1 g once weekly for 2 doses (days 8 and 15).1 During cycles 2-6, the recommended dosage of obinutuzumab is 1 g every 4 weeks (day 1 of each cycle).1 Patients who do not complete the day 1 dose in cycle 1 may proceed to receive the day 2 dose if continued therapy with the drug is appropriate.1
If a dose is missed, the missed dose should be administered as soon as possible; waiting until the next scheduled dose is not recommended.1 The schedule of administration should be adjusted to maintain the recommended 4-week interval between doses.1
Although volume of distribution and steady-state clearance of obinutuzumab increase with increasing body weight, the manufacturer states that dosage adjustment based on body weight is not necessary.1
Therapy Interruption for Toxicity
If infusion-related reactions occur, the infusion rate should be reduced or obinutuzumab therapy should be interrupted depending on the severity of the reaction, and appropriate symptomatic and supportive therapy should be provided.1 (See Rate of Administration under Dosage and Administration: Administration.) If a grade 4 infusion-related reaction occurs, obinutuzumab therapy should be permanently discontinued.1
If grade 3 or 4 cytopenia occurs, temporary interruption of obinutuzumab therapy should be considered.1
If infection occurs, temporary interruption of obinutuzumab therapy should be considered.1
If grade 2 or greater nonhematologic toxicity occurs, temporary interruption of obinutuzumab therapy should be considered.1
There are no special population dosage recommendations at this time.1 Obinutuzumab has not been studied in patients with hepatic impairment or in patients with renal impairment with a creatinine clearance of less than 30 mL/minute.1 The recommended adult dosage for treatment of CLL is based on clinical trial experience mainly in geriatric patients.1 (See Specific Populations under Cautions: Warnings/Precautions.)
The manufacturer states there are no known contraindications to the use of obinutuzumab.1
Patients Infected with Hepatitis B Virus
Reactivation of hepatitis B virus (HBV) infection has been reported in patients receiving anti-CD20 monoclonal antibodies, such as obinutuzumab, and has resulted in fulminant hepatitis, hepatic failure, and death.1, 5, 6, 7, 8 HBV reactivation has been reported in patients who are hepatitis B surface antigen-positive [HBsAg-positive]; HBsAg-negative and hepatitis B core antibody-positive [anti-HBc-positive]; or HBsAg-negative, anti-HBc-positive, and hepatitis B surface antibody-positive [anti-HBs-positive].1, 5
Following review of the Adverse Event Reporting System (AERS) database, the US Food and Drug Administration (FDA) identified 106 cases of fatal HBV-related acute liver injury in patients receiving rituximab (between November 1997 and August 2012) and 3 such cases in patients receiving ofatumumab (between October 2009 and August 2012); 32 of these case reports contained sufficient data to meet the criteria for HBV reactivation.5 In this review, acute liver injury was attributed to HBV reactivation if seroconversion of HBsAg from negative to positive occurred in those with either anti-HBc or a history of HBV, or if an increase in serum HBV DNA level occurred in those who were HBsAg-positive prior to therapy with an anti-CD20 monoclonal antibody (i.e., rituximab, ofatumumab).5 HBV reactivation was diagnosed by seroconversion of HBsAg in most (69%) cases.5 In this review, the duration of rituximab or ofatumumab therapy prior to diagnosis of HBV reactivation was highly variable, ranging from 63 days after initiation of the drug to 12 months following the last dose;5 however, delayed onset of HBV reactivation (up to 24 months following completion of rituximab therapy) has been reported.6, 12 Among patients with HBV reactivation, 10% had received HBV antiviral prophylaxis and 28% had received antiviral treatment for HBV reactivation.5 All of the patients experiencing HBV reactivation had received recent or concomitant therapy with other immunosuppressive agents.5
