CLINICAL NEWS
PERSPECTIVES
“From a practical standpoint, the major problems with ruxolitinib
monotherapy remain the lack of any effect on MF-related anemia and
the lack of any apparent effect on the disease itself, as measured by
BM fibrosis.
Perhaps most encouraging from this study was that 19 of 31 evalu-
able patients (61%) had improvement in marrow morphology, and
13 of 16 evaluable patients had a decrease in the JAK2 allele burden,
with a few having a >50 percent reduction. This suggests that this
combination might be affecting the disease pathogenesis – at least in
RITUXAN HYCELA ®
(rituximab and hyaluronidase human)
injection, for subcutaneous use
Initial U.S. Approval: 2017
This is a brief summary of information about
RITUXAN HYCELA. Before prescribing, please
see the full Prescribing Information.
WARNING: SEVERE MUCOCUTANEOUS
REACTIONS, HEPATITIS B VIRUS
REACTIVATION and PROGRESSIVE
MULTIFOCAL LEUKOENCEPHALOPATHY
Severe Mucocutaneous Reactions
Severe, including fatal, mucocutaneous
reactions can occur in patients receiving
rituximab-containing products, including
RITUXAN HYCELA [see Warnings and
Precautions (5.1)].
Hepatitis B Virus (HBV) Reactivation
HBV reactivation can occur in patients
treated with rituximab-containing products,
including RITUXAN HYCELA, in some
cases resulting in fulminant hepatitis,
hepatic failure, and death. Screen all
patients for HBV infection before treatment
initiation, and monitor patients during and
after treatment with RITUXAN HYCELA.
Discontinue RITUXAN HYCELA and
concomitant medications in the event
of HBV reactivation [see Warnings and
Precautions (5.2)].
Progressive Multifocal Leukoencephalopathy
(PML), including fatal PML, can occur in
patients receiving rituximab-containing
products, including RITUXAN HYCELA
[see Warnings and Precautions (5.3) and
Adverse Reactions (6.1)].
1 INDICATIONS AND USAGE
1.1 Follicular Lymphoma (FL)
RITUXAN HYCELA is indicated for the treatment
of adult patients with:
• Relapsed or refractory, follicular lymphoma as
a single agent.
• Previously untreated follicular lymphoma in
combination with first line chemotherapy and, in
patients achieving a complete or partial response
to rituximab in combination with chemotherapy,
as single-agent maintenance therapy.
• Non-progressing (including stable disease),
follicular lymphoma as a single agent after first-line
cyclophosphamide, vincristine, and prednisone
(CVP) chemotherapy.
some patients.
One limitation of the study is the platelet range at study entry: The
range was 125 to 1,070×10 9 /L, but a large proportion of patients with
MF have platelet counts lower than this range. Thus, these patients
might not be good candidates for this type of combination therapy.”
including rituximab-containing products. HBV
reactivation is defined as an abrupt increase in HBV
replication manifesting as a rapid increase in serum
HBV DNA levels 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. In severe cases increase in bilirubin levels,
liver failure, and death can occur.
Screen all patients for HBV infection by measuring
HBsAg and anti-HBc before initiating treatment
with a rituximab-containing product. For patients
who show evidence of prior hepatitis B infection
(HBsAg positive [regardless of antibody status] or
HBsAg negative but anti-HBc positive), consult with
physicians with expertise in managing hepatitis B
regarding monitoring and consideration for HBV
antiviral therapy before and/or during treatment with
a rituximab-containing product. 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
RITUXAN HYCELA. HBV reactivation has been
reported up to 24 months following completion of
therapy containing rituximab.
In patients who develop reactivation of HBV while
on RITUXAN HYCELA, immediately discontinue
treatment and any concomitant chemotherapy, and
institute appropriate treatment. Insufficient data
exist regarding the safety of resuming RITUXAN
HYCELA treatment in patients who develop HBV
reactivation. Resumption of RITUXAN HYCELA
treatment in patients whose HBV reactivation
resolves should be discussed with physicians
with expertise in managing HBV.
5.3 Progressive Multifocal
Leukoencephalopathy (PML)
JC virus infection resulting in PML and death
has been observed in patients receiving rituximab-
containing products, including RITUXAN HYCELA.
Consider the diagnosis of PML in any patient
presenting with new-onset neurologic manifestations.
