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BENDAMUSTINE HYDROCHLORIDE POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

Active substance(s): BENDAMUSTINE HYDROCHLORIDE

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Package leaflet:
Information for the user

Bendamustine Hydrochloride 2.5mg/ml Powder
for Concentrate for Solution for Infusion
Read all of this leaflet carefully before
you start using this medicine because it
contains important information for you.
• Keep this leaflet. You may need to read it
again.
• If you have any further questions, ask
your doctor or pharmacist.
• If you get any side effects, talk to your
doctor or pharmacist. This includes any
possible side effects not listed in this
leaflet. See section 4.
• The full name of this medicine is
Bendamustine Hydrochloride 2.5mg/ml
Powder for Concentrate for Solution for
Infusion but within the leaflet it will be
referred to as Bendamustine Powder.

Children and adolescents

What is in this leaflet
1 What Bendamustine Powder is
and what it is used for
2 What you need to know before
you use Bendamustine Powder
3 How to use Bendamustine Powder
4 Possible side effects
5 How to store Bendamustine
Powder
6 Contents of the pack and other
information
1 What Bendamustine Powder is
and what it is used for

Medicines such as bendamustine (cytostatic
medicines) may diminish the effectiveness of
live virus vaccination. Additionally cytostatic
medicines increase the risk of an infection
after vaccination with live vaccines (e.g. viral
vaccination).

Bendamustine Powder is a medicine which
is used for the treatment of certain types of
cancer (cytotoxic medicine).

Bendamustine Powder is used alone
(monotherapy) or in combination with other
medicines for the treatment of the following
forms of cancer:
• chronic lymphocytic leukaemia in
cases where fludarabine combination
chemotherapy is not appropriate for you.
• non‑Hodgkin’s lymphomas, which had not,
or only shortly, responded to prior rituximab
treatment.
• Multiple myeloma in cases where highdose
chemotherapy with autologous stem cell
transplantation, thalidomide or bortezomib
containing therapy is not appropriate for
you.

2 What you need to know before

you use Bendamustine Powder

Do not use Bendamustine Powder:

• if you are allergic to bendamustine
hydrochloride or any of the other ingredients
of this medicine (listed in section 6).
• while breastfeeding.
• if you have severe liver dysfunction (damage
to the functional cells of the liver).
• if you have yellowing of the skin or whites of
the eyes caused by liver or blood problems
(jaundice).
• if you have severely disturbed bone marrow
function (bone marrow depression) and
serious changes in your number of white
blood cells and platelets in the blood (white
blood cells and/or thrombocyte values drop
to < 3,000 /μl or < 75,000 /μl, respectively).
• if you have had major surgical operations
less than 30 days before starting treatment.
• if you have an infection, especially one
accompanied by a reduction in white blood
cells (leucocytopenia).
• in combination with yellow fever vaccines.

Warnings and precautions

Talk to your doctor before or during treatment
with Bendamustine Powder:
• in case of reduced capability of the bone
marrow to replace blood cells. You should
have your number of white blood cells
and platelets in the blood checked before
starting treatment with Bendamustine
Powder, before each subsequent course
of treatment and in the intervals between
courses of treatment.
• in case of infections. You should contact
your doctor if you have signs of infection,
including fever or lung symptoms.
• in case of reactions on your skin during
treatment with Bendamustine Powder. The
reactions may increase in severity.
• in cases of existing heart disease (e.g. heart
attack, chest pain, severely disturbed heart
rhythms).
• in case you notice any pain in your side,
blood in your urine or reduced amount of
urine. When your disease is very severe, your
body may not be able to clear all the waste
products from the dying cancer cells. This is
called tumour lysis syndrome and can cause
kidney failure and heart problems within
48 hours of the first dose of Bendamustine
Powder. Your doctor will be aware of this
and may give you other medicines to help
prevent it.
• in case of severe allergic or hypersensitivity
reactions. You should pay attention to
infusion reactions after your first cycle of
therapy, with symptoms such as fever, chills,
itching and rash.
Men receiving treatment with Bendamustine
Powder are advised not to conceive a child
during treatment and for up to 6 months
afterwards. Before starting treatment, you
should seek advice on storing sperm because
of the possibility of permanent infertility.
Unintentional injection into the tissue outside
blood vessels (extravasal injection) should be
stopped immediately. The needle should be
removed after a short aspiration. Thereafter
the affected area of tissue should be cooled.
The arm should be elevated. Additional
treatments like the use of corticosteroids are
not of clear benefit (see section 4).

There is no experience in children and
adolescents with Bendamustine Powder.