All patients should be screened for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with obinutuzumab.1 Hepatitis experts should be consulted regarding monitoring and use of antiviral therapy in those with evidence of HBV infection (HBsAg-positive with any antibody status or HBsAg-negative and anti-HBc-positive);1 although data are limited, treatment guidelines from some experts recommend the use of prophylactic antiviral therapy in patients who are chronic carriers of HBV.9, 10, 11 Patients with evidence of current or prior HBV infection should be monitored for clinical and laboratory evidence of hepatitis or HBV reactivation during obinutuzumab therapy and for several months thereafter,1 since reactivation has occurred more than 12 months following completion of anti-CD20 monoclonal antibody therapy.5, 6, 12 Obinutuzumab and any concomitant chemotherapy should be discontinued immediately if HBV reactivation occurs, and appropriate treatment for HBV infection should be initiated.1 Experts in the management of HBV infection should be consulted regarding resumption of obinutuzumab therapy once control of the reactivated HBV infection has been achieved.1 It has not been established whether obinutuzumab can be safely readministered in patients who develop HBV reactivation.1
Progressive Multifocal Leukoencephalopathy
JC virus infection causing progressive multifocal leukoencephalopathy (PML), which can be fatal, has been reported in patients receiving obinutuzumab.1 The possible diagnosis of PML should be considered in any patient receiving obinutuzumab who experiences new onset or worsening of neurologic manifestations suggestive of PML (e.g., confusion, vision changes, changes in speech or walking, dizziness or vertigo).1 If PML is suspected, the drug should be withheld and diagnostic evaluation, including consultation with a neurologist, brain magnetic resonance imaging (MRI) scan, and lumbar puncture, should be considered.1 If PML is confirmed, obinutuzumab should be permanently discontinued; dosage reduction or discontinuance of concomitant immunosuppressive therapy should be considered.1
Other Warnings and Precautions
Infusion-related reactions, sometimes severe or life-threatening, have been reported in patients receiving obinutuzumab.1, 2 Infusion-related reactions generally occur more frequently during the first 2 infusions (total dose of 1 g) than during subsequent infusions of the drug; infusion-related reactions have occurred within 24 hours of administration.1 Infusion-related effects may include bronchospasm, larynx and throat irritation, wheezing, dyspnea, laryngeal edema, flushing, hypertension, hypotension, tachycardia, nausea, vomiting, diarrhea, pyrexia, headache, and chills.1
In the phase 3 clinical trial evaluating obinutuzumab in patients with chronic lymphocytic leukemia (CLL), infusion-related reactions occurred in most (89%) of the first 53 patients who received the drug; during cycle 1 of therapy, these patients received obinutuzumab 1 g at weekly intervals for 3 doses.1 Subsequent study protocol amendments resulted in the initial 1-g dose of obinutuzumab being divided and administered as 2 infusions (100 mg on day 1 and 900 mg on day 2 of cycle 1) and also led to changes in premedication requirements.1, 2, 19 In a subgroup of 45 patients who received the drug following these protocol amendments, 47% experienced infusion-related reactions following the first 2 infusions (total dose of 1 g), and less than 2% experienced infusion-related reactions during subsequent infusions.1 Among patients receiving the drug either before or after the protocol modifications, infusion-related reactions occurred in approximately two-thirds of patients after administration of the first 1 g of obinutuzumab and were severe or life-threatening (grade 3 or 4) in approximately 21% of patients; infusion-related reactions (all less than grade 3) occurred in 3% of patients after administration of the second 1-g dose of obinutuzumab (day 8 of cycle 1) and in less than 1% of patients after subsequent doses.1, 2
To minimize the risk of infusion-related reactions, patients receiving obinutuzumab should be premedicated with acetaminophen, an antihistamine, and a corticosteroid prior to administration of the drug.1 (See Dosage and Administration: General.) Patients should be monitored closely during infusions of the drug for manifestations of infusion-related reactions.1 Patients with preexisting cardiac or pulmonary conditions may be at greater risk for severe infusion-related reactions; more frequent monitoring during and following an infusion is indicated in these patients.1 Because hypotension may occur during administration of obinutuzumab, withholding antihypertensive therapy should be considered.1 (See Dosage and Administration: General.)
