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

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

Do not use Bendamustina Accord

• if you are allergic to bendamustina hydrochloride or any of the other ingredients of this medicine (listed in section 6)
• if you are breast-feeding. If treatment with Bendamustina Accord 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 (depression of the bone marrow) 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 before starting 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 Bendamustina Accord

• if your bone marrow's ability to produce blood cells is reduced. Your doctor will check your blood cell count before, during, and after treatment with Bendamustina Accord.
• if you have any infections. If you have signs of infection, such as fever or respiratory symptoms, you must contact your doctor.
• if you have skin reactions during treatment with Bendamustina Accord. Skin reactions can increase in intensity.
• if you have a rash or blisters on the mucous membranes (e.g., mouth or 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 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 Bendamustina Accord. 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 reactions or hypersensitivity, 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 can be due to a rare but serious brain infection that can be fatal (progressive multifocal leukoencephalopathy or PML).

Using Bendamustina Accord with other medicines

Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines, including those bought without a prescription.

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

Cytostatics can 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 Accord may cause genetic damage and has caused birth defects 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 your doctor to explain the risk of possible side effects for your child. Genetic counseling is recommended.

If you are a woman of childbearing age, you must use effective contraceptive measures before and during treatment with this medicine. You must not become pregnant during treatment with this medicine and for at least 6 months after the last dose. If you become pregnant during treatment with this medicine, you should inform your doctor immediately and seek genetic counseling.

Breast-feeding

Bendamustina should not be administered during breast-feeding. If treatment with this medicine is necessary during breast-feeding, you must stop breast-feeding.

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

Contraception in men and women

If you are a woman, you must not become pregnant during treatment with this medicine and for at least 6 months after the last dose.

If you are a man, you should take appropriate precautions to ensure that your partner does not become pregnant during treatment with this medicine and for at least 3 months after the last dose.

Fertility

Men treated with this medicine are advised not to father a child during treatment and for 3 months after the last dose. Before starting treatment, you should be advised on the conservation of sperm, as there is a possibility that this medicine may cause permanent infertility.

Driving and using machines

No studies on the effects on the ability to drive and use machines have been performed. Do not drive or use machines if you experience side effects such as dizziness or lack of coordination.

3. How to use Bendamustina Accord

Use this medicine exactly as your doctor or pharmacist has told you. Talk to your doctor or pharmacist if you are not sure.

Bendamustina Accord 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) 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) and/or platelet count 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 based on the degree of liver function impairment (more than 30% in case of moderate liver function 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

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

Your doctor will administer the infusion solution after proper 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 Bendamustina Accord has 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 Accord, talk to your doctor or nurse.

If you miss a dose of Bendamustina Accord

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

If you stop treatment with Bendamustina Accord

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 reactions mentioned below may be found after your doctor has performed some tests.

The following frequencies are used to evaluate adverse reactions:

Very frequent: may affect more than 1 in 10 people

Frequent: may affect up to 1 in 10 people

Infrequent: 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 estimated from the available data

In very rare cases, tissue alterations (due to cell damage resulting in premature cell death) have been observed after unintentional injection into the tissue surrounding blood vessels (extravascular). If the product is administered outside a vessel, there may be a burning sensation at the needle insertion site. The consequences of administration in this way can be pain and skin healing problems.

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

Very frequent:

• Reduction of white blood cell count (blood defenses)
• Reduction of red blood cell pigment (hemoglobin: a protein in red blood cells that transports oxygen throughout the body)
• Reduction of platelet count (colorless blood cells that collaborate in blood coagulation)
• Infections
• Nausea
• Vomiting
• Mucosal inflammation
• Increased blood concentration of creatinine (a chemical waste product produced by your muscles)
• Increased blood concentration of urea (a waste chemical product)
• Fever
• Fatigue
• Headache

Frequent:

• 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 necessary to fight infections)
• Hypersensitivity reactions, such as allergic skin inflammation (dermatitis) or hives
• Elevation of liver enzymes AST/ALT that may indicate inflammation or damage to liver cells
• Increased alkaline phosphatase enzyme (an enzyme mainly produced in the liver and bones)
• Increased bile pigment (a substance generated during the normal degradation of red blood cells)
• Decrease in blood potassium level (a nutrient necessary for the functioning of nerve and muscle cells, including those of the heart)
• Cardiac function disorder (cardiac dysfunction)
• Cardiac rhythm disorder (arrhythmia)
• Elevation or decrease in blood pressure (hypotension or hypertension)
• Pulmonary function disorder
• Diarrhea
• Constipation
• Mouth ulcers (stomatitis)
• Lack of appetite
• Hair loss
• Skin disorders
• Absence of menstrual period (amenorrhea)
• Pain
• Insomnia
• Chills
• Dehydration
• Dizziness
• Itchy rash (urticaria)

