BENDAMUSTINE KABI 2.5 mg/ml POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the User

Bendamustine Kabi 2.5 mg/ml powder for concentrate for solution for infusion EFG

Bendamustine hydrochloride

Read all of this leaflet carefully before you start 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 you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you experience any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

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

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

Bendamustine Kabi is a medicine used to treat certain types of cancer (it is a cytotoxic medicine).

Bendamustine Kabi is used alone (monotherapy) or in combination with other medicines to treat the following types of cancer:

• chronic lymphocytic leukemia, if combination chemotherapy with fludarabine is not suitable for you.
• non-Hodgkin lymphoma, which has not responded, or has responded only for a short period, to previous treatment with rituximab
• multiple myeloma, if treatments containing thalidomide or bortezomib are not suitable for you.

2. What you need to know before you use Bendamustine Kabi

Do not use Bendamustine Kabi

• if you are allergic to bendamustine hydrochloride or any of the other ingredients of this medicine (listed in section 6).
• during breast-feeding; if treatment with bendamustine hydrochloride is necessary during breast-feeding, you must stop breast-feeding (see section Pregnancy, breast-feeding and fertility).
• if you have severe liver dysfunction (damage to the functional cells of the liver);
• if you have yellowing of the skin or the whites of the eyes caused by liver or blood problems (jaundice);
• if you have a severe disorder of bone marrow function (bone marrow depression) and severe changes in the number of white blood cells and platelets in the blood;
• if you have had major surgery in the 30 days prior to the start of treatment;
• if you have had any infection, especially if it has been accompanied by a reduction in the number of white blood cells (leucopenia).
• in combination with yellow fever vaccines.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before you start using Bendamustine Kabi

• if your bone marrow's ability to produce blood cells is reduced. Your white blood cell and platelet counts should be measured before you start treatment with Bendamustine Kabi, before each treatment cycle, and in the intervals between cycles.
• if you have infections. If you have signs of infection, such as fever or respiratory symptoms, you should contact your doctor.
• Tell your doctor immediately if, at any time during or after treatment, you or someone else notices: memory loss, difficulty thinking, difficulty walking, or loss of vision; this may be due to a rare but serious brain infection (progressive multifocal leukoencephalopathy or PML).
• if you have skin reactions during treatment with Bendamustine Kabi. Skin reactions can increase in intensity.
• Tell your doctor if you notice any suspicious changes in your skin, as you may be at a higher risk of certain types of skin cancer (non-melanoma skin cancer) with the use of this medicine.
• if you have a painful red or purple rash that spreads and forms blisters and/or other lesions on the mucous membranes (e.g. mouth and lips), especially if you have had sensitivity to light, respiratory infections (e.g. bronchitis), and/or fever.
• if you have heart disease (e.g. heart attack, chest pain, severe heart rhythm disorders).
• if you have pain on one side or if you notice blood in your urine or that you urinate less. If your disease is very severe, your body may not be able to eliminate all the waste products from the dying cancer cells. This is called tumor lysis syndrome and can cause kidney failure and heart problems within 48 hours of the first dose of Bendamustine Kabi. Your doctor may need to make sure you are properly hydrated and give you other medicines to prevent this from happening.
• if you have severe allergic or hypersensitivity reactions, you should be aware of infusion reactions after your first cycle of treatment.

Using Bendamustine Kabi and other medicines

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.

If bendamustine hydrochloride is used in combination with medicines that inhibit blood cell production in the bone marrow, the effect on the bone marrow may be increased.

If bendamustine hydrochloride is used in combination with medicines that alter the immune response, this effect may be increased.

Cytostatic medicines may reduce the effectiveness of some live virus vaccines.

In addition, cytostatic medicines increase the risk of infection after vaccination with live vaccines (e.g. viral vaccination).

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

Pregnancy

Bendamustine hydrochloride may cause genetic damage and has caused malformations in animal studies. Bendamustine Kabi should not be used during pregnancy unless your doctor considers it clearly necessary. If you receive this treatment, you should ask your doctor to explain the risk of possible side effects for your child. Genetic counseling is recommended.

If you become pregnant during treatment with Bendamustine Kabi, you should inform your doctor immediately and seek genetic counseling.

