Bendamustine accord

Package leaflet: Information for the user

Bendamustine Accord, 2.5 mg/ml, powder for concentrate for solution for infusion
Bendamustini hydrochloridum
The name of the medicine is "Bendamustine Accord 2.5 mg/ml, powder for concentrate for solution for infusion", but in the remainder of this leaflet the term "Bendamustine Accord" will be used.
Please read all of this leaflet carefully before taking 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, please ask your doctor, pharmacist or nurse.
• This medicine has been prescribed for you personally. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, 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 you are given Bendamustine Accord
3. How to take 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 (severe impairment of liver parenchymal cells);
• if the patient has jaundice (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) with significant changes in white blood cell and platelet counts;
• if the patient has undergone major surgery within 30 days prior to starting treatment;
• if the patient has an infection, especially accompanied by low 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 function in producing blood cells. The doctor will check white blood cell and platelet counts before starting treatment with Bendamustine Accord, before each subsequent cycle, and during treatment breaks.
• if the patient has an infection. Contact the doctor immediately if signs of infection occur, including fever or respiratory symptoms.
• if skin changes occur during treatment with Bendamustine Accord. These changes may worsen.
• if a painful, red or purple, spreading rash with blisters and/or other mucosal lesions (e.g. in the mouth or on the lips) develops, especially if the patient previously had photosensitivity, a 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, 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 cardiac complications within 48 hours after the first dose of Bendamustine Accord. The doctor should ensure adequate hydration and may administer additional medications to prevent this condition.
• if severe allergic or hypersensitivity reactions occur. The infusion site should be monitored after the first treatment cycle.
• immediately inform the doctor 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 are observed, contact the doctor due to an increased risk of certain types of skin cancer (non-melanoma skin cancer) associated with the use of this medicine.

Bendamustine Accord and other medicines
Tell your doctor or pharmacist about all medicines the patient is currently taking, has recently taken, or plans to take.
When Bendamustine Accord is used together with other medicines that suppress bone marrow function and blood cell formation, the effect on bone marrow may be intensified.
The use of Bendamustine Accord in combination with medicines that affect the immune response may enhance this effect.
Cytostatic drugs may reduce the effectiveness of vaccines containing live viruses. Cytostatic drugs also increase the risk of infection following vaccination with live vaccines (e.g. antiviral vaccines).

Pregnancy, breastfeeding and fertility

If the patient is pregnant, breastfeeding, suspects she may be pregnant, or plans 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 has been shown to cause developmental abnormalities in animals. Bendamustine Accord must not be used during pregnancy unless the doctor considers it absolutely necessary. Pregnancy must be avoided during treatment with Bendamustine Accord and for at least 6 months after the last dose. If treatment must begin, 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. If a woman becomes pregnant during treatment with Bendamustine Accord, she must immediately inform her doctor and undergo genetic testing.

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

Contraception in women and men
Women must avoid becoming pregnant during treatment with Bendamustine Accord and for at least 6 months after the last dose.
Men must 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 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 must 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 a single anticancer agent (monotherapy) or in combination with other medicines.
Treatment should 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 leukemia

Non-Hodgkin's lymphomas

Multiple myeloma

Treatment should be discontinued when the white blood cell (leukocyte) count and (or) platelet count fall below the level established by the physician. Treatment may be continued once the 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 case of moderate liver function impairment).

Dose adjustment is not required in patients with renal impairment.

The treating physician will decide whether dose modification is necessary.

Method of administration

Treatment with Bendamustine Accord should be initiated only by physicians experienced in cancer therapy. 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 lasting 30–60 minutes.

Duration of treatment

There is no universally established time limit for treatment with Bendamustine Accord.

The duration of treatment depends on the disease and how the patient responds to therapy.

In case of 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 treatment

The treating physician will decide whether to discontinue treatment or switch to another medication.

For any further doubts concerning the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse reactions

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

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

• 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 the mucous membranes)
• Increased serum creatinine levels (a metabolic product from muscle metabolism)
• Increased serum urea levels (a metabolic product in the body)
• Fever
• Fatigue
• Headache

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

• Bleeding (haemorrhage)
• Metabolic disturbances related to release of tumour cell contents into the bloodstream
• Reduced number of red blood cells, possibly causing pallor, fatigue, or shortness of breath (anaemia)
• Low neutrophil count (a type of white blood cell important for fighting infections)
• Hypersensitivity reactions, such as allergic dermatitis, urticaria
• Increased activity of liver enzymes AspAT/AlAT (may indicate inflammation or damage to liver cells)
• Increased activity of alkaline phosphatase enzyme (an enzyme produced mainly in the liver and bones)
• Increased levels of bilirubin (a bile pigment formed during the 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 patients):

• Fluid accumulation in the pericardial sac (pericardial effusion)
• Ineffective blood cell production in the bone marrow (spongy structure inside bones)
• Acute leukaemia
• Myocardial infarction, chest pain
• Heart failure

Rare (may affect up to 1 in 1000 patients):

