Calendar
3rd Annual Leukemia & Lymphoma Society
Roundtable Discussion
November 29, 2018
San Diego, CA
At its roundtable discussions, the Leukemia & Lym-
phoma Society’s panel of experts will discuss innova-
tions in cancer research, including updates from the Beat
AML initiative.
MARK YOUR CALENDAR
2018 American Society of Hematology
Annual Meeting
December 1 – 4, 2018
San Diego, CA
The 60th ASH Annual Meeting and Exposition will
provide an invaluable educational experience and
the opportunity to review thousands of scientific
abstracts highlighting updates in the hottest topics
in hematology.
GAZYVA ® (obinutuzumab) injection, for
intravenous use
Initial U.S. Approval: 2013
This is a brief summary of information about
GAZYVA. Before prescribing, please see full
Prescribing Information.
WARNING: HEPATITIS B VIRUS
REACTIVATION and PROGRESSIVE
MULTIFOCAL LEUKOENCEPHALOPATHY
• Hepatitis B Virus (HBV) reactivation, in
some cases resulting in fulminant hepatitis,
hepatic failure, and death, can occur in
patients receiving CD20-directed cytolytic
antibodies, including GAZYVA. Screen all
patients for HBV infection before treatment
initiation. Monitor HBV-positive patients
during and after treatment with GAZYVA.
Discontinue GAZYVA and concomitant
medications in the event of HBV
reactivation [see Warnings and Precautions
(5.1)].
• Progressive Multifocal Leukoencephalopathy
(PML) including fatal PML, can occur in
patients receiving GAZYVA [see Warnings
and Precautions (5.2)].
1 INDICATIONS AND USAGE
1.1 Chronic Lymphocytic Leukemia (CLL)
GAZYVA, in combination with chlorambucil, is
indicated for the treatment of patients with
previously untreated chronic lymphocytic leukemia
[see Clinical Studies (14.1)].
1.2 Follicular Lymphoma (FL)
GAZYVA, in combination with bendamustine
followed by GAZYVA monotherapy, is indicated for
the treatment of patients with follicular lymphoma
who relapsed after, or are refractory to, a rituximab-
containing regimen [see Clinical Studies (14.2)].
GAZYVA, in combination with chemotherapy
followed by GAZYVA monotherapy in patients
achieving at least a partial remission, is indicated
for the treatment of adult patients with previously
untreated stage II bulky, III or IV follicular lymphoma
[see Clinical Studies (14.2)].
4 CONTRAINDICATIONS
GAZYVA is contraindicated in patients with known
hypersensitivity reactions (e.g., anaphylaxis) to
obinutuzumab or to any of the excipients, or serum
sickness with prior obinutuzumab use [see Warnings
and Precautions Section (5.4)].
5 WARNINGS AND PRECAUTIONS
5.1 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.
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5.2 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.
5.3 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 of GAZYVA infused. Thirty-eight percent
of patients with relapsed or refractory NHL and
60% of patients with previously untreated NHL
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). The most
frequently reported symptoms include nausea,
fatigue, chest discomfort, dyspnea, dizziness,
vomiting, diarrhea, rash, hypertension, hypotension,
flushing, headache, pyrexia, and chills [see Adverse
Reactions (6.1)].
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 (2)].
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 (2)].
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.
5.4 Hypersensitivity Reactions Including
Serum Sickness
Hypersensitivity reactions have been reported
in patients treated with GAZYVA. Signs of
immediate-onset hypersensitivity included dyspnea,
bronchospasm, hypotension, urticaria and
tachycardia. Late-onset hypersensitivity diagnosed
as serum sickness has also been reported, with
symptoms that include chest pain, diffuse arthralgia
and fever. Hypersensitivity reactions may be difficult
to clinically distinguish from infusion related reactions.
However, hypersensitivity very rarely occurs with the
first infusion and, when observed, often occurs after
previous exposure. If a hypersensitivity reaction is
suspected during or after an infusion, the infusion
must be stopped and treatment permanently
discontinued. Patients with known hypersensitivity
reactions to GAZYVA, including serum sickness, must
not be retreated.
5.5 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 10 9 /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 (2.3)].
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.
5.6 Infections
Fatal and serious bacterial, fungal, and new or
reactivated viral infections can occur during and
following GAZYVA therapy. When GAZYVA is
administered with chemotherapy followed by
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GAZYVA monotherapy, Grade 3 to 5 infections
have been reported in up to 8% of patients during
combination therapy, up to 13% of patients
during monotherapy, and up to 8% of patients
after treatment [see Adverse Reactions (6.1)]. 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.
In GALLIUM, more Grade 3 to 5 infections
were reported in the recipients of GAZYVA and
bendamustine (117/410 patients, 29%), as
compared to GAZYVA plus CHOP or CVP (43/281
patients, 15%). More fatal infections were reported
in patients treated with GAZYVA and bendamustine
(3%), as compared to GAZYVA plus CHOP or CVP
(< 1%), including during the monotherapy phase
and after completion of treatment.
5.7 Neutropenia
Severe and life threatening neutropenia, including
febrile neutropenia, has been reported during
treatment with GAZYVA. Monitor patients with Grade
3 to 4 neutropenia 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 (GCSF) 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. Consider antiviral and
antifungal prophylaxis.
5.8 Thrombocytopenia
Severe and life threatening thrombocytopenia has
been reported during treatment with GAZYVA in
combination with chemotherapy. Fatal hemorrhagic
events have been reported in patients with NHL
and CLL treated with GAZYVA in combination with
chemotherapy, including during Cycle 1.
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.
5.9 Immunization
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.
6 ADVERSE REACTIONS
The following adverse reactions are discussed in
greater detail in other sections of the label:
• Hepatitis B virus reactivation [see Warnings and
Precautions (5.1)]
• Progressive multifocal leukoencephalopathy
[see Warnings and Precautions (5.2)]
• Infusion reactions [see Warnings and Precautions (5.3)]
• Hypersensitivity reactions including serum
sickness [see Warnings and Precautions (5.4)]
• Tumor lysis syndrome [see Warnings and
Precautions (5.5)]
• Infections [see Warnings and Precautions (5.6)]
• Neutropenia [see Warnings and Precautions (5.7)]
• Thrombocytopenia [see Warnings and
Precautions (5.8)]
6.1 Clinical Trial Experience
Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed
in the clinical trials of a drug cannot be directly
compared to rates in the clinical trials of another drug
and may not reflect the rates observed in practice.
Summary of Clinical Trial Experience in
Chronic Lymphocytic Leukemia
The data described in Tables 4-5 below are based
on a safety population of 773 previously untreated
patients with CLL in the CLL11 study. Patients
were treated with chlorambucil alone, GAZYVA
in combination with chlorambucil, or rituximab
product in combination with chlorambucil. The
Stage 1 analysis compared GAZYVA in combination
with chlorambucil vs. chlorambucil alone, and
Stage 2 compared GAZYVA in combination with
chlorambucil vs. rituximab product in combination
with chlorambucil. Adverse reactions rates and
laboratory abnormalities from the Stage 2 phase
are presented below and are consistent with the