ASH News Daily 2017 - Issue 2 - C-28

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR
BENDEKA® (bendamustine hydrochloride) injection, for intravenous use
SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Chronic Lymphocytic Leukemia (CLL)
BENDEKA® (bendamustine hydrochloride) injection is indicated for
the treatment of patients with chronic lymphocytic leukemia. Efficacy
relative to first line therapies other than chlorambucil has not been
established.
1.2
Non-Hodgkin Lymphoma (NHL)
BENDEKA (bendamustine hydrochloride) injection is indicated for the
treatment of patients with indolent B-cell non-Hodgkin lymphoma that
has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.
2
DOSAGE AND ADMINISTRATION
2.1
Dosing Instructions for CLL
Recommended Dosage:
The recommended dose is 100 mg/m2 administered intravenously over
10 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles.
Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL:
BENDEKA (bendamustine hydrochloride) injection administration
should be delayed in the event of Grade 4 hematologic toxicity or
clinically significant greater than or equal to Grade 2 non-hematologic
toxicity. Once non-hematologic toxicity has recovered to less than or
equal to Grade 1 and/or the blood counts have improved [Absolute
Neutrophil Count (ANC) greater than or equal to 1 x 109/L, platelets
greater than or equal to 75 x 109/L], BENDEKA (bendamustine hydrochloride) injection can be reinitiated at the discretion of the treating
physician. In addition, dose reduction may be warranted. [see Warnings and Precautions (5.1)]
Dose modifications for hematologic toxicity: for Grade 3 or greater
toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle;
if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on
Days 1 and 2 of each cycle.
Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days
1 and 2 of each cycle.
Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician.
2.2
Dosing Instructions for NHL
Recommended Dosage:
The recommended dose is 120 mg/m2 administered intravenously over
10 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles.
Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL:
BENDEKA (bendamustine hydrochloride) injection administration
should be delayed in the event of a Grade 4 hematologic toxicity or
clinically significant greater than or equal to Grade 2 non-hematologic
toxicity. Once non-hematologic toxicity has recovered to less than or
equal to Grade 1 and/or the blood counts have improved [Absolute
Neutrophil Count (ANC) greater than or equal to 1 x 109/L, platelets
greater than or equal to 75 x 109/L], BENDEKA (bendamustine hydrochloride) injection can be reinitiated at the discretion of the treating
physician. In addition, dose reduction may be warranted.
Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce
the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity
recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle.
Dose modifications for non-hematologic toxicity: for Grade 3 or greater
toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle;
if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on
Days 1 and 2 of each cycle.
2.3
Preparation for Intravenous Administration
BENDEKA (bendamustine hydrochloride) injection is a cytotoxic drug.
Follow applicable special handling and disposal procedures.1
BENDEKA is in a multiple-dose vial. At room temperature, BENDEKA is
a clear, and colorless to yellow ready-to-dilute solution. Store BENDEKA
at recommended refrigerated storage conditions (2-8°C or 36-46°F).
When refrigerated, the contents may partially freeze. Allow the vial to
reach room temperature (15-30°C or 59-86°F) prior to use. If particulate matter is observed after achieving room temperature, the product
should not be used.
Intravenous Infusion
* Aseptically withdraw the volume needed for the required dose from the
25 mg/mL solution as per Table A below and immediately transfer the
solution to a 50 mL infusion bag of one of the following diluents:
− 0.9% Sodium Chloride Injection, USP; or
− 2.5% Dextrose/0.45% Sodium Chloride Injection, USP; or
− 5% Dextrose Injection, USP.
The resulting final concentration of bendamustine hydrochloride in the
infusion bag should be within 1.85 mg/mL - 5.6 mg/mL. After transferring, thoroughly mix the contents of the infusion bag. The admixture
should be a clear, and colorless to yellow solution.
No other diluents have been shown to be compatible. The 5% Dextrose Injection, USP, offers a sodium-free method of administration for
patients with certain medical conditions requiring restricted sodium
intake.
2.4
Admixture Stability
BENDEKA (bendamustine hydrochloride) injection contains no antimicrobial preservative. The admixture should be prepared as close as
possible to the time of patient administration.
If diluted with 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is
stable for 24 hours when stored refrigerated (2-8°C or 36-46°F) or
for 6 hours when stored at room temperature (15-30°C or 59-86°F)
and room light. Administration of diluted BENDEKA (bendamustine
hydrochloride) injection must be completed within this period of time.
In the event that 5% Dextrose Injection, USP is utilized, the final
admixture is stable for 24 hours when stored refrigerated (2-8°C or
36-46°F) or for only 3 hours when stored at room temperature (1530°C or 59-86°F) and room light. Administration of diluted BENDEKA
must be completed within this period of time.
Retain the partially used vial in original package to protect from light and
store refrigerated (2-8°C or 36-46°F) if additional dose withdrawal from
the same vial is intended.
2.5
Stability of Partially Used Vials (Needle Punched Vials)
BENDEKA is supplied in a multiple-dose vial. Although it does not
contain any antimicrobial preservative, BENDEKA is bacteriostatic. The
partially used vials are stable for up to 28 days when stored in its
original carton under refrigeration (2-8°C or 36-46°F). Each vial is not
recommended for more than a total of six (6) dose withdrawals.

