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

Introduction

Package Leaflet: Information for the User

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

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

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

Bendamustina Glenmark 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 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 Bendamustina Glenmark

Do not use Bendamustina Glenmark

• if you are allergic to bendamustine hydrochloride or any of the other ingredients of this medicine (listed in section 6).
• if you are breast-feeding. If treatment with Bendamustina Glenmark is necessary during breast-feeding, you must stop breast-feeding (see section Warnings and precautions).
• 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 (depression of the bone marrow) and severe alterations 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

Talk to your doctor before you start using Bendamustina Glenmark.

• 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 Bendamustina Glenmark, 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.
• if you have skin reactions during treatment with Bendamustina Glenmark. Reactions can increase in intensity.
• if you have widespread painful red or purple rashes and blisters and/or other lesions that start to appear on the mucous membranes (e.g. mouth and lips), particularly if you have had previous 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 notice pain in your side or if you see blood in your urine or if 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 in the 48 hours following the administration of the first dose of Bendamustina Glenmark. Your doctor will make sure you are properly hydrated and will 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.
• 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).

Children and adolescents

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

Using Bendamustina Glenmark with other medicines

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

If Bendamustina Glenmark 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 Bendamustina Glenmark is used in combination with medicines that alter your immune response, this effect may be increased.

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).

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

If you are a woman of childbearing age, you must use effective contraceptive measures before and during treatment with Bendamustina Glenmark. If you become pregnant during treatment with Bendamustina Glenmark, you should inform your doctor immediately and seek genetic counseling.

Breast-feeding

Bendamustina Glenmark should not be administered during breast-feeding. If treatment with bendamustine hydrochloride is necessary during breast-feeding, you must stop breast-feeding.

Ask your doctor or pharmacist for advice before taking any medicine.

Fertility

Men treated with Bendamustina Glenmark are advised not to father a child during treatment and for up to 6 months after treatment. Before starting treatment, you should be advised on the conservation of sperm, as there is a possibility that it may cause permanent infertility.

If you are a man, you should not father a child during treatment with Bendamustina Glenmark and for 6 months after treatment. There is a risk that treatment with Bendamustina Glenmark may cause infertility; you may want to seek advice on the conservation of sperm before starting treatment.

Driving and using machines

Bendamustina Glenmark has a major influence on the ability to drive and use machines. Do not drive or use machines if you experience side effects such as dizziness or lack of coordination.

3. How to use Bendamustina Glenmark

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.

Bendamustina Glenmark 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 (leukocyte) and/or platelet count is below the determined levels.

Your doctor will measure these values periodically.

Chronic lymphocytic leukemia

Non-Hodgkin's lymphoma

Multiple myeloma

Treatment will be stopped if the white blood cell (leukocyte) and/or platelet count falls below the determined levels. Treatment can be restarted when the leukocyte and platelet count has increased.

Kidney or liver impairment

The dose may need to be adjusted according to the degree of liver function impairment (by 30% in case of moderate liver impairment; if well tolerated, your doctor may consider returning to the normal dose). 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

Bendamustina Glenmark can only be administered by doctors with experience in the treatment of tumors. Your doctor will administer the exact dose of Bendamustina Glenmark and take the necessary precautions.

Your doctor 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 Bendamustina Glenmark has not been defined. The duration of treatment depends on the disease and response to treatment.

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

If you miss a dose of Bendamustina Glenmark

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

If you stop treatment with Bendamustina Glenmark

Your doctor will decide whether to stop treatment or use 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, Bendamustina Glenmark can cause adverse effects, although not all people suffer from them. Some of the results listed below may be found after tests performed by your doctor.

To evaluate adverse effects, the following definitions are used, based on frequency:

Very common: may affect more than 1 in 10 people.

Common: may affect up to 1 in 10 people.

Uncommon: may affect up to 1 in 100 people.

Rare: may affect up to 1 in 1,000 people.

Very rare: may affect up to 1 in 10,000 people.

Unknown: the frequency cannot be calculated from the available data.

In very rare cases, tissue degradation (necrosis) has been observed after extravasation of bendamustina in the tissue surrounding blood vessels (extravascular). If the product extravasates 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 is an alteration of bone marrow function, which usually normalizes. The suppression of bone marrow function can lead to a reduction in blood cell counts, which in turn can lead to an increased risk of infection, anemia, or an increased risk of bleeding.

