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BENDAMUSTINE HYDROCHLORIDE 2.5 MG/ML POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

Active substance(s): BENDAMUSTINE HYDROCHLORIDE / BENDAMUSTINE HYDROCHLORIDE MONOHYDRATE

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PACKAGE LEAFLET: INFORMATION FOR THE USER

Bendamustine hydrochloride 2.5 mg/ml powder for concentrate for solution for infusion
Bendamustine hydrochloride

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, pharmacist or nurse.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side
effects not listed in this leaflet. See section 4.
What is in this leaflet
1. What Bendamustine hydrochloride is and what it is used for
2. What you need to know before you use Bendamustine hydrochloride
3. How to use Bendamustine hydrochloride
4. Possible side effects
5. How to store Bendamustine hydrochloride
6. Contents of the pack and other information

1. What Bendamustine hydrochloride is and what it is used for
Bendamustine hydrochloride is a medicine which is used for the treatment of certain types of cancer
(cytotoxic medicine).
Bendamustine hydrochloride 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 lymphomas, which had not, or only shortly, responded to prior rituximab treatment,
- multiple myeloma in cases where high-dose 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 hydrochloride
Do not use Bendamustine hydrochloride
- if you are allergic to bendamustine hydrochloride or any of the other ingredients of this medicine (listed
in section 6);
- while breast-feeding;
- 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 platelet values
dropped 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.

Warning and precautions
Talk to your doctor, pharmacist or nurse before using bendamustine hydrochloride
-

-

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
hydrochloride, 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 cases of existing heart disease (e.g. heart attack, chest pain, severely disturbed heart rhythms).

Talk to your doctor, pharmacist or nurse during use of bendamustine hydrochloride
- in case of nausea, vomiting. Your doctor may give you a drug to reduce nausea (antiemetic).
- 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 hydrochloride Your doctor will be aware of this and may give
you other medicines to help prevent it.
- in case of reactions on your skin during treatment with bendamustine hydrochloride. The reactions may
increase in severity.
In case of severe allergic or hypersensitivity reactions. You should pay attention to infusion reactions
after your first cycle of therapy.
Men receiving treatment with bendamustine hydrochloride 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).
Children and adolescents
There is no experience in children and adolescents with bendamustine hydrochloride.
Other medicines and Bendamustine hydrochloride
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
If bendamustine hydrochloride 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 hydrochloride is used in combination with medicines which alter your immune response,
this effect may be intensified.
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).
Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your
doctor or pharmacist for advice before taking this medicine.
Pregnancy
Bendamustine hydrochloride can cause genetic damage and has caused malformations in animal studies. You
should not use bendamustine hydrochloride during pregnancy unless clearly indicated by your doctor. In case

of treatment you should have medical consultation about the risk of potential adverse effects of your therapy
for the unborn child and genetic consultation is recommended.
If you are a woman of childbearing potential you must use an effective method of contraception both before
and during treatment with bendamustine hydrochloride. If pregnancy occurs during your treatment with
bendamustine hydrochloride you must immediately inform your doctor and should have genetic consultation.
Breast-feeding
Bendamustine hydrochloride must not be administered during breast-feeding. If treatment with bendamustine
hydrochloride is necessary during lactation you must discontinue breast-feeding.
Fertility
If you are a man, you should avoid fathering a child during treatment with bendamustine hydrochloride and
for up to 6 months after treatment has stopped. There is a risk that treatment with bendamustine
hydrochloride will lead to infertility and you may wish to seek advice on conservation of sperm before
treatment starts.
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 hydrochloride
Bendamustine hydrochloride 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 your white blood cells (leukocytes) have fallen to counts below 3,000
cells/µl and/or your blood platelets have fallen to counts below 75,000 cells/µl.
Your doctor will determine these values at regular intervals.
Chronic lymphocytic leukaemia
Bendamustine hydrochloride 2.5 mg/ml powder for concentrate for
solution for infusion 100 mg per square metre of your body surface
area (based on your height and weight)
Repeat the cycle after 4 weeks

on Days 1+2

Non-Hodgkin lymphomas
Bendamustine hydrochloride 2.5 mg/ml powder for concentrate for
solution for infusion 120 mg per square metre of your body surface
area (based on your height and weight)
Repeat the cycle after 3 weeks

