Prospect: information for the user

Bendamustine Accord 2.5 mg/ml powder for concentrate for solution for infusion EFG

Bendamustine hydrochloride

The name of your medicine is Bendamustine Accord 2.5 mg/ml powder for concentrate for solution for infusion but in the rest of the prospect it will appear as Bendamustine Accord.

Read the entire prospect carefully before starting to use the medicine, because it contains important information for you.

• Keep this prospect, as you may have to read it again.
• If you have any doubts, consult your doctor or pharmacist.
• This medicine has been prescribed only to you and should not be given to other people, even if they have the same symptoms as you, as it may harm them.
• If you experience adverse effects, consult your doctor, pharmacist or nurse, even ifthey do not appear in this prospect.See section 4.

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

2. What you need to know before starting to use Bendamustine Accord

3. How to use Bendamustine Accord

4. Possible adverse effects

5. Storage of Bendamustine Accord

6. Contents of the package and additional information

Bendamustina Accord is a medication used for the treatment of certain types of cancer (it is a cytotoxic medication)

Bendamustina Accord is used alone (monotherapy) or in combination with other medications for the treatment of the following types of cancer:

• Chronic lymphocytic leukemia, if combination chemotherapy with fludarabine is not suitable for you.
• Non-Hodgkin lymphomas that have not responded, or have only responded for a short period, after previous treatment with rituximab.
• Multiple myeloma, if treatments containing thalidomide or bortezomib are not suitable for you.

No use Bendamustina Accord

• If you are allergic to bendamustine hydrochloride or any of the other components of this medication (listed in section 6)
• During breastfeeding, if treatment with Bendamustina Accord is necessary during breastfeeding, stop breastfeeding (see Pregnancy, breastfeeding and fertility section)
• If you have severe liver dysfunction (liver cell damage)
• If you have a yellowish discoloration of the skin or the white part of the eyes, caused by liver or blood problems (jaundice)
• If you have a severe bone marrow disorder (bone marrow depression) and severe alterations in the number of white blood cells and platelets in the blood
• If you have undergone major surgery within 30 days of starting treatment
• If you have had any infection, especially if accompanied by a reduction in the number of white blood cells (leucocytopenia)
• In combination with yellow fever vaccines

Warnings and precautions

Consult your doctor, pharmacist or nurse before starting to use Bendamustina Accord

• If your bone marrow has reduced ability to replace blood cells. Your doctor should measure the number of white blood cells and platelets in your blood before starting treatment with Bendamustina Accord, before each treatment cycle, and between cycles.
• If you have infections. If you have signs of infection, such as fever or respiratory symptoms, 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 red or purple painful blisters on the mucous membrane (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 a heart disease (e.g. heart attack, chest pain, severe heart rhythm disorders).
• If you experience pain in the side or if you notice 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 of 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 ensure you are well hydrated and give you other medications to prevent this from happening.
• If you have severe allergic or hypersensitivity reactions, pay attention to reactions during your first treatment cycle.
• At any time during or after treatment, immediately inform your doctor if 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).

Use of Bendamustina Accord with other medications

Inform your doctor or pharmacist if you are using, have used recently or may need to use any other medication, including over-the-counter medications.

If Bendamustina Accord is used in combination with medications that inhibit blood cell formation in the bone marrow, the effect on the bone marrow may be intensified.

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

Cytostatics can 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, breastfeeding and fertility

If you are pregnant or breastfeeding, or if you think you may be pregnant or plan to become pregnant, consult your doctor or pharmacist before using this medication.

Pregnancy

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

Fertility

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

If you are a man, you should not father children during treatment with Bendamustina Accord and for 6 months after treatment. There is a risk that treatment with Bendamustina Accord may cause permanent sterility; you may want to seek advice on sperm preservation before starting treatment.

Men treated with Bendamustina Accord should not father children during treatment or for 6 months after treatment. Before starting treatment, you should seek advice on sperm preservation, as there is a possibility that it may cause permanent sterility.

Breastfeeding

Bendamustina Accord should not be administered during breastfeeding. If you need treatment with Bendamustina Accord during breastfeeding, you should stop breastfeeding.

Consult your doctor or pharmacist before using any medication.

Driving and operating machinery

No studies have been conducted on the effects on the ability to drive and operate machinery. Do not drive or operate machinery if you experience adverse effects such as dizziness or lack of coordination.

Use this medication exactly as your doctor or pharmacist has told you. Talk to your doctor or pharmacist if you are unsure.

Bendamustine Accord is administered through a vein over 30 to 60 minutes in various doses, either alone (monotherapy) or in combination with other medications.

