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5.10 Immunization
The safety of immunization with live viral vaccines
following rituximab-containing products, including
RITUXAN HYCELA, therapy has not been studied
and vaccination with live virus vaccines is not
recommended before or during treatment.
5.11 Embryo-Fetal Toxicity
Based on human data, rituximab-containing
products can cause fetal harm due to B-cell
lymphocytopenia in infants exposed to rituximab
in-utero. Advise pregnant women of the risk to
a fetus. Females of childbearing potential should
use effective contraception while receiving
RITUXAN HYCELA and for 12 months following
the last dose of rituximab-containing products,
including RITUXAN HYCELA.
6 ADVERSE REACTIONS
The following serious adverse reactions are
discussed in greater detail in other sections
of the labeling:
• Mucocutaneous reactions [see Warnings and
Precautions (5.1)]
• Hepatitis B reactivation including fulminant
hepatitis [see Warnings and Precautions (5.2)]
• Progressive multifocal leukoencephalopathy
[see Warnin gs and Precautions (5.3)]
• Hypersensitivity and other administration reactions
[see Warnings and Precautions (5.4)]
• Tumor lysis syndrome [see Warnings and
Precautions (5.5)]
• Infections [see Warnings and Precautions (5.6)]
• Cardiac arrhythmias [see Warnings and
Precautions (5.7)]
• Renal toxicity [see Warnings and Precautions (5.8)]
• Bowel obstruction and perforation [see Warnings
and Precautions (5.9)]
6.1 Clinical Trials 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
clinical practice.
The data described below reflect exposure to
RITUXAN HYCELA in 892 patients in four controlled
trials with exposures ranging from a single injection
up to 27 months of treatment.
The population included 382 patients with follicular
lymphoma (FL), 369 patients with diffuse large B-cell
lymphoma (DLBCL), and 141 patients with chronic
lymphocytic leukemia (CLL). The population was
aged 18–85 years (with a median age of 60 years),
53% male and 47% female. Most of the patients
were Caucasians (84%). In the SABRINA study
patients with FL received a full dose of a rituximab
product by intravenous infusion, followed by
RITUXAN HYCELA (1,400 mg rituximab/23,400 Units
hyaluronidase human), in combination with
chemotherapy for up to 7 doses (i.e., total of
8 doses in combination with chemotherapy), or
as monotherapy for up to 12 doses (maintenance
treatment). In the MabEase study patients with
DLBCL received a full dose of a rituximab product
by intravenous infusion, followed by RITUXAN
HYCELA (1,400 mg rituximab/23,400 Units
hyaluronidase human), given in combination with
chemotherapy for up to 7 doses (i.e., up to a total
of 8 doses). In the SAWYER study patients with
CLL on part 2 received a full dose of a rituximab
product by intravenous infusion, followed by
RITUXAN HYCELA (1,600 mg rituximab/26,800
Units hyaluronidase human) for up to 5 doses,
in combination with fludarabine and
cyclophosphamide (i.e., total of 6 doses).
The most common adverse reactions (≥ 20%) of
RITUXAN HYCELA observed in patients with FL on
the SABRINA study were: infections, neutropenia,
nausea, constipation, cough, and fatigue.
The most common adverse reactions (≥ 20%)
of RITUXAN HYCELA observed in patients with
DLBCL on the MabEase study were: infections,
neutropenia, alopecia, nausea, and anemia.
The most common adverse reactions (≥ 20%) of
RITUXAN HYCELA observed in patients with CLL
on part 2 of the SAWYER study were: infections,
neutropenia, nausea, thrombocytopenia, pyrexia,
vomiting, and injection site erythema.
Administration-related reactions (ARRs)
Administration-related reactions (ARRs) with
RITUXAN HYCELA were defined as all the adverse
reactions related to the administration of RITUXAN
HYCELA within the 24 hours post injection.
