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Rx Monotherapy for indolent non-Hodgkin's

Bendamustine hydrochloride
for Injection 100mg
1. NAME OF THE MEDICINAL
PRODUCT
Bendamustine hydrochloride for Injection
100mg Taj Pharma
2. QUALITATIVE AND
QUANTITATIVE COMPOSITION
Each lyophilized vial contains:
Bendamustine Hydrochloride 100mg
Excipients q.s.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Concentrate for solution for infusion.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
First-line treatment of chronic lymphocytic
leukaemia (Binet stage B or C) in patients for
whom fludarabine combination chemotherapy is
not appropriate.
Indolent non-Hodgkin's lymphomas
monotherapy in patients who have progressed
during or within 6 months following treatment
with rituximab or a rituximab containing
regimen.
Front line treatment of multiple myeloma
(Durie-Salmon stage II with progress or stage
III) in combination with prednisone for patients
older than 65 years who are not eligible for
autologous stem cell transplantation and who
have clinical neuropathy at time of diagnosis
precluding the use of thalidomide or bortezomib
containing treatment.
4.2 Posology and method of administration
Posology
Monotherapy for chronic lymphocytic
leukaemia
100 mg/m² body surface area bendamustine
hydrochloride on days 1 and 2; every 4 weeks.
lymphomas refractory to rituximab
120 mg/m² body surface area bendamustine
hydrochloride on days 1 and 2; every 3 weeks.
Multiple myeloma
120 - 150 mg/m² body surface area
bendamustine hydrochloride on days 1 and 2, 60
mg/m² body surface area prednisone i.v. or per
os on days 1 to 4; every 4 weeks.
Poor bone marrow function is related to
increased chemotherapy-induced haematological
toxicity. Treatment should not be started if
leukocyte and/or platelet values have dropped to
< 3,000/µl or < 75,000/µl, respectively (see
section 4.3).
Treatment should be terminated or delayed if
leukocyte and/or platelet values have dropped to
< 3,000/µl or < 75,000/µl, respectively.
Treatment can be continued after leukocyte
values have increased to > 4,000/µl and platelet
values to > 100,000/µl.
The leukocyte and platelet Nadir is reached after
14-20 days with regeneration after 3-5 weeks.
During therapy free intervals strict monitoring of
the blood count is recommended (see section
4.4).
as
In case of non-haematological toxicity dose
reductions have to be based on the worst CTC
grades in the preceding cycle. A 50% dose
reduction is recommended in case of CTC grade
3 toxicity. An interruption of treatment is
recommended in case of CTC grade 4 toxicity.
If a patient requires a dose modification the
individually calculated reduced dose must be
given on day 1 and 2 of the respective treatment
cycle.
Hepatic impairment
On the basis of pharmacokinetic data, no dose
adjustment is necessary in patients with mild
hepatic impairment (serum bilirubin < 1.2
mg/dl). A 30% dose reduction is recommended
in patients with moderate hepatic impairment
(serum bilirubin 1.2 - 3.0 mg/dl).
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No data is available in patients with severe - Infections, especially involving leukocytopenia

hepatic impairment (serum bilirubin values of > - Yellow fever vaccination
3.0 mg/dl) (see section 4.3).
4.4 Special warnings and precautions for use
Renal impairment Myelosuppression
On the basis of pharmacokinetic data, no dose Patients treated with bendamustine
adjustment is necessary in patients with a hydrochloride may experience
creatinine clearance of > 10 ml/min. Experience myelosuppression. In the event of treatment-
in patients with severe renal impairment is related myelosuppression, leukocytes, platelets,
limited. haemoglobin, and neutrophils must be
Paediatric population monitored at least weekly. Prior to the initiation
The safety and efficacy of bendamustine of the next cycle of therapy, the following
hydrochloride in children have not yet been parameters are recommended: Leukocyte and/or
established. Current available data is not platelet values > 4,000/µl or > 100,000/µl,
sufficient to make a recommendation on respectively.