Other medicines and Bendamustine
Powder

Tell your doctor or pharmacist if you are
taking, have recently taken or might take any
other medicines.
If Bendamustine Powder is used in
combination with medicines which inhibit the
formation of blood in the bone marrow, the
effect on the bone marrow may be intensified.
If Bendamustine Powder is used in
combination with medicines which alter
your immune response, e.g. ciclosporin and
tacrolimus, this effect may be intensified.

If Bendamustine Powder is used in
combination with medicines which inhibit
the enzyme CYP1A2, such as fluvoxamine
(antidepressant), ciprofloxacin (used to treat
bacterial infections), acyclovir (used to treat
virus infections) and cimetidine (used to
treat heartburn and stomach ulcers), these
medicines can interfere with each other.

Pregnancy, breast-feeding and
fertility

If you are pregnant or breast-feeding, think
you might be pregnant or are planning to
have a baby, ask your doctor for advice before
taking any medicine.

Pregnancy

Bendamustine Powder can cause genetic
damage and has caused malformations
in animal studies. You should not use
Bendamustine Powder during pregnancy
unless certainly indicated by your doctor. In
case of treatment you should seek medical
consultation about the risk of potential
adverse effects of your therapy for the
unborn child and genetic consultation is
recommended.

Fertility

If you are a woman of childbearing potential
you must use an effective method of
contraception both before and during
treatment with Bendamustine Powder. If
pregnancy occurs during your treatment with
Bendamustine Powder you must immediately
inform your doctor and seek genetic
consultation.
If you are a man, you should avoid fathering
a child during treatment with Bendamustine
Powder and for up to 6 months after
treatment has stopped. There is a risk that
treatment with Bendamustine Powder will
lead to infertility and you may wish to seek
advice on conservation of sperm before
treatment starts.

Breast-feeding

Bendamustine Powder must not be
administered during breast-feeding. If
treatment with Bendamustine Powder
is necessary during lactation you must
discontinue breast-feeding.

Driving and using machines

No studies on the effects on the ability to drive
and to use machines have been performed.
Do not drive or operate machines if you
experience side effects, such as dizziness or
lack of coordination.

3 How to use Bendamustine Powder
Bendamustine Powder is administered into a
vein over 30‑60 minutes in various dosages,
either alone (monotherapy) or in combination
with other medicines.

Treatment should not be started if you have
low white blood cell (leukocyte) and/or blood
platelet counts. Your doctor will measure these
at regular intervals.
Chronic lymphocytic leukaemia
Bendamustine Powder 100mg per on Days
square metre of your body surface 1 + 2
area (based on your height and
weight)
Repeat the cycle after 4 weeks
Non-Hodgkin’s lymphomas
Bendamustine Powder 120mg
per square metre of your body
surface area (based on your
height and weight)

on Days
1+2

Repeat the cycle after 3 weeks
Multiple myeloma
Bendamustine Powder 120 –
150mg per square metre of your
body surface area (based on your
height and weight)
Prednisone 60mg per square
metre of your body surface
area (based on your height and
weight) i.v. or per os.
Repeat the cycle after 4 weeks

on Days
1+2

on Days
1–4

Treatment should be terminated if white
blood cell (leukocyte) and/or platelet values
drop too low. Treatment can be continued
after white blood cell and platelet values have
improved.

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Bendamustine Hydrochloride 2.5mg/ml Powder for Concentrate for Solution for Infusion
The following information is intended for healthcare professionals only:
As with all similar cytotoxic substances, stricter
safety precautions apply as far as nursing staff
and doctors are concerned, due to the potentially
genome damaging and cancer causing effect
of the preparation. Avoid inhalation (breathing
in) and contact with the skin and mucous
membranes when handling Bendamustine
Powder (wear gloves, protective clothing, and
possibly a face mask!). If any parts of the body
become contaminated, clean them carefully with
soap and water, and flush the eyes with 0.9%
(isotonic) saline solution. If possible, it is advisable
to work on a special safety work bench (laminar
flow) with a disposable absorbent sheet that is
impermeable to liquids. Contaminated articles
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are cytostatic waste. Please comply with national
guidelines on the disposal of cytostatic material!
Pregnant staff must be excluded from working
with cytostatics.
The solution ready for use must be prepared
in two stages (by using sterile techniques), as
follows:
1. Preparation of the concentrate
• One injection vial of Bendamustine Powder
containing 25mg of bendamustine
hydrochloride is first dissolved in 10ml of
water for injections by shaking.

