Bendamustine kabi

Package leaflet: Information for the user

Bendamustine Kabi, 2.5 mg/mL, powder for concentrate for solution for infusion
Bendamustini hydrochloridum
Please read all of this leaflet carefully before using this medicine, because it contains
important information for the patient.
­ Keep this leaflet, as you may need to read it again.
­ If you have any questions, please consult your doctor or pharmacist.
­ This medicine has been prescribed for a specific individual. Do not pass it on to others. It may harm someone else, even if their symptoms are the same.
­ If the patient experiences any adverse reactions, including any not listed in this leaflet, inform the doctor, pharmacist, or nurse. See section 4.
Table of contents of the leaflet

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

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

Bendamustine Kabi is a medicine used to treat certain types of cancer (a cytostatic agent).
Bendamustine Kabi is used either as a single agent (monotherapy) or in combination with other medicines in the treatment of 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 Kabi

When not to use Bendamustine Kabi:

• if the patient has hypersensitivity (allergy) to bendamustine or to any of the other ingredients of this medicine (listed in section 6);
• during breastfeeding; breastfeeding must be discontinued during treatment with bendamustine (see section Pregnancy, breastfeeding and fertility);
• if the patient has severe liver damage (severe impairment of liver parenchymal function);
• 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 marked 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 a low white blood cell count (leukopenia);
• if the patient has been vaccinated against yellow fever.

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

• if the patient has reduced bone marrow capacity to produce blood cells. White blood cell and platelet counts should be monitored before starting treatment with Bendamustine Kabi, before each subsequent cycle, and during treatment intervals.
• if the patient has an infection. Contact your doctor if signs of infection occur, including fever and respiratory symptoms.
• if at any time during or after completion of treatment the following symptoms occur: memory loss, problems with thinking, 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. Inform your doctor immediately.
• if skin changes occur during treatment with Bendamustine Kabi. Skin reactions may worsen.
• if any suspicious skin changes are observed. Contact your doctor due to increased risk of certain types of skin cancer (non-melanoma skin cancer) during treatment with this medicine.
• 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.
• if the patient has an existing heart condition (e.g. myocardial infarction, chest pain, severe cardiac arrhythmias).
• if the patient experiences any 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 Kabi. The doctor should ensure adequate hydration and may administer additional medications to prevent this condition.
• if severe allergic reactions or hypersensitivity reactions occur. The infusion site should be monitored after the first treatment cycle.

Bendamustine Kabi 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 is used in combination with medicines that suppress bone marrow function, its effect on the bone marrow may be enhanced.
Bendamustine used together with immunosuppressive medicines may increase 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 or breastfeeding, suspects she may be pregnant, or plans to become pregnant, she should consult her doctor or pharmacist before using this medicine.

Pregnancy
Bendamustine may cause genetic damage and has been shown to cause developmental abnormalities in animal studies. Bendamustine Kabi should not be used during pregnancy unless the physician considers it absolutely necessary. If treatment is initiated, the patient should discuss potential adverse effects on the unborn child with her doctor and undergo genetic testing.
If a patient becomes pregnant during treatment with Bendamustine Kabi, she should inform her doctor immediately and undergo genetic testing.

Pregnancy precautions for men and women
Men
Men should not attempt to father a child during treatment with Bendamustine Kabi and for 3 months after completion of treatment.
Women
Women of childbearing potential must use an effective method of contraception during treatment and for 6 months after the last dose of Bendamustine Kabi.

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

Fertility
Men
There is a risk that treatment with Bendamustine Kabi may cause infertility. Men who wish to have children should consider sperm cryopreservation before starting treatment.
Women
Women who wish to have children after completing treatment should consult their doctor.

Driving and operating machinery
Bendamustine has a marked 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 coordination problems.