posology. Infections
Elderly patients Serious and fatal infections have occurred with
There is no evidence that dose adjustments are bendamustine hydrochloride, including bacterial
necessary in elderly patients (see also section (sepsis, pneumonia) and opportunistic infections
5.2). such as Pneumocystis jirovecii pneumonia
(PJP), varicella zoster virus (VZV) and
Method of administration cytomegalovirus (CMV). Treatment with
For intravenous infusion over 30 - 60 minutes bendamustine hydrochloride may cause
(see section 6.6). prolonged lymphocytopenia (< 600/μl) and low
Infusion must be administered under the CD4-positive T-cell (T-helper cell) counts (<
supervision of a physician qualified and 200/μl) for at least 7–9 months after the
experienced in the use of chemotherapeutic completion of treatment. Lymphocytopenia and
agents. CD4-positive T-cell depletion are more
pronounced when bendamustine is combined
Precautions to be taken before handling or with rituximab. Patients with lymphopenia and
administering the medicinal product
low CD4-positive T-cell count following
For instructions on dilution of the medicinal treatment with bendamustine hydrochloride are
product before administration, see section 6.6. more susceptible to (opportunistic) infections. In
4.3 Contraindications case of low CD4-positive T-cell counts (< 200
- Hypersensitivity to the active substance or to µ/l) Pneumocystis jirovecii pneumonia (PJP)
any of the excipients listed in section 6.1 prophylaxis should be considered. All patients
should be monitored for respiratory signs and
- During breastfeeding
symptoms throughout treatment. Patients should
- Severe hepatic impairment (serum bilirubin > be advised to report new signs of infection,
3.0 mg/dl) including fever or respiratory symptoms
- Jaundice promptly. Discontinuation of bendamustine
- Severe bone marrow suppression and severe hydrochloride should be considered if there are
blood count alterations (leukocyte and/or platelet signs of (opportunistic) infections.
values dropped to < 3,000/µl or < 75,000/µl, Hepatitis B reactivation
respectively) Reactivation of hepatitis B in patients who are
- Major surgery less than 30 days before start of chronic carriers of this virus has occurred after
treatment these patients received bendamustine
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hydrochloride. Some cases resulted in acute Fatal cases of myocardial infarction and cardiac
hepatic failure or a fatal outcome. Patients failure have been reported with bendamustine
should be tested for HBV infection before hydrochloride treatment. Patients with
initiating treatment with bendamustine concurrent or history of cardiac disease should
hydrochloride. Experts in liver disease and in the be observed closely.
treatment of hepatitis B should be consulted Nausea, vomiting
before treatment is initiated in patients with
positive hepatitis B tests (including those with An antiemetic may be given for the symptomatic
active disease) and for patients who test positive treatment of nausea and vomiting.
for HBV infection during treatment. Carriers of Tumour lysis syndrome
HBV who require treatment with bendamustine Tumour lysis syndrome (TLS) associated with
hydrochloride should be closely monitored for bendamustine treatment has been reported in
signs and symptoms of active HBV infection patients in clinical trials. The onset tends to be
throughout therapy and for several months within 48 hours of the first dose of
following termination of therapy (see section bendamustine and, without intervention, may
4.8). lead to acute renal failure and death. Preventive
Skin reactions measures such as adequate hydration and close
A number of skin reactions have been reported. monitoring of blood chemistry, particularly
These events have included rash, severe potassium and uric acid levels, and the use of
cutaneous reactions and bullous exanthema. hypouricemic agents (allopurinol and
Cases of Stevens – Johnson syndrome (SJS), rasburicase) should be considered prior to
Toxic Epidermal Necrolysis (TEN) and Drug therapy. There have been a few cases of
Reaction with Eosinophilia and Systemic Stevens-Johnson Syndrome and Toxic
Symptoms (DRESS), some fatal, have been Epidermal Necrolysis reported when
reported with the use of bendamustine bendamustine and allopurinol were administered
hydrochloride. Patients should be advised of the concomitantly.
