Bendamustine medac

Package leaflet: Information for the user

Bendamustyna medac, 2.5 mg/ml, powder for solution for infusion concentrate
Bendamustine hydrochloride
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet as you may need to read it again.
• If you have any further questions, please ask your doctor or pharmacist.
• If you experience any adverse reactions, including any not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Contents of the leaflet

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

1. What Bendamustyna medac is and what it is used for

Bendamustyna medac is a medicine containing the active substance bendamustine hydrochloride (hereinafter referred to as bendamustine).
Bendamustine is a medicine used to treat certain types of cancer (a cytotoxic agent).
Bendamustine is used either as a single agent (monotherapy) or in combination with other medicines to treat the following cancers:

• Chronic lymphocytic leukemia 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 high-dose chemotherapy with autologous stem cell transplantation or treatment regimens containing thalidomide or bortezomib are not indicated.

2. Important information before using Bendamustyna medac

When not to use Bendamustyna medac:

• 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 Bendamustyna medac is necessary during lactation, breastfeeding must be discontinued (see section Pregnancy, breastfeeding and fertility),
• if the patient has severe liver damage (damage to the functional liver cells),
• if the patient has jaundice (yellowing of the skin or whites of the eyes) caused by liver dysfunction or blood disorders,
• 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 a low white blood cell count (leukopenia),
• if the patient has been vaccinated against yellow fever.

Warnings and precautions
Before starting treatment with Bendamustyna medac, discuss the following with your doctor or nurse:

• in case of reduced ability of the bone marrow to produce blood cells. Your doctor will check your white blood cell and platelet counts before starting treatment with Bendamustyna medac, before each subsequent treatment cycle, and during treatment breaks.
• in case of infection. Contact your doctor if you develop signs of infection, including fever and lung-related symptoms.
• in case of pre-existing heart disease (e.g. heart attack, chest pain, severe heart rhythm disorders).

Inform your doctor immediately at any time during or after treatment if the patient experiences any of the following symptoms: memory loss, thinking problems, difficulty walking, or loss of vision — 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 your doctor due to an increased risk of certain types of skin cancer (non-melanoma skin cancer) associated with the use of this medicine.
During treatment with Bendamustyna medac, discuss the following with your doctor or nurse:

• in case of nausea and vomiting. Your doctor may prescribe an anti-nausea (antiemetic) medication.
• if experiencing pain in the side, blood in the urine, or reduced urine output. In patients with advanced disease, the body may be unable to eliminate waste products from dying tumor cells. This phenomenon is known as tumor lysis syndrome and may lead to kidney failure and heart problems within 48 hours after the first dose of Bendamustyna medac. Your doctor should ensure adequate hydration and may administer additional medications to prevent this condition.
• if skin reactions occur during treatment with Bendamustyna medac. These reactions may worsen over time.
• if a painful, red or purple, spreading rash with blisters and/or mucosal lesions (e.g. in the mouth and on the lips) develops, especially if the patient previously had photosensitivity, a respiratory tract infection (e.g. bronchitis), and/or fever.
• in case of severe allergic reactions or hypersensitivity reactions. Be vigilant for infusion-related reactions, particularly after the first treatment cycle.

Men receiving Bendamustyna medac are advised not to plan fathering a child during treatment and for 6 months after its completion. Before starting treatment, patients should seek advice regarding sperm preservation due to the risk of permanent infertility (see section Pregnancy, breastfeeding and fertility).

Children and adolescents
There is no experience with the use of bendamustine hydrochloride in children and adolescents.