BENDEKA® (bendamustine hydrochloride) injection

BENDEKA® (bendamustine hydrochloride) injection

After first use, the partially used vial should be stored in the refrigerator
in the original carton at 2°-8°C or 36-46°F and then discarded after
28 days.
4
CONTRAINDICATIONS
BENDEKA (bendamustine hydrochloride) injection is contraindicated
in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine, polyethylene glycol 400, propylene glycol, or monothioglycerol.
5
WARNINGS AND PRECAUTIONS
5.1
Myelosuppression
Bendamustine hydrochloride caused severe myelosuppression (Grade
3-4) in 98% of patients in the two NHL studies (see Table 4). Three
patients (2%) died from myelosuppression-related adverse reactions;
one each from neutropenic sepsis, diffuse alveolar hemorrhage with
Grade 3 thrombocytopenia, and pneumonia from an opportunistic
infection (CMV).
BENDEKA (bendamustine hydrochloride) injection causes myelosuppression. Monitor complete blood counts, including leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials,
blood counts were monitored every week initially. Hematologic nadirs
occurred predominantly in the third week of therapy. Myelosuppression
may require dose delays and/or subsequent dose reductions if recovery
to the recommended values has not occurred by the first day of the next
scheduled cycle. Prior to the initiation of the next cycle of therapy, the
ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L.
5.2
Infections
Infection, including pneumonia, sepsis, septic shock, hepatitis and death
has occurred in adult and pediatric patients in clinical trials and in postmarketing reports for bendamustine hydrochloride. Patients with myelosuppression following treatment with bendamustine hydrochloride are
more susceptible to infections. Advise patients with myelosuppression
following BENDEKA (bendamustine hydrochloride) injection treatment
to contact a physician immediately if they have symptoms or signs of
infection.
Patients treated with bendamustine hydrochloride are at risk for
reactivation of infections including (but not limited to) hepatitis B,
cytomegalovirus, Mycobacterium tuberculosis, and herpes zoster.
Patients should undergo appropriate measures (including clinical and
laboratory monitoring, prophylaxis, and treatment) for infection and
infection reactivation prior to administration.
5.3
Anaphylaxis and Infusion Reactions
Infusion reactions to bendamustine hydrochloride have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and
rash. In rare instances, severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles
of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions
after their first cycle of therapy. Patients who experienced Grade 3 or
worse allergic-type reactions were not typically rechallenged. Consider
measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have
experienced Grade 1 or 2 infusion reactions. Discontinue BENDEKA
(bendamustine hydrochloride) injection for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusion reactions
as clinically appropriate considering individual benefits, risks, and supportive care.
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. Preventive 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 bendamustine 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
severity 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 bendamustine 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 reports of pre-malignant and malignant diseases that have
developed 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
postmarketing 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 admixture 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/m2 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/m2 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
randomized 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 bendamustine 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
continued



