Bendamustine Zentiva

Leaflet attached to the packaging: information for the user

Bendamustine Zentiva, 2.5 mg/ml, powder for concentrate for solution for infusion

Bendamustine hydrochloride

You should carefully read the contents of the leaflet before using the medicine, as it contains important information for the patient.

• You should keep this leaflet, so that you can read it again if you need to.
• If you have any further questions, you should ask your doctor or pharmacist.
• This medicine has been prescribed specifically for you. Do not pass it on to others. The medicine may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, including those not listed in this leaflet, you should tell your doctor or pharmacist. See section 4.

Table of contents of the leaflet

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

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

Bendamustine Zentiva is a medicine that contains the active substance bendamustine hydrochloride (hereinafter referred to as bendamustine). Bendamustine is a medicine used to treat certain types of cancer (cytostatic medicine). Bendamustine is used alone (as monotherapy) or in combination with other medicines to treat the following types of cancer:

• chronic lymphocytic leukemia when fludarabine-containing chemotherapy is not indicated,
• non-Hodgkin's lymphoma that has not responded or has responded too briefly to previous rituximab treatment,
• multiple myeloma when talidomide or bortezomib-containing chemotherapy is not indicated.

2. Important information before using Bendamustine Zentiva

When not to use Bendamustine Zentiva:

• if you are allergic to bendamustine hydrochloride or any of the other ingredients of this medicine (listed in section 6);
• during breastfeeding; if the use of Bendamustine Zentiva is necessary during this period, you should stop breastfeeding (see section Warnings and precautions and Breastfeeding)
• if you have severe liver function disorders (liver cell damage);
• if you have jaundice (yellowing of the skin or whites of the eyes) due to liver or blood disorders;
• if you have severe bone marrow function disorders (bone marrow depression) and significant changes in white blood cell and platelet counts;
• if you have undergone extensive surgery within 30 days before starting treatment;
• if you have an infection, especially with accompanying leukopenia (reduced white blood cell count);
• if you have been vaccinated against yellow fever.

You should not use bendamustine if any of the above conditions apply to you. In case of doubt, you should consult your doctor or pharmacist before starting to use this medicine.

Warnings and precautions

Before starting to use Bendamustine Zentiva, you should consult your doctor or pharmacist:

• in case of reduced bone marrow function. Your doctor will check your white blood cell and platelet counts before starting treatment with Bendamustine Zentiva, before each subsequent administration of the medicine, and during breaks between administrations;
• in case of infection. You should contact your doctor if you experience any symptoms of infection, including fever and respiratory symptoms;
• if you experience skin changeswhile using Bendamustine Zentiva; skin changes may worsen;
• if you experience a painful, red, or purple rash with blistersand (or) other changes in the mucous membranes (e.g., in the mouth and on the lips), especially if you have previously experienced hypersensitivity to light, respiratory infection (e.g., bronchitis), and (or) fever;
• in case of concomitant heart disease(e.g., heart attack, chest pain, severe arrhythmias);
• in case of pain, blood in the urine, or decreased urine output. When you are in an advanced stage of cancer, the breakdown products of dying cancer tissue may be removed from the body with delay. This condition is called tumor lysis syndrome and may lead to kidney failure and heart problems within 48 hours after the first dose of Bendamustine Zentiva. Your doctor should ensure that you are properly hydrated and may administer other medicines to prevent this phenomenon;
• in case of severe allergic reactions or hypersensitivity reactions. You should be monitored at the injection site after the first treatment cycle.

You should immediately tell your doctor if you experience any of the following symptoms at any time during or after treatment: memory loss, thinking problems, difficulty walking, or vision loss — they may be caused by a very rare but serious brain infection (progressive multifocal leukoencephalopathy, PML), which can be fatal. If you notice any suspicious skin changes, you should contact your doctor due to the increased risk of certain types of skin cancer (non-melanoma skin cancer) that may occur during treatment with this medicine.

