Bendamustine Accord

PACKAGE LEAFLET: INFORMATION FOR THE USER

Bendamustina Accord 2.5 mg/ml powder for concentrate for solution for infusion

Equivalent medicinal product
Your medicine is Bendamustina Accord 2.5 mg/ml powder for concentrate for solution for infusion, but
in the remainder of this leaflet it will be referred to as "Bendamustina Accord".
Please read this leaflet carefully before using this medicine as it contains important
information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Never give it to other people, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet

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

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

Bendamustina Accord is a medicine used to treat certain types of cancer (cytotoxic drug).
Bendamustina Accord is used alone (monotherapy) or in combination with other anticancer medicines to treat the following forms of cancer:

• chronic lymphocytic leukemia in cases where combination chemotherapy with fludarabine is not suitable for you,
• non-Hodgkin’s lymphomas that have not responded or have responded only briefly to previous treatment with rituximab,
• multiple myeloma in cases where thalidomide or bortezomib is not suitable for you.

2. What you should know before using Bendamustina Accord

Do not take Bendamustina Accord

• if you are allergic to bendamustine hydrochloride or to any of the other ingredients of this medicine (listed in section 6);
• during breastfeeding; if treatment with Bendamustina Accord is necessary during breastfeeding, you must stop breastfeeding (see section Warnings and precautions during breastfeeding);
• if you have severe liver dysfunction (damage to the functional liver cells);
• if you have yellowing of the skin or the whites of the eyes due to liver or blood problems (jaundice);
• if you have a severe disorder of bone marrow function (bone marrow depression) and significant changes in the number of white blood cells and platelets in the blood;
• if you have undergone major surgery less than thirty days before starting treatment;
• if you have an infection, especially if it is accompanied by a reduction in white blood cells (leucopenia);
• in combination with the yellow fever vaccine.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Bendamustina Accord

• if you have reduced bone marrow capacity to regenerate blood cells. You must check your white blood cell and platelet counts before starting treatment with Bendamustina Accord, before each subsequent treatment cycle, and during the intervals between treatment cycles;
• if you have infections. Contact your doctor if you experience symptoms of infection, including fever or respiratory symptoms;
• if you experience skin reactions during treatment with Bendamustina Accord. The severity of skin reactions may increase;
• if you develop a painful red or purplish rash that spreads and forms blisters and/or other lesions starting in the mucous membranes (e.g., mouth and lips), especially if you previously had light sensitivity, respiratory tract infections (e.g., bronchitis), and/or fever;
• if you have pre-existing heart disease (e.g., heart attack, chest pain, severely disturbed heart rhythm);
• if you notice any kind of hip pain, blood in the urine, or reduced urine output. When your disease is very severe, your body may be unable to eliminate all waste products from destroyed tumor cells. This is called "tumor lysis syndrome" and may cause kidney failure and heart problems within 48 hours after the first dose of Bendamustina Accord. Your doctor will ensure you are adequately hydrated and may give you other medications to help prevent it;
• if you experience a severe allergic reaction or hypersensitivity reactions. Be alert for infusion reactions after the first treatment cycle;
• at any time during or after treatment, immediately inform your doctor if you or someone else notices: memory loss, difficulty thinking, difficulty walking, or loss of vision; these symptoms could be due to a very rare but serious brain infection, which can be fatal (progressive multifocal leukoencephalopathy, or PML);
• contact your doctor if you notice any suspicious changes in your skin, as use of this medicine may increase the risk of certain types of skin cancer (non-melanoma skin cancer).

Other medicines and Bendamustina Accord
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
If Bendamustina Accord is taken together with medicines that suppress blood cell formation in the bone marrow, the effect on the bone marrow may be intensified.
If Bendamustina Accord is taken together with medicines that alter the immune response, this effect may be intensified.
Cytostatic medicines may reduce the effectiveness of vaccination with live viruses. Additional cytostatic medicines increase the risk of infection after vaccination with live vaccines (e.g., antiviral vaccination).

Pregnancy, breastfeeding, and fertility

If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor or pharmacist before using this medicine.

Pregnancy
Bendamustina Accord can cause genetic damage and has caused birth defects in animal studies. You must not use Bendamustina Accord during pregnancy unless clearly indicated by your doctor. If you are treated, discuss with your doctor the potential risk of adverse effects of therapy on the unborn child, and genetic counselling is recommended.
If you are a woman of childbearing potential, you must use an effective method of contraception both before and during treatment with Bendamustina Accord. If you become pregnant during treatment with Bendamustina Accord, you must immediately inform your doctor and seek genetic counselling.