Continued over page

Impaired liver or kidney function
Dependent on the degree of impairment
of your liver function it may be necessary to
adjust your dose (by 30% in case of moderate
liver dysfunction). Bendamustine Powder
should not be used if you suffer from severe
liver dysfunction. No dose adjustment is
necessary in case of impairment of kidney
function. Your attending doctor will decide
whether a dosage adjustment is necessary.

There is no time limit laid down as a general
rule for treatment with Bendamustine
Powder. Duration of treatment depends on
disease and response to treatment.

Very rare (may affect up to 1 in 10,000
people):
• primary atypical inflammation of the lungs
(pneumonia)
• break down of red blood cells
• rapid decrease in blood pressure
sometimes with skin reactions or rash
(anaphylactic shock)
• disturbed sense of taste
• altered sensations (paraesthesia)
• malaise and pain in the limbs (peripheral
neuropathy)
• disease of the nervous system
(anticholinergic syndrome)
• neurological disorders
• lack of coordination (ataxia)
• inflammation of the brain (encephalitis)
• increased heart rate (tachycardia)
• heart attack, chest pain (myocardial infarct)
• heart failure
• inflammation of the veins (phlebitis)
• formation of tissue in the lungs (fibrosis of
the lungs)
• bleeding and inflammation of the gullet
(haemorrhagic oesophagitis)
• bleeding of stomach or gut
• infertility
• multiple organ failure.

If you are at all worried or have any questions
regarding treatment with Bendamustine
Powder, please speak to your doctor or nurse.

Not know (frequency cannot be estimated
from the available data):
• liver failure.

If you forget to use Bendamustine
Powder

There have been reports of secondary
tumours (myelodysplastic syndrome,
acute myeloid leukaemia (AML), bronchial
carcinoma) following treatment with
bendamustine. No clear relationship with
bendamustine could be determined.

How it is administered

Treatment with Bendamustine Powder
should be undertaken only by doctors
experienced in tumour therapy. Your doctor
will give you the exact dose of Bendamustine
Powder and use the necessary precautions.
Your attending doctor will administer the
solution for infusion after preparation as
prescribed. The solution is administered into
a vein as a short‑term infusion over 30‑60
minutes.

Duration of use

If a dose of Bendamustine Powder has been
forgotten, your doctor will usually retain the
normal dosage schedule.

If you stop using Bendamustine
Powder

The doctor treating you will decide whether
to interrupt the treatment or to change over
to a different preparation.
If you have any further questions on the
use of this this medicine, ask your doctor or
pharmacist.

4 Possible side effects

Like all medicines, this medicine can cause
side effects, although not everybody gets
them.
Tissue changes (necrosis) have been
observed very rarely following unintentional
injection into the tissue outside blood vessels
(extravascular). A burning sensation where
the infusion needle is inserted may be a sign
for administration outside the blood vessels.
The consequence of administration in this
way can be pain and poorly healing skin
defects.
The dose limiting side effects of
Bendamustine Powder is impaired bone
marrow function, which usually returns
to normal after treatment. Suppressed
bone marrow function increases the risk of
infection.
Very common (may affect more than 1 in 10
people):
• low counts of white blood cells
(leukocytopenia)
• decrease in the red pigment of the blood
(haemoglobin)
• low counts of platelets (thrombocytopenia)
• infections
• feeling sick (nausea)
• vomiting
• mucosal inflammation
• increased blood level of creatinine
• increased blood level of urea
• fever
• fatigue.
Common (may affect up to 1 in 10 people):
• bleeding (haemorrhage)
• disturbed metabolism caused by dying
cancer cells releasing their contents into the
blood stream (tumour lysis syndrome)
• reduction in red blood cells which can
make the skin pale and cause weakness or
breathlessness (anaemia)
• low counts of neutrophils (neutropenia)
• hypersensitivity reactions such as allergic
inflammation of the skin (dermatitis), nettle
rash (urticaria)
• a rise in liver enzymes AST/ALT
• a rise in the enzyme alkaline phosphatase
• a rise in bile pigment
• low potassium blood levels
• disturbed function (dysfunction) of the
heart, such as feeling your heartbeat
(palpitations) or chest pain (angina pectoris)
• disturbed heart rhythms (arrhythmia)
• low or high blood pressure (hypotension or
hypertension)
• disturbed lung function
• diarrhoea
• constipation
• sore mouth (stomatitis)
• loss of appetite
• hair loss
• skin changes
• missed periods (amenorrhoea)
• pain
• insomnia
• chills
• dehydration.

