Included as part of the PRECAUTIONS section.
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).
BELRAPZO 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 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 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
BELRAPZO treatment to contact a physician immediately if they have symptoms or
signs of infection.
Patients treated with BELRAPZO 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 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 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 BELRAPZO
for patients with Grade 4 infusion reactions. Consider discontinuation for Grade
3 infusion reactions as clinically appropriate considering individual benefits,
risks, and supportive care.
Tumor Lysis Syndrome
Tumor lysis syndrome associated with bendamustine
hydrochloride has occurred in patients in clinical trials and in post-marketing
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. [see
Fatal and serious skin reactions have been reported with
bendamustine hydrochloride 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 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
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 Infections] Most cases were reported
within the first three months of starting therapy. Monitor liver chemistry
tests prior to and during BELRAPZO therapy.
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
bendamustine hydrochloride therapy has not been determined.
Bendamustine hydrochloride extravasations have been
reported in postmarketing resulting in hospitalizations from erythema, marked
swelling, and pain. Assure good venous access prior to starting BELRAPZO
infusion and monitor the intravenous infusion site for redness, swelling, pain,
infection, and necrosis during and after administration of BELRAPZO.
Based on findings from animal reproduction studies and
the drugÃ¢â¬™s mechanism of action, BELRAPZO can cause fetal harm when administered
to a pregnant woman. Single intraperitoneal doses of bendamustine (that
approximated the maximum recommended human dose based on body surface area) to
pregnant mice and rats during organogenesis caused adverse developmental
outcomes, including an increase in resorptions, skeletal and visceral
malformations, and decreased fetal body weights. Advise pregnant women of the
potential risk to a fetus. Advise females of reproductive potential to use an
effective method of contraception during treatment with BELRAPZO and for at
least 6 months after the final dose. Advise males with female partners of
reproductive potential to use effective contraception during treatment with
BELRAPZO and for at least 3 months after the final dose. [see Use In Specific
Populations and CLINICAL PHARMACOLOGY]
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Bendamustine was carcinogenic in mice. After
intraperitoneal injections at 37.5 mg/m²/day (the lowest dose tested,
approximately 0.3 times the maximum recommended human dose [MRHD]) and 75 mg/m²/day
(approximately 0.6 times the MRHD) for 4 days, peritoneal sarcomas in female
AB/jena mice were produced. Oral administration at 187.5 mg/m²/day (the only
dose tested, approximately 1.6 times the MRHD)for 4 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, approximately 0.3 times the MRHD).
Bendamustine induced morphologic abnormalities in
spermatozoa in mice. Following tail vein injection of bendamustine at 120 mg/m²
or a saline control on days 1 and 2 for a total of three weeks, the number of
spermatozoa with morphologic abnormalities was 16% higher in the
bendamustine-treated group as compared to the saline control group.
Use In Specific Populations
In animal reproduction studies, intraperitoneal
administration of bendamustine to pregnant mice and rats during organogenesis
at doses 0.6 to 1.8 times the maximum recommended human dose (MRHD) resulted in
embryo-fetal and/or infant mortality, structural abnormalities, and alterations
to growth (see Data). There are no available data on bendamustine
hydrochloride use in pregnant women to evaluate for a drug-associated risk of
major birth defects, miscarriage or adverse maternal or fetal outcomes. Advise
pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and
miscarriage for the indicated population is unknown. All pregnancies have a
background risk of birth defect, loss, or other adverse outcomes. In the U.S.
general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
Bendamustine hydrochloride was intraperitoneally
administered once to mice from 210 mg/m² (approximately 1.8 times the MRHD)
during organogenesis and 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
administration of bendamustine hydrochloride in mice on gestation days 7-11
resulted in an increase in resorptions from 75 mg/m² (approximately 0.6 times
the MRHD) and an increase in abnormalities from 112.5 mg/m² (approximately 0.9
times the MRHD), similar to those seen after a single intraperitoneal
Bendamustine hydrochloride was intraperitoneally
administered once to rats from 120 mg/m² (approximately the MRHD) on gestation
days 4, 7, 9, 11, or 13 and 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
There are no data on the presence of bendamustine
hydrochloride or its metabolites in either human or animal milk, the effects on
the breastfed child, or the effects on milk production. Because of the
potential for serious adverse reactions in the breastfed child, advise patients
that breastfeeding is not recommended during treatment with BELRAPZO, and for
at least 1 week after the last dose.
Females And Males Of Reproductive Potential
BELRAPZO can cause fetal harm when administered to a
pregnant woman [see WARNINGS AND PRECAUTIONS and Use In Specific
Pregnancy testing is recommended for females of
reproductive potential prior to initiation of treatment with BELRAPZO [see Use
In Specific Populations].
BELRAPZO can cause embryo-fetal harm when administered to
pregnant women [see Use In Specific Populations]. Advise female patients
of reproductive potential to use effective contraception during treatment with
BELRAPZO and for 6 months after the final dose.
Based on genotoxicity findings, advise males with female
partners of reproductive potential to use effective contraception during
treatment with BELRAPZO and for at least 3 months after the final dose [see Nonclinical
Based on findings from clinical studies, BELRAPZO may
impair male fertility. 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. Advise
patients of the potential risk to their reproductive capacities.
Based on findings from animal studies, BELRAPZO may
impair male fertility due to an increase in morphologically abnormal
spermatozoa. The long-term effects of BELRAPZO on male fertility, including the
reversibility of adverse effects, have not been studied (see Nonclinical
Safety and effectiveness in pediatric patients have not
Safety, pharmacokinetics and efficacy were assessed in a
single open-label trial (NCT01088984) in patients aged 1-19 years with relapsed
or refractory acute leukemia, including 27 patients with acute lymphocytic
leukemia (ALL) and 16 patients with acute myeloid leukemia (AML). Bendamustine
hydrochloride was administered as an intravenous infusion over 60 minutes on
Days 1 and 2 of each 21-day cycle. There was no treatment response (CR+ CRp) in
any patient. The safety profile in these patients was consistent with that seen
in adults, and no new safety signals were identified.
The pharmacokinetics of bendamustine in 43 patients, aged
1 to 19 years (median age of 10 years) were within range of values previously
observed in adults given the same dose based on body surface area.
No overall differences in safety were observed between
patients ≥65 years of age and younger patients. Efficacy was lower in
patients 65 and over with CLL receiving bendamustine hydrochloride based upon
an overall response rate of 47% for patients 65 and over and 70% for younger
patients. Progression free survival was also longer in younger patients with
CLL receiving bendamustine (19 months vs. 12 months). No overall differences in
efficacy in patients non-Hodgkin Lymphoma were observed between geriatric
patients and younger patients.
Do not use BELRAPZO in patients with creatinine clearance
(CLcr) < 30 mL/min [see CLINICAL PHARMACOLOGY].
Do not use BELRAPZO in patients with AST or ALT 2.5-10 Ã—
upper limit of normal (ULN) and total bilirubin 1.5-3 Ã— ULN, or total bilirubin
> 3 Ã— ULN [see CLINICAL PHARMACOLOGY]