Bendamustine Zentiva and other medicines

You should tell your doctor or pharmacistabout all medicines you are currently taking or have recently taken, as well as any medicines you plan to take. When using Bendamustine Zentiva in combination with other medicines that suppress bone marrow function, the effect of Bendamustine Zentiva on bone marrow function may be enhanced. When using Bendamustine Zentiva in combination with medicines that affect the immune response, this effect may be enhanced. Cytostatic medicines may reduce the effectiveness of vaccinations using live viruses. Additionally, cytostatic medicines increase the risk of infection after vaccination with live vaccines (e.g., live viral vaccines).

Pregnancy, breastfeeding, and fertility

In case of pregnancy, suspected pregnancy, planning a child, or breastfeeding, you should consult your doctor or pharmacist before using the medicine. Pregnancy Bendamustine Zentiva may cause genetic damage and birth defects in animals. You should not use Bendamustine Zentiva during pregnancy unless your doctor considers it absolutely necessary. If treatment is necessary, you should discuss possible side effects in the unborn child and undergo genetic testing if recommended. Breastfeeding You should not use Bendamustine Zentiva during breastfeeding. If treatment with Bendamustine Zentiva is necessary, you should stop breastfeeding. Fertility Women of childbearing age should use effective contraceptive methods both before and during treatment with Bendamustine Zentiva. If you become pregnant during treatment with Bendamustine Zentiva, you should immediately inform your doctor and undergo genetic testing. Men should not father a child during treatment with Bendamustine Zentiva and for 6 months after the end of treatment. There is a risk that treatment with Bendamustine Zentiva may cause infertility; therefore, men should consult their doctor about sperm preservation before starting treatment. Men receiving Bendamustine Zentiva are advised not to plan to father a child during treatment and for 6 months after its completion. Before starting treatment, you should consult your doctor about the possibility of sperm preservation due to the risk of permanent infertility.

Driving and using machines

No studies have been conducted on the effects on the ability to drive and use machines. You should not drive a car or operate machines if you experience side effects such as dizziness or coordination problems.

3. How to use Bendamustine Zentiva

The medicine should always be used exactly as directed by your doctor or pharmacist. In case of doubt, you should consult your doctor or pharmacist. Bendamustine Zentiva is administered intravenously over 30-60 minutes, in different doses, alone as a single anticancer medicine (as monotherapy) or in combination with other medicines. Treatment should not be started if the white blood cell count (leukocytes) decreases below the level established by your doctor. Your doctor will check these blood parameters at regular intervals. Chronic lymphocytic leukemia

Non-Hodgkin's lymphoma

Multiple myeloma

Treatment should be discontinued if the white blood cell count (leukocytes) and (or) platelet count decrease below the level established by your doctor. Treatment can be continued when the white blood cell and platelet counts increase. Liver or kidney function disorders Depending on the degree of liver function disorders, it may be necessary to adjust the dose (reduce by 30% in case of moderate liver function disorders). It is not necessary to adjust the dose if you have kidney function disorders. Your doctor will decide whether it is necessary to adjust the dose. Method of administrationTreatment with Bendamustine Zentiva should only be initiated by doctors experienced in the treatment of cancer. Your doctor will administer the appropriate dose of Bendamustine Zentiva and take necessary precautions. Your doctor will administer the solution for infusion after preparing it according to the instructions. The solution is administered intravenously as a short infusion over 30-60 minutes. Duration of treatmentThere is no generally applicable time limit for treatment with Bendamustine Zentiva. The duration of treatment depends on the disease and how you respond to treatment. In case of doubt or questions about treatment with Bendamustine Zentiva, you should consult your doctor or nurse.

Missing a dose of Bendamustine Zentiva

If you miss a dose of Bendamustine Zentiva, your doctor will usually continue treatment according to the adopted dosing schedule.

Stopping treatment with Bendamustine Zentiva

Your doctor will decide whether to stop treatment or change the medicine to another one. In case of any further doubts related to the use of this medicine, you should consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of the side effects listed below may only be recognized after evaluation by your doctor. Very rarely, after unintentional leakage of Bendamustine Zentiva outside the blood vessel (extravasation), tissue necrosis (necrosis) has been observed. A symptom of leakage of the medicine outside the blood vessel may be a burning sensation at the injection site. Consequences of leakage of the medicine may include pain and poor wound healing. The dose-limiting side effect of bendamustine is bone marrow function disorder, which usually returns to normal after treatment. Bone marrow suppression may lead to a decrease in blood cell count, which may increase the risk of infection, bleeding, or anemia. Very commonside effects (may occur in more than 1 in 10 patients):