Breastfeeding
Bendamustina Accord must not be administered during breastfeeding. If treatment with Bendamustina Accord is necessary during the breastfeeding period, you must stop breastfeeding.

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

Fertility
If you are a man, you must avoid fathering a child during treatment with Bendamustina Accord and for up to 6 months after the end of treatment. There is a risk that Bendamustina Accord may cause infertility, and before starting treatment you may need counselling on sperm preservation.
Men being treated with Bendamustina Accord should be aware not to father a child during treatment and for up to 6 months afterwards. Before starting treatment, you should seek information on sperm preservation due to the possibility of permanent infertility.

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

3. How to use Bendamustina Accord

Use this medicine exactly as instructed by your doctor or pharmacist. If you have any doubts,
consult your doctor or pharmacist.
Bendamustina Accord is administered intravenously over 30–60 minutes at various dosage levels, either alone (monotherapy)
or in combination with other medicines.
Treatment must not be started if your white blood cell count (leukocytes) and/or your platelet count
has fallen below certain levels.
Your doctor will determine these values at regular intervals.
Chronic lymphocytic leukemia

Non-Hodgkin lymphoma

Multiple myeloma

Treatment must be discontinued if white blood cell (leukocyte) and/or platelet counts drop to certain levels. Treatment may be continued once white blood cell and platelet counts have increased.

Impaired renal or hepatic function
Depending on the degree of hepatic impairment, dose adjustment may be necessary (by 30% in case of moderate hepatic dysfunction). No dose adjustment is required in case of impaired renal function. Your physician will decide whether dose adjustment is needed.

How to take Bendamustina Accord
Treatment with Bendamustina Accord must be administered only by physicians experienced in cancer therapy. Your doctor will give you the exact dose of Bendamustina Accord, using the necessary precautions.

Your physician will administer the infusion solution after preparation as prescribed. The solution is given intravenously as a short infusion lasting 30–60 minutes.

Duration of treatment
There is generally no predefined time limit for treatment with Bendamustina Accord. The duration of treatment depends on the disease and the response to therapy.

If you are concerned or have any questions regarding treatment with Bendamustina Accord, speak with your doctor or pharmacist.

If you forget to take Bendamustina Accord
If a dose of Bendamustina Accord has been missed, your doctor will usually maintain the normal dosing schedule.

If you interrupt treatment with Bendamustina Accord
Your physician will decide whether to discontinue treatment or switch to a different preparation.

If you have any doubts about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, Bendamustina Accord can cause side effects, although not everybody will experience them. Some of the effects listed below may only become evident through tests requested by your doctor.
Very rarely, tissue changes (necrosis) have been observed following accidental injection of Bendamustina Accord into tissue outside the blood vessels (extravasation). A burning sensation at the site where the infusion needle was inserted may indicate extravasation. Consequences of such administration may include pain and skin lesions due to poor healing.
The side effect of Bendamustina Accord that limits its dosage is worsening of bone marrow function, which usually returns to normal after treatment. Suppression of bone marrow function may lead to a reduced number of blood cells, which in turn may increase the risk of infection, anaemia, or bleeding.

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

• Low white blood cell count (blood cells that fight disease)
• Decrease in red blood pigment (haemoglobin: protein in red blood cells that carries oxygen throughout the body)
• Low platelet count (colourless blood cells that help blood clotting)
• Infections
• Feeling unwell (nausea)
• Vomiting
• Inflammation of mucous membranes
• Increased creatinine levels in the blood (a waste substance produced by your muscles)
• Increased urea levels in the blood (a waste chemical)
• Fever
• Fatigue
• Headache

Common (may affect up to 1 in 10 people)

