| GAZYVA (obinutuzumab), 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 (FL). |
| This indication is based on the
results of the Phase III, randomized GALLIUM trial, which studied GAZYVA
and rituximab head-to-head in over 1,200 patients when each was
combined with chemotherapy and followed by GAZYVA or rituximab
monotherapy, respectively. |
| GALLIUM Trial: Efficacy |
| GALLIUM
demonstrated that GAZYVA is the first and only approved therapy in
previously untreated stage II bulky, III, or IV FL to deliver superior
PFS vs rituximab when each was combined with chemotherapy* and followed
by GAZYVA or rituximab monotherapy. The IRC assessment showed the GAZYVA
regimen reduced risk of disease progression or death by 28% vs the
rituximab regimen (HR=0.72; 95% CI, 0.56-0.93; P=0.0118; 38-month median observation time). Median PFS has not been reached in either arm of the trial. |
 |
| GALLIUM Trial Design and Patient Population |
| Patients
were randomized to receive GAZYVA (n=601) or rituximab (n=601) in
combination with chemotherapy (CHOP, CVP, or bendamustine) for 6 or 8
cycles. Patients who achieved complete or partial response to the
initial 6 or 8 cycles continued to receive GAZYVA or rituximab
monotherapy, respectively, every 2 months until disease progression or
for a maximum of 2 years. |
| The
trial population (n=1,202) was inclusive of a broad range of previously
untreated FL patient types, enrolling patients with disease Grades
1-3a, and stage II/III/IV, with 44% having bulky disease (≥7 cm)
overall. Each investigator site chose to combine GAZYVA or rituximab
with bendamustine (57%), CHOP (33%), or CVP (10%). All patients received the chosen chemotherapy at that site for the duration of the induction. |
| The treatment arms were generally balanced with respect to demographic factors and baseline disease characteristics.2 |
| GALLIUM Trial: Safety Information |
| Common adverse reactions (≥10% incidence and ≥2% greater in the GAZYVA arm), in patients with previously untreated NHL1 |
 |
| A
randomized, open-label multicenter trial (GALLIUM) evaluated the safety
of GAZYVA as compared to rituximab product in 1,385 patients with
previously untreated follicular lymphoma (86%) or marginal zone lymphoma
(14%). |
| Common
new or worsening laboratory abnormalities (≥10% incidence and ≥2%
greater in the GAZYVA arm) in patients with previously untreated NHL1,a |
 |
| GAZYVA monotherapy investigator-reported adverse reactions1 |
| • |
The
common adverse reactions (incidence ≥10%) observed at least 2% more with
GAZYVA were upper respiratory tract infection (40%), cough (23%),
musculoskeletal pain (20%), neutropenia (19%) and herpes virus infection
(13%) |
|
| GAZYVA monotherapy hematological laboratory abnormalities1 |
| • |
New-onset
Grade 3 or 4 neutropenia was reported in 21% of patients in the GAZYVA
arm (Grade 4, 10%) and 17% of patients in the rituximab product arm
(Grade 4, 9%) |
|
| Adverse events leading to treatment withdrawal1 |
| • |
18% in the GAZYVA arm vs 15% in the rituximab arm |
|
| Select Trial Safety Information |
| • |
Infusion Reactions: Overall 72% of patients in the GAZYVA treated arm experienced an
infusion reaction (all grades). The incidence of Grade 3 to 4 infusion
reactions for these patients was 12%. In Cycle 1, the incidence of
infusion reactions (all grades) was 62% in the GAZYVA treated arm with
Grade 3 to 4 infusion reactions reported in 10%. The incidence of
infusion reactions (all grades) was highest on Day 1 (60%) and decreased
on Days 8 and 15 (9% and 6% respectively). During Cycle 2, the
incidence of infusion reactions (all grades) in the GAZYVA treated arm
was 13% and decreased with subsequent cycles. During GAZYVA monotherapy
treatment, infusion reactions (all grades) were observed in 9% of
patients. Overall, 1% of patients experienced an infusion reaction
leading to discontinuation of GAZYVA |
| • |
Neutropenia: The incidence of neutropenia was higher in the GAZYVA treated arm (53%)
compared to the rituximab product treated arm (47%). Cases of prolonged
neutropenia (1%) and late onset neutropenia (4%) were also reported in
the GAZYVA treated arm. The incidence of neutropenia was higher during
treatment with GAZYVA in combination with chemotherapy (45%) compared to
the GAZYVA monotherapy treatment phase (20%) |
| • |
Infection: The incidence of infection was 82% in the GAZYVA treated arm and 73% in
the rituximab product treated arm, with Grade 3 to 4 events reported in
21% and 17%, respectively. In the GAZYVA arm, fatal infections occurred
in 2% of patients compared to <1% in the rituximab product arm. The
incidence of Grade 3 to 4 infections in the GAZYVA and rituximab product
treated arms was lower in patients receiving GCSF prophylaxis (14%;
16%) compared with patients not receiving GCSF prophylaxis (24%; 18%).