The incidence of ARRs with RITUXAN HYCELA
was 34% in FL/DLBCL in combination with
chemotherapy with injection site erythema (5%),
chills (3%), dyspnea, erythema, flushing, injection
site pain, nausea, pruritus, pyrexia, rash, and throat
irritation (2% each) being the most common ARRs.
The incidence of ARRs in FL maintenance setting
was 20%. The most common ARRs were injection
site erythema (7%), erythema (4%), injection site
pain/edema, myalgia, and rash (2% each).
The incidence of ARRs with RITUXAN HYCELA in
CLL was 44%.
With the exception of Local Cutaneous Reactions,
the incidence and profile of adverse reactions
reported for RITUXAN HYCELA were comparable
with those for rituximab. The overall incidence
of adverse reactions for intravenous rituximab
versus RITUXAN HYCELA in combination with
chemotherapy for FL/DLBCL was 93% versus
95% (BSA ≤ 1.73 m 2 ), 89% versus 93%
(1.73 < BSA ≤ 1.92 m 2 ), and 94% versus 94%
(BSA > 1.92 m 2 ). The overall incidence of adverse
reactions for rituximab versus RITUXAN HYCELA in
CLL was 89% versus 100% (BSA ≤ 1.81 m 2 ), 97%
versus 88% (1.82 < BSA ≤ 1.99 m 2 ), and
88% versus 93% (BSA > 2.00 m 2 ).
Summary of Clinical Trial Experience
in Follicular Lymphoma (FL)
The data in Table 1 were obtained in the SABRINA
study, a two-stage randomized, controlled study
in patients with previously untreated FL. The study
compared patients receiving RITUXAN HYCELA
(1,400 mg rituximab/23,400 Units hyaluronidase
human; n=197) with patients receiving a rituximab
product by intravenous infusion (375 mg/m 2 ; n=210),
both in combination with CHOP or CVP followed by
maintenance treatment with RITUXAN HYCELA
or a rituximab product by intravenous infusion.
The majority of patients completed all 8 cycles of
combination treatment with chemotherapy (91%
RITUXAN HYCELA vs. 90% rituximab). In addition,
69% of patients in each of the treatment groups
completed all 20 cycles of combination plus
maintenance treatment. In both RITUXAN HYCELA
and rituximab groups, patients experienced similar
median duration of exposure (27.1 months for
each arm).
Across the two stages, the overall demographics
and baseline characteristics were balanced
between the treatment groups. However, there
were more female patients (53%) randomized in
the study than male patients (47%) and a higher
proportion of females were randomized to receive
RITUXAN HYCELA (59% female) compared with the
rituximab group (48%). The treatment groups in the
combined Stage 1 and 2 population were otherwise
balanced in regard to baseline demographics,
characterized by a median age of 57 years (56.0
years [range 28–85 years] for RITUXAN HYCELA and
57 years [range 28–86 years] for rituximab) and
median BSA of 1.83 m 2 (1.80 and 1.84 m 2 for
RITUXAN HYCELA and rituximab, respectively).
The incidence of all adverse reactions was 96% for
RITUXAN HYCELA vs. 95% for rituximab (Table 1).
Grade 3–4 adverse reactions were reported in 55%
of patients receiving RITUXAN HYCELA vs. 53%
in patients receiving rituximab. Serious adverse
reactions were reported in 37% of patients receiving
RITUXAN HYCELA vs. 34% of patients receiving
rituximab. The most common adverse reactions
(occurring in ≥ 20% of patients in any arm) were
infections, neutropenia, nausea, constipation,
cough, and fatigue.
A total of 36 patients died, including 14/197 patients
(7%) who received RITUXAN HYCELA and 22/210
patients (10%) who received rituximab. Of these 36
patients, 19 patients (7 patients RITUXAN HYCELA
[4%] vs. 12 patients rituximab [6%]) died due to
adverse reactions and 13 patients (6 patients
RITUXAN HYCELA [3%] vs. 7 patients rituximab
[3%]) died due to disease progression.