signs and symptoms of these reactions by their Anaphylaxis
prescribers and should be told to seek medical Infusion reactions to bendamustine
attention immediately if they develop these hydrochloride have occurred commonly in
symptoms. Some events occurred when clinical trials. Symptoms are generally mild and
bendamustine hydrochloride was given in include fever, chills, pruritus and rash. In rare
combination with other anticancer agents, so the instances severe anaphylactic and anaphylactoid
precise relationship is uncertain. Where skin reactions have occurred. Patients must be asked
reactions occur, they may be progressive and about symptoms suggestive of infusion reactions
increase in severity with further treatment. When after their first cycle of therapy. Measures to
skin reactions are progressive, bendamustine prevent severe reactions, including
should be withheld or discontinued. For severe antihistamines, antipyretics and corticosteroids
skin reactions with suspected relationship to must be considered in subsequent cycles in
bendamustine hydrochloride, treatment should patients who have previously experienced
be discontinued. infusion reactions.
Cardiac disorders Patients who experienced Grade 3 or worse
During treatment with bendamustine allergic-type reactions were typically not re-
hydrochloride the concentration of potassium in challenged.
the blood of patients with cardiac disorders must Contraception
be closely monitored and potassium supplement
must be given when K+ <3.5 mEq/l and ECG Bendamustine hydrochloride is teratogenic and
mutagenic.
measurement must be performed.
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Women should not become pregnant during CYP1A2 inhibitors such as fluvoxamine,
treatment. Male patients should not father a ciprofloxacin, acyclovir and cimetidine exists.
child during and up to 6 months after treatment. Paediatric population
They should seek advice about sperm
conservation prior to treatment with Interaction studies have only been performed in
bendamustine hydrochloride because of possible adults.
irreversible infertility. 4.6 Fertility, pregnancy and lactation
Extravasation Pregnancy
An extravasal injection should be stopped There are insufficient data from the use of
immediately. The needle should be removed bendamustine in pregnant women. In nonclinical
after a short aspiration. Thereafter the affected studies bendamustine hydrochloride was
area of tissue should be cooled. The arm should embryo-/fetolethal, teratogenic and genotoxic
be elevated. Additional treatments like the use of (see section 5.3). During pregnancy
corticosteroids are not of clear benefit. bendamustine should not be used unless clearly
necessary. The mother should be informed about
Dilution the risk to the foetus. If treatment with
Bendamustine requires appropriate dilution bendamustine is absolutely necessary during
before use. The concentration of bendamustine pregnancy or if pregnancy occurs during
in Bendamustine differs from other treatment, the patient should be informed about
bendamustine products (see section 6.6 for the risks for the unborn child and be monitored
further instructions on dilution). carefully. The possibility of genetic counselling
4.5 Interaction with other medicinal products should be considered.
and other forms of interaction Fertility
No in-vivo interaction studies have been Women of childbearing potential must use
performed. effective methods of contraception both before
When bendamustine is combined with and during bendamustine therapy.
myelosuppressive agents, the effect of Men being treated with bendamustine are
bendamustine and/or the co-administered advised not to father a child during and for up to
medicinal products on the bone marrow may be 6 months following cessation of treatment.
potentiated. Any treatment reducing the patient's Advice on conservation of sperm should be
performance status or impairing bone marrow sought prior to treatment because of the
function can increase the toxicity of possibility of irreversible infertility due to
bendamustine. therapy with bendamustine.