Evaluation of PML includes, but is not limited to,
consultation with a neurologist, brain MRI, and
lumbar puncture.
Discontinue RITUXAN HYCELA and consider
discontinuation or reduction of any concomitant
chemotherapy or immunosuppressive therapy
in patients who develop PML [see Adverse
Reactions (6.1)].
5.4 Hypersensitivity and
other Administration Reactions
Systemic Reactions
Patients must receive at least one full dose of a
rituximab product by intravenous infusion before
receiving RITUXAN HYCELA due to the higher risk
of
hypersensitivity and other acute reactions during
1.2 Diffuse Large B-Cell Lymphoma (DLBCL)
the first infusion [see Dosage and Administration
RITUXAN HYCELA is indicated for the treatment
(2.1)].
Beginning therapy with a rituximab product
of adult patients with previously untreated
by intravenous infusion allows management of
diffuse large B-cell lymphoma in combination
hypersensitivity and other administration reactions
with cyclophosphamide, doxorubicin, vincristine,
by slowing or stopping the intravenous infusion.
prednisone (CHOP) or other anthracycline-based
Rituximab-containing products, including
chemotherapy regimens.
RITUXAN HYCELA, are associated with
1.3 Chronic Lymphocytic Leukemia (CLL)
hypersensitivity and other administration reactions,
RITUXAN HYCELA is indicated, in combination
which may be related to release of cytokines and/or
with fludarabine and cyclophosphamide (FC), for
other chemical mediators. Cytokine release
the treatment of adult patients with previously
syndrome may be clinically indistinguishable
untreated and previously treated CLL.
from acute hypersensitivity reactions.
This set of reactions which includes syndrome
1.4 Limitations of Use
of cytokine release, tumor lysis syndrome and
• Initiate treatment with RITUXAN HYCELA only
anaphylactic and hypersensitivity reactions are
after patients have received at least one full dose
described below. They are not specifically related
of a rituximab product by intravenous infusion
to
the route of administration of a rituximab-
[see Dosage and Administration (2.1) and
containing product.
Warnings and Precautions (5.4)].
Severe infusion-related reactions with fatal
• RITUXAN HYCELA is not indicated for the
outcome have been reported with the use of
treatment of non-malignant conditions.
intravenous formulations of rituximab products,
4 CONTRAINDICATIONS
with an onset ranging within 30 minutes to 2 hours
None
after starting the first intravenous infusion. They
were characterized by pulmonary events in addition
5 WARNINGS AND PRECAUTIONS
to fever, chills, rigors, hypotension, urticaria,
angioedema and other symptoms.
5.1 Severe Mucocutaneous Reactions
Mucocutaneous reactions, some with fatal outcome, Anaphylactic and other hypersensitivity reactions
can occur in patients treated with rituximab-
can also occur. In contrast to cytokine release
containing products, including RITUXAN HYCELA.
syndrome, true hypersensitivity reactions typically
These reactions include paraneoplastic pemphigus,
occur within minutes after starting infusion.
Stevens-Johnson syndrome, lichenoid dermatitis,
Severe cytokine release syndrome is characterized
vesiculobullous dermatitis, and toxic epidermal
by severe dyspnea, often associated by
necrolysis. Discontinue RITUXAN HYCELA in
bronchospasm and hypoxia, in addition to fever,
patients who experience a severe mucocutaneous
chills, rigors, urticaria, and angioedema. This
reaction. The safety of re-administration of a
syndrome may be associated with acute respiratory
rituximab-containing product, including RITUXAN
failure and death [see Warnings and Precautions
HYCELA, to patients with severe mucocutaneous
(5.5)]. Cytokine release syndrome may occur within
reactions has not been determined.
1–2 hours of initiating the infusion. Patients with
a history of pulmonary insufficiency or those with
5.2 Hepatitis B Virus Reactivation
pulmonary tumor infiltration may be at a greater risk
Hepatitis B virus (HBV) reactivation, in some cases
of poor outcome. Rituximab product administration
resulting in fulminant hepatitis, hepatic failure and
should be interrupted immediately and aggressive
death, can occur in patients treated with drugs
symptomatic treatment initiated.
classified as CD20-directed cytolytic antibodies,
Peter Emanuel, MD
CHI St. Vincent
Little Rock, AR
During RITUXAN HYCELA administration, the
injection should be interrupted immediately when
observing signs of a severe reaction and aggressive
symptomatic treatment should be initiated.
