Bendamustine accord

Package leaflet: Information for the user

Bendamustine Accord, 25 mg/ml, concentrate for solution for infusion
Bendamustini hydrochloridum
Please read all of this leaflet carefully before 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 a specific individual. Do not pass it on to others. It may harm other people, even if their symptoms are the same as yours.
• If you experience any adverse reactions, including any not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of the leaflet

1. What Bendamustine Accord is and what it is used for
2. What you need to know before using Bendamustine Accord
3. How to use Bendamustine Accord
4. Possible side effects
5. How to store Bendamustine Accord
6. Contents of the pack and other information

1. What Bendamustine Accord is and what it is used for

Bendamustine Accord is a medicine used to treat certain types of cancer (a cytotoxic agent).
Bendamustine Accord is used either alone (monotherapy) or in combination with other medicines to treat the following cancers:

• chronic lymphocytic leukaemia when treatment regimens containing fludarabine are not indicated,
• non-Hodgkin’s lymphomas that did not respond or responded only briefly to prior treatment with rituximab,
• multiple myeloma when treatment regimens containing thalidomide or bortezomib are not indicated.

2. Important information before using Bendamustine Accord

When not to use Bendamustine Accord

• if the patient is allergic to bendamustine hydrochloride or any of the other ingredients of this medicine (listed in section 6);
• during breastfeeding; if treatment with Bendamustine Accord is necessary during this period, breastfeeding must be discontinued (see section "Warnings and precautions" and "Pregnancy, breastfeeding and fertility");
• if the patient has severe liver damage (damage to the functional liver cells);
• if the patient has yellowing of the skin or whites of the eyes caused by liver dysfunction or blood disorders (jaundice);
• if the patient has severe bone marrow dysfunction (bone marrow suppression) and significant changes in white blood cell and platelet counts;
• if the patient has undergone major surgery within 30 days before starting treatment;
• if the patient has an infection, especially accompanied by reduced white blood cell count (leukopenia);
• if the patient has been vaccinated against yellow fever.

Warnings and precautions
Before starting treatment with Bendamustine Accord, discuss the following with your doctor, pharmacist, or nurse:

• if the patient has reduced bone marrow capacity to produce blood cells. The doctor will check the white blood cell and platelet counts before starting treatment with Bendamustine Accord, before each subsequent cycle, and during treatment breaks.
• if the patient has infections. Contact the doctor immediately if signs of infection occur, including fever and lung-related symptoms.
• if skin changes develop during treatment with Bendamustine Accord. These skin changes may worsen.
• if painful, red or purple, spreading rash with blisters and/or other mucosal changes (e.g. in the mouth and on the lips) occur, especially if the patient previously experienced photosensitivity, respiratory tract infection (e.g. bronchitis), and/or fever.
• if the patient has pre-existing heart disease (e.g. myocardial infarction, chest pain, severe cardiac arrhythmias).
• if the patient experiences pain, presence of blood in the urine, or reduced urine output. In advanced stages of disease, waste products from dying tumor tissue may be eliminated slowly from the body. This phenomenon is known as tumor lysis syndrome and may lead to kidney failure and heart complications within 48 hours after the first dose of Bendamustine Accord. The doctor should ensure adequate hydration and may administer other medications to prevent this condition.
• if severe allergic reactions or hypersensitivity reactions occur. The infusion site should be monitored after the first treatment cycle.

Inform the doctor immediately if, at any time during or after treatment, the patient experiences any of the following symptoms: memory loss, thinking difficulties, walking difficulties, or vision loss – these may be caused by a very rare but serious brain infection (progressive multifocal leukoencephalopathy, PML), which can be fatal.
If any suspicious skin changes occur, contact the doctor due to increased risk of certain types of skin cancer (non-melanoma skin cancer) associated with the use of this medicine.

Bendamustine Accord and other medicines
Inform the doctor or pharmacist about all medicines currently used, recently taken, or planned for use.
When Bendamustine Accord is used in combination with other medicines that suppress blood cell formation in the bone marrow, the effect on bone marrow function may be intensified.
Bendamustine Accord used together with medicines affecting the immune response may enhance this effect.
Cytostatic drugs may reduce the effectiveness of vaccines containing live viruses. Cytostatic drugs additionally increase the risk of infection following vaccination with live vaccines (e.g. viral vaccines).

Pregnancy, breastfeeding and fertility

If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult her doctor or pharmacist before using this medicine.