You will not be able to 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 Lymphomas

Multiple Myeloma

Treatment will end if your white blood cell count (leukocytes) and/or platelet count is below certain levels. Treatment may be resumed when your leukocyte and platelet counts have increased.

Renal or Hepatic Insufficiency

Dose adjustment may be necessary based on the degree of liver function deterioration (up to 30% in case of moderate liver function deterioration). No dose adjustment is necessary in case of renal function alteration. Your doctor will decide if a dose adjustment is necessary.

Administration

Bendamustine Accord can only be administered by experienced oncologists. Your doctor will administer the exact dose of Bendamustine Accord and take necessary precautions.

Your doctor will administer the prepared solution for infusion. The solution is administered through a vein as a brief infusion over 30 to 60 minutes.

Treatment Duration

No specific treatment duration has been defined for Bendamustine Accord. Treatment duration depends on the disease and response to treatment.

If you have any concerns or doubts about treatment with Bendamustine Accord, talk to your doctor or pharmacist.

Missed Dose

If you miss a dose of Bendamustine Accord, your doctor will usually continue with the normal dosing schedule.

Discontinuing Treatment

Your doctor will decide if treatment should be discontinued or if a different preparation should be used.

If you have any other questions about using this medication, ask your doctor, pharmacist, or nurse.

Like all medicines, Bendamustina Accord can cause side effects, although not everyone will experience them. Some of the reactions mentioned below may occur after your doctor has performed some blood tests.

The following frequencies are used to evaluate adverse reactions:

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 estimated from available data

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

The dose-limiting side effect of Bendamustina Accord is a bone marrow function alteration, which usually normalizes. Bone marrow function suppression may lead to low blood cell levels, which in turn may increase the risk of infection, anemia, or intensify the risk of bleeding.

Very common:

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

Common:

• Bleeding (hemorrhage)
• Metabolic alteration caused by dying cancer cells, which release their contents into the circulatory system
• Decreased red blood cells, which may cause pale skin and cause weakness or difficulty breathing (anemia)
• Abnormally low neutrophil concentration in the blood, resulting in increased sensitivity to infections (neutropenia)
• Hypersensitivity reactions, such as skin inflammation (dermatitis) or urticaria
• Elevation of liver enzymes AST/ALT, which may indicate liver inflammation or damage
• Increased alkaline phosphatase enzyme (an enzyme primarily produced in the liver and bones)
• Increased bilirubin pigment (a substance generated during normal red blood cell degradation)
• Low potassium blood levels (a nutrient necessary for nerve and muscle cell function, including heart cells)
• Cardiac function alteration (disfunction)
• Cardiac rhythm alteration (arrhythmia)
• Elevated or decreased blood pressure (hypotension or hypertension)
• Pulmonary function alteration
• Dyspepsia
• Constipation
• Mouth ulcers (stomatitis)
• Loss of appetite
• Hair loss
• Skin alterations
• Amenorrhea (absence of menstruation)
• Pain
• Insomnia
• Chills
• Dehydration
• Dizziness
• Rash with itching (urticaria)

Uncommon:

• Accumulation of fluid in the sac surrounding the heart (pericardial effusion)
• Ineffective production of all blood cells (the spongy material inside bones where blood cells are produced)
• Acute leukemia
• Myocardial infarction, chest pain (myocardial infarction)
• Heart failure

Rare:

• Blood infection (sepsis)
• Severe allergic and hypersensitivity reactions (anaphylactic reactions)
• Reactions similar to anaphylactic reactions (anaphylactoid reactions)
• Drowsiness
• Loss of voice (aphonia)
• Acute circulatory failure (failure of blood circulation primarily of cardiac origin with failure to maintain oxygen and nutrient supply to tissues and removal of toxins)
• Redness of the skin (erythema)
• Skin inflammation (dermatitis)
• Itching (pruritus)
• Maculopapular rash (exanthema)
• Excessive sweating (hyperhidrosis)
• Reduction in bone marrow function that may make you feel unwell or appear in your blood test results

Very rare:

• Atypical primary lung inflammation (pneumonia)
• Red blood cell destruction
• Rapid decrease in blood pressure, sometimes with skin reactions (anaphylactic shock)
• Alteration of taste
• Alteration of sensitivity (paresthesias)
• Discomfort and pain in the limbs (peripheral neuropathy)
• Anticholinergic syndrome (inhibition of physiological action of acetylcholine, especially as a neurotransmitter)
• Neurological disorders (diseases of the brain, spinal cord, and nerves that connect them)
• Ataxia (lack of coordination)
• Encephalitis (inflammation of the brain)
• Increased heart rate (tachycardia)
• Vein inflammation (phlebitis)
• Pulmonary tissue formation (pulmonary fibrosis)
• Haemorrhagic oesophagitis (inflammation of the oesophagus with bleeding)
• Gastric or intestinal bleeding
• Infertility
• Multi-organ failure