In patients experiencing infusion-related reactions, interruption of the infusion or a reduction in the infusion rate may be necessary.1 (See Rate of Administration under Dosage and Administration: Administration.) For patients experiencing a grade 4 infusion-related reaction (e.g., anaphylaxis, acute life-threatening respiratory symptoms, other life-threatening infusion-related reaction), the manufacturer recommends permanent discontinuance.1 Appropriate treatment and supportive care (e.g., corticosteroid, epinephrine, bronchodilator, oxygen) should be provided as clinically indicated for infusion-related reactions.1
Tumor lysis syndrome consisting of rapid reduction in tumor volume followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia, may occur within 12-24 hours of completion of the initial infusion of obinutuzumab.1 In the phase 3 clinical trial evaluating obinutuzumab combined with chlorambucil in patients with previously untreated CLL, grade 3 or 4 tumor lysis syndrome was reported in 2% of obinutuzumab-treated patients compared with none of those receiving chlorambucil alone.1 The risk of tumor lysis syndrome is increased in patients with a high number of circulating malignant cells (lymphocyte count of 25,000/mm3 or greater) or a large tumor burden.1 Appropriate measures (e.g., prophylactic antihyperuricemic therapy and adequate hydration beginning 12-24 hours prior to obinutuzumab infusion) should be used in patients at high risk for tumor lysis syndrome.1 If tumor lysis syndrome develops, patients should receive appropriate medical treatment, including correction of electrolyte abnormalities, monitoring of renal function and fluid balance, and supportive care (e.g., dialysis) as clinically indicated.1
Serious bacterial, new or reactivated viral, or fungal infections may occur during and following completion of obinutuzumab therapy.1 In the phase 3 clinical trial evaluating obinutuzumab combined with chlorambucil in patients with previously untreated CLL, the incidence of infection was similar between obinutuzumab-treated patients and those receiving chlorambucil alone; infection was reported in 38% of obinutuzumab-treated patients and was grade 3 or 4 in severity in 9% of patients.1 The manufacturer states that obinutuzumab should not be used in patients with active infections.1 The risk of infection may be increased in patients with a history of recurring or chronic infections.1
Grade 3 or 4 neutropenia and thrombocytopenia have been reported in patients receiving obinutuzumab in combination with chlorambucil.1, 2 In the phase 3 clinical trial evaluating obinutuzumab combined with chlorambucil in patients with previously untreated CLL, delayed-onset neutropenia (occurring 28 days or more after completion of therapy) was reported in 16% of obinutuzumab-treated patients compared with 12% of those receiving chlorambucil alone.1 Prolonged neutropenia (lasting longer than 28 days) also may occur.1 Acute-onset thrombocytopenia (occurring within 24 hours after completion of therapy) occurred in 5% of obinutuzumab-treated patients.1
Complete blood cell counts (CBCs) and platelet counts should be monitored at regular intervals during obinutuzumab therapy; if grade 3 or 4 neutropenia or thrombocytopenia occurs, the manufacturer recommends more frequent hematologic monitoring until resolution.1 If neutropenia occurs, the manufacturer strongly recommends anti-infective prophylaxis during therapy with obinutuzumab; antiviral and antifungal prophylaxis should be considered.1 Clinicians should monitor for signs or symptoms of infection; if infection develops, appropriate treatment should be instituted.1 Transfusion of blood products (i.e., platelets) may be necessary.1
The safety and efficacy of immunization with live or attenuated viral vaccines during or following obinutuzumab therapy have not been established.1 The manufacturer recommends that live viral vaccines be avoided during obinutuzumab therapy and until B-cell counts have recovered.1
Antibodies to obinutuzumab have been detected in patients receiving the drug; the clinical relevance of such antibodies is not known.1 Anti-obinutuzumab antibodies were detected in approximately 13% of obinutuzumab-treated patients at 1 or more time points during a 12-month follow-up period.1 Neutralizing antibodies have not been assessed.1
Category C.1 (See Users Guide.)
