Included as part of the PRECAUTIONS section.
TREANDA 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).
In the event of treatment-related myelosuppression,
monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In
the clinical trials, blood counts were monitored every week initially.
Hematologic nadirs were observed 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. [see DOSAGE AND ADMINISTRATION]
Infection, including pneumonia, sepsis, septic shock,
hepatitis, and death have occurred in adult and pediatric patients in clinical
trials and in postmarketing reports. Patients with myelosuppression following
treatment with TREANDA are more susceptible to infections. Advise patients with
myelosuppression following TREANDA treatment to contact a physician if they
have symptoms or signs of infection.
Patients treated with TREANDA 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
Anaphylaxis And Infusion Reactions
Infusion reactions to TREANDA 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 experience Grade 3 or worse allergic-type reactions should not be
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
TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation
for Grade 3 infusions reactions as clinically appropriate considering
individual benefits, risks, and supportive care.
Tumor Lysis Syndrome
Tumor lysis syndrome associated with TREANDA treatment
has occurred in patients in clinical trials and in postmarketing reports. The
onset tends to be within the first treatment cycle of TREANDA 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 TREANDA therapy. However, there may be an increased
risk of severe skin toxicity when TREANDA and allopurinol are administered
concomitantly [see Skin Reactions].
Skin reactions have been reported with TREANDA treatment
in clinical trials and postmarketing safety reports, including rash, toxic skin
reactions and bullous exanthema. Some events occurred when TREANDA was given in
combination with other anticancer agents.
In a study of TREANDA (90 mg/m²) in
combination with rituximab, one case of toxic epidermal necrolysis (TEN)
occurred. TEN has been reported for rituximab (see rituximab package insert).
Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported
when TREANDA was administered concomitantly with allopurinol and other
medications known to cause these syndromes. The relationship to TREANDA cannot
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
There are reports of pre-malignant and malignant diseases
that have developed in patients who have been treated with TREANDA, including
myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia
and bronchial carcinoma. The association with TREANDA therapy has not been
TREANDA extravasations have been reported in post
marketing resulting in hospitalizations from erythema, marked swelling, and
pain. Assure good venous access prior to starting TREANDA infusion and monitor
the intravenous infusion site for redness, swelling, pain, infection, and
necrosis during and after administration of TREANDA.
TREANDA 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. [see Use in
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Bendamustine was carcinogenic in mice. After
intraperitoneal injections at 37.5 mg/m²/day (12.5 mg/kg/day, the
lowest dose tested) and 75 mg/m²/day (25 mg/kg/day) for four days,
peritoneal sarcomas in female AB/jena mice were produced. Oral administration
at 187.5 mg/m²/day (62.5 mg/kg/day, the only dose tested) for four
days induced mammary carcinomas and pulmonary adenomas.
Bendamustine is a mutagen and clastogen. In a reverse
bacterial mutation assay (Ames assay), bendamustine was shown to increase
revertant frequency in the absence and presence of metabolic activation.
Bendamustine was clastogenic in human lymphocytes in vitro, and in rat bone
marrow cells in vivo (increase in micronucleated polychromatic erythrocytes)
from 37.5 mg/m², the lowest dose tested.
Impaired spermatogenesis, azoospermia, and total germinal
aplasia have been reported in male patients treated with alkylating agents,
especially in combination with other drugs. In some instances spermatogenesis
may return in patients in remission, but this may occur only several years
after intensive chemotherapy has been discontinued. Patients should be warned
of the potential risk to their reproductive capacities.
Use In Specific Populations
Pregnancy Category D
[see WARNINGS AND PRECAUTIONS]
TREANDA can cause fetal harm
when administered to a pregnant woman. Bendamustine caused malformations in
animals, when a single dose was administered to pregnant animals. Advise women
to avoid becoming pregnant while receiving TREANDA and for 3 months after
therapy has stopped. If this drug is used during pregnancy, or if the patient
becomes pregnant while receiving this drug, the patient should be apprised of
the potential hazard to a fetus. Advise men receiving TREANDA to use reliable
contraception for the same time period.
Single intraperitoneal doses of
bendamustine from 210 mg/m² (70 mg/kg) in mice administered during
organogenesis caused an increase in resorptions, skeletal and visceral
malformations (exencephaly, cleft palates, accessory rib, and spinal
deformities) and decreased fetal body weights. This dose did not appear to be
maternally toxic and lower doses were not evaluated. Repeat intraperitoneal
dosing in mice on gestation days 7-11 resulted in an increase in resorptions
from 75 mg/m² (25 mg/kg) and an increase in abnormalities from 112.5
mg/m² (37.5 mg/kg) similar to those seen after a single intraperitoneal
administration. Single intraperitoneal doses of bendamustine from 120 mg/m² (20 mg/kg) in rats administered on gestation days 4, 7, 9, 11, or 13
caused embryo and fetal lethality as indicated by increased resorptions and a
decrease in live fetuses. A significant increase in external [effect on tail,
head, and herniation of external organs (exomphalos)] and internal
(hydronephrosis and hydrocephalus) malformations were seen in dosed rats. There
are no adequate and well-controlled studies in pregnant women. If this drug is
used during pregnancy, or if the patient becomes pregnant while taking this
drug, the patient should be apprised of the potential hazard to the fetus.