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

• Reduction of white blood cell count (cells that fight diseases in your blood)
• Reduction of red blood cell pigment (hemoglobin: a protein in red blood cells that carries oxygen throughout the body)
• Reduction of platelet count (colorless blood cells that help with blood clotting)
• Infections
• Nausea
• Vomiting
• Inflammation of the mucous membranes
• Headache
• Increased blood concentration of creatinine (a chemical waste product produced by your muscle)
• Increased blood concentration of urea (a chemical waste product)
• Fever
• Fatigue

Common (may affect up to 1 in 10 people):

• Bleeding (hemorrhage)
• Metabolic disorder caused by dying cancer cells releasing their contents into the bloodstream
• Decrease in red blood cells, which can cause pale skin and weakness or difficulty breathing (anemia)
• Reduction of neutrophil count (a common type of white blood cell necessary to fight infections)
• Hypersensitivity reactions, such as allergic inflammation of the skin (dermatitis) or hives
• Elevation of liver enzymes AST/ALT (may indicate inflammation or damage to liver cells)
• Increased alkaline phosphatase enzyme (an enzyme synthesized mainly in the liver and bones)
• Increased bile pigment (a substance produced during the normal breakdown of red blood cells)
• Decreased blood potassium level (a nutrient necessary for the function of nerve and muscle cells, including those of the heart)
• Cardiac dysfunction
• Cardiac 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
• Pruritic skin rash (hives)

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 all 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)
• 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 (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 (maculopapular exanthem)
• Excessive sweating (hyperhidrosis)

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

• Atypical primary inflammation of the lungs (pneumonia)
• Destruction of red blood cells
• Rapid decrease in blood pressure, sometimes with reactions or skin rashes (anaphylactic shock)
• Alteration of taste
• Alteration of sensitivity (paresthesias)
• 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)
• Vein inflammation (phlebitis)
• Tissue formation in the lungs (pulmonary fibrosis)
• Hemorrhagic inflammation of the throat (hemorrhagic esophagitis)
• Gastric or intestinal bleeding
• Infertility
• Multorgan failure

Unknown: The frequency cannot be estimated from the available data:

• Liver failure
• Kidney failure
• Irregular and often rapid heartbeats (atrial fibrillation)
• Widespread painful red or purple rashes and blisters and/or other lesions that begin to appear on the mucous membrane (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 therapy with rituximab.
• Pneumonitis
• Pulmonary alveolar hemorrhage
• Excessive urination, even at night, and excessive thirst even after drinking liquids (nephrogenic diabetes insipidus)

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

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

Severe skin rash, including Stevens-Johnson syndrome and toxic epidermal necrolysis. This may appear as red spots with a target shape 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 rashes, elevated body temperature, increased lymph nodes, and involvement of other organs (drug reaction with eosinophilia and systemic symptoms, also known as DRESS or drug hypersensitivity syndrome).

Reporting of Adverse Effects

If you experience any type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is an adverse effect that does not appear in this leaflet. 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 Glenmark

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

Do not use this medicine after the expiration date that appears on the label and on the packaging after "EXP". The expiration date is the last day of the month indicated.

Store the vial in the outer packaging to protect the contents from light.

Check the validity period before opening or preparing the solution.

The prepared infusion solutions, according to the instructions indicated at the end of this leaflet, are stable inpolyethylene bags at room temperature / 60% relative humidity for 3.5 hours and in the refrigerator between 2°C - 8°C for 2 days. Bendamustina Glenmark does not contain preservatives. The solution should not be used after this time period.

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 medicines you no longer need. This will help protect the environment.

6. Container Contents and Additional Information

Composition of Bendamustina Glenmark

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.

Appearance of the Product and Container Contents

White or almost white lyophilized powder with a brown glass vial with a rubber stopper and aluminum flip-off cap.

A 25 ml Type I glass vial containing 25 mg of bendamustine hydrochloride is presented in packs of 1, 5, 10, and 20 vials.

A 50 ml Type I glass vial containing 100 mg of bendamustine hydrochloride is presented in packs of 1 and 5 vials.