Combination of bendamustine with cyclosporine Breastfeeding
or tacrolimus may result in excessive
immunosuppression with risk of It is not known whether bendamustine passes
lymphoproliferation. into the breast milk, therefore, bendamustine is
contraindicated during breastfeeding (see section
Cytostatics can reduce antibody formation 4.3). Breastfeeding must be discontinued during
following live-virus vaccination and increase the treatment with bendamustine.
risk of infection which may lead to fatal
outcome. This risk is increased in subjects who 4.7 Effects on ability to drive and use
are already immunosuppressed by their machines
underlying disease. Bendamustine has major influence on the ability
to drive and use machines. Ataxia, peripheral
Bendamustine metabolism involves cytochrome neuropathy and somnolence have been reported
P450 (CYP) 1A2 isoenzyme (see section 5.2). during treatment with bendamustine (see section
Therefore, the potential for interaction with 4.8). Patients should be instructed that if they
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experience these symptoms they should avoid asms ur dyspla

potentially hazardous tasks such as driving and benig lysis stic
using machines. n, syndro syndro
4.8 Undesirable effects malig me me,
Summary of safety profile nant Acute
myelo
The most common adverse reactions with
id
bendamustine hydrochloride are hematological
leuke
adverse reactions (leukopenia, thrombopenia),
mia
dermatologic toxicities (allergic reactions),
constitutional symptoms (fever), gastrointestinal Blood Leukop Haem Pancyt Bone Haem
symptoms (nausea, vomiting). and enia orrhag openia marro olysis
lymph NOS*, e, w
Tabulated list of adverse reactions atic Thromb Anae failur
The table below reflects the data obtained with syste ocytope mia, e
bendamustine hydrochloride. m nia, Neutr
Med Very Com Unco Rare Very Not disord Lymph openia
DRA commo mon mmon ≥1/10 rare kno ers openia
syste n ≥1/10 ≥1/10 ≥1/1,0 ,000<1/10, wn Immu Hyper Anap Anap
m 0 to 00 to to 000 (can ne sensiti hylact hylact
organ <1/10 <1/10 <1/1, not syste vity ic ic
class 0 000 be m NOS* reacti shock
esti disord on,
mate ers Anap
d hylact
from oid
the reacti
avail on
able Nervo Headac Insom Somn Dysge
data us he nia, olenc usia,
) syste Dizzin e, Paraes
Infecti Infectio Pneu Sepsi Pneu m ess Apho thesia,
ons n mocys s monia disord nia Periph
and NOS*, tis prima ers eral
infest includi jirove ry sensor
ations ng cii atypic y
opportu pneum al neuro
nistic onia pathy,
infectio Antic
n (e.g. holine
Herpes rgic
zoster, syndr
cytome ome,
galovir Neuro
us, logica
hepatiti l
s B) disord
Neopl Tumo Myelo ers,
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Ataxi obiliar tic

a, y failur
Encep disord e
halitis er
Cardi Cardia Perica Tachy Atria Skin Alope Eryth Stev
ac c rdial cardia l and cia, ema, ens –
disord dysfun effusi fibril subcut Skin Derm John
ers ction, on, latio aneou disord atitis, son
such Myoc n s ers Prurit synd
as ardial tissue NOS* us, rome
palpita infarct disord , Macu ,
tions, ion, ers Urtica lopap Toxi
angina Cardia ria ular c
pector c rash, Epid
is, failure Hyper erma
Arrhyt hidros l
hmia is Necr
Vascu Hypot Acute Phlebi olysi
lar ension circul tis s
disord , atory (TE
ers Hyper failur N),
tensio e Drug
n Reac
Respir Pulmo Pulmo Pneu tion
atory, nary nary moni with
thorac dysfun fibrosi tis, Eosi
ic and ction s Pulm noph
media onar ilia
stinal y and
disord alveo Syste
ers lar mic
haem Sym
orrha ptom
ge s
(DR
Gastr Nausea, Diarrh Haem ESS)
ointes Vomiti oea, orrhag
tinal ng Consti ic Renal Rena
disord pation oesop and l
ers , hagiti urinar failur
Stoma s, y e
titis Gastr disord
ointes ers
tinal Repro Amen Inferti
haem ductiv orrhea lity
orrhag e
e syste
Hepat Hepa m and
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breast important. It allows continued monitoring of the

disord benefit/risk balance of the medicinal product.