Pregnancy
Bendamustine Accord may cause damage to genetic material and cause developmental abnormalities in animals. Bendamustine Accord must not be used during pregnancy unless the doctor considers it absolutely necessary. If treatment must be initiated, discuss with the doctor possible adverse effects on the unborn child and undergo genetic testing if recommended.
Women of childbearing potential must use effective contraception both before and during treatment with Bendamustine Accord. Pregnancy must be avoided during treatment with Bendamustine Accord and for at least 6 months after the last dose. If a patient becomes pregnant during treatment with Bendamustine Accord, she must immediately inform her doctor and should undergo genetic testing.

Breastfeeding
Bendamustine Accord must not be used during breastfeeding. If treatment with Bendamustine Accord is necessary, the patient must stop breastfeeding.
Consult the doctor before using any medicine.

Contraception in men and women
Women must avoid becoming pregnant during treatment and for at least 6 months after the last dose. Men should take appropriate precautions to prevent their partner from becoming pregnant during treatment with Bendamustine Accord and for at least 3 months after the last dose.

Fertility
Men receiving Bendamustine Accord are advised not to plan fathering a child during treatment and for 3 months after the last dose. Before starting treatment, patients should seek advice regarding the possibility of sperm preservation due to the risk of permanent infertility.

Driving and operating machinery
Bendamustine Accord has a major influence on the ability to drive and operate machinery. Patients should not drive or operate mechanical equipment if they experience adverse effects such as dizziness or coordination problems.

3. How to take Bendamustine Accord

Always use this medicine exactly as directed by your doctor or pharmacist.
If in doubt, consult your doctor or pharmacist.
Bendamustine Accord is administered intravenously over 30–60 minutes, at various doses, either alone as
the sole anticancer agent (monotherapy) or in combination with other medicines.
Treatment must not be initiated if the white blood cell (leukocyte) and/or platelet count falls
below the level determined by the doctor.
Your doctor will monitor these parameters at regular intervals.
Chronic lymphocytic leukaemia

Non-Hodgkin's lymphomas

Multiple myeloma

Treatment should be discontinued when white blood cell (leukocyte) and/or platelet counts fall below the levels determined by the physician. Treatment may be resumed when white blood cell and platelet counts have increased.

Liver or kidney function disorders
Depending on the degree of liver function impairment, dose adjustment may be necessary (by 30% in the case of moderate liver dysfunction). Dose adjustment is not required in patients with renal impairment. The treating physician will decide whether dose adjustment is necessary.

Method of administration
Treatment with Bendamustine Accord should only be initiated by physicians experienced in the treatment of malignancies. The physician will administer the appropriate dose of Bendamustine Accord and apply necessary precautions.

The treating physician will administer the infusion solution after preparing it according to the recommendations. The solution is given intravenously as a short-term infusion over 30–60 minutes.

Duration of treatment
There is no generally established time limit for treatment with Bendamustine Accord.
The duration of treatment depends on the disease and how the patient responds to therapy.

If you have any doubts or questions regarding treatment with Bendamustine Accord, consult your doctor or nurse.

Missed dose of Bendamustine Accord
If a dose of Bendamustine Accord is missed, the physician will usually continue treatment according to the established dosing schedule.

Discontinuation of Bendamustine Accord
The treating physician will decide whether to discontinue treatment or switch to another medication.

If you have any further questions about the use of this medicinal product, consult your doctor or pharmacist.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
Some of the adverse reactions described below may only be detected after tests have been performed and results evaluated by a physician.
Very rarely, tissue changes (necrosis) have been observed following accidental injection of Bendamustine Accord into tissue outside the blood vessel (extravasation).
A sign of extravasation may be a burning sensation at the site of needle insertion. Consequences of such administration may include pain and poorly healing skin damage.
The dose-limiting adverse reaction of Bendamustine Accord is bone marrow suppression, which usually resolves after treatment.
Bone marrow suppression may lead to reduced blood cell counts, increasing the risk of infection, bleeding, or anaemia.

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

• Decreased number of white blood cells (immune cells)
• Reduced levels of red pigment (haemoglobin: the protein in red blood cells responsible for oxygen transport to cells) in blood
• Decreased number of platelets (blood cells responsible for blood clotting)
• Infections
• Nausea
• Vomiting
• Mucositis (inflammation of mucous membranes)
• Increased serum creatinine levels (a product of muscle metabolism)
• Increased serum urea levels (a product of body metabolism)
• Fever
• Fatigue
• Headache

Common (may affect up to 1 in 10 people):