Although obinutuzumab did not produce teratogenic effects when administered to pregnant cynomolgus monkeys from early gestation until parturition, the presence of the drug was detected and B-cell depletion was observed in the offspring on day 28 postpartum; B-cell count and immune function returned to normal within 6 months of birth.1 Women of childbearing potential should use effective contraceptive methods during treatment and for 12 months following obinutuzumab therapy.1
It is not known whether obinutuzumab is distributed into human milk.1 Because human immunoglobulin G (IgG) is distributed into milk in humans, and because of the potential for serious adverse reactions to obinutuzumab in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1
Safety and efficacy of obinutuzumab have not been established in pediatric patients.1
In the phase 3 clinical trial evaluating obinutuzumab in combination with chlorambucil for the treatment of previously untreated CLL, 82% of patients were 65 years of age or older and 45% were 75 years of age or older.1 Although no overall differences in efficacy were observed between geriatric and younger patients, the incidences of serious adverse events (45 versus 30%, respectively) and fatal adverse events (5 versus 2%, respectively) were higher among patients 75 years of age or older compared with younger patients.1 Age does not appear to affect the pharmacokinetics of obinutuzumab.1
Obinutuzumab has not been studied in patients with hepatic impairment.1
A population pharmacokinetic analysis indicated that the pharmacokinetics of obinutuzumab are not influenced by baseline creatinine clearance exceeding 30 mL/minute.1 Obinutuzumab has not been studied in patients with baseline creatinine clearance less than 30 mL/minute.1
Adverse effects reported in 5% or more of patients receiving obinutuzumab in combination with chlorambucil and at an incidence that is at least 2% higher than that reported with chlorambucil alone include infusion-related reactions,1 pyrexia,1 cough,1 and musculoskeletal disorders.1
Laboratory abnormalities reported in 5% or more of patients receiving obinutuzumab in combination with chlorambucil and at an incidence that is at least 2% higher than that reported with chlorambucil alone include neutropenia,1 lymphopenia,1 leukopenia,1 thrombocytopenia,1 hypocalcemia,1 hyperkalemia,1 hyponatremia,1 elevated aminotransferase (i.e., AST, ALT) concentrations,1 elevated serum creatinine concentration,1 hypoalbuminemia,1 elevated serum alkaline phosphatase concentration,1 and hypokalemia.1
Obinutuzumab, a recombinant humanized anti-CD20 monoclonal antibody, is an antineoplastic agent;1, 4 the drug also is referred to as a type II anti-CD20 monoclonal antibody.13, 15, 16 The drug is an IgG1 kappa immunoglobulin produced by recombinant DNA technology in mammalian cell (Chinese hamster ovary) culture.1, 4, 15 Obinutuzumab binds specifically to the class II epitope of antigen CD20,1, 13, 17 a glycoprotein expressed on the surface of normal and malignant B-lymphocytes, including B-cell chronic lymphocytic leukemia (B-CLL) cells.13, 14, 16 Following binding of obinutuzumab to antigen CD20, the Fc domain triggers host immune responses (i.e., antibody-dependent cell-mediated cytotoxicity [ADCC], antibody-dependent cellular phagocytosis [ADCP], complement-dependent cytotoxicity [CDC]) causing lysis of the B-cells.1, 17
Unlike rituximab (a type I anti-CD20 monoclonal antibody), obinutuzumab (a type II anti-CD20 monoclonal antibody) is relatively ineffective in inducing CDC activity, but elicits more potent homotypic adhesion and direct induction of programmed cell death.15, 17, 18 Obinutuzumab is an anti-CD20 monoclonal antibody with a nonfucosylated Fc domain engineered to enhance the binding affinity of the drug for Fcγ receptors, activating Fc receptors expressed by immune effectors (e.g., natural killer [NK] cells, macrophages), which results in enhanced ADCC against malignant B cells relative to rituximab.13, 15, 16, 17, 18 In addition, modification of elbow hinge sequences within the antibody may account for enhanced type II antibody properties of the drug, such as increased direct induction of programmed cell death.13, 17 Obinutuzumab was tenfold to 25-fold more potent than rituximab at depleting B-cells in blood obtained from healthy individuals and also was more effective than rituximab in depleting B-cells in blood obtained from an individual with chronic lymphocytic leukemia (CLL).15
In patients with CLL, obinutuzumab caused circulating CD19+ B-cell depletion (defined as a CD19+ B-cell count less than 70 cells/mm3).1 Initial B-cell recovery occurred approximately 9 months following completion of obinutuzumab therapy in some patients; however, in other patients, B-cell depletion persisted at 18 months.1 Depletion of B-cells has not been shown to be directly correlated to clinical response.1 Obinutuzumab exhibits linear and time-dependent nonlinear clearance.1 Following repeated administration of obinutuzumab during a treatment course, clearance by the nonlinear pathway diminishes.1 The terminal half-life of obinutuzumab is approximately 28-30 days in patients with CLL.1, 19
Risk of infusion-related reactions; importance of reporting signs and symptoms of such reactions, including dizziness, nausea, chills, fever, vomiting, diarrhea, breathing difficulty, or chest pain.1
Risk of tumor lysis syndrome; importance of reporting symptoms of tumor lysis syndrome (e.g., nausea, vomiting, diarrhea, lethargy).1
Risk of infection; importance of reporting signs or symptoms of infection (e.g., cough, fever).1
Risk of progressive multifocal leukoencephalopathy; importance of reporting new or worsening neurologic symptoms (e.g., confusion, dizziness or loss of balance, difficulty speaking or walking, changes in vision).1
Risk of reactivation of hepatitis B virus (HBV) infection; importance of reporting worsening fatigue or icteric changes.1 Importance of informing clinician of presence of HBV carrier state or of any history of HBV infection.5
Advise patients that they should not receive a live viral vaccine if they have recently received obinutuzumab.1
Importance of routine monitoring of blood cell counts.1
Necessity of advising women to avoid pregnancy and breast-feeding while receiving therapy.1 Necessity of advising women receiving obinutuzumab to use an effective method of contraception during therapy and for 12 months after the last dose of obinutuzumab.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions April 6, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Genentech Inc. Gazyva® (obinutuzumab) injection for IV infusion prescribing information. South San Francisco, CA; 2013 Nov.
