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

Introduction

Package Leaflet: Information for the User

Bendamustina Baxter2.5mg/mlpowder for concentrate for solution for infusion EFG

Bendamustina, 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 get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

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

1. What is Bendamustina Baxter and what is it used for

Bendamustina Baxter is a medicine used to treat certain types of cancer (it is a cytotoxic medicine).

Bendamustina Baxter 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's lymphoma, which has not responded or has responded for only a short period of time, after previous treatment with rituximab;
• multiple myeloma, if treatments with talidomide or bortezomib are not suitable for you.

2. What you need to know before you use Bendamustina Baxter

Do not use Bendamustina Baxter

• if you are allergic to bendamustina hydrochloride or any of the other ingredients of this medicine (listed in section 6);
• during breast-feeding; if you need treatment with Bendamustina Baxter during breast-feeding, you must stop breast-feeding (see section "Warnings and precautions" on breast-feeding);
• 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 the bone marrow (bone marrow depression) and severe changes in the number of white blood cells and platelets in the blood;
• if you have undergone 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

At any time during or after treatment, tell your doctor immediately if you notice or someone notices in you: memory loss, cognitive difficulties, difficulty walking or vision loss. These symptoms may be due to a rare but serious brain infection that can be fatal (progressive multifocal leukoencephalopathy or PML).

Contact your doctor if you notice any suspicious changes in your skin, as the use of this medicine may increase the risk of certain types of skin cancer (non-melanoma skin cancer).

Consult your doctor, pharmacist, or nurse before starting treatment with Bendamustina Baxter:

• in case your bone marrow's ability to replace blood cells is reduced. Your doctor will determine your white blood cell and platelet count before starting treatment with bendamustina, before each treatment cycle, and in the intervals between cycles;
• in case of infections. If you have signs of infection, such as fever or respiratory symptoms, you should contact your doctor;
• if you have skin reactions during treatment with bendamustina. Reactions can increase in intensity;
• in case of painful red or purple rashes that spread and blisters or other lesions that begin to appear on the mucous membranes (e.g., mouth and lips), particularly if you have previously had sensitivity to light, respiratory infections (e.g., bronchitis), and/or fever;
• if you have a heart condition (e.g., heart attack, chest pain, severe heart rhythm disorders);
• if you experience pain on one side or if you notice blood in your urine or that you urinate less. If your disease is very severe, it is possible that your body cannot eliminate all the waste products of the dying cancer cells. This is called tumor lysis syndrome and can cause kidney failure and heart problems within 48 hours of administration of the first dose of bendamustina. Your doctor will ensure that you are adequately hydrated and will give you other medications to prevent this from happening;
• in case of severe allergic or hypersensitivity reactions. You should pay attention to infusion reactions after your first cycle of treatment.

Using Bendamustina Baxter with other medicines

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

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

If bendamustina is used in combination with medicines that alter your immune response, this effect may be intensified.

Cytostatics may reduce the effectiveness of live virus vaccines. Additionally, cytostatics increase the risk of infection after vaccination with live virus vaccines (e.g., viral vaccination).

Bendamustina should not be used with fluvoxamine, ciprofloxacin, acyclovir, or cimetidine due to the possibility of interactions.

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

Bendamustina may cause genetic damage and has caused malformations in animal studies. It should not be used during pregnancy unless your doctor clearly indicates it. If you receive treatment, you should consult your doctor about the risk of possible adverse effects of the treatment on the fetus. Genetic counseling is recommended.

If you are a woman of childbearing age, you should use effective contraceptive methods before and during treatment with bendamustina. If you become pregnant during treatment with bendamustina, you should inform your doctor immediately and undergo genetic counseling.

Breast-feeding

Bendamustina should not be administered during breast-feeding. If you need treatment with bendamustina during breast-feeding, you must stop breast-feeding.

Consult your doctor or pharmacist before using any medicine.