Pregnancy precautions for men and women

Men:

Men being treated with Bendamustine Kabi should avoid fathering a child during treatment with Bendamustine Kabi and for 3 months after treatment has finished.

Women:

Women of childbearing age should use effective contraceptive methods during treatment and for 6 months after the last dose of Bendamustine Kabi.

Breast-feeding

Bendamustine Kabi should not be administered during breast-feeding. If you need treatment with Bendamustine Kabi during breast-feeding, you should stop breast-feeding.

Fertility

Men:

There is a risk that treatment with Bendamustine Kabi may lead to infertility in men. Male patients who wish to have children after the end of treatment should seek advice on sperm conservation before treatment begins.

Women:

Patients who wish to have children after the end of treatment should consult their doctor.

Driving and using machines

Bendamustine hydrochloride may affect your ability to drive or use machines. Do not drive or use machines if you experience side effects such as dizziness or lack of coordination.

3. How to use Bendamustine Kabi

Follow exactly the instructions for administration of this medicine given by your doctor or pharmacist. If you are unsure, ask your doctor or pharmacist again.

Bendamustine Kabi is administered into a vein over 30 to 60 minutes in various doses, either alone (monotherapy) or in combination with other medicines.

You cannot start treatment if your white blood cell count (leukocytes) and/or your platelet count is below certain levels.

Your doctor will measure these values periodically.

Chronic lymphocytic leukemia

Non-Hodgkin lymphoma

Multiple myeloma

Treatment will be stopped if your white blood cell count (leukocytes) is below certain levels. Treatment can be restarted when your white blood cell and platelet counts have increased.

Kidney or liver impairment

The dose may need to be adjusted according to the degree of liver function impairment (initial reduction of 30% in case of moderate liver impairment). No dose adjustment is necessary in case of kidney function impairment. Your doctor will decide if a dose adjustment is necessary.

How it is administered

Treatment with Bendamustine Kabi can only be administered by doctors with experience in the treatment of tumors. Your healthcare professional will administer the exact dose of Bendamustine Kabi and take the necessary precautions.

Your healthcare professional will administer the solution for infusion after proper preparation. The solution is administered into a vein as a short infusion over 30 to 60 minutes.

Duration of treatment

The duration of treatment with Bendamustine Kabi has not been defined. The duration of treatment depends on the disease and response to treatment.

If you are concerned about anything or have any questions about treatment with Bendamustine Kabi, talk to your doctor or nurse.

If you miss a dose of Bendamustine Kabi

If you miss a dose of Bendamustine Kabi, your doctor will normally continue with the normal dosage regimen.

If you stop treatment with Bendamustine Kabi

Your doctor will decide whether to stop treatment or use a different preparation.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

Some of the findings listed below may be found after tests performed by your doctor.

In very rare cases, tissue breakdown (necrosis) has been observed after the extravasation of Bendamustina Kabi in the tissue surrounding blood vessels (extravascular). If the product is extravasated outside a vessel, there may be a burning sensation at the needle insertion site. The consequences can be pain and skin healing problems.

The dose-limiting adverse effect of Bendamustina Kabi is an alteration of bone marrow function, which usually normalizes. Bone marrow function suppression can lead to low blood cell counts, which in turn can lead to an increased risk of infection, anemia, or high risk of bleeding.

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

• Reduction of white blood cell count (cells that fight diseases in the blood)
• Reduction of red blood pigment (hemoglobin: a protein in red blood cells that carries oxygen throughout the body)
• Reduction of platelet count (colorless blood cells that help blood clot)
• Infections
• Discomfort (nausea)
• Vomiting
• Mucosal inflammation
• Increased blood concentration of creatinine (a chemical waste product produced in muscles)
• Increased blood concentration of urea (a chemical waste product)
• Fever
• Fatigue
• Headache

Common (may affect up to 1 in 10 patients)