It is not known whether this
drug is excreted in human milk. Because many drugs are excreted in human milk
and because of the potential for serious adverse reactions in nursing infants
and tumorigenicity shown for bendamustine in animal studies, a decision should
be made whether to discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the mother.
The effectiveness of TREANDA in
pediatric patients has not been established. TREANDA was evaluated in a single
Phase ½ trial in pediatric patients with leukemia. The safety profile for
TREANDA in pediatric patients was consistent with that seen in adults, and no
new safety signals were identified.
The trial included pediatric
patients from 1-19 years of age with relapsed or refractory acute leukemia, including
27 patients with acute lymphocytic leukemia (ALL) and 16 patients with acute
myeloid leukemia (AML). TREANDA was administered as an intravenous infusion
over 60 minutes on Days 1 and 2 of each 21-day cycle. Doses of 90 and 120 mg/m² were evaluated. The Phase 1 portion of the study determined that the
recommended Phase 2 dose of TREANDA in pediatric patients was 120 mg/m² .
A total of 32 patients entered
the Phase 2 portion of the study at the recommended dose and were evaluated for
response. There was no treatment response (CR+ CRp) in any patient at this
dose. However, there were 2 patients with ALL who achieved a CR at a dose of 90
mg/m² in the Phase 1 portion of the study.
In the above-mentioned
pediatric trial, the pharmacokinetics of TREANDA at 90 and 120 mg/m² doses
were evaluated in 5 and 38 patients, respectively, aged 1 to 19 years (median
age of 10 years).
The geometric mean body surface
adjusted clearance of bendamustine was 14.2 L/h/m². The exposures
(AUC0-24 and Cmax ) to bendamustine in pediatric patients following a 120 mg/m² intravenous infusion over 60 minutes were similar to those in adult
patients following the same 120 mg/m² dose.
In CLL and NHL studies, there
were no clinically significant differences in the adverse reaction profile
between geriatric ( ≥ 65 years of age) and younger patients.
Chronic Lymphocytic Leukemia
In the randomized CLL clinical
study, 153 patients received TREANDA. The overall response rate for patients
younger than 65 years of age was 70% (n=82) for TREANDA and 30% (n=69) for
chlorambucil. The overall response rate for patients 65 years or older was 47%
(n=71) for TREANDA and 22% (n=79) for chlorambucil. In patients younger than 65
years of age, the median progression-free survival was 19 months in the TREANDA
group and 8 months in the chlorambucil group. In patients 65 years or older,
the median progression-free survival was 12 months in the TREANDA group and 8
months in the chlorambucil group.
Efficacy (Overall Response Rate
and Duration of Response) was similar in patients < 65 years of age and
patients ≥ 65 years. Irrespective of age, all of the 176 patients
experienced at least one adverse reaction.
No formal studies assessing the
impact of renal impairment on the pharmacokinetics of bendamustine have been
conducted. TREANDA should be used with caution in patients with mild or
moderate renal impairment. TREANDA should not be used in patients with CrCL
< 40 mL/min. [see CLINICAL PHARMACOLOGY]
No formal studies assessing the
impact of hepatic impairment on the pharmacokinetics of bendamustine have been
conducted. TREANDA should be used with caution in patients with mild hepatic
impairment. TREANDA 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. [see CLINICAL PHARMACOLOGY]
Effect of Gender
No clinically significant
differences between genders were seen in the overall incidences of adverse
reactions in either CLL or NHL studies.
Chronic Lymphocytic Leukemia
In the randomized CLL clinical study, the overall
response rate (ORR) for men (n=97) and women (n=56) in the TREANDA group was
60% and 57%, respectively. The ORR for men (n=90) and women (n=58) in the
chlorambucil group was 24% and 28%, respectively. In this study, the median
progression-free survival for men was 19 months in the TREANDA treatment group
and 6 months in the chlorambucil treatment group. For women, the median
progression-free survival was 13 months in the TREANDA treatment group and 8
months in the chlorambucil treatment group.
The pharmacokinetics of
bendamustine were similar in male and female patients with indolent NHL. No
clinically-relevant differences between genders were seen in efficacy (ORR and