Fertility

Men receiving treatment with bendamustina are advised not to father a child during treatment and for 6 months after the end of treatment. Before starting treatment, you should be advised on sperm preservation due to the possibility of permanent infertility.

Driving and using machines

Bendamustina's influence on the ability to drive and use machines is significant. Do not drive or use machines if you experience side effects such as drowsiness, lack of coordination, or peripheral nervous system disorders.

3. How to use Bendamustina Baxter

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

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

Do not start treatment if your white blood cell (leukocyte) and/or platelet count falls below certain levels.

Your doctor will determine these values periodically.

Chronic lymphocytic leukemia

Bendamustina Baxter 100 mg per square meter of body surface area (calculated based on weight and height) on days 1 and 2.

This cycle will be repeated every 4 weeks and up to 6 times.

Non-Hodgkin's lymphoma

Bendamustina Baxter 120 mg per square meter of body surface area (calculated based on weight and height) on days 1 and 2.

This cycle will be repeated every 3 weeks at least 6 times.

Multiple myeloma

Bendamustina Baxter 120-150 mg per square meter of body surface area (calculated based on weight and height) on days 1 and 2.

Prednisone 60 mg per square meter of body surface area (calculated based on weight and height) on days 1 and 2 by intravenous or oral route on days 1 to 4.

This cycle will be repeated every 4 weeks at least 3 times.

Treatment should be interrupted if the white blood cell (leukocyte) and/or platelet count falls below certain levels. Treatment can be resumed when the white blood cell and platelet count have increased.

Renal or hepatic impairment

Depending on the degree of hepatic impairment, it may be necessary to adjust the dose (by 30% in case of moderate hepatic impairment). No dose adjustment is necessary in case of renal impairment. Your doctor will decide if a dose adjustment is necessary.

How it is administered

Only doctors with experience in the treatment of tumors should administer Bendamustina Baxter. Your doctor will administer the exact dose of Bendamustina Baxter and take the necessary precautions.

Your doctor will administer the solution for infusion after its correct 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 Bendamustina Baxter has not been defined. The duration of treatment depends on the disease and the response to treatment.

If you have any concerns or questions about treatment with Bendamustina Baxter, talk to your doctor or nurse.

Use in children and adolescents

The safety and efficacy of bendamustina hydrochloride in children have not been established yet. The currently available data are not sufficient to make a posological recommendation.

If you miss a dose of Bendamustina Baxter

If you miss a dose of Bendamustina Baxter, your doctor will normally continue with the normal dosing schedule.

If you stop treatment with Bendamustina Baxter

Your treating doctor will decide whether to interrupt treatment or change to a different preparation.

If you have any other questions about 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 manifestations listed below may be observed after the tests performed by your doctor.

In very rare cases, tissue damage (necrosis) has been observed after the extravasation of bendamustine in the tissue surrounding the blood vessels (extravascular). If the medicine leaks out of a vessel, there may be a burning sensation at the needle insertion site. The consequences can be pain and defects in poorly healed skin.

The dose-limiting adverse effect of bendamustine is bone marrow failure, which usually normalizes after treatment. Suppression of bone marrow function can cause a decrease in the number of blood cells, which in turn can lead to a higher risk of infection, anemia, or bleeding.

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

• Infections.
• Decrease in the number of white blood cells (cells in the blood that fight diseases).
• Decrease in the number of platelets (colorless cells in the blood that help with blood clotting).
• Nausea.
• Vomiting.
• Inflammation of the mucous membranes.
• Fatigue.
• Fever.
• Decrease in the red pigment of the blood (hemoglobin: a protein in red blood cells that transports oxygen throughout the body).
• Increase in creatinine levels (a chemical waste product produced by muscle) in the blood.
• Increase in urea levels (a chemical waste product) in the blood.
• Headache.

