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.

What is in this leaflet j What Bendamustine Powder is and what it is used for What you need to know before you use Bendamustine Powder 1| How to use Bendamustine Powder ^ Possible side effects Jj How to store Bendamustine Powder

Contents of the pack and other information

j What Bendamustine Powder is and what it is used for

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.

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 /gl or < 75,000 /gl, 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).

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Children and adolescents

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.

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).

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.

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.

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 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.

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.

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

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.

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

If you forget to use Bendamustine Powder

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.

^ 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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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.

Not know (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. No clear relationship with bendamustine 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 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.

T| 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 25°C/60% RH, in normal light conditions and 2 days at 2°C to 8°C, 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 2°C to 8°C, 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.

« 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.

Reykjavikurvegi 76-78, 220 HafnarfjorSur, Iceland

Manufacturer

S.C. SINDAN-PHARMA S.R.L.

11^th 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.

v actavis

Actavis, Barnstaple, EX32 8NS, UK