• Bleeding (hemorrhage)
• Metabolic disorder caused by dying cancer cells releasing their contents into the bloodstream
• Decrease in red blood cells, which can make the skin pale and cause weakness or difficulty breathing (anemia)
• Reduction of neutrophil count (a common type of white blood cell important for fighting infections)
• Hypersensitivity reactions, such as allergic skin inflammation (dermatitis) or hives
• Elevation of liver enzymes AST/ALT (which can indicate inflammation or damage to liver cells)
• Increased alkaline phosphatase enzyme (an enzyme mainly generated in the liver and bones)
• Increased bile pigment (a substance generated during the normal breakdown of red blood cells)
• Decreased blood potassium level (a nutrient necessary for the function of nerve and muscle cells, including heart cells)
• Cardiac function disorder (dysfunction), such as feeling your heartbeat (palpitations) or chest pain (angina pectoris)
• Cardiac rhythm disorder (arrhythmia)
• Elevation or decrease in blood pressure (hypotension or hypertension)
• Pulmonary function disorder
• Diarrhea
• Constipation
• Mouth ulcers (stomatitis)
• Loss of appetite
• Hair loss
• Skin disorders
• Absence of menstrual period (amenorrhea)
• Pain
• Insomnia
• Chills
• Dehydration
• Dizziness
• Itchy skin rash (urticaria)

Uncommon (may affect up to 1 in 100 patients)

• Fluid accumulation in the sac surrounding the heart (fluid leakage in the pericardial space)
• Ineffective production of blood cells in the bone marrow (the spongy material inside bones where blood cells are produced)
• Acute leukemia
• Heart attack, chest pain (myocardial infarction)
• Heart failure

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

• Blood infection (sepsis)
• Severe allergic and hypersensitivity reactions (anaphylactic reactions)
• Decreased bone marrow function, which can make you feel unwell or appear in your blood tests
• Signs similar to anaphylactic reactions (anaphylactoid reactions)
• Somnolence
• Voice loss (aphonia)
• Acute circulatory failure (circulatory failure mainly of cardiac origin with insufficient oxygen and nutrient supply to tissues and removal of toxins)
• Redness of the skin (erythema)
• Skin inflammation (dermatitis)
• Itching (pruritus)
• Skin rash (maculopapular exanthema)
• Excessive sweating (hyperhidrosis)

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

• Atypical primary pulmonary inflammation (pneumonia)
• Destruction of red blood cells
• Rapid decrease in blood pressure, sometimes with skin reactions or rashes (anaphylactic shock)
• Taste disorder
• Sensitivity disorder (paresthesia)
• Discomfort and pain in the limbs (peripheral neuropathy)
• Severe condition resulting from the blockade of specific nervous system receptors
• Nervous system disorders
• Lack of coordination (ataxia)
• Brain inflammation (encephalitis)
• Increased heart rate (tachycardia)
• Vein inflammation (phlebitis)
• Tissue formation in the lungs (pulmonary fibrosis)
• Hemorrhagic inflammation of the throat (hemorrhagic esophagitis)
• Gastric or intestinal bleeding
• Infertility
• Multi-organ failure

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

• Liver failure
• Kidney failure
• Irregular and often rapid heart rhythm (atrial fibrillation)
• Painful red or purple rash that spreads and forms blisters and/or other lesions on mucous membranes (e.g., mouth and lips), particularly if you have previously had sensitivity to light, respiratory infections (e.g., bronchitis), and/or fever.
• Drug rash in combination treatment with rituximab
• Pneumonitis
• Pulmonary bleeding
• Excessive urination, even at night, and excessive thirst even after drinking fluids (nephrogenic diabetes insipidus)

There have been reports of tumors (myelodysplastic syndromes, acute myeloid leukemia, bronchial carcinoma) after treatment with bendamustine hydrochloride. A clear relationship with bendamustine hydrochloride could not be determined.

Consult your doctor or seek medical attention immediately if you notice any of the following adverse effects (frequency not known):

Severe skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis. These can appear as reddish spots with a target-like appearance or circular patches on the trunk, often with blisters in the center, skin peeling, mouth ulcers, throat, nose, genitals, and eyes, and may be preceded by fever and flu-like symptoms.

Widespread skin rash, high body temperature, increased lymph nodes, and involvement of other body organs (drug reaction with eosinophilia and systemic symptoms, also known as DRESS or drug hypersensitivity syndrome).

If any of the adverse effects worsen or if you experience adverse effects not listed in this prospectus, please inform your doctor.

