BENDAMUSTINE AUROVITAS 2.5 mg/ml POWDER FOR CONCENTRATE FOR PERFUSION SOLUTION

Introduction

Package Leaflet: Information for the User

Bendamustine Aurovitas 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, pharmacist, or nurse.
• 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, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

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

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

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

Bendamustine 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, 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 Aurovitas

Do not use Bendamustine Aurovitas

• 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 you need treatment with bendamustine hydrochloride 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 (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

Consult your doctor, pharmacist, or nurse before you start using bendamustine.

• if your bone marrow's ability to produce blood cells is reduced. The number of white blood cells and platelets in your blood should be measured before you start treatment with bendamustine hydrochloride, 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 bendamustine hydrochloride. Skin 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), especially 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, 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 in the 48 hours following the administration of the first dose of bendamustine hydrochloride. Your doctor will ensure that you are adequately hydrated and will give you other medicines to prevent this from happening.
• if you have severe allergic or hypersensitivity reactions. You should pay attention to infusion reactions after your first cycle of treatment.
• at any time during or after treatment, inform 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 detect 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).

Other medicines and Bendamustine Aurovitas

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 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

Bendamustine hydrochloride may cause genetic damage and has caused malformations in animal studies. This medicine 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 of the treatment for your child. Genetic counseling is recommended.

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

Breast-feeding

This medicine should not be administered during breast-feeding. If you need treatment with bendamustine hydrochloride during breast-feeding, you must stop breast-feeding.

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

Fertility

If you are a man, you should not father a child during treatment with bendamustine hydrochloride and for at least 6 months after treatment. There is a risk that treatment with bendamustine hydrochloride may cause infertility; you may want to seek advice on sperm preservation before starting treatment.

Driving and using machines

Bendamustine hydrochloride 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 Bendamustine Aurovitas

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

This medicine 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 based on 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

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

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

Duration of treatment

No specific duration of treatment with bendamustine hydrochloride has 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 bendamustine hydrochloride, talk to your doctor or nurse.

If you miss a dose of Bendamustine Aurovitas

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

If you stop treatment with Bendamustine Aurovitas

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, 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.

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

In very rare cases, tissue degradation (necrosis) has been observed after extravasation of bendamustine hydrochloride 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 bendamustine hydrochloride is an alteration of bone marrow function, which usually normalizes. Suppression of bone marrow function can lead to a reduction in blood cell counts, which in turn can result in an increased risk of infection, anemia, or an increased risk of bleeding.

Very frequent:

• Low white blood cell counts (cells that fight disease in your blood).
• Reduction of the red pigment of the blood (hemoglobin: a protein of red blood cells that carries oxygen throughout the body).
• Low platelet counts (colorless blood cells that help 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.

Frequent:

• Bleeding (hemorrhage).
• Alteration of metabolism 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).
• Low neutrophil counts (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.
• Alteration of heart rhythm (arrhythmia).
• Elevation or decrease of blood pressure (hypotension or hypertension).
• Alteration of lung function.
• Diarrhea.
• Constipation.
• Ulcers in the mouth (stomatitis).
• Lack of appetite.
• Hair loss.
• Skin disorders.
• Absence of menstruation (amenorrhea).
• Pain.
• Insomnia.
• Chills.
• Dehydration.
• Dizziness.
• Itchy rash (urticaria).

Uncommon:

• Accumulation of fluid in the sac that surrounds 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:

• Blood infection (sepsis).
• Severe allergic and hypersensitivity reactions (anaphylactic reactions).
• Decrease in 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 exanthema).
• Excessive sweating (hyperhidrosis).

Very rare:

• Atypical primary inflammation of the lungs (pneumonia).
• Destruction of red blood cells.
• Rapid decrease in blood pressure, sometimes with skin reactions or rashes (anaphylactic shock).
• Alteration of taste.
• Alteration of sensitivity (paresthesias).
• Discomfort and pain in the limbs (peripheral neuropathy).
• Severe condition that causes the blockade 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.
• Infertility.
• Multi-organ failure.