The incidence of administration-related reactions
(ARRs) due to the subcutaneous route of
administration associated with RITUXAN HYCELA
was assessed in combination with chemotherapy
and during maintenance. Thirty patients (15%)
experienced an ARR during the first administration
of RITUXAN HYCELA (Cycle 2). Incidence of ARRs
generally decreased at subsequent cycles with 18
patients (9%) reporting ARR at Cycle 3, 13 patients
(7%) at Cycle 4, 11 patients (6%) at Cycles 5 and
6, 12 patients (7%) at Cycle 7, and 8 patients (4%)
at Cycle 8. During RITUXAN HYCELA monotherapy
in the maintenance setting the incidence of ARRs
at each cycle was ≤ 7% and was observed in 24
patients (14%) overall. Grade 1–2 ARRs constituted
96% of the overall ARRs. Grade 3 ARRs were
reported during the first administration of RITUXAN
HYCELA at Cycle 2 by 2 patients. Of the reported
ARRs, local cutaneous reactions with RITUXAN
HYCELA were reported in 32 patients. These events
resolved within a median of 2 days from the onset
(range 1 to 37 days). Majority of these reactions
were Grade 1 and 2 and were observed in 31
patients (16%).
Table 1: Incidence of Adverse Reactions in
≥ 5% of Patients with Previously Untreated
Follicular Lymphoma Receiving RITUXAN
HYCELA or Rituximab in Combination with
CHOP or CVP and as Monotherapy for
Maintenance Treatment
Body System/
Adverse
Reactions
RITUXAN HYCELA
(n=197)
All AEs
%
Rituximab
(n=210)
Grade 3–4 All AEs
%
%
Gastrointestinal Disorders
Nausea
31
0
Constipation
25
0
Diarrhea
18
2
Abdominal Pain
14
0
Vomiting
14
0
Dyspepsia
8
0
Stomatitis
6
0
Abdominal Pain
Upper
5
0
Grade 3–4
%
22
26
16
12
12
7
5 0
< 1
< 1
< 1
< 1
0
0
5 0
General Disorders and Administration
Site Conditions
Fatigue
20
0
18
Asthenia
17
1
13
Pyrexia
15
< 1
16
Injection Site
Erythema
13
0
0
Injection Site Pain 8
0
0
Chills
8
0
9
Chest Pain
6
1
3
Edema Peripheral
5
< 1
6
Mucosal
Inflammation
5
1
6
Influenza Like Illness 3
0
6
Infections
Upper Respiratory
Tract Infection
15
Pneumonia
11
Nasopharyngitis
10
Bronchitis
8
Urinary Tract
Infection
8
Sinusitis
7
Conjunctivitis
5
Influenza
4
< 1
0
< 1
0
0
0
0
0
< 1
0
< 1
5
0
< 1 10
4
10
8 0
2
0
< 1
1
< 1
0
0 14
4
5
6 < 1
0
0
< 1
Blood and Lymphatic System Disorders
Neutropenia
32
26
27
Anemia
15
5
13
Febrile Neutropenia 8
7
6
Leukopenia
6
4
11
21
0
6
2
Musculoskeletal and Connective Tissue
Disorders
Arthralgia
13
< 1
10
0
Bone Pain
10
< 1
8
0
Pain In Extremity
10
0
5
0
Back Pain
9
< 1
12
< 1
Muscle Spasms
8
0
3
0
Myalgia
8
0
5
0
Nervous System Disorders
Paresthesia
16
0
Headache
13
0
Neuropathy
Peripheral
12
2
Dizziness
7
0
12
9 0
0
14
7 < 1
0
Skin and Subcutaneous Tissue Disorders
Alopecia
14
< 1
10
< 1
Pruritus
10
0
12
< 1
Rash
10
0
7
0
Erythema
9
0
5
0
Respiratory, Thoracic and Mediastinal
Disorders
Cough
23
0
13
Dyspnea
11
1
8
Oropharyngeal Pain 9
0
8
< 1
2
0
Psychiatric Disorders
Insomnia
9 0 9 0
Vascular Disorders
Hypertension
6 1 6 0