Unknown:

• Renal failure
• Liver failure
• Atrial fibrillation (irregular and usually rapid heart rhythm)
• Rash or blisters, red or lilac, 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.
• Pneumonitis
• Bleeding from the lungs

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

Contact your doctor or seek immediate medical attention if you experience any of the following side effects (unknown frequency):

Severe skin eruptions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. These may appear as circular, red spots with central blisters on the trunk, peeling, mouth ulcers, throat, nose, genitals, and eyes, which may be preceded by fever and flu-like symptoms.

Widespread rash, high body temperature, swollen lymph nodes, and other organ alterations (Drug Reaction with Eosinophilia and Systemic Symptoms, also known as DRESS or drug hypersensitivity syndrome).

If any side effects worsen, or if you notice any side effects not included in this leaflet, please inform your doctor.

Reporting of side effects

If you experience side effects, consult your doctor, hospital pharmacist, or nurse, even if they are side effects not listed in this leaflet. You can also report them directly through theSpanish System for Pharmacovigilance of Medicines for Human Use:www.notificaRAM.es. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

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

This medication 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.

Prepared solutions for infusion according to the instructions listed at the end of this leaflet 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 disposed of through drains or in the trash. Ask your pharmacist how to dispose of the packaging and unused medications. This will help protect the environment.

Composition of Bendamustine Accord

The active ingredient ishydrochloride ofbendamustine.

A vial contains 25 mg ofhydrochloride ofbendamustine (ashydrochloride ofbendamustine monohydrate).

A vial contains 100 mg ofhydrochloride ofbendamustine (ashydrochloride ofbendamustine monohydrate).

After reconstitution, 1 ml of concentrate contains 2.5 mg ofhydrochloride ofbendamustine (ashydrochloride ofbendamustine monohydrate).

The other component is mannitol.

Appearance of the product and contents of the pack

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

Bendamustine Accord is marketed in packs containing 5, 10 and 20 vials with 25 mg ofhydrochloride ofbendamustine and 1 and 5 vials with 100 mg ofhydrochloride ofbendamustine.

Not all pack sizes may be marketed.

Marketing Authorization Holder

Accord Healthcare, S.L.U.

World Trade Center

Moll de Barcelona, s/n

Edifici Est, 6th floor

08039 Barcelona

Manufacturer Responsible

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

Ul Lutomierska, 50

95-200 Pabianice

Poland

This medicinal product isauthorisedin the member states of the European Economic Area under the following names:

Last update of this leaflet:February 2021

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

This information is intended solely for medical professionals or healthcare professionals:

As with all similar cytotoxics, nursing staff and doctors must take extreme precautions of safety, due to the potential genotoxicity and carcinogenicity of the preparation. Avoid inhalation (inspiration) and contact with the skin and mucous membranes while handling Bendamustine 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 isotonic saline solution (0.9%). If possible, it is recommended to work on a special safety workbench (laminar flow) with a disposable impermeable to liquids. Contaminated items are cytostatic waste. Please follow national guidelines for the disposal of cytostatic material! Pregnant nursing staff should not work with cytotoxics.

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

1. Preparation of the concentrate

• First, dissolve a Bendamustine Accord vial containing 25 mg ofhydrochloride ofbendamustine in 10 ml, agitating it.

• First, dissolve a Bendamustine Accord vial containing 100 mg ofhydrochloride ofbendamustine in 40 ml, agitating it.

2. Preparation of the infusion solution

As soon as a clear solution is obtained (usually within 5 to 10 minutes), dissolve the total recommended dose of Bendamustine Accord in isotonic saline solution (0.9%) to obtain a final volume of approximately 500 ml. Bendamustine Accord should not be dissolved with other infusion or injection solutions. Bendamustine Accord should not be mixed with other substances in infusion.

3. Administration

The solution is administered by intravenous infusion over 30-60 minutes. The vials are for single use. The elimination of unused medication and all materials that have come into contact with it will be carried out in accordance with local regulations.

Immediately interrupt the unintended injection into the tissues outside the blood vessels (extravasal injection). The needle should be removed after a brief aspiration. The affected tissue area should then be cooled. The arm should be elevated. It is not clear whether additional treatments, such as the use of corticosteroids, are beneficial (see section 4).