Obinutuzumab

Severe and life-threatening (grade 3 and 4) neutropenia (including neutropenic fever) has been observed in clinical trials. Neutropenia may have a late onset (>28 days after therapy completion) and/or be prolonged (duration >28 days). Consider administration of granulocyte colony-stimulating factors in patients who develop grade 3 or 4 neutropenia. Monitor for signs/symptoms of infection; antimicrobial prophylaxis is recommended in neutropenic patients with severe neutropenia that lasts more than 1 week (continue prophylaxis until neutropenia improves to ≤ grade 2). Antiviral and/or antifungal prophylaxis should also be considered. Severe and life-threatening thrombocytopenia has also been reported when used in combination with chemotherapy. In a small percentage of patients, thrombocytopenia occurred acutely (within 24 hours) after obinutuzumab administration; platelet transfusions may be necessary. Fatal hemorrhagic events have been reported; monitor frequently for thrombocytopenia and bleeding episodes, particularly during the initial cycle. Thrombocytopenia may require dose delays of obinutuzumab and chemotherapy and/or dose reductions of chemotherapy. Consider withholding platelet inhibitors, anticoagulants, or other medications which may increase bleeding risk (especially during the first cycle). Leukopenia, lymphopenia, and anemia commonly occur. Monitor blood counts frequently throughout therapy.

Hepatitis B virus (HBV) reactivation may occur with use of CD20-directed cytolytic antibodies (including obinutuzumab) and may result in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) prior to therapy initiation; monitor patients for clinical and laboratory signs of hepatitis or HBV during and for several months after treatment. Discontinue obinutuzumab (and concomitant chemotherapy) if viral hepatitis develops and initiate appropriate antiviral therapy. Reactivation has occurred in patients who are HBsAg positive as well as in those who are HBsAg negative but are anti-HBc positive; HBV reactivation has also been observed in patients who had previously resolved HBV infection. HBV reactivation has been reported for other CD20-directed antibodies after therapy discontinuation. Reactivation of HBV replication is often followed by hepatitis. Use cautiously in patients who show evidence of prior HBV infection (eg, HBsAg positive [regardless of antibody status] or HBsAG negative but anti-HBc positive); consult with appropriate clinicians regarding monitoring and consideration of antiviral therapy before and/or during obinutuzumab treatment. The safety of resuming obinutuzumab treatment following HBV reactivation is not known; discuss reinitiation of therapy in patients with resolved HBV reactivation with physicians experienced in HBV management. American

Hypersensitivity reactions have been reported in patients who have received obinutuzumab. Signs of immediate-onset hypersensitivity included dyspnea, bronchospasm, hypotension, urticaria, and tachycardia. Late-onset hypersensitivity (diagnosed as serum sickness) has also been reported with obinutuzumab; symptoms included chest pain, diffuse arthralgia, and fever. Hypersensitivity reactions may be difficult to clinically differentiate from infusion-related reactions. However, hypersensitivity very rarely occurs with the initial infusion and generally occurs after a prior exposure. If a hypersensitivity reaction is suspected during or after an infusion, stop the infusion and permanently discontinue treatment. Do not retreat with obinutuzumab in patients with known hypersensitivity reactions, including serum sickness.

Bacterial, fungal, and new or reactivated viral infections may occur during and/or following therapy; serious and/or fatal infections have been reported. Grade 3 and higher infections have been observed (during and after treatment) when obinutuzumab was administered in combination with chemotherapy followed by obinutuzumab monotherapy. A higher incidence of grade 3 to 5 infections (including during monotherapy and after treatment) have been observed when obinutuzumab was administered in combination with bendamustine (compared to CHOP or CVP). Do not administer to patients with an active infection. Patients with a history of recurrent or chronic infections may be at increased risk; monitor closely for signs/symptoms of infection.

May cause severe and life-threatening infusion reactions; reactions may include bronchospasm, dyspnea, chest discomfort, tachycardia, larynx and throat irritation, wheezing, laryngeal edema, flushing, rash, hypertension, hypotension, fever, dizziness, nausea, vomiting, diarrhea, headache, fatigue, and/or chills. Infusion reactions occur more frequently with the first 1,000 mg infused or on day 1 of the infusion. Delayed reactions (up to 24 hours later) and reactions with subsequent infusions have occurred. Premedicate with acetaminophen, an antihistamine, and an IV glucocorticoid (dexamethasone or methylprednisolone) prior to infusion. Hydrocortisone has not been effective in reducing the rate of infusion reactions and is not recommended. Infusion reactions may require rate reduction, interruption of therapy, or treatment discontinuation. Monitor during the entire infusion; monitor patients with preexisting cardiac or pulmonary conditions closely. Consider temporarily withholding antihypertensive therapies for 12 hours prior to, during, and for 1 hour after administration. Administer in a facility with immediate access to resuscitative measures (eg, glucocorticoids, epinephrine, bronchodilators, and/or oxygen).

Progressive multifocal leukoencephalopathy (PML) resulting in death may occur with treatment. PML is due to JC virus infection. Consider PML in any patient with new onset or worsening neurological symptoms and if PML is suspected, discontinue obinutuzumab (consider discontinuation or dose reduction of any concomitant chemotherapy or immunosuppressive therapy) and evaluate promptly.

Tumor lysis syndrome (TLS) has been reported with obinutuzumab (some cases fatal). Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia may occur. Administer prophylaxis (antihyperuricemic therapy [eg, allopurinol or rasburicase] and adequate hydration) in patients at high risk (high circulating lymphocyte counts [>25,000/mm3], high tumor burden, or renal impairment) prior to initiating obinutuzumab therapy (administer prior to each subsequent cycle if needed). Monitor lab parameters during initial treatment days in patients at risk for TLS. Correct electrolyte abnormalities; monitor renal function and hydration status, and administer supportive care, including dialysis as indicated. Concurrent drug therapy issues:

Due to the risk for hypotension, consider temporarily withholding antihypertensive therapies for 12 hours prior to, during, and for 1 hour after administration.

Due to the risk for thrombocytopenia and hemorrhagic events (particularly during the first cycle), consider withholding anticoagulants, platelet inhibitors, or other medications which may increase bleeding risk.

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Administration of live virus vaccines during treatment (and until B-cell recovery) is not recommended; the safety and efficacy of immunization with live or attenuated viral vaccines during or after obinutuzumab therapy has not been determined. If obinutuzumab exposure occurs during pregnancy, the safety and timing of live virus vaccinations for the infant should be evaluated.