Adverse Effect Reporting

If you experience adverse effects, consult your doctor, hospital pharmacist, or nurse, even if they are adverse effects that do not appear in this prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Bendamustina Kabi

Keep this medicine out of sight and reach of children.

Do not use this medicine after the expiration date shown on the vial and packaging after CAD. The expiration date is the last day of the month indicated.

This medicine does not require special storage conditions.

Check the validity period before opening or preparing the solution

The correctly prepared infusion solutions according to the instructions included at the end of this prospectus are stable in polyethylene bags at room temperature / 60% relative humidity for 3.5 hours and in the refrigerator for 2 days. Bendamustina Kabi does not contain preservatives. Therefore, the solution should not be used after these periods.

From a microbiological point of view, the solution should be used immediately. If not used immediately, the storage times and conditions before use are the responsibility of the user and should not normally exceed 24 hours between 2 and 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

Do not use this medicine if you observe visible signs of deterioration.

Medicines should not be thrown away through wastewater or household waste. Ask your pharmacist how to dispose of packaging and medicines you no longer need. This will help protect the environment.

6. Package Contents and Additional Information

Bendamustina Kabi Composition

• The active ingredient is bendamustine hydrochloride.

1 vial contains 25 mg of bendamustine hydrochloride

1 vial contains 100 mg of bendamustine hydrochloride

After reconstitution, 1 ml of concentrate contains 2.5 mg of bendamustine hydrochloride.

• The other component is mannitol.

Product Appearance and Package Contents

Topaz-colored glass vials with a rubber stopper and sealed with a green or blue flip-off aluminum cap. The powder is a white or almost white lyophilized tablet or powder.

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

Only some package sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Fresenius Kabi España S.A.U.

Torre Mapfre – Vila Olímpica

Marina 16-18

08005 Barcelona

Spain

Manufacturer

Fresenius Kabi Deutschland GmbH

Pfingstweide 53

61169 Friedberg

Germany

Date of Last Revision of this Prospectus: May 2024

Detailed and updated information on this medicine is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es

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This information is intended only for healthcare professionals:

As with all similar cytotoxics, nursing staff and doctors should take extreme safety precautions due to the potential genotoxic and carcinogenic effects of the preparation. Avoid inhalation (breathing) and contact with skin and mucous membranes when handling Bendamustina Kabi (wear gloves, protective clothing, and, if possible, a mask). If any part of the body is contaminated, clean it carefully with water and soap, and rinse the eyes with 9 mg/ml (0.9%) isotonic saline solution. If possible, it is recommended to work on a special safety bench (laminar flow) with a disposable, liquid-impermeable absorbent sheet. Contaminated items are cytostatic waste. Please follow national guidelines for the disposal of cytostatic material. Pregnant women in the nursing staff should not work with cytostatics.

The vials are for single use.

The ready-to-use solution should be prepared by dissolving the contents of a Bendamustina Kabi vial exclusively in water for injectable preparations, as indicated below:

1. Concentrate preparation
   • First, dissolve a Bendamustina Kabi vial containing 25 mg of bendamustine hydrochloride in 10 ml, shaking it.
   • First, dissolve a Bendamustina Kabi vial containing 100 mg of bendamustine hydrochloride in 40 ml, shaking it.

1. Preparation of the infusion solution

As soon as a clear solution is obtained (after 5 to 10 minutes, usually), dissolve the total recommended dose of Bendamustina Kabi in 9 mg/ml (0.9%) isotonic saline solution to achieve a final volume of approximately 500 ml. Bendamustina Kabi should not be dissolved with other infusion or injection solutions. Bendamustina Kabi should not be mixed in infusion with other substances.

1. Administration

The solution is administered by intravenous infusion over 30-60 minutes.

The vials are for single use.

Any remaining medicine or waste material should be disposed of in accordance with local regulations. If the product is unintentionally injected into the tissue surrounding blood vessels (extravascular injection), the infusion should be stopped immediately. The needle should be withdrawn after brief aspiration. Then, the affected tissue area should be cooled. The arm should be elevated. It is not clear whether the use of additional treatments (such as corticosteroids) is beneficial (see section 4).