ASH News Daily 2017 - Issue 3 - C-29

BENDEKA® (bendamustine hydrochloride) injection
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
Metabolism and
nutrition disorders
Hyperuricemia
11 (7)
3 (2)
2 (1)
0
Respiratory,
thoracic and
mediastinal
disorders
Cough
6 (4)
1 (<1)
7 (5)
1 (<1)
Skin and
subcutaneous
tissue disorders
Rash
12 (8)
4 (3)
7 (5)
3 (2)
Pruritus
8 (5)
0
2 (1)
0
The Grade 3 and 4 hematology laboratory test values by treatment
group in the randomized CLL clinical study are described in Table 2.
These findings confirm the myelosuppressive effects seen in patients
treated with bendamustine hydrochloride. Red blood cell transfusions
were administered to 20% of patients receiving bendamustine hydrochloride compared with 6% of patients receiving chlorambucil.
Table 2: Incidence of Hematology Laboratory Abnormalities in
Patients Who Received bendamustine hydrochloride or Chlorambucil
in the Randomized CLL Clinical Study
Bendamustine
Hydrochloride
Chlorambucil
Laboratory
N=150
N=141
Abnormality
All Grades Grade 3/4 All Grades Grade 3/4
n (%)
n (%)
n (%)
n (%)
Hemoglobin
134 (89)
20 (13)
115 (82)
12 (9)
Decreased
Platelets
116 (77)
16 (11)
110 (78)
14 (10)
Decreased
Leukocytes
92 (61)
42 (28)
26 (18)
4 (3)
Decreased
Lymphocytes
102 (68)
70 (47)
27 (19)
6 (4)
Decreased
Neutrophils
113 (75)
65 (43)
86 (61)
30 (21)
Decreased
In the randomized CLL trial, 34% of patients had bilirubin elevations,
some without associated significant elevations in AST and ALT. Grade
3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST
and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with bendamustine hydrochloride may also have
changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant
deterioration does not occur.
6.3
Clinical Trials Experience in NHL
The data described below reflect exposure to bendamustine hydrochloride in 176 patients with indolent B-cell NHL treated in two singlearm studies. The population was 31-84 years of age, 60% male, and
40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received bendamustine
hydrochloride at a dose of 120 mg/m2 intravenously on Days 1 and 2 for
up to eight 21-day cycles.
The adverse reactions occurring in at least 5% of the NHL patients,
regardless of severity, are shown in Table 3. The most common
non-hematologic adverse reactions (≥30%) were nausea (75%),
fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%).
The most common non-hematologic Grade 3 or 4 adverse reactions
(≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia,
hypokalemia and dehydration, each reported in 5% of patients.
Table 3: Non-Hematologic Adverse Reactions Occurring in at Least
5% of NHL Patients Treated with bendamustine hydrochloride by
System Organ Class and Preferred Term (N=176)
System organ class
Number (%) of patients*
Preferred Term
All Grades
Grade 3/4
Total number of patients with
176 (100)
94 (53)
at least 1 adverse reaction
Cardiac Disorders
Tachycardia
13 (7)
0
Gastrointestinal disorders
Nausea
132 (75)
7 (4)
Vomiting
71 (40)
5 (3)
Diarrhea
65 (37)
6 (3)
Constipation
51 (29)
1 (<1)
Stomatitis
27 (15)
1 (<1)
Abdominal pain
22 (13)
2 (1)
Dyspepsia
20 (11)
0
Gastroesophageal reflux disease
18 (10)
0
Dry mouth
15 (9)
1 (<1)
Abdominal pain upper
8 (5)
0
Abdominal distension
8 (5)
0
General disorders and administration site conditions
Fatigue
101 (57)
19 (11)
Pyrexia
59 (34)
3 (2)
Chills
24 (14)
0
Edema peripheral
23 (13)
1 (<1)
Asthenia
19 (11)
4 (2)
Chest pain
11 (6)
1 (<1)