Common (may affect up to 1 in 10 people)

• Metabolic disorder caused by cancer cells dying, releasing their contents into the bloodstream (tumor lysis syndrome).
• Bleeding (hemorrhage).
• Decrease in red blood cells, which can cause pale skin and weakness or difficulty breathing (anemia).
• Decrease in the number of neutrophils (a common type of white blood cell needed to fight infections).
• Hypersensitivity reactions, such as allergic skin inflammation (dermatitis) or hives.
• Insomnia.
• Cardiac dysfunction (such as angina pectoris).
• Cardiac arrhythmia.
• Low or high blood pressure (hypotension or hypertension).
• Pulmonary function disorder.
• Diarrhea.
• Constipation.
• Mouth ulcers (stomatitis).
• Hair loss.
• Skin changes.
• Absence of menstruation (amenorrhea).
• Pain.
• Chills.
• Dehydration.
• Dizziness.
• Itchy rash (urticaria).
• Loss of appetite.
• Increase in liver enzymes AST/ALT (may indicate liver cell inflammation or damage).
• Increase in alkaline phosphatase enzyme (an enzyme produced mainly in the liver and bones).
• Increase in bile pigment (a substance produced during the normal breakdown of red blood cells).
• Low potassium levels (a nutrient necessary for nerve and muscle cell function, including heart cells) in the blood.

Uncommon (may affect up to 1 in 100 people)

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

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

• Blood infection (sepsis).
• Severe allergic and hypersensitivity reactions (anaphylactic reactions).
• Signs similar to anaphylactic reactions (anaphylactoid reactions).
• Decrease in bone marrow function, which can cause illness or show up in blood tests.
• Drowsiness.
• Loss of voice (aphonia).
• Acute circulatory failure (mainly cardiac failure with inability to maintain oxygen and nutrient supply to tissues and elimination of toxins).
• Redness of the skin (erythema).
• Skin inflammation (dermatitis).
• Itching (pruritus).
• Skin rash (macular exanthema).
• Excessive sweating (hyperhidrosis).

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

• Atypical primary inflammation of the lungs (pneumonia).
• Breakdown of red blood cells in the blood.
• Rapid drop in blood pressure, sometimes with reactions or skin rashes (anaphylactic shock).
• Alteration of taste.
• Alteration of sensitivity (paresthesia).
• Discomfort and pain in the limbs (peripheral neuropathy).
• Severe condition that causes blockage of specific receptors in the nervous system.
• Nervous system disorders.
• Lack of coordination (ataxia).
• Brain inflammation (encephalitis).
• Increased heart rate (tachycardia).
• Inflammation of the veins (phlebitis).
• Tissue formation in the lungs (pulmonary fibrosis).
• Hemorrhagic inflammation of the throat (hemorrhagic esophagitis).
• Gastric or intestinal bleeding.
• Sterility.
• Multi-organ failure.

Frequency not known (cannot be estimated from available data)

• Liver failure.
• Kidney failure.
• Irregular and often rapid heart rate (atrial fibrillation).
• Painful rashes of red or purple color that spread and blisters or other lesions that begin to appear on the mucous membranes (e.g., mouth and lips), particularly if you have previously had sensitivity to light, respiratory infections (e.g., bronchitis), and/or fever.
• Medication rash in combination therapy with rituximab.
• Pneumonitis.
• Lung bleeding.

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

Consult your doctor or seek medical attention immediately if you observe 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 or patches, often with central blisters on the trunk, skin peeling, mouth ulcers, throat, nose, genitals, and eyes, and may be preceded by fever and flu-like symptoms.

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

If you consider any of the adverse effects you are experiencing to be serious or if you notice any adverse effect not mentioned in this leaflet, inform your doctor.

Adverse Effect Reporting

If you experience any type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is a possible adverse effect that does not appear in this leaflet. You can also report them directly through the national reporting system, 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 Bendamustine Baxter

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiration date stated on the label and carton after EXP. The expiration date is the last day of the month indicated.

No special storage conditions are required.