Table of Contents for the Digital Edition of ASH News Daily 2017 - Issue 2

ASH News Daily 2017 - Issue 2 - A-1
ASH News Daily 2017 - Issue 2 - A-2
ASH News Daily 2017 - Issue 2 - A-3
ASH News Daily 2017 - Issue 2 - A-4
ASH News Daily 2017 - Issue 2 - A-5
ASH News Daily 2017 - Issue 2 - A-6
ASH News Daily 2017 - Issue 2 - A-7
ASH News Daily 2017 - Issue 2 - A-8
ASH News Daily 2017 - Issue 2 - A-9
ASH News Daily 2017 - Issue 2 - A-10
ASH News Daily 2017 - Issue 2 - A-11
ASH News Daily 2017 - Issue 2 - A-12
ASH News Daily 2017 - Issue 2 - A-13
ASH News Daily 2017 - Issue 2 - A-14
ASH News Daily 2017 - Issue 2 - A-15
ASH News Daily 2017 - Issue 2 - A-16
ASH News Daily 2017 - Issue 2 - A-17
ASH News Daily 2017 - Issue 2 - A-18
ASH News Daily 2017 - Issue 2 - A-19
ASH News Daily 2017 - Issue 2 - A-20
ASH News Daily 2017 - Issue 2 - A-21
ASH News Daily 2017 - Issue 2 - A-22
ASH News Daily 2017 - Issue 2 - A-23
ASH News Daily 2017 - Issue 2 - A-24
ASH News Daily 2017 - Issue 2 - A-25
ASH News Daily 2017 - Issue 2 - A-26
ASH News Daily 2017 - Issue 2 - A-27
ASH News Daily 2017 - Issue 2 - A-28
ASH News Daily 2017 - Issue 2 - B-1
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ASH News Daily 2017 - Issue 2 - B-3
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ASH News Daily 2017 - Issue 2 - B-28
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ASH News Daily 2017 - Issue 2 - B-37
ASH News Daily 2017 - Issue 2 - B-38
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ASH News Daily 2017 - Issue 2 - B-48
ASH News Daily 2017 - Issue 2 - B-49
ASH News Daily 2017 - Issue 2 - B-50
ASH News Daily 2017 - Issue 2 - B-51
ASH News Daily 2017 - Issue 2 - B-52
ASH News Daily 2017 - Issue 2 - B-53
ASH News Daily 2017 - Issue 2 - B-54
ASH News Daily 2017 - Issue 2 - B-55
ASH News Daily 2017 - Issue 2 - B-56
ASH News Daily 2017 - Issue 2 - C-1
ASH News Daily 2017 - Issue 2 - C-2
ASH News Daily 2017 - Issue 2 - C-3
ASH News Daily 2017 - Issue 2 - C-4
ASH News Daily 2017 - Issue 2 - C-5
ASH News Daily 2017 - Issue 2 - C-6
ASH News Daily 2017 - Issue 2 - C-7
ASH News Daily 2017 - Issue 2 - C-8
ASH News Daily 2017 - Issue 2 - C-9
ASH News Daily 2017 - Issue 2 - C-10
ASH News Daily 2017 - Issue 2 - C-11
ASH News Daily 2017 - Issue 2 - C-12
ASH News Daily 2017 - Issue 2 - C-13
ASH News Daily 2017 - Issue 2 - C-14
ASH News Daily 2017 - Issue 2 - C-15
ASH News Daily 2017 - Issue 2 - C-16
ASH News Daily 2017 - Issue 2 - C-17
ASH News Daily 2017 - Issue 2 - C-18
ASH News Daily 2017 - Issue 2 - C-19
ASH News Daily 2017 - Issue 2 - C-20
ASH News Daily 2017 - Issue 2 - C-21
ASH News Daily 2017 - Issue 2 - C-22
ASH News Daily 2017 - Issue 2 - C-23
ASH News Daily 2017 - Issue 2 - C-24
ASH News Daily 2017 - Issue 2 - C-25
ASH News Daily 2017 - Issue 2 - C-26
ASH News Daily 2017 - Issue 2 - C-27
ASH News Daily 2017 - Issue 2 - C-28
ASH News Daily 2017 - Issue 2 - C-29
ASH News Daily 2017 - Issue 2 - C-30
ASH News Daily 2017 - Issue 2 - C-31
ASH News Daily 2017 - Issue 2 - C-32
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