ASH Clinical News Focus on Myeloid Malignancies | Page 7

BENDEKA ® (bendamustine hydrochloride) injection BENDEKA ® (bendamustine hydrochloride) injection
5.4
Tumor Lysis Syndrome
Tumor lysis syndrome associated with bendamustine hydrochloride has
occurred in patients in clinical trials and in postmarketing reports. The onset
tends to be within the first treatment cycle of bendamustine hydrochloride
and, without intervention, may lead to acute renal failure and death. Pre-
ventive measures include vigorous hydration and close monitoring of blood
chemistry, particularly potassium and uric acid levels. Allopurinol has also
been used during the beginning of bendamustine hydrochloride therapy.
However, there may be an increased risk of severe skin toxicity when ben-
damustine hydrochloride and allopurinol are administered concomitantly.
5.5
Skin Reactions
Fatal and serious skin reactions have been reported with bendamustine
hydrochloride injection treatment in clinical trials and postmarketing safety
reports, including toxic skin reactions [Stevens-Johnson Syndrome (SJS),
toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia
and systemic symptoms (DRESS)], bullous exanthema, and rash. Events
occurred when bendamustine hydrochloride injection was given as a single
agent and in combination with other anticancer agents or allopurinol.
Where skin reactions occur, they may be progressive and increase in sever-
ity with further treatment. Monitor patients with skin reactions closely. If
skin reactions are severe or progressive, withhold or discontinue BENDEKA
(bendamustine hydrochloride) injection.
5.6
Hepatotoxicity
Fatal and serious cases of liver injury have been reported with bendamus-
tine hydrochloride injection. Combination therapy, progressive disease or
reactivation of hepatitis B were confounding factors in some patients [see
Warnings and Precautions (5.2)]. Most cases were reported within the first
three months of starting therapy. Monitor liver chemistry tests prior to and
during bendamustine therapy.
5.7
Other Malignancies
There are r eports of pre-malignant and malignant diseases that have devel-
oped in patients who have been treated with bendamustine hydrochloride,
including myelodysplastic syndrome, myeloproliferative disorders, acute
myeloid leukemia and bronchial carcinoma. The association with BENDEKA
(bendamustine hydrochloride) injection therapy has not been determined.
5.8
Extravasation Injury
Bendamustine hydrochloride extravasations have been reported in post-
marketing resulting in hospitalizations from erythema, marked swelling,
and pain. Assure good venous access prior to starting drug infusion and
monitor the intravenous infusion site for redness, swelling, pain, infection,
and necrosis during and after administration of BENDEKA (bendamustine
hydrochloride) injection.
5.9
Embryo-fetal Toxicity
Bendamustine hydrochloride can cause fetal harm when administered to a
pregnant woman. Single intraperitoneal doses of bendamustine in mice and
rats administered during organogenesis caused an increase in resorptions,
skeletal and visceral malformations, and decreased fetal body weights.
6.1
Adverse Events in Clinical Trials
The data described below reflect exposure to bendamustine hydrochloride
in 329 patients who participated in an actively controlled trial (N=153) for
the treatment of CLL and two single arm studies (N=176) for the treatment
of indolent B cell NHL. 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.
The safety of BENDEKA (bendamustine hydrochloride) injection administered
IV as a 50 mL admixture over a 10-minute infusion is supported by clinical
trials using bendamustine hydrochloride administered IV as a 500 mL admix-
ture over 30-60 minutes infusion time, as well as an open-label, crossover
study in 81 ‘end-of-life’ cancer patients treated with BENDEKA. In total, safety
data from clinical studies are available from over 400 cancer patients exposed
to bendamustine hydrochloride at doses in the range used in the treatment of
CLL and NHL.
No clinically significant differences in the adverse event profile were noted
among bendamustine hydrochloride administered as a 500 mL admixture
over standard infusion time (30-60 minutes) and BENDEKA administered as
a 50 mL admixture in a ‘short-time’ infusion over 10 minutes.