3. How to use Bendamustine Kabi

This medicine should always be used exactly as your doctor or pharmacist has told you.
If you are unsure, you should contact your doctor or pharmacist.
Bendamustine Kabi is administered intravenously over 30-60 minutes, at various doses, either as a single agent (in monotherapy) or in combination with other medicines.
Treatment should not be initiated if the number of white blood cells (leukocytes) and (or) the number of platelets falls below the level determined by your doctor. Your doctor will monitor these parameters at regular intervals.
Chronic lymphocytic leukemia

Non-Hodgkin's lymphomas

Multiple myeloma

Treatment should be discontinued if the white blood cell (leukocyte) and/or platelet count falls below the level determined 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 kidney function disorders. The treating physician will decide whether dose adjustment is necessary.
Method of administration
Bendamustine Kabi therapy should only be initiated by physicians experienced in cancer treatment. The physician will administer the appropriate dose of Bendamustine Kabi and apply necessary precautions.
The treating physician will administer the infusion solution after preparing it according to the recommended instructions. 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 Kabi. The duration of treatment depends on the disease and the response to therapy.
If in doubt or if you have any questions regarding the use of Bendamustine Kabi, consult your doctor or nurse.
Missed dose of Bendamustine Kabi
If a dose of Bendamustine Kabi is missed, the physician will usually continue treatment according to the established dosing schedule.
Discontinuation of Bendamustine Kabi treatment
The treating physician will decide whether to discontinue treatment or switch to another medication.
If you have any doubts regarding the use of the medicine, consult your doctor or pharmacist.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.
Some of the adverse effects listed below can be detected through tests performed by a doctor.
Very rarely, tissue necrosis (tissue death) has been observed following extravasation of Bendamustine Kabi into surrounding tissues outside the blood vessel (extravascular administration). A sign of extravasation may be a burning sensation at the injection site. This may result in pain and poor healing of the skin.

The dose-limiting adverse effect of Bendamustine Kabi is bone marrow suppression, which usually resolves after treatment. Suppression of bone marrow function may lead to a reduction in blood cells, increasing the risk of infection, anaemia, or bleeding.

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

• Low number of white blood cells (immune cells);
• Reduced levels of haemoglobin (the red blood cell pigment responsible for oxygen transport to cells);
• Low platelet count (blood cells responsible for blood clotting);
• Infections;
• Nausea;
• Vomiting;
• Mucositis (inflammation of the mucous membranes);
• Increased serum creatinine levels (a product of muscle metabolism);
• Increased serum urea levels (a metabolic waste product);
• Fever;
• Weakness;
• Headache.

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

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

Uncommon (may occur in up to 1 in 100 patients):

• Fluid accumulation in the pericardial sac (pericardial effusion);
• Ineffective blood cell production in the bone marrow (the spongy tissue inside bones where blood cells are formed);
• Acute leukaemia;
• Myocardial infarction, chest pain (myocardial infarction);
• Heart failure.

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

• Blood infection (septicaemia);
• Severe hypersensitivity reactions (anaphylactic reactions);
• Bone marrow suppression leading to worsening general condition or evident in blood test results;
• Symptoms resembling anaphylactic reactions (pseudo-anaphylactic reactions);
• Drowsiness;
• Loss of voice (aphonia);
• Acute circulatory collapse (cessation of blood flow, mainly of cardiac origin, leading to cellular hypoxia, inadequate nutrition, and inability to eliminate toxins);
• Skin redness (erythema);
• Dermatitis;
• Itching;
• Skin rash (maculopapular rash);
• Excessive sweating.

Very rare (may occur in 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 or rash (anaphylactic shock);
• Disturbance of taste;
• Sensory disturbances (paraesthesia);
• General malaise and limb pain (peripheral neuropathy);
• Severe condition resulting from blockade of certain receptors in the nervous system;
• Nervous system disorders;
• Impaired movement coordination (ataxia);
• Encephalitis;
• Increased heart rate (tachycardia);
• Phlebitis (vein inflammation);
• Tissue formation in the lungs (pulmonary fibrosis);
• Haemorrhagic oesophagitis (haemorrhagic inflammation of the oesophageal mucosa);
• Bleeding from the stomach or intestines;
• Infertility;
• Multi-organ failure.

Frequency not known (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 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-induced rash during combination therapy with rituximab;
• Pneumonia;
• Pulmonary haemorrhage;
• Excessive urination, including at night, and excessive thirst even after drinking fluids (nephrogenic diabetes insipidus).

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

Seek immediate medical advice if any of the following adverse effects occur (frequency not known):
Severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. These may present as red or circular skin spots, often with central blisters on the trunk, skin peeling, oral, throat, nasal, genital, or ocular 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 of the adverse effects worsen or if any adverse effects not listed in this leaflet occur, inform your doctor.