• Infections
• Decreased white blood cell count (leukopenia)
• Decreased hemoglobin level (anemia)
• Decreased platelet count (thrombocytopenia)
• Headache
• Nausea; vomiting
• Mucositis; fatigue; fever
• Increased creatinine level in serum; increased urea level in serum

Commonside effects (may occur in up to 1 in 10 patients):

• Metabolic disorders related to the release of cancer cell contents into the bloodstream
• Bleeding (hemorrhage)
• Anemia (decreased red blood cell count)
• Decreased neutrophil count (neutropenia)
• Hypersensitivity reactions, such as allergic dermatitis
• Insomnia, dizziness
• Cardiac disorders, arrhythmias
• Low or high blood pressure (hypotension or hypertension)
• Respiratory disorders
• Diarrhea, constipation, oral mucositis
• Hair loss, skin changes, pruritus (itching)
• Amenorrhea (absence of menstruation)
• Pain, chills, dehydration, loss of appetite
• Increased liver enzyme activity (ASAT/ALAT); increased alkaline phosphatase activity
• Increased bilirubin level in blood
• Decreased potassium level in blood

Uncommonside effects (may occur in up to 1 in 100 patients):

• Acute leukemia
• Failure to produce all types of blood cells (bone marrow failure)
• Fluid accumulation in the pericardial sac (pericardial effusion)
• Myocardial infarction, chest pain (angina pectoris), heart failure

Rareside effects (may occur in up to 1 in 1,000 patients):

• Blood infection (sepsis)
• Bone marrow suppression, which may cause poor general condition or be visible in blood test results
• Severe allergic reactions (anaphylactic reactions)
• Symptoms similar to anaphylactic reactions (anaphylactoid reactions)
• Somnolence
• Voice loss (aphonia)
• Acute circulatory failure (cardiac arrest)
• Redness of the skin (erythema)
• Dermatitis
• Pruritus (itching)
• Rash (exanthema)
• Excessive sweating (hyperhidrosis)

Very rareside effects (may occur in up to 1 in 10,000 patients):

• Primary atypical pneumonia
• Red blood cell destruction (hemolysis)
• Sudden decrease in blood pressure, sometimes with skin reactions or rash (anaphylactic shock)
• Taste disturbance
• Paresthesia (abnormal sensation)
• Poor general condition and limb pain (peripheral neuropathy)
• Severe condition resulting from blockage of certain receptors in the nervous system, nervous system disorders
• Ataxia (coordination disorder)
• Encephalitis (brain inflammation)
• Tachycardia (rapid heart rate)
• Phlebitis (vein inflammation)
• Pulmonary fibrosis (scarring of lung tissue)
• Hemorrhagic esophagitis (bleeding esophagitis)
• Gastrointestinal bleeding
• Infertility
• Multisystem failure

Side effects with unknown frequency(frequency cannot be estimated from available data):

• Irregular or rapid heartbeat (atrial fibrillation)
• Pneumonia (pneumonitis), pulmonary bleeding
• Liver failure
• Kidney failure

There have been reports of the development of tumors (myelodysplastic syndrome, acute myeloid leukemia, lung cancer) in patients using Bendamustine Zentiva. However, the relationship between their occurrence and the use of Bendamustine Zentiva has not been definitively established.

You should immediately contact your doctor if you experience any of the following side effects (frequency unknown):

• Severe skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis. They may appear as red or circular spots on the skin, often with central blisters on the torso, skin peeling, mouth and throat ulcers, and genital and eye lesions, and may be preceded by fever and flu-like symptoms.
• Widespread rash, high body temperature, lymph node enlargement, and symptoms affecting various organs (drug rash with eosinophilia and systemic symptoms, also known as DRESS or hypersensitivity syndrome).

Reporting suspected side effects After the marketing authorization of the medicinal product, it is important to report any suspected side effects. This allows for continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected side effects via the Department of Adverse Reaction Monitoring of Medicinal Products, Medical Devices, and Biocides of the Office for Registration of Medicinal Products, Medical Devices, and Biocides Al. Jerozolimskie 181C, 02-222 Warsaw Tel.: +48 22 49 21 301, fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl Side effects can also be reported to the marketing authorization holder or its representative in Poland.