• Bleeding (haemorrhage)
• Metabolic disturbances related to release of tumour cell contents into the bloodstream
• Reduced number of red blood cells, which may cause paleness, fatigue, or shortness of breath (anaemia)
• Low neutrophil count (a type of white blood cell important in fighting infections)
• Hypersensitivity reactions such as allergic dermatitis, urticaria
• Increased activity of liver enzymes AspAT/AlAT (may indicate inflammation or liver cell damage)
• Increased alkaline phosphatase enzyme activity (an enzyme produced mainly in the liver and bones)
• Increased levels of bile pigment (bilirubin formed during breakdown of red blood cells)
• Low blood potassium levels (important for normal function of nerve and muscle cells, including the heart muscle)
• Cardiac dysfunction
• Heart rhythm disorders (arrhythmia)
• Low or high blood pressure (hypotension or hypertension)
• Pulmonary dysfunction
• Diarrhoea
• Constipation
• Herpes-like oral mucositis
• Loss of appetite
• Hair loss
• Skin changes
• Absence of menstruation (amenorrhoea)
• Pain
• Insomnia
• Tremor
• Dehydration
• Dizziness
• Itchy rash (urticaria)

Uncommon (may affect up to 1 in 100 people):

• Fluid accumulation in the pericardial sac (fluid leakage into the pericardial space)
• Ineffective production of all types of blood cells in the bone marrow (spongy structure inside bones)
• Acute leukaemia
• Myocardial infarction, chest pain
• Heart failure

Rare (may affect up to 1 in 1,000 people):

• Blood infection (septicaemia)
• Severe hypersensitivity reactions (anaphylactic reactions)
• Symptoms similar to anaphylactic reactions (anaphylactoid reactions)
• Somnolence
• Loss of voice (aphonia)
• Acute circulatory collapse (arrest of blood flow, mainly of cardiac origin, leading to cellular hypoxia, malnutrition, and inability to eliminate toxins)
• Skin redness (erythema)
• Dermatitis (skin inflammation)
• Itching (pruritus)
• Skin rash (maculopapular eruption)
• Excessive sweating
• Bone marrow suppression, which may cause worsening general condition or be evident in blood test results

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

• Primary atypical pneumonia
• Red blood cell haemolysis
• Sudden drop in blood pressure sometimes with skin reactions (anaphylactic shock)
• Disturbance of taste
• Sensory disturbances (paraesthesia)
• Poor general condition and limb pain (peripheral neuropathy)
• Severe condition causing blockade of a specific receptor in the nervous system
• Neurological disorders
• Lack of motor coordination (ataxia)
• Encephalitis (inflammation of the brain)
• Increased heart rate (tachycardia)
• Phlebitis (vein inflammation)
• Tissue formation in the lungs (pulmonary fibrosis)
• Haemorrhagic oesophagitis
• Bleeding from the stomach or oesophagus
• Infertility
• Multi-organ failure

Frequency not known (cannot be estimated from available data):

• Renal failure
• Hepatic failure
• Irregular or rapid heartbeat (atrial fibrillation)
• Painful red or purple spreading rash with blisters and/or other mucosal lesions (e.g. in mouth and lips), especially if the patient previously had photosensitivity, respiratory infection (e.g. bronchitis), and/or fever
• Drug rash associated with combination therapy including rituximab
• Pneumonitis (lung inflammation)
• Bleeding from the lungs
• Excessive urination, including at night, and excessive thirst even after drinking fluids (nephrogenic diabetes insipidus)

There have been reports of development of tumours (myelodysplastic syndrome, acute myeloid leukaemia, bronchial carcinoma) in patients receiving Bendamustine Accord. However, a definitive causal relationship between these tumours and the use of Bendamustine Accord has not been established.

Seek immediate medical advice if any of the following adverse reactions occur (frequency not known): Severe skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis. These may present as red or round skin lesions, often with central blisters on the trunk, skin peeling, oral, throat, nose, genital, or eye mucosal ulcers, and may be preceded by fever and flu-like symptoms.
Widespread rash, high fever, swollen lymph nodes, and multi-organ involvement (drug reaction with eosinophilia and systemic symptoms, also known as DRESS syndrome or drug hypersensitivity syndrome).

If any adverse reaction worsens or if any adverse reaction not listed in this leaflet occurs, inform your doctor.

Reporting of adverse reactions
If you experience any adverse reactions, including those not mentioned in this leaflet, inform your doctor, pharmacist, or nurse. Adverse reactions can be reported directly to the Department of Monitoring of Adverse Drug Reactions, Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Al. Jerozolimskie 181C
02-222 Warsaw
Phone: +48 22 49 21 301
Fax: +48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the responsible entity.
Reporting adverse reactions helps provide more information on the safety of this medicine.

5. How to store Bendamustine Accord

Keep this medicine out of sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and vial after EXP.
The expiry date refers to the last day of the stated month.
Store and transport in a refrigerated state (2-8°C). Do not freeze.
Do not use this medicine if particles are visible or if the solution is not clear and colourless to yellow.