The safety and tolerability of BENDEKA was evaluated in an 8-week clinical
study of BENDEKA in 81 ‘end-of-life’ cancer patients, diagnosed with solid
tumors and hematologic malignancies (excluding CLL). The population was
40-82 years of age, 58% females, 84% white, 12.3% Black, 1.2% Asian
and 2.5% were classified as ‘other’. BENDEKA was administered IV at a
120 mg/m 2 dose as a 50 mL admixture over 10 minutes. Patients in the
study received BENDEKA (50 mL IV, over 10 minutes) or bendamustine
hydrochloride (500 mL IV, over 60 minutes) on Days 1 and 2 every 28 days
for two consecutive 2-day cycles. Adverse reactions (any grade) that occurred with a frequency greater than
5% during BENDEKA infusion and within one hour post-infusion were nausea
(8.2%) and fatigue (5.5%).
Adverse reactions (any grade) that occurred with a frequency greater than
5% within 24 hours of BENDEKA were nausea (10.9%) and fatigue (8.2%).
Adverse reactions leading to study withdrawal in 4 patients receiving
BENDEKA were pyrexia (1.2%), nausea (1.2%), vomiting (1.2%), pneumonia
(1.2%) and fatigue (1.2%).
6.2
Clinical Trials Experience in CLL
The data described below reflect exposure to bendamustine hydrochloride in
153 patients. Bendamustine hydrochloride was studied in an active-controlled
randomized trial. The population was 45-77 years of age, 63% male, 100%
white, and had treatment naïve CLL. All patients started the study at a dose
of 100 mg/m 2 intravenously over 30 minutes on Days 1 and 2 every 28 days.
Adverse reactions were reported according to NCI CTC v.2.0. In the ran-
domized CLL clinical study, non-hematologic adverse reactions (any grade)
in the bendamustine hydrochloride group that occurred with a frequency
greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%).
Other adverse reactions seen frequently in one or more studies included
asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough;
constipation; headache; mucosal inflammation and stomatitis.
Worsening hypertension was reported in 4 patients treated with bendamus-
tine hydrochloride in the randomized CLL clinical study and in none treated
with chlorambucil. Three of these 4 adverse reactions were described as a
hypertensive crisis and were managed with oral medications and resolved.
The most frequent adverse reactions leading to study withdrawal for
patients receiving bendamustine hydrochloride were hypersensitivity (2%)
and pyrexia (1%).
Table 1 contains the treatment emergent adverse reactions, regardless of
attribution, that were reported in ≥ 5% of patients in either treatment group
in the randomized CLL clinical study.
Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized
CLL Clinical Study in at Least 5% of Patients
Number (%) of patients
Bendamustine
Hydrochloride
Chlorambucil
(N=153)
(N=143)
System organ class
Preferred term
All Grades Grade 3/4 All Grades Grade 3/4
Total number of
patients with at least 1
adverse reaction
121 (79)
52 (34)
96 (67)
25 (17)
Gastrointestinal
disorders
Nausea
31 (20)
1 (<1)
21 (15)
1 (<1)
Vomiting
24 (16)
1 (<1)
9 (6)
0
Diarrhea
14 (9)
2 (1)
5 (3)
0
General disorders and
administration site
conditions
Pyrexia
36 (24)
6 (4)
8 (6)
2 (1)
Fatigue
14 (9)
2 (1)
8 (6)
0
Asthenia
13 (8)
0
6 (4)
0
Chills
9 (6)
0
1 (<1)
0
Immune system
disorders
Hypersensitivity
7 (5)
2 (1)
3 (2)
0
Infections and
infestations
Nasopharyngitis
10 (7)
0
12 (8)
0
Infection
9 (6)
3 (2)
1 (<1)
1 (<1)
Herpes simplex
5 (3)
0
7 (5)
0
Investigations
Weight decreased
11 (7)
0
5 (3)
0
Metabolism and
nutrition disorders
Hyperuricemia
11 (7)
3 (2)
2 (1)
0
continued