What it is and what it is used for

for Bendamustine hydrochloride 2.5mg/ml Powder for concentrate for solution for infusion is a medicine containing an active substance called bendamustine hydrochloride (hereafter called bendamustine). Bendamustine is a medicine which is used for the treatment of certain types of cancer (cytotoxic medicine). Bendamustine 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 thalidomide or bortezomib containing therapy is not appropriate for you.

What you need to know before you take it

e bendamustine Do not use bendamustine

• if you are allergic to bendamustine hydrochloride or any of the other ingredients of this medicine (listed in section 6).
• while breastfeeding, if treatment with bendamustine is necessary during lactation you must discontinue breast-feeding (see section warnings and precautions on 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.
• 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. Do not use this product if the above applies to you. If you are not sure, talk to your doctor or pharmacist before using bendamustine. Warnings and precautions Talk to your doctor or pharmacist before using bendamustine
• 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, 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. The skin reactions may increase in severity.
• in case of painful red or purplish rash that spreads and blisters and/or other lesions begin to appear in the mucous membrane (e.g. mouth and lips), in particular if you had before light sensitivity, infections of the respiratory system (e.g. bronchitis) and/or fever.
• 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. Your doctor may ensure you are adequately hydrated and 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.

At any time during or after your treatment, tell your doctor immediately if you notice or someone notices in you: Memory loss, trouble thinking, difficulty walking or sight loss – these may be due to a very rare but serious brain infection which can be fatal (progressive multifocal leukoencephalopathy or PML). Contact your doctor if you notice any suspicious skin changes because there may be an increased risk of certain types of skin cancer (non-melanoma skin cancer) with the use of this medicine. Other medicines and bendamustine Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. If bendamustine 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 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, breastfeeding 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 using this medicine. Pregnancy Bendamustine can cause genetic damage and has caused malformations in animal studies. You should not use bendamustine during pregnancy unless certainly indicated by your doctor. In case of treatment you should use medical consultation about the risk of potential adverse effects of your therapy for the unborn child and genetic consultation is recommended. Breast-feeding Bendamustine must not be administered during breast-feeding. If treatment with bendamustine is necessary during lactation you must discontinue breast-feeding. Fertility If you are a woman of childbearing potential you must use an effective method of contraception both before and during treatment with bendamustine. If pregnancy occurs during your treatment with bendamustine you must immediately inform your doctor and should use genetic consultation. If you are a man, you should avoid fathering a child during treatment with bendamustine and for up to 6 months after treatment has stopped. There is a risk that treatment with bendamustine will lead to infertility and you may wish to seek advice on conservation of sperm before treatment starts. Men receiving treatment with bendamustine 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. 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 take it

bendamustine Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. Bendamustine 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 determined levels. Your doctor will determine these values at regular intervals. Chronic lymphocytic leukaemia Bendamustine 100 mg per square metre of your body surface area (based on your height and weight)

on Days 1+2

Repeat the cycle after 4 weeks up to 6 times Non-Hodgkin's lymphomas on Days 1+2 Bendamustine 120 mg per square metre of your body surface area (based on your height and weight) Repeat the cycle after 3 weeks at least 6 times Multiple myeloma Bendamustine 120 – 150 mg per square metre of your body surface area (based on your height and weight)

on Days 1+2

Prednisone 60 mg per square metre of your body surface area (based on your height and weight) i.v. or per os

on Days 1-4

Repeat the cycle after 4 weeks at least 3 times Treatment should be terminated if white blood cell (leukocyte) and/or platelet values dropped to determined levels. Treatment can be continued after white blood cell and platelet values have increased. 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). No dose adjustment is necessary in case of impairment of kidney function. Your attending doctor will decide whether a dosage adjustment is necessary.

____________________________________________________________________________________ The following information is intended for medical or 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 cancercausing effect of the preparation. Avoid inhalation (breathing in) and contact with the skin and mucous membranes when handling bendamustine (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.

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How it is administered Treatment with bendamustine should be undertaken only by doctors experienced in tumour therapy. Your doctor will give you the exact dose of bendamustine 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. Duration of treatment depends on disease and response to treatment. If you are at all worried or have any questions regarding treatment with bendamustine, please speak to your doctor or nurse. If you forget to use bendamustine If a dose of bendamustine has been forgotten, your doctor will usually retain the normal dosage schedule. If you stop using bendamustine 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 or pharmacist. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of the findings listed below may be found after tests are performed by your doctor. Tissue decay (necrosis) has been observed very rarely following leakage of bendamustine into the tissue outside the blood vessels (extravascular). A burning sensation where the infusion needle is inserted may be a sign of leakage outside the blood vessels. The consequence can be pain and poorly healing skin defects. The dose-limiting side-effect of bendamustine is impaired bone-marrow function, which usually returns to normal after treatment. Suppressed bone marrow function may lead to low blood cells, which in turn may lead to an increased risk of infection, anaemia or a heightened risk of bleeding. Very common side effects (may affect more than 1 in 10 people)