2. Goede V, Fischer K, Busch R et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med . 2014; 370:1101-10. [PubMed 24401022]
3. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2014 Apr 25. [Web]
4. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125486Orig1s000: Pharmacology review(s). From FDA website. [Web]
5. Food and Drug Administration. Drug safety communication: Boxed warning and new recommendations to decrease risk of hepatitis B reactivation with the immune-suppressing and anti-cancer drugs Arzerra (ofatumumab) and Rituxan (rituximab) [2013 Sep 25]. From FDA website. [Web]
6. Chew E, Thursky K, Seymour JF. Very late onset hepatitis-B virus reactivation following rituximab despite lamivudine prophylaxis: the need for continued vigilance. Leuk Lymphoma . 2013; :.
7. Oh MJ, Lee HJ. A study of hepatitis B virus reactivation associated with rituximab therapy in real-world clinical practice: a single-center experience. Clin Mol Hepatol . 2013; 19:51-9. [PubMedCentral][PubMed 23593610]
8. Yang JD, Girotra M, Vaid A et al. Hepatitis B reactivation in patient with non-Hodgkin's lymphoma receiving rituximab-based chemotherapy: need for education and attention. J Ark Med Soc . 2013; 110:110-2. [PubMed 24367885]
9. Artz AS, Somerfield MR, Feld JJ et al. American Society of Clinical Oncology provisional clinical opinion: chronic hepatitis B virus infection screening in patients receiving cytotoxic chemotherapy for treatment of malignant diseases. J Clin Oncol . 2010; 28:3199-202. [PubMed 20516452]
10. European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol . 2012; 57:167-85. [PubMed 22436845]
11. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology . 2009; 50:661-2. [PubMed 19714720]
12. Biogen Idec/Genentech. Rituxan® (rituximab) injection for IV infusion prescribing information. South San Francisco, CA; 2013 Sep.
13. Patz M, Isaeva P, Forcob N et al. Comparison of the in vitro effects of the anti-CD20 antibodies rituximab and GA101 on chronic lymphocytic leukaemia cells. Br J Haematol . 2011; 152:295-306. [PubMed 21155758]
14. Teeling JL, Mackus WJ, Wiegman LJ et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol . 2006; 177:362-71. [PubMed 16785532]
15. Mössner E, Brünker P, Moser S et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood . 2010; 115:4393-402. [PubMedCentral][PubMed 20194898]
16. Rafiq S, Butchar JP, Cheney C et al. Comparative assessment of clinically utilized CD20-directed antibodies in chronic lymphocytic leukemia cells reveals divergent NK cell, monocyte, and macrophage properties. J Immunol . 2013; 190:2702-11. [PubMedCentral][PubMed 23418626]
17. Klein C, Lammens A, Schäfer W et al. Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties. MAbs . 2013 Jan-Feb; 5:22-33.
18. Alduaij W, Ivanov A, Honeychurch J et al. Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies. Blood . 2011; 117:4519-29. [PubMedCentral][PubMed 21378274]
19. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 125486Orig1s000: Medical review(s). From FDA website. [Web]