The incidence of fatal infections in patients receiving GCSF prophylaxis
in the GAZYVA and rituximab product treated arms was 2% and 0%,
respectively, and was 2% and <1% in patients not receiving GCSF
prophylaxis |
| • |
Thrombocytopenia: Thrombocytopenia was reported as an adverse reaction in 14% of the
GAZYVA treated arm and 8% of the rituximab product treated arm, with the
incidence of Grade 3 to 4 events being 7% and 3% respectively. The
difference in incidences between the treatment arms is driven by events
occurring during the first cycle. The incidence of thrombocytopenia (all
grades) in the first cycle were 9% in the GAZYVA and 3% in the
rituximab product treated arms, with Grade 3 to 4 rates being 5% and 1%,
respectively. Both treatment arms had a 12% overall incidence of
hemorrhagic events and a <1% incidence of fatal hemorrhagic events |
| • |
Tumor Lysis Syndrome (TLS): The incidence of Grade 3 or 4 TLS was 0.9% in the GAZYVA treated arm |
| • |
Musculoskeletal Disorders: Musculoskeletal disorders were reported in 54% of patients in the
GAZYVA treated arm and 49% of patients in the rituximab product treated
arm |
| • |
Gastrointestinal Perforation: Cases of gastrointestinal perforation have been reported in patients receiving GAZYVA, mainly in NHL |
| • |
Worsening of Pre-existing Cardiac Conditions: Fatal cardiac events have been reported in patients treated with GAZYVA |
|
| For more information on the
efficacy and safety of GAZYVA in previously untreated FL, visit our
website. |
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|
| Important Safety Information |
| BOXED WARNINGS: 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 |
| • |
Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA |
|
| 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 |
|
| Warnings and Precautions |
| Hepatitis B Virus (HBV) 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 including GAZYVA. HBV reactivation has been
reported in patients who are hepatitis B surface antigen (HBsAg)
positive and 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 (ie, 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, ie, 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 |
| • |
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 (PML) |
| • |
JC
virus infection resulting in 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 percent
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, and laryngeal edema). Most frequently reported symptoms
include nausea, fatigue, chest discomfort, dyspnea, dizziness, vomiting,
diarrhea, rash, hypertension, hypotension, flushing, headache, pyrexia,
and chills |
| • |
Premedicate
patients with acetaminophen, an antihistamine, and a glucocorticoid.
Institute medical management for infusion reactions as needed. Closely
monitor patients during the entire infusion. Infusion reactions within
24 hours of receiving GAZYVA have occurred |
| • |
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 |
| • |
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 and 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 |
|
| 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 occur 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 |
|
| Tumor Lysis Syndrome (TLS) |
| • |
Tumor
lysis syndrome, 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 antihyperuricemics (eg,
allopurinol or rasburicase) and hydration prior to the infusion of
GAZYVA. 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 |
|
| 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 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. 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 |
|
| 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 |
|
| 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 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 or anticoagulants), especially during the first
cycle |
|
| 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 |
|
| Pregnancy |
| • |
There
are no data with GAZYVA use in pregnant women to inform a
drug-associated risk. GAZYVA is likely to cause fetal B-cell depletion.
GAZYVA should be used during pregnancy and/or breastfeeding only if the
potential benefit justifies the potential risk to the fetus and/or
infant. Mothers who have been exposed to GAZYVA during pregnancy should
discuss the safety and timing of live virus vaccinations for their
infants with their child’s healthcare providers |
|
| Geriatric Use |
| • |
Of
the 691 patients in GALLIUM treated with GAZYVA plus chemotherapy as
first-line therapy, 33% were 65 and over, while 7% were 75 and over. Of
patients 65 and over, 63% experienced serious adverse reactions and 26%
experienced adverse reactions leading to treatment withdrawal, while in
patients under 65, 43% experienced serious adverse reactions and 13% had
an adverse reaction leading to treatment withdrawal. No clinically
meaningful differences in efficacy were observed between these patients
and younger patients |
|
| Additional Important Safety Information |
| • |
A
randomized, open-label multicenter trial (GALLIUM) evaluated the safety
of GAZYVA as compared to rituximab product in 1,385 patients with
previously untreated follicular lymphoma (86%) or marginal zone lymphoma
(14%) |
| • |
Serious
adverse reactions occurred in 50% of patients on the GAZYVA arm and 43%
of patients on the rituximab product arm. Fatal adverse reactions were
reported during treatment in 3% in the GAZYVA arm and 2% in the
rituximab product arm, most often from infections in the GAZYVA arm.
During treatment and follow-up combined, fatal adverse reactions were
reported in 5% of the GAZYVA arm and 4% of the rituximab product arm,
with infections and second malignancies being leading causes. In the
GAZYVA arm, fatal infections occurred in 2% of patients compared to
<1% in the rituximab product arm |
| • |
Neutropenia,
infusion related reactions, febrile neutropenia and thrombocytopenia
were the most common Grade 3 to 5 adverse reactions (incidence ≥5%)
observed more frequently in the GAZYVA arm |
|
|
|
|
|
| • |
Throughout
treatment and follow-up, the most common adverse reactions (incidence
≥20%) observed at least 2% more in the GAZYVA arm were infusion related
reactions, neutropenia, upper respiratory tract infection, cough,
constipation and diarrhea |
| • |
During the monotherapy
period, the common adverse reactions (incidence ≥10%) observed at least
2% more with GAZYVA were upper respiratory infection (40%), cough (23%),
musculoskeletal pain (20%), neutropenia (19%) and herpesvirus infection
(13%) |
|
| You are encouraged to report side
effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/medwatch, or calling 1-800-FDA-1088. |
| Please see the full Prescribing Information for additional Important Safety Information, including BOXED WARNINGS. |
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