BENDAMUSTINE HYDROCHLORIDE 2.5 MG / ML POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION - patient leaflet, side effects, dosage

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

Bendamustine hydrochloride

The name of your medicine is Bendamustine hydrochloride Powder for concentrate for solution for infusion 2.5 mg/ml powder for concentrate for solution for infusion’, but in the rest of the leaflet it will be called “Bendamustine hydrochloride 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.
• <This medicine has been prescribed for you only. Do not pass it on to others. It may harm them even if their signs of illness are the same as yours.>
• 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.

What is in this leaflet

• 1. What Bendamustine hydrochloride Powder for concentrate for solution for infusion is and what it is used for

• 2. What you need to know before you use Bendamustine hydrochloride Powder for concentrate for solution for infusion

• 3. How to use Bendamustine hydrochloride Powder for concentrate for solution for infusion 4. Possible side effects

• 5. How to store Bendamustine hydrochloride Powder for concentrate for solution for infusion

• 6. Contents of the pack and other information

1. what bendamustine hydrochloride powder for concentrate for solution for infusion is and what it is used for

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

Bendamustine hydrochloride Powder for concentrate for solution for infusion 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 thalidomide or bortezomib containing therapy is not appropriate for you.

2. what you need to know before you use bendamustine hydrochloride powder for concentrate for solution for infusion

Do not use Bendamustine hydrochloride Powder for concentrate for solution for infusion:

• – if you are allergic to bendamustine hydrochloride or any of the other ingredients of this medicine (listed in section 6);

• – while breast-feeding; if treatment with Bendamustine hydrochloride Powder for concentrate for solution for infusion 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.

Warnings and precautions

Talk to your doctor <or> pharmacist <or nurse> before using Bendamustine hydrochloride Powder for concentrate for solution for infusion

• – 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 Powder for concentrate for solution for infusion, 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 hydrochloride Powder for concentrate for solution for infusion. 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 hydrochloride Powder for concentrate for solution for infusion. 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.

Other medicines and Bendamustine hydrochloride Powder for concentrate for solution for infusion

Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.

If Bendamustine hydrochloride Powder for concentrate for solution for infusion 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 Powder for concentrate for solution for infusion 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 using this medicine.

Pregnancy

Bendamustine hydrochloride Powder for concentrate for solution for infusion can cause genetic damage and has caused malformations in animal studies. You should not use Bendamustine hydrochloride Powder for concentrate for solution for infusion 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.

If you are a woman of childbearing potential, you must use an effective method of contraception both before and during treatment with Bendamustine hydrochloride Powder for concentrate for solution for infusion. If pregnancy occurs during your treatment with Bendamustine hydrochloride Powder for concentrate for solution for infusion you must immediately inform your doctor and should use genetic consultation.

Breast-feeding

Bendamustine hydrochloride Powder for concentrate for solution for infusion must not be administered during breast-feeding. If treatment with Bendamustine hydrochloride Powder for concentrate for solution for infusion is necessary during lactation you must discontinue breast-feeding.

Ask your doctor or pharmacist for advice before taking any medicine.

Fertility

Men receiving treatment with Bendamustine hydrochloride Powder for concentrate for solution for infusion are advised not to father 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.

If you are a man, you should avoid fathering a child during treatment with Bendamustine hydrochloride Powder for concentrate for solution for infusion and for up to 6 months after treatment has stopped. There is a risk that treatment with Bendamustine hydrochloride Powder for concentrate for solution for infusion will lead to infertility and you may wish to seek advice on conservation of sperm before treatment starts.

Driving and using machines

Bendamustine hydrochloride Powder for concentrate for solution for infusion has major influence on the ability to drive and to use machines.

Do not drive or operate machines if you experience side effects, such as dizziness or lack of coordination.

3. how to use bendamustine hydrochloride powder for concentrate for solution for infusion

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 hydrochloride Powder for concentrate for solution for infusion 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) and/or your blood platelets have fallen to counts below determined levels.

Your doctor will determine these values at regular intervals.

Chronic lymphocytic leukaemia

Non-Hodgkin lymphomas

Multiple myeloma

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.

How it is administered

Treatment with Bendamustine hydrochloride Powder for concentrate for solution for infusion should be undertaken only by doctors experienced in tumour therapy. Your doctor will give you the exact dose of Bendamustine hydrochloride Powder for concentrate for solution for infusion 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 Powder for concentrate for solution for infusion. 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 Powder for concentrate for solution for infusion, please speak to your doctor or pharmacist.

If you forget to use Bendamustine hydrochloride Powder for concentrate for solution for infusion

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

If you stop using of Bendamustine hydrochloride Powder for concentrate for solution for infusion

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 product, ask your doctor or pharmacist.

4. possible side effects

Like all medicines, Bendamustine hydrochloride Powder for concentrate for solution for infusion can cause side-effects, although not everybody will experience these effects. Some of the findings listed below may be found after tests performed by your doctor.

The following definitions of frequency are used when assessing side-effects:.