ers 4.9 Overdose
Gener Mucosa Pain, Multi After application of a 30 min infusion of
al l Chills, organ bendamustine hydrochloride once every 3 weeks
disord inflam Dehyd failure the maximum tolerated dose (MTD) was 280
ers mation, ration, mg/m². Cardiac events of CTC grade 2 which
and Fatigue, Anore were compatible with ischaemic ECG changes
admin Pyrexia xia occurred which were regarded as dose limiting.
istrati In a subsequent study with a 30 min infusion of
on bendamustine hydrochloride at day 1 and 2
site every 3 weeks the MTD was found to be 180
condit mg/m2. The dose limiting toxicity was grade 4
ions thrombocytopenia. Cardiac toxicity was not dose
Invest Haemo AST limiting with this schedule.
igatio globin increa Counter measures
ns decreas se,
e, ALT There is no specific antidote. Bone marrow
Creatini increa transplantation and transfusions (platelets,
ne se, concentrated erythrocytes) may be made or
increas Alkali haematological growth factors may be given as
e, Urea ne effective countermeasures to control
increas phosp haematological side effects.
e hatase Bendamustine hydrochloride and its metabolites
increa are dialyzable to a small extent.
se,
Biliru 5. PHARMACOLOGICAL
bin PROPERTIES
increa 5.1 Pharmacodynamic properties
se, Pharmacotherapeutic group: Antineoplastic
Hypok agents, alkylating agents,
alemia
Bendamustine hydrochloride is an alkylating
NOS = Not otherwise specified antitumour agent with unique activity. The
Description of selected adverse reactions antineoplastic and cytocidal effect of
There have been isolated reports of necrosis bendamustine hydrochloride is based essentially
after accidental extra-vascular administration on a cross-linking of DNA single and double
and tumour lysis syndrome, and anaphylaxis. strands by alkylation. As a result, DNA matrix
functions and DNA synthesis and repair are
The risk of myelodysplastic syndrome and acute
impaired. The antitumour effect of
myeloid leukaemias is increased in patients
bendamustine hydrochloride has been
treated with alkylating agents (including
demonstrated by several in vitro studies in
bendamustine). The secondary malignancy may
different human tumour cell lines (breast cancer,
develop several years after chemotherapy has
non-small cell and small cell lung cancer,
been discontinued.
ovarian carcinoma and different leukaemia)
Reporting of suspected adverse reactions and in vivo in different experimental tumour
Reporting suspected adverse reactions after models with tumours of mouse, rat and human
authorisation of the medicinal product is origin (melanoma, breast cancer, sarcoma,
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lymphoma, leukaemia and small cell lung The indication for indolent non-Hodgkin's
cancer). lymphomas relied on two uncontrolled phase II
Bendamustine hydrochloride showed an activity trials.
profile in human tumour cell lines different to In the pivotal prospective, multi-centre, open
that of other alkylating agents. The active study 100 patients with indolent B-cell non-
substance revealed no or very low cross- Hodgkin´s lymphomas refractory to rituximab
resistance in human tumour cell lines with mono- or combination therapy were treated with
different resistance mechanisms at least in part BEN single agent. Patients had received a
due to a comparatively persistent DNA median of 3 previous chemotherapy or
interaction. Additionally, it was shown in biological therapy courses. The median number
clinical studies that there is no complete cross- of previous rituximab-containing courses was 2.
resistance of bendamustine with anthracyclines, The patients had had no response or there had
alkylating agents or rituximab. However, the been progression within 6 months after
number of assessed patients is small. rituximab treatment. The dose of BEN was 120
Chronic lymphocytic leukaemia mg/m² i.v. on days 1 and 2 planned for at least 6
cycles. Duration of treatment depended on
The indication for use in chronic lymphocytic response (6 cycles planned). The overall
leukaemia is supported by a single open label response rate was 75% including 17% complete
study comparing bendamustine with (CR and CRu) and 58% partial response as
chlorambucil. In the prospective, multi-centre, assessed by independent review committee. The
randomised study, 319 previously untreated median duration of remission was 40 weeks.
patients with chronic lymphocytic leukaemia BEN was generally well tolerated when given in
stage Binet B or C requiring therapy were this dose and schedule.
