ASH News Daily 2016 - Issue 1 - A-8

ASH News Daily

Page A-8

Saturday, December 3, 2016

Ham-Wasserman
«« From Page A-1

are negative, like the ALIFE study,
we have saved a lot of pregnant
women eight months of burdensome
and expensive injections. Of course,
it's much more rewarding if you find
a therapy that works, but I think that
it's equally important to find out that
a therapy doesn't work."
Dr. Marc Rodger of The Ottawa
Hospital's Ottawa Blood Disease
Center and chair of the International Network of Venous Thrombosis Networks (www.invent-vte.
com) has always been a huge fan of
Dr. Middeldorp and her research:
"Saskia's contributions to women's

health through her research in venous thrombosis and thrombophilia
have been practice changing. She is
currently conducting multiple trials that will no doubt change future
practice in this area." He adds that
her research success comes from her
strength, impeccable research methods, persistence, and phenomenal
collaborative skills. "She's a leader in
our field."
Dr. Middeldorp has come a long
way, from completing a resident
research project to running multinational clinical trials. She is a professor of medicine, co-chair of the
Department of Vascular Medicine at
the Academic Medical Center of the
University of Amsterdam, director

GAZYVA® (obinutuzumab)
injection, for intravenous infusion
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
GAZYVA, in combination with chlorambucil, is
indicated for the treatment of patients with previously
untreated chronic lymphocytic leukemia (CLL) [see
Clinical Studies (14.1)].
1.2 Follicular Lymphoma
GAZYVA, in combination with bendamustine followed
by GAZYVA monotherapy, is indicated for the
treatment of patients with follicular lymphoma (FL)
who relapsed after, or are refractory to, a rituximabcontaining regimen [see Clinical Studies (14.2)].
4 CONTRAINDICATIONS
None.
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 antiHBc 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 antiHBc 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 CD20directed 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.
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

"Saskia's contributions to
women's health through her
research in venous thrombosis and thrombophilia have
been practice changing. She
is currently conducting
multiple trials that will no
doubt change future
practice in this area."

of the vascular medicine residency
program, vice-chair of the INVENT
network, and principal investigator
of two ongoing multinational clinical trials - HighLow and ALIFE2.

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 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 (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 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 (2.2)].
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.
5.5 Infections
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.
5.6 Neutropenia
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.
5.7 Thrombocytopenia
Severe and life threatening thrombocytopenia has
been reported during treatment with GAZYVA in
combination with chlorambucil or bendamustine.

The HighLow trial evaluates two
different doses of low-molecularweight heparin (LMWH) during
pregnancy to prevent recurrent venous thrombosis, and the ALIFE2
trial evaluates the role of LMWH
to prevent recurrent pregnancy loss
in women with inherited thrombophilia.
If you see a woman in your clinic who is heterozygote for factor V
Leiden with recurrent pregnancy
loss, what treatment would you
recommend for her future pregnancy? According to Dr. Middeldorp,
"There is only one answer: enroll
her in ALIFE2. And if not, I don't
»» HAM-WASSERMAN Page A-9

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.
5.8 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 reactivation [see Warnings and
Precautions (5.1)]
* Progressive multifocal leukoencephalopathy
[see Warnings and Precautions (5.2)]
* Infusion reactions [see Warnings and
Precautions (5.3)]
* Tumor lysis syndrome [see Warnings and
Precautions (5.4)]
* Infections [see Warnings and Precautions (5.5)]
* Neutropenia [see Warnings and Precautions
(5.6)]
* Thrombocytopenia [see Warnings and
Precautions (5.7)]
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. Patients were treated with
chlorambucil alone, GAZYVA in combination with
chlorambucil, or rituximab 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 in
combination with chlorambucil. Adverse reactions
rates and laboratory abnormalities from the Stage
2 phase are presented below and are consistent
with the rates in Stage 1. In addition to the adverse
reactions observed in Stage 2, in Stage 1 back pain
(5% vs. 2%), anemia (12% vs. 10%) and cough
(10% vs. 7%) were observed at a higher incidence
in the obinutuzumab treated patients. The incidence
of Grade 3-4 back pain (<1% vs. 0%), cough (0%
vs. <1%) and anemia (5% vs. 4%) was similar in
both treatment arms. With regard to laboratory
abnormalities, in Stage 1 hyperkalemia (33% vs.
18%), creatinine increased (30% vs. 20%) and
alkaline phosphatase increased (18% vs. 11%) were
observed at a higher incidence in patients treated
with obinutuzumab with similar incidences of Grade
3-4 abnormalities between the two arms.
Patients received three 1000 mg doses of GAZYVA
on the first cycle and a single dose of 1000 mg once
every 28 days for 5 additional cycles in combination
with chlorambucil (6 cycles of 28 days each in total).
In the last 140 patients enrolled, the first dose of
GAZYVA was split between day 1 (100 mg) and day
2 (900 mg) [see Dosage and Administration (2.1)]. In
total, 81% of patients received all 6 cycles (of 28
days each) of GAZYVA-based therapy.
The most common adverse reactions (incidence ≥
10%) observed in patients with CLL in the GAZYVA
containing arm were infusion reactions, neutropenia,
thrombocytopenia, anemia, pyrexia, cough, nausea,
and diarrhea.
The most common Grade 3-4 adverse reactions
(incidence ≥ 10%) observed in patients with CLL
in the GAZYVA containing arm were neutropenia,
infusion reactions, and thrombocytopenia.

Table of Contents for the Digital Edition of ASH News Daily 2016 - Issue 1