Bendamustyna medac and other medicines
Inform your doctor or pharmacist about all medicines the patient is currently taking, has recently taken, or plans to take.
Bendamustine hydrochloride may affect the action of other medicines. Likewise, other medicines may affect the action of bendamustine hydrochloride. Interactions with bendamustine hydrochloride may occur:
When Bendamustyna medac is used in combination with other medicines that suppress bone marrow function, the effect on bone marrow may be intensified.
Bendamustyna medac used in combination with medicines affecting the immune response may enhance this effect.
Cytostatic medicines may reduce the effectiveness of vaccines containing live viruses.
Cytostatic medicines additionally increase the risk of infection following vaccination with live vaccines (e.g. viral 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.
Women of childbearing potential must use an effective method of contraception during treatment with bendamustine and for 6 months after treatment ends.
Men must use an effective method of contraception and must not attempt to father a child during treatment with bendamustine and for 3 months after treatment ends.

Pregnancy
Bendamustine may cause damage to genetic material and has been shown to cause developmental abnormalities in animals. This medicine should not be used during pregnancy unless the physician considers it absolutely necessary. If treatment is required, discuss with your doctor the potential adverse effects on the unborn child. Genetic counseling is recommended.

Breastfeeding
Bendamustine must not be used during breastfeeding. If treatment with this medicine is necessary, the patient must discontinue breastfeeding.

Fertility
In men, there is a risk that treatment with bendamustine may cause infertility; therefore, advice on sperm preservation should be sought before starting treatment.

Always consult your doctor or pharmacist before taking any medicine.

Driving and operating machinery
Bendamustine hydrochloride has a significant influence on the ability to drive and operate machinery. Patients should not drive or operate machinery if they experience adverse effects such as dizziness or lack of coordination.

3. How to use Bendamustyna medac

Bendamustyna medac is administered intravenously over 30–60 minutes, in various doses, either as a single agent (monotherapy) or in combination with other medicinal products.
Treatment should not be initiated if white blood cell (leukocyte) and/or platelet counts fall below a defined threshold.
Your doctor will monitor these parameters at regular intervals.

Chronic lymphocytic leukemia

• Bendamustyna medac 100 mg/m² body surface area (calculated based on height and body weight): on days 1 and 2.
• Repeat cycle every 4 weeks up to 6 times.

Non-Hodgkin's lymphomas

• Bendamustyna medac 120 mg/m² body surface area (calculated based on height and body weight): on days 1 and 2.
• Repeat cycle every 3 weeks for at least 6 cycles.

Multiple myeloma

• Bendamustyna medac 120–150 mg/m² body surface area (calculated based on height and body weight): on days 1 and 2.
• Prednisone 60 mg/m² body surface area (calculated based on height and body weight), administered intravenously or orally: on days 1–4.
• Repeat cycle every 4 weeks for at least 3 cycles.

Treatment should be interrupted if white blood cell and/or platelet counts decrease to a defined level. Treatment may be resumed once white blood cell and platelet counts have recovered.

Hepatic or renal impairment
Depending on the degree of hepatic dysfunction, dose adjustment may be required (by 30% in case of moderate hepatic impairment). Bendamustyna medac should not be used in patients with severe hepatic impairment. Dose adjustment is not necessary in patients with renal impairment. The treating physician will decide whether dose modification is needed.

How the medicine is administered
Treatment with Bendamustyna medac should only be initiated and supervised by physicians experienced in the treatment of malignancies. The physician will administer the appropriate dose of Bendamustyna medac and apply necessary precautions.
The treating physician will administer the infusion solution after preparing it according to the instructions. The solution is given intravenously as a short-term infusion over 30–60 minutes.

Duration of treatment
There is no universally established time limit for treatment with Bendamustyna medac. The duration of therapy depends on the disease and the patient's response to treatment.
In case of any doubts or questions regarding treatment with Bendamustyna medac, please consult your doctor or nurse.

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

Discontinuation of Bendamustyna medac
The treating physician will decide whether to discontinue treatment or switch to another medicinal product.
If you have any further questions or uncertainties regarding the use of this medicine, please consult your doctor or pharmacist.