Uncommon (may affect up to 1 in 100
people):
• accumulation of fluid in the heart sac
(escape of fluid into the pericardial space).
Rare (may affect up to 1 in 1,000 people):
• infection of the blood (sepsis)
• severe allergic hypersensitivity reactions
(anaphylactic reactions)
• signs similar to anaphylactic reactions
(anaphylactoid reactions)
• drowsiness
• loss of voice (aphonia)
• acute circulatory collapse
• reddening of the skin (erythema)
• inflammation of the skin (dermatitis)
• itching (pruritus)
• skin rash (macular exanthema)
• excessive sweating (hyperhidrosis).

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A small number of cases of severe skin
reactions (Stevens‑Johnson Syndrome
and Toxic Epidermal Necrolysis) have been
reported. The relationship with Bendamustine
Powder is unclear.

Reporting of side effects

If you get any side effects, talk to your doctor,
pharmacist or nurse. This includes any
possible side effects not listed in this leaflet.
You can also report side effects directly via the
Yellow Card Scheme Website:
www.mhra.gov.uk/yellowcard
By reporting side effects you can help provide
more information on the safety of this
medicine.

5 How to store Bendamustine

Powder

Keep this medicine out of the sight and reach
of children.
Do not use this medicine after the expiry date
which is stated on the label and carton after
‘EXP’. The expiry date refers to the last day of
that month.

Unopened

This medicinal product does not require any
special storage conditions.

Reconstituted concentrate

The powder should be reconstituted
immediately after opening of the vial.
The reconstituted concentrate should be
diluted immediately with 0.9% sodium
chloride solution (see instructions at the end
of this leaflet).

Solution for infusion

After reconstitution and dilution, chemical
and physical stability has been demonstrated
for 3.5 hours at 25ºC/60% RH, in normal
light conditions and 2 days at 2ºC to 8ºC,
protected from light, in polyethylene bags.
From a microbiological point of view, the
solution should be used immediately. If not
used immediately, in use storage times and
conditions prior to use are the responsibility
of the user and would normally not be
longer than 24 hours at 2ºC to 8ºC, unless
reconstitution/dilution has taken place in
controlled and validated aseptic conditions.
Do not use this medicine if you notice any
visible signs of deterioration or damage to the
vials. Following reconstitution and dilution,
the product should be inspected visually
for particulate matter or discolouration. The
solution should only be used if the solution is
clear and free from particles.

6 Contents of the pack and other

information

What Bendamustine Powder contains
• The active substance is bendamustine
hydrochloride. After reconstitution, 1ml of
concentrate contains 2.5mg bendamustine
hydrochloride. One vial contains 25mg or
100mg bendamustine hydrochloride.
• The other ingredient is mannitol.

What Bendamustine Powder looks
like and contents of the pack.
White to off white lyophilisate powder.

Type I amber glass vials of 26ml or 60ml with
type I rubber (bromobutyl) lyo-stopper and
an aluminium cap with polypropylene disk.
Vials are sheathed in protective sleeve.
26ml - vials contain 25mg bendamustine
hydrochloride and are supplied in packs of
5 and 20 vials.
60ml - vials contain 100mg bendamustine
hydrochloride and are supplied in packs of
5 vials.

Marketing Authorisation Holder

Actavis Group PTC ehf.
Reykjavíkurvegi 76-78, 220 Hafnarfjörður,
Iceland

Manufacturer

S.C. SINDAN-PHARMA S.R.L.
11th Ion Mihalache Boulevard, 011171,
Bucharest 1, Romania
This leaflet was last revised in
November 2015.

If you would like a
leaflet with larger text,
please contact
01271 385257.
Actavis, Barnstaple, EX32 8NS, UK

• One injection vial of Bendamustine Powder
containing 100mg of bendamustine
hydrochloride is first dissolved in 40ml of
water for injections by shaking.

Administration
The solution is administered by infusion into a
vein over 30-60 min.
The vials are for single use only.

The reconstituted concentrate contains
2.5mg bendamustine hydrochloride per ml
and appears as a clear colourless solution.

Any unused medicinal product or waste material
should be disposed of in accordance with local
requirements.

2. Preparation of the solution for infusion
 As soon as a clear solution is obtained
(generally after 5‑10 minutes), the total
recommended dose of Bendamustine
Powder is immediately diluted with
0.9% (isotonic) saline solution to obtain
a final volume of approximately 500ml.
Bendamustine Powder must not be diluted
with other solutions for infusion or injection.
Bendamustine Powder must not be mixed in
an infusion with other substances.
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AAAI4780

Actavis, Barnstaple, EX32 8NS, UK

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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