Patient leaflet - Bendamustine Hydrochloride 25 mg / ml concentrate for solution for infusion

1. What Bendamustine is and what it is used for

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 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

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 breast-feeding, if treatment with Bendamustine is necessary during lactation you must discontinue breast-feeding (see section warnings and precautions on 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;
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 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.
infections. You should contact your doctor if you have signs of infection, including fever or lung symptoms.
reactions on your skin during treatment with Bendamustine. The skin reactions may increase in severity.
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.
existing heart disease (e.g. heart attack, chest pain, severely disturbed heart rhythms).
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.
- 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, 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 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.

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.

Breast-feeding

Bendamustine must not be administered during breast-feeding. If treatment with Bendamustine 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 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 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.

Driving and using machines

Bendamustine 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

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) and/or your blood platelets 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 on Days 1+2 surface area (based on your height and weight)

Repeat the cycle after 4 weeks up to 6 times

Non-Hodgkin lymphomas

Bendamustine 120 mg per square metre of your body on Days 1 + 2 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 on Days 1 + 2 surface area (based on your height and weight)

Prednisone 60 mg per square metre of your body on Days 1 - 4 surface area (based on your height and weight) by injection or orally

Repeat the cycle after 4 weeks at least 3 times

Treatment should be terminated if white blood cell (leukocyte) and/or platelet values have 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 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 pharmacist.

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 product, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, Bendamustine 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 counts of blood cells, which in turn may lead to an increased risk of infection, anaemia or a heightened risk of bleeding.

Very common (may affect more than 1 in 10 people):

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 (colourless blood cells that help blood clot)
Infections
Feeling sick (nausea)
Vomiting
Mucosal inflammation

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 (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 absorbing sheet that is impermeable to liquids. Contaminated articles are cytotoxic waste. Please comply with national guidelines on the disposal of cytotoxic material. Pregnant staff must be excluded from working with cytotoxics.

The concentrate for solution for infusion has to be diluted with sodium chloride 9 mg/ml (0.9%) solution for injection and then administered by intravenous infusion. Aseptic technique is to be used.

1. Dilution

Aseptically withdraw the volume needed for the required dose from the Bendamustine 25 mg/ml vial. Dilute the total recommended dose of Bendamustine 25 mg/ml with 0.9% sodium chloride solution to produce a final volume of about 500 ml.

While diluting the product it should be noted that the concentration (25 mg/ml) of bendamustine in Bendamustine is higher than in usual bendamustine concentrates resulting from reconstitution of bendamustine powder containing medicinal products.

Bendamustine 25 mg/ml must be diluted with 0.9% NaCl solution and not with any other injectable solutions.

Dilution, as recommended, results in a clear colourless to yellowish solution, practically free from visible particles.

2. Administration

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

The vials are for multiple dose use.

Product should be inspected before use. When inspected, visible particles in the solution or discolouration of solution are a sign of deterioration. Deteriorated medicinal product must not be used.

Any unused medicinal 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.

		-
	Customer	Accord
	Description	Bendamustine Hydro
	Market	UK
	Language	English
		450 x 450 mm (PIL) (Final Fold size - 80 x 45 mm)
		9
	Version No.	3 (Page 2 of 2)
	Date	03_02_22 (Bendamustine Hydro (ACC-UK) PIL)

Increased blood level of creatinine (a chemical waste product that is produced by your muscles)
Increased blood levels of urea (a chemical waste product)
Fever
Fatigue
Headache

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
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)
Abnormally low concentration of neutrophils (a type of white blood cell) in the blood leading to increased susceptibility to infection (neutropenia)
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 (may affect up to 1 in 100 people):

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 leukaemia
Heart attack, chest pain (myocardial infarct)
Heart failure

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 (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)
Reduction in your bone marrow function, which may make you feel unwell or show up in your blood tests

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

Primary atypical inflammation of the lungs (pneumonia)
Breakdown 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 conditions resulting in the blockade of specific receptors in the nervous system
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 (frequency cannot be estimated from the available data):

Renal failure
Liver 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 get 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: 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.

5. How to store 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 and the carton after EXP. The expiry date refers to the last day of that month.

Store and transport refrigerated (2 - 8°C). Do not freeze.

Do not use this medicine if you notice visible particles or if the solution is not clear, colourless to yellow.

After opening of the vial

Chemical, physical and microbiological in use stability has been demonstrated for 28 days at 2 - 8°C.

Once opened, the product may be stored for a maximum of 28 days at 2 - 8°C.

Solution for infusion

After dilution, chemical and physical stability has been demonstrated for 3.5 hours at 25 ºC and 2 days at 2 - 8ºC 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.

Minimisation of the risk of contamination of the multidose vial during withdrawal of each dose is the responsibility of the user. Record date and time of the first dose withdrawal on the vial label. Between uses do not balance product solution with water for injection or any diluent and return the multidose vial to the recommended storage condition of 2 - 8°C.

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 to protect the environment.

6. Contents of the pack and other information

What Bendamustine contains

The active substance is bendamustine hydrochloride.

Each ml of concentrate for solution for infusion contains 25 mg bendamustine hydrochloride (as monohydrate).

Each vial of 4 ml contains 100 mg bendamustine hydrochloride (as monohydrate).

The other ingredients are butylhydroxytoluene (E 321) and macrogol.

What Bendamustine looks like and contents of the pack

Clear colourless to yellow solution in an amber glass vial with chlorobutyl rubber stopper and aluminium seal with plastic flip off cap. Vials are sheathed in a protective sleeve.

Bendamustine is available in packs containing 1 or 5 vials. Not all pack sizes may be marketed.

Marketing Authorisation Holder

Accord Healthcare Limited

Sage House, 319 Pinner Road

North Harrow, Middlesex

HA1 4HF

United Kingdom

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