4. Possible adverse reactions

Like any medicine, this medicine can cause adverse reactions, although they do not occur in everyone.
You should contact your doctor immediately if any of the following adverse reactions occur (frequency unknown):
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 desquamation, oral, throat, nasal, genital or ocular mucosal ulcers, and may be preceded by fever and flu-like symptoms.
Widespread rash, high fever, lymph node enlargement and symptoms affecting various organs (drug reaction with eosinophilia and systemic symptoms, also known as DRESS syndrome or drug hypersensitivity syndrome).
Very rarely, following accidental injection of the medicine into tissue outside the blood vessel (extravasation), tissue damage (necrosis) has been observed. A sign of extravasation may be a burning sensation at the injection site. Consequences of such administration may include pain and poor healing of skin lesions.
The dose-limiting adverse reaction of Bendamustyna medac is bone marrow dysfunction, which however usually returns to normal after treatment. Suppression of bone marrow function may lead to a reduction in blood cell counts, which in turn may increase the risk of infections, anaemia or bleeding.

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

• Decreased number of white blood cells (leukopenia)
• Reduced level of red pigment (haemoglobin) in the blood
• Decreased number of platelets (thrombocytopenia)
• Infections
• Nausea
• Vomiting
• Mucositis
• Increased blood creatinine levels
• Increased blood urea levels
• Fever
• Fatigue
• Headache

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

• Bleeding (haemorrhage)
• Metabolic disturbances associated with the release of tumour cell contents into the bloodstream (tumour lysis syndrome)
• Decreased number of red blood cells, which may cause pallor, weakness or shortness of breath (anaemia)
• Decreased number of neutrophils (neutropenia)
• Hypersensitivity reactions, such as allergic dermatitis, urticaria
• Increased activity of liver enzymes AspAT/AlAT
• Increased activity of alkaline phosphatase enzyme
• Increased level of bile pigment
• Low potassium levels in the blood
• Cardiac dysfunction (palpitations, angina pectoris)
• Heart rhythm disturbances (arrhythmia)
• Low or high blood pressure (hypotension or hypertension)
• Pulmonary dysfunction
• Diarrhoea
• Constipation
• Oral mucositis
• Loss of appetite
• Hair loss
• Skin changes
• Absence of menstruation (amenorrhoea)
• Pain
• Insomnia
• Chills
• Dehydration
• Dizziness
• Itchy rash (urticaria)

Uncommon (may affect up to 1 in 100 treated patients):

• Fluid accumulation in the pericardial sac (pericardial effusion)
• Ineffective production of all types of blood cells (myelodysplastic syndrome)
• Acute leukaemia
• Myocardial infarction, chest pain
• Heart failure

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

• Blood infection (septicaemia)
• Severe hypersensitivity reactions (anaphylactic reactions)
• Symptoms resembling anaphylactic reactions (pseudoanaphylactic reactions)
• Somnolence
• Loss of voice (aphonia)
• Acute circulatory collapse
• Skin redness (erythema)
• Dermatitis
• Itching (pruritus)
• Skin rash (maculopapular rash)
• Excessive sweating
• Impaired bone marrow function, possibly causing worsening general condition or evident in blood test results

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

• Primary atypical pneumonia
• Red blood cell breakdown (haemolysis)
• Sudden drop in blood pressure sometimes with skin reactions (anaphylactic shock)
• Taste disturbance
• Sensory disturbances (paraesthesia)
• Poor general condition and limb pain (peripheral neuropathy)
• Nervous system disorder (anticholinergic syndrome)
• Neurological disorders
• Lack of coordination of movements (ataxia)
• Encephalitis
• Rapid heart rate (tachycardia)
• Phlebitis
• Tissue formation in the lungs (pulmonary fibrosis)
• Haemorrhagic oesophagitis
• Bleeding from the stomach or intestines
• Infertility
• Multiorgan failure

Frequency unknown (frequency cannot be estimated from available data):