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 hydrochloride Powder for concentrate for solution for infusion is impaired bone-marrow function, which usually returns to normal after treatment. Suppressed bone marrow function may lead to low counts of blood cells, which in turn may lead to an increased risk of infection, anemia or a heightened risk of bleeding.

Very common

• Low counts of white blood cells (disease-fighting 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 (colorless blood cells that help blood clot)
• Infections
• Feeling sick (nausea)
• Vomiting
• Mucosal inflammation
• Headache
• Increased blood level of creatinine (a chemical waste product that is produced by your muscles)
• Increased blood level of urea (a chemical waste product)
• Fever
• Fatigue

Common

• Bleeding (haemorrhage)
• Disturbed metabolism caused by dying cancer cells releasing their contents into the blood stream
• 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), nettle rash (urticaria)
• 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)
• 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)
• Loss of appetite
• Hair loss
• Skin changes
• Missed periods (amenorrhoea)
• Pain
• Insomnia
• Chills
• Dehydration
• Dizziness
• Itchy rash (urticaria)

Uncommon

• Accumulation of fluid in the heart sac (escape of fluid into the pericardial space)
• Ineffective production of all blood cells in the bone marrow (the spongy material

inside your bones where blood cells are made)

• Acute leukemia
• Heart attack, chest pain (myocardial infarct)
• Heart failure

Rare

• Infection of the blood (sepsis)
• Severe allergic hypersensitivity reactions (anaphylactic reactions)
• Reduction in your bone marrow function, which may make you feel unwell or show up in your blood tests
• 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

• 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)
• 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:

• Liver failure
• Renal failure
• Irregular and often rapid heart rate (atrial fibrillation)
• Painful red or purplish rash that spreads and blisters and/or other lesions begin to appear in the mucous membranes (e.g. mouth and lips), in particular if you had before light sensitivity, infections of the respiratory system (e.g. bronchitis) and/or fever.
• Drug rash in combination therapy with rituximab
• Pneumonitis
• Bleeding from the lungs

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 Stevens-Johnson 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).

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

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: or search 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.

5. how to store bendamustine hydrochloride powder for concentrate for solution for infusion

Keep this medicine out of the sight and reach of children.

Do not use Bendamustine hydrochloride Powder for concentrate for solution for infusion 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 medicinal product does not require any special storage conditions.

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 25°C for 3.5 hours, and at 2°C to 8°C they are stable for 2 days.

Bendamustine hydrochloride Powder for concentrate for solution for infusion contains no preservatives. 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.

It is the responsibility of the user to maintain aseptic conditions.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. contents of the pack and other information

What Bendamustine hydrochloride Powder for concentrate for solution for infusion contains

The active substance is bendamustine hydrochloride.

One vial contains 25 mg of bendamustine hydrochloride (as bendamustine hydrochloride monohydrate).

One 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 (E421).

What Bendamustine hydrochloride Powder for concentrate for solution for infusion looks like and contents of the pack

Amber glass vials with bromobutyl rubber stopper and an aluminium flip-off cap.

Bendamustine hydrochloride Powder for concentrate for solution for infusion is available in packs containing 1, 5, 10 and 20 vials with 25 mg of bendamustine hydrochloride (as bendamustine hydrochloride monohydrate) and 1 and 5 vials with 100 mg of bendamustine hydrochloride (as bendamustine hydrochloride monohydrate).

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Koanaa Healthcare GmbH

Fehrgasse 7

Fischamend

A-2401

Austria

Manufacturer

Wave Pharma Limited,

4th Floor Cavendish House,

369 Burnt Oak, Broadway,

Edgware, HA8 5AW,

United Kingdom

This medicinal product is authorised in the Member States of the EEA under the following names:

Austria Bendamustine hydrochloride Powder for concentrate for solution for infusion 2,5 mg/ml, Pulver fur ein Konzentrat zur Herstellung einer Infusionslosung

Germany Bendamustine hydrochloride Powder for concentrate for solution for infusion 2,5 mg/ml, Pulver fur ein Konzentrat zur Herstellung einer Infusionslosung

United Kingdom Bendamustine hydrochloride 2.5 mg/ml Powder for concentrate for solution for infusion

This leaflet was last revised in 03/2019

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 cancer-causing effect of the preparation. Avoid inhalation (breathing in) and contact with the skin and mucous membranes when handling Bendamustine hydrochloride Powder for concentrate for solution for infusion (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 by dissolving the contents of a vial of Bendamustine hydrochloride Powder for concentrate for solution for infusion exclusively in water for Injections, as follows:

1. Preparation of the concentrate

• One vial of Bendamustine hydrochloride Powder for concentrate for solution for infusion containing 25 mg of bendamustine hydrochloride is first dissolved in 10 ml by shaking
• One vial of Bendamustine hydrochloride containing 100 mg of 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 2 – 5 minutes), the total recommended dose of Bendamustine hydrochloride 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 Powder for concentrate for solution for infusion must not be diluted with other solutions for infusion or injection. Bendamustine hydrochloride Powder for concentrate for solution for infusion must not be mixed in an infusion with other substances.

3. Administration

The solution is administered by intravenous infusion over 30–60 min.

The vials are for single use only.

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

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).

11