included. The first line therapy with
bendamustine hydrochloride 100 mg/m² i.v. on The indication is further supported by another
days 1 and 2 (BEN) was compared to treatment prospective, multi-centre, open study including
with chlorambucil 0.8 mg/kg days 1 and 15 77 patients. The patient population was more
(CLB) for 6 cycles in both arms. Patients heterogeneous including: indolent or
received allopurinol in order to prevent tumour transformed B-cell non-Hodgkin's lymphomas
lysis syndrome. refractory to rituximab mono- or combination
therapy. The patients had no response or there
Patients with BEN had a significantly longer had been progression within 6 months or had
median progression free survival than patients had an untoward reaction to prior rituximab
with CLB treatment (21.5 versus 8.3 months, p treatment. Patients had received a median of 3
< 0.0001 in the latest follow-up). Overall previous chemotherapy or biological therapy
survival was not statistically significantly courses. The median number of previous
different (median not reached). The median rituximab-containing courses had been 2. The
duration of remission was 19 months with BEN overall response rate was 76% with a median
and 6 months with CLB treatment (p < 0.0001). duration of response of 5 months (29 [95% CI
The safety evaluation in both treatment arms did 22.1, 43.1] weeks).
not reveal any unexpected undesirable effects in
nature and frequency. The dose of BEN was Multiple myeloma
reduced in 34% of the patients. Treatment with In a prospective, multi-centre, randomised, open
BEN was discontinued in 3.9% of patients due study 131 patients with advanced multiple
to allergic reactions. myeloma (Durie-Salmon stage II with
Indolent non-Hodgkin's lymphomas progression or stage III) were included. The first
line therapy with bendamustine hydrochloride in
combination with prednisone (BP) was
compared to treatment with melphalan and
 Bendamus tine H yd rochlorid e 100mg Pow der fo r Injectio n TajPhar ma : U s es , Side Effects , Interac tions , Pictures , W arni ngs , Bendamus ti ne H ydrochlori de Dos age & Rx Info | B endamus ti ne H ydrochlori de U s es , Side Effects - Anticancer, Bendam us tine H ydrochlo ride : Indicati ons , Side Effects , W arnings , Ben damus tine H ydr ochloride - Dr ug Info rmati on - TajPha rma, Be ndamus tin e H ydrochlori de dos e Taj phar maceuticals Bendam us tine H ydrochlo ride inte ractions , Taj Pha rmaceutical Ben damus tine H ydr ochloride con train dications , Benda mus tine H ydrochl oride p rice, Benda mus tine H ydrochlo ride TajPh arma An ticancer Powde r fo r Injection S mPC - TajP harma S tay connected to all upda ted on Be ndamus tin e H ydrochlorid e Taj Phar maceuticals Taj pharmaceu ticals Mumbai. Pa tient I nfor mation Lea flets , SmPC.

prednisone (MP). Neither transplant-eligibility In-vitro bendamustine does not inhibit CYP
nor the presence of specific co-morbidities 1A4, CYP 2C9/10, CYP 2D6, CYP 2E1 or CYP
played a role for inclusion into the trial. The 3A4.
dose was bendamustine hydrochloride 150 Elimination
mg/m² i.v. on days 1 and 2 or melphalan 15
mg/m² i.v. on day 1 each in combination with The mean total clearance after 30 min i.v.
prednisone. Duration of treatment depended on infusion of 120 mg/m2 body surface area to 12
response and averaged 6.8 cycles in the BP and subjects was 639.4 ml/minute. About 20% of the
8.7 cycles in the MP group. administered dose was recovered in urine within
24 hours. Amounts excreted in urine were in the
Patients with BP treatment had a longer median order monohydroxy-bendamustine >
progression free survival than patients with MP bendamustine > dihydroxy-bendamustine >
(15 [95% CI 12-21] versus 12 [95% CI 10-14] oxidised metabolite > N-desmethyl
months) (p=0.0566). The median time to bendamustine. In the bile, primarily polar
treatment failure was 14 months with BP and 9 metabolites are eliminated.
