July 29, 2016
Recommended Topic Related To:


"The U.S. Food and Drug Administration today expanded the approved use of Imbruvica (ibrutinib) for chronic lymphocytic leukemia (CLL) patients who have received at least one previous therapy.

CLL is a rare blood and bone marrow disease"...





Included as part of the PRECAUTIONS section.


Hepatitis B Virus Reactivation

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with anti-CD20 antibodies such as GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).

HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death.

Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.

Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with GAZYVA. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following completion of therapy.

In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation.

Progressive Multifocal Leukoencephalopathy

JC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, was observed in patients treated with GAZYVA. Consider the diagnosis of PML in any patient presenting with new onset or changes to preexisting neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue GAZYVA therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.

Infusion Reactions

GAZYVA can cause severe and life-threatening infusion reactions. Sixty-five percent of patients with CLL experienced a reaction to the first 1000 mg infused of GAZYVA. Thirty-eight percent of iNHL patients experienced a reaction on Day 1 of GAZYVA infusion. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). Most frequently reported symptoms include nausea, fatigue, dizziness, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills [see ADVERSE REACTIONS].

Premedicate patients with acetaminophen, antihistamine, and a glucocorticoid. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion reactions as needed. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving GAZYVA have occurred [see DOSAGE AND ADMINISTRATION].

For patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently discontinue GAZYVA therapy.

For patients with Grade 1, 2, or 3 infusion reactions: Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms [see DOSAGE AND ADMINISTRATION].

For patients with preexisting cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction. Consider withholding antihypertensive treatments for 12 hours prior to, during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their antihypertensive medication as is suggested here.

Tumor Lysis Syndrome

Tumor Lysis Syndrome (TLS), including fatal cases, has been reported in patients receiving GAZYVA. Patients with high tumor burden, high circulating lymphocyte count ( > 25 x 109/L) or renal impairment are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol or rasburicase) and hydration prior to the infusion of GAZYVA [see DOSAGE AND ADMINISTRATION].

During the initial days of GAZYVA treatment, monitor the laboratory parameters of patients considered at risk for TLS. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated.


Serious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy. Fatal infections have been reported with GAZYVA. Do not administer GAZYVA to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection.


Severe and life threatening neutropenia, including febrile neutropenia, has been reported during treatment with GAZYVA. Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection. Consider administration of granulocyte colony-stimulating factors (G-CSF) in patients with Grade 3 or 4 neutropenia.

Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days).

Consider dose delays in the case of Grade 3 or 4 neutropenia. Patients with severe and long lasting ( > 1 week) neutropenia are strongly recommended to receive antimicrobial prophylaxis until resolution of neutropenia to Grade 1 or 2. Antiviral and antifungal prophylaxis should be considered.


Severe and life threatening thrombocytopenia has been reported during treatment with GAZYVA in combination with chlorambucil or bendamustine. Fatal hemorrhagic events during Cycle 1 have also been reported in patients with CLL treated with GAZYVA.

Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of GAZYVA and chemotherapy or dose reductions of chemotherapy. Transfusion of blood products (i.e., platelet transfusion) may be necessary. Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle.


The safety and efficacy of immunization with live or attenuated viral vaccines during or following GAZYVA therapy have not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No carcinogenicity or genotoxicity studies have been conducted with obinutuzumab.

No specific studies have been conducted to evaluate potential effects on fertility; however, no adverse effects on male or female reproductive organs were observed in the 26-week repeat-dose toxicity study in cynomolgus monkeys.

Use In Specific Populations


Risk Summary

GAZYVA is likely to cause fetal B-cell depletion based on findings from animal studies and the drug's mechanism of action [see CLINICAL PHARMACOLOGY]. There are no data with GAZYVA use in pregnant women to inform a drug-associated risk. Monoclonal antibodies are transferred across the placenta. In animal reproduction studies, weekly intravenous administration of obinutuzumab to pregnant cynomolgus monkeys from day 20 of pregnancy until parturition which includes the period of organogenesis at doses with exposures up to 2.4 times the exposure at the clinical dose of 1000 mg monthly produced opportunistic infections and immune complex mediated hypersensitivity reactions. No embryo-toxic or teratogenic effects were observed in the monkeys [see Data]. Consider the potential risk to the fetus when prescribing GAZYVA to a pregnant woman.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

GAZYVA is likely to cause fetal B-cell depletion [see Data]. Avoid administering live vaccines to neonates and infants exposed to GAZYVA in utero until B-cell recovery occurs [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].


Animal Data

In a pre-and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition, which includes the period of organogenesis. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. There were no embryo-toxic or teratogenic effects in animals. Secondary opportunistic infections, immune complex mediated hypersensitivity reactions, or a combination of both were observed in exposed dams. When first measured on day 28 postpartum, obinutuzumab was detected in offspring at levels in the range of maternal serum levels on the same day, and B-cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.

Obinutuzumab was measured in the milk of lactating cynomolgus monkeys on day 28 postpartum after weekly intravenous administration from day 20 of pregnancy until parturition. Concentrations in milk were approximately 0.04% and 0.13% of concentrations in maternal serum in the 25 and 50 mg/kg groups, respectively.


Risk Summary

There is no information regarding the presence of GAZYVA in human milk, the effects on the breastfed infant, or the effects on milk production. However, low levels of obinutuzumab were present in the milk of lactating cynomolgus monkeys [see Use in Specific Populations]. Human IgG is known to be present in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for GAZYVA and any potential adverse effects on the breastfed infant from GAZYVA or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of GAZYVA in pediatric patients have not been established.

Geriatric Use

Chronic Lymphocytic Leukemia

Of 336 patients with previously untreated CLL who received GAZYVA in combination with chlorambucil, 81% were 65 years and older, while 46% were 75 and older. Of the patients 75 years and older, 46% experienced serious adverse events and 7% experienced adverse events leading to death. Of the patients younger than 75, 33% experienced a serious adverse event and 2% an adverse event leading to death. No significant differences in efficacy were observed between younger and older patients [see Clinical Studies].

Non-Hodgkin Lymphoma

Of 194 patients with iNHL treated with GAZYVA plus bendamustine, 44% were 65 and over, while 14% were 75 and over. In patients 65 and over, 52% of patients experienced serious adverse events and 26% experienced adverse events leading to treatment withdrawal while in patients under 65, 28% and 12% experienced serious adverse events and adverse events leading to treatment withdrawal, respectively. No clinically meaningful differences in efficacy were observed between these patients and younger patients.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 3/7/2016


Report Problems to the Food and Drug Administration


You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.

Women's Health

Find out what women really need.