Frequency not known:

• 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), especially if you have previously had sensitivity to light, respiratory infections (e.g., bronchitis), and/or fever.
• Drug rash in combination therapy with rituximab.
• Pneumonitis.
• Bleeding from the lungs.
• 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 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 resembling a target, or circular patches that often have central blisters on the torso, 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).

Reporting of adverse effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that is not listed 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 Bendamustine Aurovitas

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 carton after EXP. The expiration date is the last day of the month indicated.

The vials may be packaged with or without a protective plastic wrapper.

Check the validity period before opening or preparing the solution.

Chemical and physical stability has been demonstrated for 3.5 hours at 25°C and up to 48 hours at 2-8°C in polyethylene bags.

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

Medicines should not be thrown away 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. Package contents and additional information

Composition of Bendamustine Aurovitas

• The active ingredient is bendamustine hydrochloride.

1 vial contains 25 mg of bendamustine hydrochloride (as monohydrate).

1 vial contains 100 mg of bendamustine hydrochloride (as monohydrate).

After reconstitution, 1 ml of concentrate contains 2.5 mg/ml of bendamustine hydrochloride (as monohydrate).

• The other component is mannitol.

Appearance and package size of the product

Powder for concentrate for solution for infusion.

White or off-white lyophilized paste or powder.

20 ml type I glass tubular vials with a 20 mm neck, closed with a 20 mm gray bromobutyl rubber stopper and sealed with an aluminum cap with a polypropylene disc.

50 ml type I glass tubular vials with a 20 mm neck, closed with a 20 mm gray bromobutyl rubber stopper and sealed with an aluminum cap with a polypropylene disc.

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

Not all package sizes may be marketed.

Marketing authorization holder and manufacturer

Marketing authorization holder

Eugia Pharma (Malta) Limited

Vault 14, Level 2, Valletta Waterfront

Floriana, FRN 1914

Malta

Manufacturer

APL Swift Services (Malta) Limited

HF26, Hal Far Industrial Estate, Hal Far

Birzebbugia, BBG 3000

Malta

Or

Generis Farmacêutica, S.A.

Rua João de Deus, nº 19, Venda Nova

2700-487 Amadora

Portugal

Or

Arrow Génériques

26 Avenue Tony Garnier

69007 Lyon

France

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

Aurovitas Spain, S.A.U.

Avda. de Burgos, 16-D

28036 Madrid

Spain

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

Germany: Bendamustin PUREN 2.5 mg/ml Pulver zur Herstellung eines Konzentrates zur Herstellung einer Infusionslösung

Belgium: Bendamustine Eugia 2.5 mg/ml poeder voor concentraat voor oplossing voor infusie / poudre pour solution à diluer pour perfusion / Pulver für ein Konzentrat zur Herstellung einer Infusionslösung

Spain: Bendamustina Aurovitas 2.5 mg/ml polvo para concentrado para solución para perfusión EFG

France: BENDAMUSTINE ARROW 2.5 mg/ml, poudre pour solution à diluer pour perfusion

Italy: Bendamustina Aurobindo

Portugal: Bendamustina Generis

Poland: Bendamustine Eugia

Date of the last revision of this leaflet:March 2024

Detailed information about this medicine 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 (breathing) and contact with the skin and mucous membranes when handling this medicine (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% saline solution (isotonic). 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. Follow national guidelines for the disposal of cytostatic material. Pregnant women in the nursing staff should not work with cytostatics.

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

1. Preparation of the concentrate
   • First, dissolve a vial of Bendamustine Aurovitas containing 25 mg of bendamustine hydrochloride in 10 ml, shaking it.
   • First, dissolve a vial of Bendamustine Aurovitas 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% saline solution (isotonic) to achieve a final volume of approximately 500 ml. Bendamustine Aurovitas should not be dissolved with other infusion or injection solutions. Bendamustine Aurovitas should not be mixed in infusion with other substances.

1. Administration

The solution is administered by intravenous infusion for 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 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).