Reporting of adverse effects
If you experience any adverse effects, including those not listed in this leaflet, inform your doctor, pharmacist, or nurse. Adverse effects can be reported directly to the Department of Monitoring 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 effects can also be reported to the responsible marketing authorisation holder.
Reporting adverse effects helps to provide more information on the safety of the medicine.

5. How to store Bendamustine Kabi

Keep the medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial and outer packaging after: EXP. The expiry date refers to the last day of the specified month.
No special storage conditions are required for this medicine.
Shelf-life after opening and preparation of the solution
The infusion solution prepared as described in the instructions at the end of this leaflet and stored in polyethylene bags remains stable for 3.5 hours at 25°C and 60% relative humidity, and for 2 days when stored refrigerated. Bendamustine Kabi does not contain preservatives; therefore, solutions should not be used beyond the specified time periods.
From a microbiological standpoint, the medicine should be used immediately. If not used immediately, the responsibility for storage duration and conditions prior to use lies with the user. Storage time should not exceed 24 hours at 2°C–8°C, provided that reconstitution and dilution were carried out under controlled, validated aseptic conditions.
Do not use this medicine if visible signs of deterioration are observed.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. Such measures help protect the environment.

6. Contents of the package and other information

What Bendamustine Kabi 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 Bendamustine Kabi looks like and contents of the pack
Vials made of orange type I glass with a chlorobutyl rubber stopper and an aluminium "flip-off" cap (green or blue).
White to off-white lyophilized powder.

Bendamustine Kabi is available in packs containing 1, 5, 10 and 20 vials with 25 mg of bendamustine hydrochloride, and in packs containing 1 and 5 vials with 100 mg of bendamustine hydrochloride.

Marketing Authorisation Holder
Fresenius Kabi Polska Sp. z o.o.
Al. Jerozolimskie 134
02-305 Warsaw
Poland

Importer
Fresenius Kabi Deutschland GmbH
Pfingstweide 53
61169 Friedberg
Germany

For further information, please contact the Marketing Authorisation Holder:
Fresenius Kabi Polska Sp. z o.o.
Al. Jerozolimskie 134
02-305 Warsaw
Poland
Tel.: +48 22 345 67 89

This medicinal product is authorised in the Member States of the European Economic Area under the following names:

Information intended exclusively for healthcare professionals:

As with all cytotoxic substances, due to the potential of the drug to cause genomic damage and neoplastic diseases, more stringent than usual precautions must be observed by nursing and medical personnel.
When handling Bendamustine Kabi, inhalation (breathing in) and contact with skin or mucous membranes must be avoided (gloves, protective clothing, and, where possible, a face mask should be worn).
If any part of the body becomes contaminated with the drug, it should be thoroughly washed with soap and water, and the eyes should be rinsed with 9 mg/mL (0.9%) (isotonic) sodium chloride solution.
Wherever possible, work should be carried out on a specially protected surface (under a laminar flow hood) using a fluid-impermeable, absorbent disposable pad.
Contaminated materials constitute cytostatic waste.
National guidelines for the disposal of materials with cytostatic properties must be followed.
Pregnant women should not prepare cytostatic drugs.
For single use only.

1. Preparation of the concentrate
   The concentrate should be prepared by dissolving the contents of the Bendamustine Kabi vial exclusively in water for injections as follows:
   - The contents of one vial of Bendamustine Kabi containing 25 mg of bendamustine hydrochloride should first be dissolved in 10 mL of water for injections by shaking.
   - The contents of one vial of Bendamustine Kabi 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
   Immediately after obtaining a clear solution (usually within 5–10 minutes), the total recommended dose of Bendamustine Kabi should be diluted with 0.9 mg/mL (0.9%) (isotonic) sodium chloride solution to a final volume of approximately 500 mL.
   Bendamustine Kabi must not be diluted with any other injection solution.
   Bendamustine Kabi must not be mixed during infusion with any other substances.

3. Administration
   The solution should be administered as an intravenous infusion over 30–60 minutes.
   For single use only.
   Any unused portions of the medicinal product or waste materials must be disposed of in accordance with local regulations.
   Accidental extravasation (paravenous administration) should be stopped immediately.
   After briefly aspirating the injected fluid, the needle should be withdrawn.
   The site of extravasation should be cooled and the arm elevated.
   It has not been established whether additional medications, such as corticosteroids, provide a clearly positive effect (see section 4).