BENDEKA® (bendamustine hydrochloride) injection
System organ class
Number (%) of patients*
Preferred Term
All Grades
Grade 3/4
General disorders and administration site conditions continued
Infusion site pain
11 (6)
0
Pain
10 (6)
0
Catheter site pain
8 (5)
0
Infections and infestations
Herpes zoster
18 (10)
5 (3)
Upper respiratory tract infection
18 (10)
0
Urinary tract infection
17 (10)
4 (2)
Sinusitis
15 (9)
0
Pneumonia
14 (8)
9 (5)
Febrile neutropenia
11 (6)
11 (6)
Oral candidiasis
11 (6)
2 (1)
Nasopharyngitis
11 (6)
0
Investigations
Weight decreased
31 (18)
3 (2)
Metabolism and nutrition disorders
Anorexia
40 (23)
3 (2)
Dehydration
24 (14)
8 (5)
Decreased appetite
22 (13)
1 (<1)
Hypokalemia
15 (9)
9 (5)
Musculoskeletal and connective tissue disorders
Back pain
25 (14)
5 (3)
Arthralgia
11 (6)
0
Pain in extremity
8 (5)
2 (1)
Bone pain
8 (5)
0
Nervous system disorders
Headache
36 (21)
0
Dizziness
25 (14)
0
Dysgeusia
13 (7)
0
Psychiatric disorder
Insomnia
23 (13)
0
Anxiety
14 (8)
1 (<1)
Depression
10 (6)
0
Respiratory, thoracic and mediastinal disorders
Cough
38 (22)
1 (<1)
Dyspnea
28 (16)
3 (2)
Pharyngolaryngeal pain
14 (8)
1 (<1)
Wheezing
8 (5)
0
Nasal congestion
8 (5)
0
Skin and subcutaneous tissue disorders
Rash
28 (16)
1 (<1)
Pruritus
11 (6)
0
Dry skin
9 (5)
0
Night sweats
9 (5)
0
Hyperhidrosis
8 (5)
0
Vascular disorders
Hypotension
10 (6)
2 (1)
*Patients may have reported more than 1 adverse reaction.
NOTE: Patients counted only once in each preferred term category and
once in each system organ class category.
Hematologic toxicities, based on laboratory values and CTC grade,
in NHL patients treated in both single arm studies combined are
described in Table 4. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1%
of patients at grade 3 or 4, in NHL patients treated in both single arm
studies combined were hyperglycemia (3%), elevated creatinine (2%),
hyponatremia (2%), and hypocalcemia (2%).
Table 4: Incidence of Hematology Laboratory Abnormalities in
Patients Who Received bendamustine hydrochloride in the NHL
Studies
Percent of Patients
Hematology Variable
All Grades
Grade 3/4
Lymphocytes Decreased
99
94
Leukocytes Decreased
94
56
Hemoglobin Decreased
88
11
Neutrophils Decreased
86
60
Platelets Decreased
86
25
In both studies, serious adverse reactions, regardless of causality,
were reported in 37% of patients receiving bendamustine hydrochloride. The most common serious adverse reactions occurring in ≥5%
of patients were febrile neutropenia and pneumonia. Other important
serious adverse reactions reported in clinical trials and/or postmarketing
experience were acute renal failure, cardiac failure, hypersensitivity, skin
reactions, pulmonary fibrosis, and myelodysplastic syndrome.
Serious drug-related adverse reactions reported in clinical trials included
myelosuppression, infection, pneumonia, tumor lysis syndrome and
infusion reactions. Adverse reactions occurring less frequently but
possibly related to bendamustine hydrochloride treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes
zoster, erythema, dermatitis, and skin necrosis.
6.4
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of bendamustine hydrochloride. Because these reactions
are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure.

