"The U.S. Food and Drug Administration today approved Gazyva (obinutuzumab) for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).
CLL is a blood and bone ma"...
ARZERRA can cause serious, including fatal, infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac events (e.g., myocardial ischemia/infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic reactions. Infusion reactions occur more frequently with the first 2 infusions. These reactions may result in temporary interruption or withdrawal of treatment [see ADVERSE REACTIONS].
Pre-medicate with acetaminophen, an antihistamine, and a corticosteroid [see DOSAGE AND ADMINISTRATION]. Infusion reactions may occur despite premedication. Interrupt infusion with ARZERRA for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia [see DOSAGE AND ADMINISTRATION]. If an anaphylactic reaction occurs, immediately and permanently discontinue ARZERRA and initiate appropriate medical treatment.
Hepatitis B Virus Reactivation
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients treated with ARZERRA. Cases have 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 also has 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 ARZERRA. 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 ARZERRA. HBV reactivation has been reported for at least 12 months following completion of therapy.
In patients who develop reactivation of HBV while receiving ARZERRA, immediately discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of ARZERRA 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 ARZERRA in patients who develop HBV reactivation.
Hepatitis B Virus Infection
Fatal infection due to hepatitis B in patients who have not been previously infected has been observed with ARZERRA. Monitor patients for clinical and laboratory signs of hepatitis.
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue ARZERRA and initiate evaluation for PML including neurology consultation.
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS), including the need for hospitalization, has occurred in patients treated with ARZERRA. Patients with high tumor burden and/or high circulating lymphocyte counts ( > 25 x 109/L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of TLS, administer aggressive intravenous hydration and anti-hyperuricemic agents, correct electrolyte abnormalities, and monitor renal function.
Severe cytopenias, including neutropenia, thrombocytopenia, and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred in patients who received ARZERRA in combination with chlorambucil. Grade 3 or 4 late-onset neutropenia (onset at least 42 days after last treatment dose) and/or prolonged neutropenia (not resolved between 24 and 42 days after last treatment dose) were reported in patients who received ARZERRA [see ADVERSE REACTIONS]. Monitor complete blood counts at regular intervals during and after conclusion of therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.
The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No carcinogenicity or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the maximum human dose (2,000 mg) of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies.
Use In Specific Populations
ARZERRA may 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 on ARZERRA use in pregnant women to inform a drug-associated risk. However, there are clinical considerations [see Clinical Considerations]. No teratogenicity was observed in animal reproduction studies with administration of ARZERRA to pregnant monkeys during organogenesis at doses 0.3 and 2.4 times the maximum recommended human dose (MRHD) of 2000 mg based on monkey geometric mean AUCinf of 213 mg.h/mL and 1646 mg.h.mL, respectively. However, ofatumumab caused depletion of maternal circulating B-cells, depletion of peripheral and splenic fetal B-cells, and decreased fetal spleen weights [see Data].
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies, respectively.
Fetal/neonatal Adverse Reactions
ARZERRA may cause fetal B-cell depletion [see Data]. Avoid administering live vaccines to neonates and infants exposed to ARZERRA in utero until B-cell recovery occurs [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
In an embryo-fetal development study, pregnant cynomolgus monkeys received 20 or 100 mg/kg/day of ofatumumab intravenously (30 minute infusion) once weekly during the period of organogenesis [Gestation Days (GD) 20 to 50] with systemic exposure throughout pregnancy due to the long half-life as drug was detected in maternal serum on GD 100 (early fetal period of development). At the end of organogenesis on GD 48, the exposure in pregnant monkeys receiving ofatumumab 20 and 100 mg/kg/day was approximately 0.3 and 2.4 times the human exposure after the 8th infusion of the MRHD of 2,000 mg based on monkey geometric mean AUCinf of 213 mg.h/mL and 1,646 mg.h/mL, respectively. Ofatumumab crossed the placenta, as it was detected in fetal cord blood on GD 100 in both dose groups. There was no maternal toxicity and no effect on pregnancy success. As expected, both dose levels of ofatumumab depleted circulating B cells in the mothers; recovery of B lymphocytes in dosed animals was not observed during the dosing-free period. Following Caesarean section at GD 100, fetuses from treated mothers exhibited decreases in mean peripheral and splenic B-cell counts (decreased to approximately 12% and 15% of control values at both dose levels, respectively and spleen weights (decreased by approximately 15% in low-dose group and by approximately 30% in high-dose group, compared with control values). There was no effect on prenatal survival and no evidence of teratogenicity in this monkey study.
The kinetics of B-lymphocyte recovery and the potential long-term effects of perinatal B-cell depletion in offspring from ofatumumab-treated maternal monkeys have not been studied.
There is no information regarding the presence of ARZERRA in human milk, the effects on the breastfed infant, or the effects on milk production. 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 ARZERRA and any potential adverse effects on the breastfed infant from ARZERRA or from the underlying maternal condition.
Safety and effectiveness of ARZERRA have not been established in children.
In patients with previously untreated CLL (Study 1), 68% (148/217) receiving ARZERRA plus chlorambucil were 65 years and older. Patients age 65 years and older experienced a higher incidence of the following Grade 3 or greater adverse reactions compared with patients younger than 65 years of age: neutropenia (30% versus 17%) and pneumonia (5% versus 1%) [see ADVERSE REACTIONS]. In patients 65 years and older, 29% experienced serious adverse events compared with 13% of patients younger than 65 years. No clinically meaningful differences in the effectiveness of ARZERRA plus chlorambucil were observed between older and younger patients [see Clinical Studies].
With extended treatment in patients with CLL (Study 2), 49% (117/237) receiving ARZERRA were 65 years and older. No clinically meaningful differences in the safety or effectiveness of ARZERRA were observed between patients age 65 years and older and those younger than 65 years of age [see ADVERSE REACTIONS, Clinical Studies].
In refractory CLL, clinical studies of ARZERRA did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects [see CLINICAL PHARMACOLOGY].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 1/27/2016
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