months with MP treatment. The duration of
remission was 18 months with BP and 12 Hepatic impairment
months with MP treatment. The difference in In patients with 30 - 70% tumour infestation of
overall survival was not significantly different the liver and mild hepatic impairment (serum
(35 months BP versus 33 months MP). bilirubin < 1.2 mg/dl) the pharmacokinetic
Tolerability in both treatment arms was in line behaviour was not changed. There was no
with the known safety profile of the respective significant difference to patients with normal
medicinal products with significantly more dose liver and kidney function with respect to Cmax,
reductions in the BP arm. tmax, AUC, t1/2ß, volume of distribution and
5.2 Pharmacokinetic properties clearance. AUC and total body clearance of
Distribution bendamustine correlate inversely with serum
bilirubin.
The elimination half-life t1/2ß after 30 min i.v.
infusion of 120 mg/m2 area to 12 subjects was Renal impairment
28.2 minutes. In patients with creatinine clearance > 10
Following 30 min i.v. infusion the central ml/min including dialysis dependent patients, no
volume of distribution was 19.3 l. Under steady- significant difference to patients with normal
state conditions following i.v. bolus injection the liver and kidney function was observed with
volume of distribution was 15.8-20.5 l. respect to Cmax, tmax, AUC, t1/2ß, volume of
distribution and clearance.
More than 95% of the substance is bound to
plasma proteins (primarily albumin). Elderly subjects
Metabolism Subjects up to 84 years of age were included in
pharmacokinetic studies. Higher age does not
A major route of clearance of bendamustine is influence the pharmacokinetics of bendamustine.
the hydrolysis to monohydroxy- and dihydroxy-
bendamustine. Formation of N-desmethyl- 5.3 Preclinical safety data
bendamustine and gamma-hydroxy- Adverse reactions not observed in clinical
bendamustine by hepatic metabolism involves studies, but seen in animals at exposure levels
cytochrome P450 (CYP) 1A2 isoenzyme. similar to clinical exposure levels and with
Another major route of bendamustine possible relevance to clinical use were as
metabolism involves conjugation with follows:
glutathione. Histological investigations in dogs showed
macroscopic visible hyperaemia of the mucosa
and haemorrhagia in the gastrointestinal tract.
 Bendamus tine H yd rochlorid e 100mg Pow der fo r Injectio n TajPhar ma : U s es , Side Effects , Interac tions , Pictures , W arni ngs , Bendamus ti ne H ydrochlori de Dos age & Rx Info | B endamus ti ne H ydrochlori de U s es , Side Effects - Anticancer, Bendam us tine H ydrochlo ride : Indicati ons , Side Effects , W arnings , Ben damus tine H ydr ochloride - Dr ug Info rmati on - TajPha rma, Be ndamus tin e H ydrochlori de dos e Taj phar maceuticals Bendam us tine H ydrochlo ride inte ractions , Taj Pha rmaceutical Ben damus tine H ydr ochloride con train dications , Benda mus tine H ydrochl oride p rice, Benda mus tine H ydrochlo ride TajPh arma An ticancer Powde r fo r Injection S mPC - TajP harma S tay connected to all upda ted on Be ndamus tin e H ydrochlorid e Taj Phar maceuticals Taj pharmaceu ticals Mumbai. Pa tient I nfor mation Lea flets , SmPC.

Microscopic investigations showed extensive label. Between uses, return the multidose vial to
changes of the lymphatic tissue indicating an the recommended storage condition of 2°– 8°C.
immunosuppression and tubular changes of 6.4 Special precautions for storage
kidneys and testis, as well as atrophic, necrotic Store and transport refrigerated (2 – 8°C). Do
changes of the prostate epithelium. not freeze.
Animal studies showed that bendamustine is Keep the vial in the outer carton in order to
embryotoxic and teratogenic. protect from light.