Only some pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder:

Glenmark Arzneimittel GmbH

Industriestr. 31

82194 Gröbenzell

Germany

Manufacturer:

Synthon Hispania SL

c/ Castelló no 1, Pol. Las Salinas

Sant Boi de Llobregat

08830 Barcelona

Spain

Synthon, s.r.o.

Brnenská 32/cp. 597

678 01 Blansko

Czech Republic

You can request more information about this medicinal product by contacting the local representative of the marketing authorization holder:

Glenmark Farmacéutica, S.L.U.

C/ Retama 7, 7th floor

28045 Madrid

Spain

This medicinal product has been authorized in the EU Member States under the following names:

Date of the last revision of this leaflet: January 2024

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

--------------------------------------------------------------------------------------------------------------------

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 (inhalation) and contact with the skin and mucous membranes when handling Bendamustina Glenmark (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 0.9% isotonic saline solution. If possible, it is recommended to work on a special safety workbench (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 on the staff should not work with cytostatics.

The ready-to-use solution must be prepared by dissolving the contents of a Bendamustina Glenmark vial exclusively in water for injectables, as follows:

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

• First, dissolve a Bendamustina Glenmark 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 bendamustine in 0.9% isotonic saline solution to achieve a final volume of approximately 500 ml. Bendamustina should not be dissolved with other infusion or injection solutions. Bendamustina should not be mixed with other substances during infusion.

1. Administration
   • The solution is administered by intravenous infusion for 30-60 minutes.
   • The vials are for single use.
   • Unused products or waste must be disposed of in accordance with local requirements.

• If the product is unintentionally injected into the tissue surrounding the blood vessels (extravascular injection), the infusion will be stopped immediately. The needle will be removed after brief aspiration. Then, the affected tissue area will be cooled. The arm will be elevated. It is not clear whether the use of additional treatments (such as corticosteroids) is beneficial (see section 4).

Composition of Bendamustina Glenmark

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.

Appearance of the Product and Container Contents

White or almost white lyophilized powder with a brown glass vial with a rubber stopper and aluminum flip-off cap.

A 25 ml Type I glass vial containing 25 mg of bendamustine hydrochloride is presented in packs of 1, 5, 10, and 20 vials.

A 50 ml Type I glass vial containing 100 mg of bendamustine hydrochloride is presented in packs of 1 and 5 vials.

Only some pack sizes may be marketed.

Marketing Authorization Holder

Glenmark Arzneimittel GmbH

Industriestr. 31, Gröbenzell,

Germany

Manufacturer

Synthon Hispania SL

c/ Castelló no 1, Pol. Las Salinas, Sant Boi de Llobregat

08830 Barcelona

Spain

Synthon, s.r.o.

Brnenská 32/cp. 597

678 01 Blansko

Czech Republic

You can request more information about this medicinal product by contacting the local representative of the marketing authorization holder:

Viso Farmacéutica, S.L.U.

c/ Retama 7, 7th floor

28045 Madrid

Spain

This medicinal product has been authorized in the EU Member States under the following names:

Date of the last revision of this leaflet: January 2024

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

--------------------------------------------------------------------------------------------------------------------

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 (inhalation) and contact with the skin and mucous membranes when handling Bendamustina Glenmark (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 0.9% isotonic saline solution. If possible, it is recommended to work on a special safety workbench (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 on the staff should not work with cytostatics.

The ready-to-use solution must be prepared by dissolving the contents of a Bendamustina Glenmark vial exclusively in water for injectables, as follows:

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

• First, dissolve a Bendamustina Glenmark 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 bendamustine in 0.9% isotonic saline solution to achieve a final volume of approximately 500 ml. Bendamustina should not be dissolved with other infusion or injection solutions. Bendamustina should not be mixed with other substances during infusion.

1. Administration
   • The solution is administered by intravenous infusion for 30-60 minutes.
   • The vials are for single use.
   • Unused products or waste must be disposed of in accordance with local requirements.

If the product is unintentionally injected into the tissue surrounding the blood vessels (extravascular injection), the infusion will be stopped immediately. The needle will be removed after brief aspiration. Then, the affected tissue area will be cooled. The arm will be elevated. It is not clear whether the use of additional treatments (such as corticosteroids) is beneficial (see section 4).