Infrequent:

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

Rare:

• Blood infection (sepsis)
• Severe allergic and hypersensitivity reactions (anaphylactic reactions)
• Signs similar to anaphylactic reactions (anaphylactoid reactions)
• Somnolence
• Voice loss (aphonia)
• Acute circulatory failure (circulatory failure mainly of cardiac origin with failure 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)
• Reduction in bone marrow function that can make you feel unwell or appear in your blood tests

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)
• Anticholinergic syndrome (inhibition of the physiological action of acetylcholine, especially as a neurotransmitter)
• Neurological disorders (diseases of the brain, spinal cord, and nerves that connect them)
• 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:

• Kidney failure
• Liver failure
• Irregular and normally rapid heart rhythm (atrial fibrillation)
• Rash or blisters that are red or purple and painful, scattered on the mucous membrane (e.g., mouth or lips), especially if you have previously had sensitivity to light, respiratory system infections (e.g., bronchitis), and/or fever.
• 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, AML, bronchial carcinoma) after treatment with bendamustine. A clear relationship with bendamustine 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 rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis. These can appear as red, circular spots or patches, often with central blisters on the trunk, peeling, mouth ulcers, throat, nose, genitals, and eyes, which can be preceded by fever and flu-like symptoms.

Widespread rash, high body temperature, enlarged lymph nodes, and other organ disorders (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 notice any adverse effect not included 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 Medicines and Health Products Agency's website: www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Conservation of Bendamustina Accord

Keep this medicine out of sight and reach of children.

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

This medicine does not require any special storage temperature.

Store in the outer packaging to protect it from light.

Check the validity period before opening or preparing the solution.

The properly prepared infusion solutions according to the instructions listed at the end of this prospectus are stable in polyethylene bags at 25°C for 3.5 hours and at 2°C - 8°C for 2 days. Bendamustina Accord does not contain preservatives. Therefore, the solution should not be used after these periods.

The user is responsible for maintaining aseptic conditions.

Medicines should not be thrown away through drains or into the trash. Ask your pharmacist how to dispose of packaging and medicines that are no longer needed. This will help protect the environment.

6. Package Contents and Additional Information

Composition of Bendamustina Accord

The active ingredient is bendamustine hydrochloride.

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

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

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

The other component is mannitol.

Product Appearance and Package Contents

Ambber glass vials with a bromobutyl rubber stopper and a flip-off aluminum cap.

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

Not all package sizes may be marketed.

Marketing Authorization Holder

Accord Healthcare, S.L.U.

World Trade Center

Moll de Barcelona, s/n

Edifici Est, 6ª planta

08039 Barcelona

Manufacturer

Accord Healthcare, S.p.z.o.o

Ul Lutomierska, 50

95-200 Pabianice

Poland

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

Date of the last revision of this prospectus: June 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

This information is intended only for doctors or healthcare professionals:

As with all similar cytotoxics, nursing staff and doctors must take extreme safety precautions due to the potential genotoxic and carcinogenic effects of the preparation. Avoid inhalation (inhalation) and contact with skin and mucous membranes when handling Bendamustina Accord (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 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 on the staff should not work with cytostatics.

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

1. Preparation of the concentrate
   • First, dissolve a vial of Bendamustina Accord containing 25 mg of bendamustine hydrochloride in 10 ml, shaking it.

• First, dissolve a vial of Bendamustina Accord 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 Accord in 0.9% isotonic saline solution to achieve a final volume of approximately 500 ml. Bendamustina Accord should not be dissolved with other infusion or injection solutions. Bendamustina Accord 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. The disposal of unused medicine and all materials that have come into contact with it will be carried out in accordance with local regulations.

Unintentional injection into tissues outside the blood vessels (extravascular injection) should be interrupted immediately. The needle should be removed after a short aspiration. Then, the affected tissue area should be cooled. The arm should be raised. It is not clear what the benefit of additional treatments such as the use of corticosteroids is (see section 4).