Bendamustine induces aberrations of the For storage conditions of the diluted medicinal
chromosomes and is mutagenic in vivo as well product, see section 6.3.
as in vitro. In long-term studies in female mice
bendamustine is carcinogenic. 6.5 Nature and contents of container
Packed in glass vial with rubber stopper.
6. Pharmaceutical particulars
Pack sizes of 1,4, or 5 vials.
6.1 List of excipients
Butylhydroxytoluene, Macrogol. Not all pack sizes may be marketed.
6.2 Incompatibilities 6.6 Special precautions for disposal and other
This medicinal product must not be mixed with handling
other medicinal products except those mentioned When handling Bendamustine, inhalation, skin
in section 6.6. contact or contact with mucous membranes
should be avoided (wear gloves and protective
6.3 Shelf life clothes!). Contaminated body parts should be
2 years. carefully rinsed with water and soap, the eyes
The concentrate should be diluted with 0.9% should be rinsed with physiological saline
sodium chloride solution. solution. If possible it is recommended to work
After opening of the vial on special safety workbenches (laminar flow)
with liquid-impermeable, absorbent disposable
Chemical and physical in use stability has been foil. Pregnant personnel should be excluded
demonstrated for 28 days at 2°– 8°C. from handling cytostatics.
From a microbiological point of view, once The concentrate for solution for infusion has to
opened the product may be stored for a be diluted with sodium chloride 9 mg/ml (0.9%)
maximum of 28 days at 2°– 8°C. Other in-use solution for injection and then administered by
storage times and conditions are the intravenous infusion. Aseptic technique is to be
responsibility of the user. used.
Solution for infusion 1. Dilution
After dilution, chemical and physical stability Aseptically withdraw the volume needed for the
has been demonstrated for 3.5 hours at required dose from the bendamustine 180 mg/4
25°C/60% RH and 2 days at 2°C– 8°C in ml vial. Dilute the total recommended dose of
polyethylene bags. Bendamustine hydrochloride 180 mg/4 ml with
From a microbiological point of view, the 0.9% sodium chloride solution to produce a final
solution should be used immediately. If not used volume of about 500 ml.
immediately, in-use storage times and conditions While diluting the product it should be noted
prior to use are the responsibility of the user. that the concentration (45 mg/ml) of
Minimisation of the risk of contamination of the bendamustine in Bendamustine is higher than in
multidose vial during withdrawal of each dose is usual bendamustine concentrates resulting from
the responsibility of the user. Record date and reconstitution of bendamustine powder
time of the first dose withdrawal on the vial containing medicinal products.
 Bendamus tine H yd rochlorid e 100mg Pow der fo r Injectio n TajPhar ma : U s es , Side Effects , Interac tions , Pictures , W arni ngs , Bendamus ti ne H ydrochlori de Dos age & Rx Info | B endamus ti ne H ydrochlori de U s es , Side Effects - Anticancer, Bendam us tine H ydrochlo ride : Indicati ons , Side Effects , W arnings , Ben damus tine H ydr ochloride - Dr ug Info rmati on - TajPha rma, Be ndamus tin e H ydrochlori de dos e Taj phar maceuticals Bendam us tine H ydrochlo ride inte ractions , Taj Pha rmaceutical Ben damus tine H ydr ochloride con train dications , Benda mus tine H ydrochl oride p rice, Benda mus tine H ydrochlo ride TajPh arma An ticancer Powde r fo r Injection S mPC - TajP harma S tay connected to all upda ted on Be ndamus tin e H ydrochlorid e Taj Phar maceuticals Taj pharmaceu ticals Mumbai. Pa tient I nfor mation Lea flets , SmPC.

Bendamustine hydrochloride 180 mg/4 ml must

be diluted with 0.9% NaCl solution and not with
any other injectable solutions.
2. Administration
The solution is administered by intravenous
infusion over 30-60 min.
The vials are for multiple dose use.
Any unused product or waste material should be
disposed of in accordance with local
requirements.

7.Manufactured in India By:

TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210
(INDIA).