Closely monitor the following patients: those with
pre-existing cardiac or pulmonary conditions, those
who experienced prior cardiopulmonary adverse
reactions, and those with high numbers
of circulating malignant cells (≥ 25,000/mm 3 )
[see Warnings and Precautions (5.5, 5.7)].
Premedicate patients with an antihistamine and
acetaminophen prior to each administration of
RITUXAN HYCELA [see Dosage and Administration
(2.5)]. Premedication with glucocorticoids should
also be considered. Observe patients for at least
15 minutes following RITUXAN HYCELA. A longer
period may be appropriate in patients with an
increased risk of hypersensitivity reactions.
Local Cutaneous Reactions
Local cutaneous reactions, including injection
site reactions, have been reported in patients
receiving RITUXAN HYCELA. Symptoms included
pain, swelling, induration, hemorrhage, erythema,
pruritus, and rash [see Adverse Reactions (6.1)].
Some local cutaneous reactions occurred more than
24 hours after RITUXAN HYCELA administration.
The incidence of local cutaneous reactions following
administration of RITUXAN HYCELA was 16%.
Reactions were mild or moderate and resolved
without any specific treatment. Local cutaneous
reactions of any Grade were most common during
the first RITUXAN HYCELA cycle (Cycle 2; 5%) with
the incidence decreasing with subsequent injections.
5.5 Tumor Lysis Syndrome (TLS)
TLS can occur within 12–24 hours after
administration of a rituximab-containing product,
including RITUXAN HYCELA. A high number of
circulating malignant cells (≥ 25,000/mm 3 ) or
high tumor burden confers a greater risk of TLS.
Administer aggressive intravenous hydration and
anti-hyperuricemic therapy in patients at high risk
for TLS. Correct electrolyte abnormalities, monitor
renal function and fluid balance, and administer
supportive care, including dialysis as indicated
[see Warnings and Precautions (5.8)].
5.6 Infections
Serious, including fatal, bacterial, fungal, and
new or reactivated viral infections can occur
during and following the completion of therapy
with rituximab-containing products, including
RITUXAN HYCELA. The incidence of infections
with RITUXAN HYCELA vs rituximab was 56%
and 49% respectively in patients with CLL, and
46% and 41% respectively in patients with
FL/DLBCL in combination with chemotherapy.
Infections have been reported in some patients
with prolonged hypogammaglobulinemia (defined
as hypogammaglobulinemia > 11 months after
rituximab exposure). New or reactivated viral
infections included cytomegalovirus, herpes
simplex virus, parvovirus B19, varicella zoster
virus, West Nile virus, and hepatitis B and
C. Discontinue RITUXAN HYCELA for serious
infections and institute appropriate anti-infective
therapy [see Adverse Reactions (6.1)].
5.7 Cardiovascular Adverse Reactions
Cardiac adverse reactions, including ventricular
fibrillation, myocardial infarction, and cardiogenic
shock may occur with rituximab-containing
products, including RITUXAN HYCELA.
Discontinue RITUXAN HYCELA for serious or life
threatening cardiac arrhythmias. Perform cardiac
monitoring during and after all administrations
of RITUXAN HYCELA for patients who develop
clinically significant arrhythmias, or who have
a history of arrhythmia or angina [see Adverse
Reactions (6.1)].
5.8 Renal Toxicity
Severe, including fatal, renal toxicity can occur after
administration of rituximab-containing products,
including RITUXAN HYCELA. Renal toxicity has
occurred in patients who experience tumor lysis
syndrome and in patients with administered
concomitant cisplatin therapy during clinical trials. The
combination of cisplatin and RITUXAN HYCELA is
not an approved treatment regimen. Monitor closely
for signs of renal failure and discontinue RITUXAN
HYCELA in patients with a rising serum creatinine
or oliguria [see Warnings and Precautions (5.5)].
5.9 Bowel Obstruction and Perforation
Abdominal pain, bowel obstruction and perforation,
in some cases leading to death, can occur in
patients receiving rituximab-containing products,
including RITUXAN HYCELA, in combination with
chemotherapy. In postmarketing reports, the mean
time to documented gastrointestinal perforation
was 6 (range 1–77) days. Evaluate if symptoms of
obstruction such as abdominal pain or repeated
vomiting occur.