BENDEKA® (bendamustine hydrochloride) injection
Blood and lymphatic systems disorders: Pancytopenia.
Cardiovascular disorders: Atrial fibrillation, congestive heart failure
(some fatal), myocardial infarction (some fatal), palpitation.
General disorders and administration site conditions: Injection site reactions (including phlebitis, pruritus, irritation, pain, swelling), infusion
site reactions (including phlebitis, pruritus, irritation, pain, swelling).
Immune system disorders: Anaphylaxis.
Infections and infestations: Pneumocystis jiroveci pneumonia.
Respiratory, thoracic and mediastinal disorders: Pneumonitis.
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome,
Toxic epidermal necrolysis, DRESS (Drug reaction with eosinophilia
and systemic symptoms).
7
DRUG INTERACTIONS
No formal clinical assessments of pharmacokinetic drug-drug interactions between bendamustine hydrochloride and other drugs have
been conducted.
Bendamustine's active metabolites, gamma-hydroxy bendamustine
(M3) and N-desmethyl-bendamustine (M4), are formed via cytochrome
P450 CYP1A2. Inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin)
have potential to increase plasma concentrations of bendamustine
and decrease plasma concentrations of active metabolites. Inducers of
CYP1A2 (e.g., omeprazole, smoking) have potential to decrease plasma
concentrations of bendamustine and increase plasma concentrations of
its active metabolites. Caution should be used, or alternative treatments
considered if concomitant treatment with CYP1A2 inhibitors or inducers
is needed.
The role of active transport systems in bendamustine distribution has
not been fully evaluated. In vitro data suggest that P-glycoprotein, breast
cancer resistance protein (BCRP), and/or other efflux transporters may
have a role in bendamustine transport.
Based on in vitro data, bendamustine is not likely to inhibit metabolism
via human CYP isoenzymes CYP1A2, 2C9/10, 2D6, 2E1, or 3A4/5, or
to induce metabolism of substrates of cytochrome P450 enzymes.
8.6
Renal Impairment
No formal studies assessing the impact of renal impairment on the
pharmacokinetics of bendamustine have been conducted. BENDEKA
(bendamustine hydrochloride) injection should be used with caution
in patients with mild or moderate renal impairment. BENDEKA (bendamustine hydrochloride) injection should not be used in patients with
CrCL < 40 mL/min.
8.7
Hepatic Impairment
No formal studies assessing the impact of hepatic impairment on the
pharmacokinetics of bendamustine have been conducted. BENDEKA
(bendamustine hydrochloride) injection should be used with caution
in patients with mild hepatic impairment. BENDEKA (bendamustine
hydrochloride) injection should not be used in patients with moderate
(AST or ALT 2.5-10 X ULN and total bilirubin 1.5-3 X ULN) or severe
(total bilirubin > 3 X ULN) hepatic impairment.
16.1 Safe Handling and Disposal
BENDEKA (bendamustine hydrochloride) injection is a cytotoxic
drug. Follow applicable special handling and disposal procedures.1
Care should be exercised in the handling and preparation of solutions
prepared from BENDEKA (bendamustine hydrochloride) injection. The
use of gloves and safety glasses is recommended to avoid exposure
in case of breakage of the vial or other accidental spillage. If a solution of BENDEKA (bendamustine hydrochloride) injection contacts the
skin, wash the skin immediately and thoroughly with soap and water.
If BENDEKA (bendamustine hydrochloride) injection contacts the
mucous membranes, flush thoroughly with water.
16.3 Storage
Store BENDEKA (bendamustine hydrochloride) injection in refrigerator, 2°-8°C (36°-46°F). Retain in original carton until time of use to
protect from light.

Distributed By:
Teva Pharmaceuticals USA, Inc.
North Wales, PA 19454
Rev. 02/2017
All rights reserved.
This Brief Summary is based on the Full Prescribing Information for
BENDEKA BEN-004.
BEN-40459 April 2017



Table of Contents for the Digital Edition of ASH News Daily 2017 - Issue 3

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ASH News Daily 2017 - Issue 3 - C-1
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ASH News Daily 2017 - Issue 3 - C-3
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ASH News Daily 2017 - Issue 3 - C-9
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ASH News Daily 2017 - Issue 3 - C-21
ASH News Daily 2017 - Issue 3 - C-22
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ASH News Daily 2017 - Issue 3 - C-24
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ASH News Daily 2017 - Issue 3 - C-27
ASH News Daily 2017 - Issue 3 - C-28
ASH News Daily 2017 - Issue 3 - C-29
ASH News Daily 2017 - Issue 3 - C-30
ASH News Daily 2017 - Issue 3 - C-31
ASH News Daily 2017 - Issue 3 - C-32
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