• Infections.
• Low counts of white blood cells (diseasefighting cells in your blood); decrease in the red pigment of the blood (haemoglobin: a protein in red blood cells that carries oxygen throughout the body); low counts of platelets (colourless blood cells that help blood clot).
• Headache.
• Feeling sick (nausea); vomiting.
• Mucosal inflammation; fatigue; fever.
• Increased blood level of creatinine (a chemical waste product that is produced by your muscle); increased blood level of urea (a chemical waste product). Common side effects (may affect up to 1 in 10 people)
• Disturbed metabolism caused by dying cancer cells releasing their contents into the blood stream.
• Bleeding (haemorrhage); reduction in red blood cells which can make the skin pale and cause weakness or breathlessness (anaemia); low counts of neutrophils (a common type of white blood cell important to fighting off infections).
• Hypersensitivity reactions such as allergic inflammation of the skin (dermatitis).
• Insomnia; dizziness.
• Disturbed function (dysfunction) of the heart; disturbed heart rhythms (arrhythmia).
• Low or high blood pressure (hypotension or hypertension).
• Disturbed lung function.
• Diarrhoea; constipation; sore mouth (stomatitis).
• Hair loss; skin changes; itchy rash (urticaria).
• Missed periods (amenorrhoea).
• Pain; chills; dehydration; loss of appetite.
• A rise in liver enzymes AST/ALT (which may indicate inflammation or damage to cells in the liver); a rise in the enzyme alkaline phosphatase (an enzyme made mostly in the liver and bones); a rise in bile pigment (a substance made during the normal breakdown of red blood cells); low potassium blood levels (a nutrient that is necessary for the function of nerve and muscle cells, including those in your heart). Uncommon side effects (may affect up to 1 in 100 people)
• Inflammation of the lungs.
• Acute leukaemia.
• Ineffective production of all blood cells (the spongy material inside your bones where blood cells are made).
• Accumulation of fluid in the heart sac (escape of fluid into the pericardial space); heart attack, chest pain (myocardial infarct); heart failure. Rare side effects (may affect up to 1 in 1,000 people)
• Infection of the blood (sepsis).
• Reduction in your bone marrow function, which may make you feel unwell or show up in your blood tests.
• Severe allergic hypersensitivity reactions (anaphylactic reactions); signs similar to anaphylactic reactions (anaphylactoid reactions).
• Drowsiness; loss of voice (aphonia).
• Acute circulatory collapse (failure of blood circulation mainly from a cardiac origin with failure to maintain the supply of oxygen and other nutrients to the tissues and removing toxins).
• Reddening of the skin (erythema); inflammation of the skin (dermatitis); itching (pruritus); skin rash (macular exanthema); excessive sweating (hyperhidrosis).

Very rare side effects (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); serious condition resulting in the blockade of specific receptor in the nervous systems; disorders of the nervous system; lack of coordination (ataxia); inflammation of the brain (encephalitis).
• Increased heart rate (tachycardia).
• 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 side effects (cannot be estimated from the available data)
• Irregular and often rapid heart rate (atrial fibrillation).
• Inflammation of air sacs in the lungs (pneumonitis); bleeding from the lungs.
• Liver failure.
• Renal failure. There have been reports of tumours (myelodysplastic syndrome, AML, bronchial carcinoma) following treatment with bendamustine. No clear relationship with bendamustine could be determined. Contact your doctor or seek medical attention immediately if you notice any of the following side effects (frequency not known): Serious skin rashes including StevensJohnson syndrome and toxic epidermal necrolysis. These can appear as reddish target-like macules or circular patches often with central blisters on the trunk, skin peeling, ulcers of mouth, throat, nose, genitals and eyes and can be preceded by fever and flu-like symptoms. Widespread rash, high body temperature, enlarged lymph nodes and other body organs involvement (drug reaction with eosinophilia and systemic symptoms which is also known as DRESS or drug hypersensitivity syndrome). Reporting of side effects If you get any side effects, talk to your doctor or nurse. This includes any possible

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 or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

How to store it

bendamustine 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 carton after 'EXP'. The first two digits indicate the month and the last four digits indicate the year. The expiry date refers to the last day of that month. Keep the container in the outer carton to protect the content from light. Note on shelf-life after opening or preparing the solution Solutions for infusions prepared according to the directions listed at the end of this leaflet are stable in polyethylene bags at room temperature / 60% relative humidity for 3.5 hours, and in a refrigerator they are stable for 2 days. Bendamustine 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 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.

Contents of the pack and other information

What bendamustine contains

• The active substance is bendamustine hydrochloride. 1 vial contains either 25 mg or 100 mg bendamustine hydrochloride. After reconstitution 1 ml of the concentrate contains 2.5 mg bendamustine hydrochloride.
• The other ingredient is mannitol. What Bendamustine looks like and contents of the pack White to off-white freeze-dried powder in an amber glass vial with a stopper and Alu-cap with flip-top. Type I glass vials of 25 ml or 50 ml. Packs containing: 25 mg: 1, 5, 10, 20 vials. 100 mg: 1, 5 vials. Not all pack sizes may be marketed. The Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder Zentiva Pharma UK Limited, 12 New Fetter Lane, London, EC4A 1JP United Kingdom. Manufacturer Synthon s.r.o. Brněská 32/čp.597, 678 01 Blansko, Czech Republic or Synthon Hispania SL, C/ Castelló no 1, Pol. Las Salinas, Sant Boi de Llobregat, Barcelona, 08830, Spain This leaflet was last revised in July 2021. 'Zentiva' is a registered trademark. © 2021 Zentiva.

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____________________________________________________________________________________ Information for healthcare professionals only, continued The solution ready for use must be prepared by dissolving the contents of an injection vial of bendamustine exclusively in water for injections, as follows: 1. Preparation of the concentrate

• One injection vial of bendamustine containing 25 mg bendamustine hydrochloride is first dissolved in 10 ml by shaking.
• One injection vial of bendamustine containing 100 mg bendamustine hydrochloride is first dissolved in 40 ml 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 is immediately diluted with 0.9% (isotonic) saline solution to obtain a final volume of approximately 500 ml. Bendamustine must not be diluted with other solutions for infusion or injection. Bendamustine must not be mixed in an infusion with other substances.

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