• Liver failure
• Kidney failure
• Irregular or rapid heartbeat (atrial fibrillation)
• Painful red or purple spreading rash with blisters and (or) other mucosal changes (e.g. in the mouth and lips), especially if the patient previously had photosensitivity, respiratory tract infection (e.g. bronchitis) and (or) fever
• Drug-induced rash (associated with rituximab combination therapy)
• Pneumonia
• Pulmonary haemorrhage
• Excessive urination, including at night, and excessive thirst even after drinking fluids (renal diabetes insipidus)

Reporting of adverse reactions
If any adverse symptoms occur, including any not listed in this leaflet, you should inform your doctor or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products:
Al. Jerozolimskie 181C, PL-02-222 Warsaw, tel.: +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 marketing authorisation holder.
Reporting adverse reactions helps provide more information on the safety of the medicine.

5. How to store Bendamustyna medac

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and carton under "Expiry date".
The first two digits indicate the month and the last four digits indicate the year.
The expiry date refers to the last day of the stated month.
Store the vial in its outer packaging to protect it from light.

Note regarding shelf-life after opening the packaging or preparing the solution
Physical and chemical stability of the medicinal product has been demonstrated for 3.5 hours at 25°C and 60% relative humidity, and for 2 days at 2°C - 8°C in polyethylene bags.
From a microbiological standpoint, the medicine should be used immediately. If it is not used immediately, the user is responsible for the storage conditions and duration. Storage should generally not exceed 24 hours at 2°C to 8°C, unless reconstitution/dilution has been carried out under controlled and validated aseptic conditions.

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

6. Contents of the package and other information

What Bendamustyna medac contains

• The active substance is bendamustine hydrochloride.

One vial contains 25 mg of bendamustine hydrochloride.
One vial contains 100 mg of bendamustine hydrochloride.
After reconstitution, 1 ml of concentrate contains 2.5 mg of bendamustine hydrochloride.

• The other ingredient is mannitol.

What Bendamustyna medac looks like and contents of the pack
A white or almost white lyophilised powder in a 25 ml vial made of amber glass of type I,
closed with a bromobutyl rubber stopper and an aluminium flip-off seal.
A 50 ml vial made of type I glass.
Bendamustyna medac is available in packs containing 1, 5 or 10 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 and Manufacturer
medac Gesellschaft für klinische Spezialpräparate mbH
Theaterstr. 6
22880 Wedel
Germany
Telephone: +48 22 43000-30
Fax: +48 22 43000-31
e-mail: [email protected]

This medicinal product is authorised in the Member States of the European Economic Area
under the following names:
Denmark Bendamustinhydrochlorid medac 2.5 mg/ml
Estonia Bendamustine medac
Finland Bendamustine medac 2.5 mg/ml
Latvia Bendamustine medac 2.5 mg/ml pulveris infūziju šķīduma koncentrāta pagatavošanai
Poland Bendamustyna medac
Portugal Bendamustina medac

Information intended exclusively for medical professionals:

As with all similar cytotoxic substances, due to the potential of this medicinal product to cause genomic damage and neoplastic diseases, nursing and medical personnel must observe more stringent precautions than usual.
When handling bendamustine, 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 soap and water and rinse eyes with 0.9% (isotonic) sodium chloride solution.
Whenever possible, handling should be performed in specially protected work areas (e.g., under a laminar flow hood), using a disposable, fluid-impermeable absorbent covering on the work surface.
Contaminated materials constitute cytotoxic 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 Bendamustyna medac exclusively in Water for Injections, as follows:

1. Preparation of the concentrate

   • One vial of Bendamustyna medac containing 25 mg of bendamustine hydrochloride should first be dissolved in 10 ml of Water for Injections by shaking.
   • One vial of Bendamustyna medac 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 recommended dose of Bendamustyna medac should be immediately further diluted in 0.9% (isotonic) sodium chloride solution to achieve a final volume of approximately 500 ml.
Bendamustyna medac must not be dissolved in other infusion or injection solutions.
Bendamustyna medac must not be mixed in the same infusion with other substances.