5. How to store Bendamustine Zentiva

The medicine should be stored out of sight and reach of children. Do not use this medicine after the expiry date stated on the carton after "EXP". 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 specified month. Store the vial in the outer carton to protect from light.

Notice regarding the shelf life of the medicine after opening the packaging or preparing the solution

A properly prepared solution for infusion (according to the instructions at the end of this leaflet) is stable in a polyethylene bag at room temperature (and 60% humidity) for 3.5 hours, and in the refrigerator — for 2 days. Bendamustine Zentiva does not contain preservatives. Therefore, the solution should not be used after the specified periods. The user is responsible for maintaining aseptic conditions. Medicines should not be disposed of via wastewater or household waste. You should ask your pharmacist how to dispose of medicines that are no longer needed. This will help protect the environment.

6. Contents of the pack and other information

What does Bendamustine Zentiva contain

• The active substance of the medicine is bendamustine hydrochloride. 1 vial contains 25 mg of bendamustine hydrochloride 1 vial contains 100 mg of bendamustine hydrochloride After reconstitution (preparation), 1 ml of the concentrate contains 2.5 mg of bendamustine hydrochloride.
• The other ingredient is mannitol.

What does Bendamustine Zentiva look like and what does the pack contain

White or almost white lyophilized powder in a vial with an orange rubber stopper and aluminum flip-top cap. Vial of 25 ml capacity made of type I glass. Vial of 50 ml capacity made of type I glass. Packs containing: 25 mg: 1, 5, 10, 20 vials. 100 mg: 1, 5 vials. Not all pack sizes may be marketed.

Marketing authorization holder and manufacturer

Marketing authorization holder

Zentiva, k.s., U kabelovny 130, Dolní Měcholupy, 102 37 Prague 10, Czech Republic

Manufacturer

Synthon Hispania SL C/ Castelló no 1, Pol. Las Salinas, Sant Boi de Llobregat, 08830 Barcelona Spain Synthon, s.r.o. Brněnská 32/čp. 597 678 01 Blansko Czech Republic

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

Poland: Bendamustine Zentiva

Romania: Bendamustină Zentiva

United Kingdom: Bendamustine hydrochloride Zentiva

For more information about this medicine, you should contact the representative of the marketing authorization holder in Poland: Zentiva Polska Sp. z o.o. ul. Bonifraterska 17 00-203 Warsaw tel.: +48 22 375 92 00

Date of last revision of the leaflet: September 2021

Information intended exclusively for healthcare professionals:

Similarly to all similar cytotoxic substances, due to the potential for genetic damage and cancer, nursing staff and doctors are subject to more stringent than usual precautions. When handling bendamustine, you should avoid inhalation (inhalation) of the medicine and its contact with the skin and mucous membranes (you should wear gloves, protective clothing, and, if possible, a face mask!). In case of contamination of any part of the body with the product, you should carefully wash it with water and soap and rinse your eyes with 0.9% (isotonic) sodium chloride solution. If possible, it is recommended to work on special, protected workstations (under a laminar flow hood) with a covering of the work surface with a single-use, fluid-impermeable absorbent sheet. Contaminated items are cytostatic waste. Please follow national guidelines for the disposal of materials with cytostatic properties! Pregnant women should not be allowed to work with cytostatic products. The ready-to-use solution should be prepared by dissolving the contents of the vial with bendamustine only in water for injections, as follows:

• 1. Preparation of the concentrate
• One vial of bendamustine containing 25 mg of bendamustine hydrochloride is first dissolved in 10 ml of water for injections by shaking.
• One vial of bendamustine containing 100 mg of bendamustine hydrochloride is first dissolved in 40 ml of water for injections by shaking.
• 2. Preparation of the solution for infusion

As soon as a clear solution is obtained (usually after 5-10 minutes), the entire dose of bendamustine is immediately dissolved in 0.9% (isotonic) sodium chloride solution to obtain a final volume of approximately 500 ml. Bendamustine should not be dissolved in other infusion or injection solutions. The infusion solution with bendamustine should not be mixed with other substances.