BENDAMUSTINE ACCORD 25 mg/ml CONCENTRATE FOR INFUSION SOLUTION

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

Do not use Bendamustina Accord

• 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 this medicine 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 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 starting treatment with this medicine

• if your bone marrow's ability to replace blood cells is reduced. The number of white blood cells and platelets in your blood should be measured before starting treatment with this medicine, 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 this medicine. Skin reactions can increase in intensity.
• if you have a rash or blisters that are red or purple and painful, spread across 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 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 this medicine. Your doctor will make sure you are properly hydrated and will give you other medicines to prevent this from happening.
• in case of severe allergic or hypersensitivity reactions, you should be aware of infusion reactions after your first cycle of treatment.

If at any time during or after treatment you notice or someone notices in you: memory loss, cognitive difficulties, difficulty walking or loss of vision. 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 suspicious changes in your skin, as there may be an increased risk of certain types of skin cancer (non-melanoma skin cancer) with the use of this medicine.

Other medicines and Bendamustina Accord

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

If this medicine 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 this medicine 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. In addition, 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

This medicine 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. 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 you need treatment with this medicine 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 adequate 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 sperm conservation, as 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.

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 will not be able to start treatment if your white blood cell (leukocyte) and/or platelet count is below certain 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 is below certain levels. Treatment may be restarted when the leukocyte and platelet counts have increased.

Kidney or liver impairment

The dose may need to be adjusted according to the degree of liver function impairment (by 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

This medicine can only be administered by doctors with experience in the treatment of tumors. Your doctor will administer the exact dose of this medicine 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

No specific duration of treatment with this medicine 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 this medicine, talk to your doctor or nurse.

If you miss a dose of Bendamustina Accord

If you miss a dose of this medicine, your doctor will normally continue with the normal 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.

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 this medicine 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 Common (may affectmore than 1 in 10 people):

• Reduction of white blood cell count (blood defenses)
• 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 collaborate in blood coagulation)
• Infections
• Nausea
• Vomiting
• Mucosal inflammation
• Increased blood concentration of creatinine (a chemical waste product produced by muscles)
• Increased blood concentration of urea (a chemical waste product)
• Fever
• Fatigue
• Headache

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

• Bleeding (hemorrhage)
• Metabolism alteration 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 combat 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 heart cells)
• Cardiac dysfunction
• Cardiac rhythm alteration (arrhythmia)
• Elevation or decrease in blood pressure (hypotension or hypertension)
• Lung function alteration
• Diarrhea
• Constipation
• Mouth ulcers (stomatitis)
• Lack of appetite
• Hair loss
• Skin alterations
• Absence of period (amenorrhea)
• Pain
• Insomnia
• Chills
• Dehydration
• Dizziness
• Itchy rash (urticaria)

Uncommon(may affect up to 1 in 100 people):

• Fluid accumulation in the sac surrounding the heart (fluid leak in the pericardial space)
• Ineffective production of all blood cells (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 people):

• Blood infection (sepsis)
• Severe allergic and hypersensitivity reactions (anaphylactic reactions)
• Signs similar to anaphylactic reactions (anaphylactoid reactions)
• Drowsiness
• Voice loss (aphonia)
• Acute circulatory failure (mainly cardiac failure to maintain oxygen and nutrient supply to tissues and toxin elimination)
• 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(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)
• 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
• Multi-organ failure

Frequency Not Known(cannot be estimated from available data):

• Kidney failure
• Liver failure
• Irregular and normally rapid heart rhythm (atrial fibrillation)
• Rash or blisters, red or purple, and painful, scattered on the mucous membrane (e.g., mouth or lips), particularly if you have previously had sensitivity to light, respiratory system infections (e.g., bronchitis), and/or fever.
• Drug eruption due to treatment combined 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, 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, often with central blisters on the trunk, scaling, 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 alterations (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 leaflet, please inform your doctor.

Adverse Effect Reporting

If you experience adverse effects, consult your doctor, hospital pharmacist, or nurse, even if they are not listed in this leaflet. You can also report them directly through the Spanish Medicines Agency's website: www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Bendamustina Accord

Keep this medicine out of sight and reach of children.

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

Store and transport refrigerated (2-8°C). Do not freeze.

Do not use this medicine if you detect visible particles in the solution or if the solution is not clear and colorless to yellowish.

After opening the vial

Chemical, physical, and microbiological stability has been demonstrated for 28 days at 2-8°C.

Once opened, the product must be stored for a maximum of 28 days at 2-8°C.

Infusion solution

After dilution, physical and chemical stability has been demonstrated for 3.5 hours at 25°C and 2 days at 2-8°C in polyethylene bags.

From a microbiological point of view, the solution should be used immediately. If not used immediately, the conditions and times of storage before use are the responsibility of the user.

The minimization of the risk of contamination of the multidose vial during the withdrawal of each dose is the responsibility of the user. Note the date and time of the first dose withdrawn on the vial label. Between uses, do not equilibrate the product solution with water for injectable preparations or any diluent, and return the multidose vial to the recommended storage condition of 2-8°C.

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

6. Package Contents and Additional Information

Bendamustina Accord Composition

The active ingredient is bendamustine hydrochloride.

Each ml of concentrate for solution for infusion contains 25 mg of bendamustine hydrochloride (as monohydrate).

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

Each 4 ml vial contains 100 mg of bendamustine hydrochloride (as monohydrate).

The other components are butylhydroxytoluene (E321) and macrogol.

Product Appearance and Package Contents

Clear, colorless to yellowish solution in a topaz glass vial with a chlorobutyl rubber stopper containing 1 ml and 4 ml of concentrate for solution for infusion. The 1 ml vial is provided with a red plastic cap and an aluminum seal, and the 4 ml vial is provided with a red aluminum seal and a white plastic cap.

Bendamustina Accord is marketed in packages containing 1 or 5 vials.

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

Spain

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 with the following names:

Date of Last Revision of this Leaflet: 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 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 (inspiration) 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 cytotoxic waste. Please follow national guidelines for the disposal of cytotoxic material. Pregnant women staff should not work with cytotoxics.

The concentrate for solution for infusion should be diluted with a 9 mg/ml (0.9%) sodium chloride injectable solution and then administered by intravenous infusion. An aseptic technique will be used.

1. Dilution

Asceptically extract the necessary volume for the required dose from the 25 mg/ml Bendamustina Accord vial. Dilute the recommended total dose of Bendamustina Accord 25 mg/ml with a 0.9% sodium chloride solution to produce a final volume of approximately 500 ml.

When diluting the product, it should be taken into account that the concentration (25 mg/ml) of bendamustine in Bendamustina Accord is higher than in usual bendamustine concentrates resulting from the reconstitution of medicines containing bendamustine in powder form.

Bendamustina Accord 25 mg/ml must be diluted with a 0.9% NaCl solution and not with any other injectable solution.

The recommended dilution results in a clear, colorless to yellowish solution, practically free of visible particles.

1. Administration

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

The vials are for multiple use.

The product must be inspected before use. When inspected, visible particles in the solution or discoloration of the solution are a sign of deterioration. Do not use the deteriorated product.

Any unused medicine or waste material must be disposed of in accordance with local requirements.

Involuntary injection into tissue outside blood vessels (extravasal injection) should be interrupted immediately. The needle should be withdrawn after brief aspiration. Then, the affected tissue area should be cooled. The arm should be elevated. Additional treatments such as the use of corticosteroids do not offer clear benefits.