Note on the validity period after opening or preparation of the solution

The prepared infusion solutions are stable in Viaflo bags made of polypropylene, polyamide, and polyethylene for 3.5 hours at room temperature and for 2 days if stored in the refrigerator. Bendamustina Baxter does not contain preservatives. From a microbiological point of view, the medicine should be used immediately. Otherwise, the storage times and conditions before use are the responsibility of the user and should not normally exceed 24 hours at a temperature between 2 and 8°C, unless the reconstitution/dilution (etc.) has taken place in controlled and validated aseptic conditions. Once these times have been exceeded, the solutions should not be used.

It is the user's responsibility to maintain aseptic conditions.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of the packaging and any unused medicines. This will help protect the environment.

6. Package Contents and Additional Information

Bendamustine Baxter Composition

• The active ingredient is bendamustine hydrochloride.

Each vial contains 25 mg of bendamustine hydrochloride.

Each vial contains 100 mg of bendamustine hydrochloride.

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

• The other component is mannitol.

Product Appearance and Package Contents

Ambber-colored glass vials with a gray rubber stopper and an overlying aluminum cap.

The powder is white to off-white and is lyophilized.

Bendamustina Baxter is marketed in packages containing

1, 5, 10, and 20 vials of 20 ml with 25 mg of bendamustine hydrochloride and 1 and 5 vials of 50 ml with 100 mg of bendamustine hydrochloride.

Not all pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Baxter, S.L.

Pouet de Camilo, 2

46394 Ribarroja del Turia (Valencia)

Spain

Manufacturer

Baxter Oncology GmbH

Kantstrasse 2

33790 Halle/Westfalen

Germany

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

Germany Bendamustin Baxter 2.5 mg/ml Powder for concentrate for solution for infusion

Spain Bendamustina Baxter 2.5 mg/ml powder for concentrate for solution for infusion EFG

France Bendamustine Baxter 2.5 mg/ml powder for solution for infusion

Netherlands Bendamustine Baxter 2.5 mg/ml powder for concentrate for solution for infusion

United Kingdom Bendamustine hydrochloride 2.5 mg/ml Powder for concentrate for solution for infusion

Date of last revision of this leaflet:December 2020

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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 the skin and mucous membranes when handling Bendamustina Baxter (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 of sodium chloride (0.9%) (isotonic) injectable solution. If possible, it is recommended to work on a special safety bench (laminar flow) with a disposable, liquid-impermeable absorbent pad. Contaminated items are cytostatic waste. Please follow national guidelines for the disposal of cytostatic material. Pregnant women should not work with cytostatics.

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

1. Preparation of the concentrate
   • First, dissolve a vial of Bendamustina Baxter containing 25 mg of bendamustine hydrochloride in 10 ml, shaking it.
   • First, dissolve a vial of Bendamustina Baxter 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 (usually within 5-10 minutes), the total recommended dose of Bendamustina Baxter should be diluted immediately with 9 mg/ml of sodium chloride (0.9%) (isotonic) injectable solution to obtain a final volume of approximately 500 ml. Bendamustina Baxter should not be diluted with other infusion or injectable solutions. Bendamustina Baxter 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.

Disposal of unused medicine and all materials that have come into contact with it will be carried out in accordance with local regulations.

If the product is unintentionally injected into the tissue surrounding the blood vessels (extravascular injection), the infusion should be stopped immediately. The needle should be withdrawn after brief aspiration. The affected tissue area should then 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).

Note on the validity period after opening or preparation of the solution

The prepared infusion solutions are stable in Viaflo bags made of polypropylene, polyamide, and polyethylene for 3.5 hours at room temperature and 60% relative humidity, and for 2 days if stored in the refrigerator. Bendamustina Baxter does not contain preservatives. From a microbiological point of view, the medicine should be used immediately. Otherwise, the storage times and conditions before use are the responsibility of the user and should not normally exceed 24 hours at a temperature between 2 and 8°C, unless the reconstitution/dilution (etc.) has taken place in controlled and validated aseptic conditions. Once these times have been exceeded, the solutions should not be used.