on Days 1 + 2

Multiple myeloma
Bendamustine hydrochloride 2.5 mg/ml powder for concentrate for
solution for infusion 120 - 150 mg per square metre of your body
surface area (based on your height and weight)
Prednisone 60 mg 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 dropped to < 3,000/µl
or < 75,000/µl, respectively. Treatment can be continued after white blood cell values have increased to >
4,000/µl and platelet values to > 100,000/µl.
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 hydrochloride 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.
How it is administered
Treatment with bendamustine hydrochloride should be undertaken only by doctors experienced in tumour
therapy. Your doctor will give you the exact dose of bendamustine hydrochloride 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
There is no time limit laid down as a general rule for treatment with bendamustine hydrochloride. Duration
of treatment depends on disease and response to treatment.
If you are at all worried or have any questions regarding treatment with bendamustine hydrochloride, please
speak to your doctor or nurse.
If you forget to use Bendamustine hydrochloride
If a dose of bendamustine hydrochloride has been forgotten, your doctor will usually retain the normal
dosage schedule.
If you stop using Bendamustine hydrochloride
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 medicine, ask your doctor, pharmacist or nurse.

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-effect of bendamustine hydrochloride 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 heart
function 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)

Very rare (may affect up to 1 in 10,000 people)









Primary atypical
inflammation of the
lungs (pneumonia)
Break-down of red
blood cell
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 inflammation
of the gullet
(haemorrhagic
oesophagitis)
Bleeding of stomach or
gut
Infertility
Multiple organ failure

Not known (frequency cannot be estimated from the available data)


Liver failure

There have been reports of secondary tumours (myelodysplastic syndrome, Acute Myeloid Leukaemia
(AML), bronchial carcinoma) following treatment with bendamustine hydrochloride. No clear relationship
with bendamustine hydrochloride could be determined.
A small number of cases of severe skin reactions (Stevens - Johnson syndrome and Toxic Epidermal
Necrolysis) have been reported. The relationship with bendamustine hydrochloride 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 at:
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 hydrochloride
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 the carton. The expiry date
refers to the last day of that month.
This medicine does not require any special storage conditions.
Note on shelf-life after opening or preparing the solution
Solutions for infusion prepared according to the directions listed at the end of this leaflet are stable in
polyethylene bags at 25°C/60% relative humidity for 3.5 hours and in a refrigerator they are stable for
36 hours. Bendamustine hydrochloride contains no preservatives. The solutions should not therefore be used
after these lengths of time.

It is the responsibility of the user to maintain aseptic conditions.
Do not use this medicine if you notice any signs of deterioration.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw
away medicines you no longer use. These measures will help protect the environment.
6. Contents of the pack and other information
What Bendamustine hydrochloride 2.5 mg/ml powder for concentrate for solution for infusion
contains
• The active substance is bendamustine hydrochloride.
1 vial contains 25 mg of bendamustine hydrochloride (as bendamustine hydrochloride monohydrate).
1 vial contains 100 mg of bendamustine hydrochloride (as bendamustine hydrochloride monohydrate).
After reconstitution 1 ml of the concentrate contains 2.5 mg bendamustine hydrochloride (as bendamustine
hydrochloride monohydrate).


The other ingredient is mannitol.

What Bendamustine hydrochloride 2.5 mg/ml powder for concentrate for solution for infusion looks
like and contents of the pack
Brown glass vial with rubber stopper and an aluminium flip-off cap.
The powder appears white to off-white.
Bendamustine hydrochloride is available in packs containing 1, 5, 10 or 20 vials with 25 mg of bendamustine
hydrochloride and 1, 5, 10 or 20 vials with 100 mg of bendamustine hydrochloride.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Mylan, Potters Bar, Hertfordshire, EN6 1TL
Manufacturer
Wessling Hungary Kft.
Fóti út 56
1047 Budapest
Hungary
This leaflet was last revised in 06/2016
Detailed information on this medicine is available on the web site of the MHRA.
<------------------------------------------------------------------------------------------------------------------------>
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
hydrochloride (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 are cytostatic waste. Please comply
with national guidelines on the disposal of cytostatic material! The vials are for single use only. Pregnant
staff must be excluded from working with cytostatics.

The concentrate and solution for infusion must be prepared as follows:
1. Preparation of the concentrate
- One vial of Bendamustine hydrochloride 2.5 mg/ml powder for concentrate for solution for infusion
containing 25 mg of bendamustine hydrochloride is first dissolved in 10 ml water for injections by
shaking;
- One vial of Bendamustine hydrochloride 2.5 mg/ml powder for concentrate solution for infusion
containing 100 mg of bendamustine hydrochloride is first dissolved in 40 ml water for injections by
shaking.
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 hydrochloride 2.5 mg/ml powder for concentrate for solution for infusion is immediately
diluted with 0.9% (isotonic) saline solution to obtain a final volume of approximately 500 ml. Bendamustine
hydrochloride 2.5 mg/ml powder for concentrate for solution for infusion must not be diluted with other
solutions for infusion or injection. Bendamustine hydrochloride must not be mixed in an infusion with other
substances.

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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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