After opening the vial
Chemical, physical and microbiological stability has been demonstrated for 28 days when stored at 2-8°C.
After opening, the product may be stored for up to 28 days at 2-8°C.

Infusion solution
After dilution, chemical and physical stability has been demonstrated for 3.5 hours at 25°C and for 2 days at 2-8°C in polyethylene bags.
From a microbiological standpoint, the solution should be used immediately. If the product is not used immediately, the user is responsible for the conditions and duration of storage.
The user is responsible for minimizing the risk of contamination of the multidose vial each time a dose is withdrawn. The date and time of the first dose withdrawal should be recorded on the vial label.
Between uses, do not replenish the product solution with water for injections or any other diluent, and store the multidose vial under the recommended storage conditions at 2-8°C.

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

6. Contents of the pack and other information

What Bendamustine Accord contains
The active substance is bendamustine hydrochloride.
Each millilitre of concentrate for solution for infusion contains 25 mg of bendamustine hydrochloride (as monohydrate).
Each 4 ml vial contains 100 mg of bendamustine hydrochloride (as monohydrate).
Each 1 ml vial contains 25 mg of bendamustine hydrochloride (as monohydrate).
The other ingredients are butylhydroxytoluene and polyethylene glycol 300.

What Bendamustine Accord looks like and contents of the pack
Clear, colourless to yellow solution in a 1 ml or 4 ml amber glass vial stoppered with a chlorobutyl rubber closure, containing concentrate for solution for infusion.
The 1 ml vial has an aluminium seal and a red plastic flip-off cap, while the 4 ml vial has an aluminium seal and a white plastic flip-off cap. The vials are protected with a tamper-evident cap. Packaged in a cardboard carton.
Bendamustine Accord is available in packs containing 1 or 5 vials.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
Accord Healthcare Polska Sp. z o.o.
Taśmowa 7 Street
02-677 Warsaw
Tel: +48 22 577 28 00

Manufacturer / Importer
Accord Healthcare Polska Sp. z o.o.
Lutomierska 50 Street
95-200 Pabianice

This medicinal product is authorised in the Member States of the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:

Information intended exclusively for healthcare professionals:

As with all similar cytotoxic substances, due to the potential of this medicinal product to cause genotoxic damage and induce neoplastic diseases, nursing and medical staff must observe more stringent precautions than usual. When handling Bendamustine Accord, inhalation (breathing in) of the drug and contact with skin or mucous membranes must be avoided (wear gloves, protective clothing, and, if possible, a face mask). In case of contamination of any body parts with the product, thoroughly wash with water and soap and rinse eyes with 0.9% (isotonic) sodium chloride solution. Whenever possible, work should be carried out in specially protected work areas (e.g. under a laminar airflow cabinet), with the work surface covered with a single-use, fluid-impermeable absorbent pad. Contaminated materials constitute cytostatic waste. Please follow national guidelines for the disposal of cytostatic materials. Pregnant women must not be involved in handling cytostatic products.

The concentrate for solution for infusion must be diluted with 9 mg/ml (0.9%) sodium chloride injection solution and then administered as an intravenous infusion. Aseptic technique must be used.

1. Dilution
   Using aseptic technique, withdraw from the vial the volume of Bendamustine Accord 25 mg/ml required to achieve the desired dose. The total recommended dose of Bendamustine Accord 25 mg/ml should be diluted with 0.9% sodium chloride solution to a final volume of approximately 500 ml.

During dilution, it should be noted that the concentration (25 mg/ml) of bendamustine in Bendamustine Accord is higher than that of standard bendamustine concentrates obtained by reconstituting medicinal products containing bendamustine in powder form.
The medicinal product Bendamustine Accord 25 mg/ml must be diluted with 0.9% NaCl solution and not with any other injection solutions.
Dilution performed according to recommendations yields a clear, colourless to slightly yellow solution, practically free from visible particles.

2. Administration
   The solution should be administered as an intravenous infusion over 30–60 minutes.

Vials are intended for multiple use.
The product should be inspected visually before use. The presence of particles or discoloration in the solution indicates deterioration. The medicinal product must not be used if signs of deterioration are observed.
Any unused medicinal product or waste material must be disposed of in accordance with local regulations.
Accidental extravasation (injection into surrounding tissue outside the blood vessel) should be stopped immediately. After brief aspiration of the injected fluid, the needle should be withdrawn. The site of extravasation should then be cooled. The patient's arm should be elevated. It has not been established whether the administration of additional medicinal products, such as glucocorticosteroids, would produce a clearly positive effect.