• Blood infection (septicaemia)
• Severe hypersensitivity reactions (anaphylactic reactions)
• Symptoms resembling anaphylactic reactions (anaphylactoid reactions)
• Somnolence
• Loss of voice (aphonia)
• Acute circulatory collapse (cessation of blood flow, primarily of cardiac origin, leading to cellular hypoxia, malnutrition, and inability to eliminate toxins)
• Skin redness (erythema)
• Dermatitis (skin inflammation)
• Itching (pruritus)
• Skin rash (maculopapular rash)
• Excessive sweating
• Bone marrow suppression, possibly causing worsening well-being or evident in blood test results

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

• Primary atypical pneumonia
• Haemolysis (breakdown of red blood cells)
• Sudden drop in blood pressure sometimes with skin reactions (anaphylactic shock)
• Disturbance of taste sensation
• 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 coordination of movements (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 the mouth and lips), especially if the patient previously had photosensitivity, respiratory tract infection (e.g. bronchitis) and (or) fever
• Drug rash with combination therapy including rituximab
• Pneumonitis (lung inflammation)
• Pulmonary haemorrhage
• Excessive urination, including at night, and excessive thirst even after drinking fluids (nephrogenic diabetes insipidus)

There have been reports of tumour development (myelodysplastic syndrome, acute myeloid leukaemia, bronchioloalveolar carcinoma) in patients treated with 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 spots, often with central blisters on the trunk, skin peeling, oral, throat, nasal, genital, or ocular ulcers, and may be preceded by fever and flu-like symptoms.
Widespread rash, high fever, lymphadenopathy, and systemic symptoms (drug reaction with eosinophilia and systemic symptoms, also known as DRESS or drug hypersensitivity syndrome).

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

Reporting of adverse reactions
If any adverse reactions occur, including those not listed in this leaflet, inform your doctor, pharmacist, or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions at the 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 the 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.
No special temperature requirements for storage of the medicinal product.
Store the vial in its original packaging to protect it from light.
Note on shelf-life after opening the packaging or preparing the solution
The infusion solution prepared according to the instructions described at the end of this leaflet is stable in polyethylene bags for 3.5 hours at 25°C and for 2 days at 2°C–8°C. Bendamustine Accord does not contain preservatives.
From a microbiological point of view, the solution should be used immediately. If the product is not used immediately, the storage conditions and duration are the responsibility of the user.
The user is responsible for maintaining aseptic conditions.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Contents of the pack and other information

What Bendamustine Accord contains
The active substance is bendamustine hydrochloride.
One vial contains 25 mg of bendamustine hydrochloride (as monohydrate).
One vial contains 100 mg of bendamustine hydrochloride (as monohydrate).
After reconstitution, 1 ml of concentrate contains 2.5 mg of bendamustine hydrochloride (as monohydrate).
The other ingredient is: mannitol.

What Bendamustine Accord looks like and contents of the pack
The vial is made of amber Type I glass, closed with a bromobutyl rubber stopper and sealed with an aluminium flip-off cap.
Bendamustine Accord is available in packs containing 5, 10 or 20 vials containing 25 mg of bendamustine hydrochloride, and 1 or 5 vials containing 100 mg of bendamustine hydrochloride.
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 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 the drug to cause genomic damage and neoplastic diseases, nursing and medical personnel must follow more stringent than usual precautions. When handling Bendamustine Accord, inhalation (breathing in) of the drug and contact with skin and mucous membranes must be avoided (wear gloves, protective clothing, and, if possible, a face mask!). If any part of the body becomes contaminated with the product, it should be thoroughly washed with soap and water, and the eyes should be rinsed with 0.9% (isotonic) sodium chloride solution. Whenever possible, work should be carried out in specially protected work areas (under laminar airflow hoods), with the work surface covered by a disposable, fluid-impermeable absorbent sheet. Contaminated materials constitute cytostatic waste. Please follow national guidelines for the disposal of materials with cytostatic properties. Pregnant women must not be involved in handling cytostatic products.

The ready-to-use solution should be prepared by dissolving the contents of the vial of Bendamustine Accord exclusively in water for injections, as follows:

1. Preparation of the concentrate

   • One vial of Bendamustine Accord containing 25 mg of bendamustine hydrochloride should first be dissolved in 10 ml of water for injections by shaking.
   • One vial of Bendamustine Accord containing 100 mg of bendamustine hydrochloride should first be dissolved in 40 ml of water for injections by shaking.

2. Preparation of the infusion solution
   Once a clear solution has been obtained (usually after 5–10 minutes), the entire dose of Bendamustine Accord should be immediately diluted in 0.9% (isotonic) sodium chloride solution to achieve a final volume of approximately 500 ml. Bendamustine Accord must not be dissolved in other infusion or injection solutions. Bendamustine Accord must not be mixed in the same infusion with other substances.

3. Administration
   The solution should be administered as a 30- to 60-minute intravenous infusion. Vials are for single use only. Any unused portions of the medicinal product or waste materials must be disposed of in accordance with local regulations.

Accidental injection of the drug into the tissue surrounding the blood vessel (extravasation) should be stopped immediately. After briefly aspirating the injected fluid, the needle should be withdrawn. The physician should cool the extravasation site and instruct the patient to elevate the affected arm. It has not been established whether the administration of additional drugs such as glucocorticoids leads to a clearly positive outcome (see section 4).