• Bleeding (haemorrhage)
• Metabolic disturbances caused by the death of tumour cells releasing their contents into the bloodstream
• Reduction in red blood cells, which may cause paleness of the skin and lead to weakness or shortness of breath (anaemia)
• Low neutrophil count (a type of white blood cell important in fighting infections)
• Abnormally low concentration of neutrophils (a type of white blood cell) in the blood, leading to increased susceptibility to infections (neutropenia)
• Hypersensitivity reactions such as allergic skin inflammation (dermatitis), skin rash (urticaria)
• Increased liver enzymes AST/ALT (which may indicate inflammation or damage to liver cells)
• Increased alkaline phosphatase enzyme (an enzyme produced mainly by the liver and bones)
• Increased bilirubin pigment (a substance produced following the normal breakdown of red blood cells)
• Low potassium levels in the blood (a nutrient necessary for nerve and muscle cell function, including those of the heart)
• Reduced heart function (dysfunction)
• Heart rhythm disorders (arrhythmia)
• Low or high blood pressure (hypotension and hypertension)
• Lung function disorders
• Diarrhoea
• Constipation
• Mouth pain (stomatitis)
• Loss of appetite
• Hair loss
• Skin changes
• Loss of menstrual period (amenorrhoea)
• Pain
• Insomnia
• Chills
• Dehydration
• Dizziness
• Itchy skin rash (urticaria)

Uncommon (may affect up to 1 in 100 people)

• Fluid accumulation in the sac around the heart (pericardial effusion)
• Deficient production of all blood cells in the bone marrow (the spongy material inside bones that produces blood cells)
• Acute leukaemia
• Heart attack, chest pain (myocardial infarction)
• Heart failure

Rare (may affect up to 1 in 1,000 people)

• Blood infection (sepsis)
• Severe allergic hypersensitivity reactions (anaphylactic reactions)
• Symptoms similar to anaphylactic reaction (anaphylactoid reactions)
• Drowsiness
• Loss of voice (aphonia)
• Acute circulatory collapse (circulatory failure, primarily of cardiac origin, resulting in inability to supply oxygen and nutrients to tissues and remove toxins)
• Skin redness (erythema)
• Skin inflammation (dermatitis)
• Itching (pruritus)
• Skin rash (macular exanthema)
• Excessive sweating (hyperhidrosis)
• Reduced bone marrow function, which may make you feel unwell or may be detected by blood tests

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

• Primary atypical inflammation of the lungs (pneumonitis)
• Rupture of red blood cells
• Rapid drop in blood pressure, sometimes with reaction and skin rash (anaphylactic shock)
• Altered sense of taste
• Altered sensations (paraesthesia)
• Discomfort and pain in limbs (peripheral neuropathy)
• Severe condition resulting in blockage of specific receptors in the nervous system
• Nervous system disorders
• Loss of coordination (ataxia)
• Inflammation of the brain (encephalitis)
• Increased heart rate (tachycardia)
• Inflammation of veins (phlebitis)
• Tissue formation in the lungs (pulmonary fibrosis)
• Bleeding inflammation of the oesophagus (haemorrhagic oesophagitis)
• Bleeding from the stomach or intestine
• Infertility
• Multi-organ failure

Not known (frequency cannot be estimated from available data)

• Kidney failure
• Liver failure
• Irregular and often rapid heart rate (atrial fibrillation)
• Painful red or purplish rash that spreads and forms blisters and/or other lesions, beginning in mucous membranes (e.g., mouth and lips), particularly if you previously had light sensitivity, respiratory tract infections (e.g., bronchitis), and/or fever
• Drug rash in combination with rituximab
• Pneumonia
• Bleeding from the lungs

Cases of tumours (myelodysplastic syndrome, AML, bronchial carcinoma) have been reported following treatment with Bendamustina Accord. A clear relationship with Bendamustina Accord has not been established.

Contact or consult your doctor immediately if you experience any of the following side effects (frequency not known):
Severe skin rashes including Stevens_Johnson Syndrome and toxic epidermal necrolysis. These may present as reddish spots or circular patches, often with central blisters on the trunk, skin peeling, mouth, throat, nose, genital, and eye ulcers, 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).

If any of the side effects worsen, or if you notice any side effect not listed in this leaflet, inform your doctor.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
Reporting side effects can help provide more information on the safety of this medicine.

5. How to store Bendamustina Accord

Keep this medicine out of the sight and reach of children.
Do not use Bendamustina Accord after the expiry date stated on the label and the carton. The expiry date refers to the last day of that month.
This medicine does not require any special storage temperature. Keep the container in the outer packaging to protect the contents from light.
Notes on expiry date after opening or preparation of the solution
Infusion solutions prepared according to the instructions listed at the end of this leaflet remain stable when stored in polyethylene bags for 3.5 hours at 25°C and for 2 days at 2°C–8°C.
Bendamustina Accord does not contain preservatives. From a microbiological standpoint, the solution should be used immediately. If not used immediately, the duration of storage in use and the conditions prior to use are the responsibility of the user.
It is the responsibility of the user to maintain aseptic conditions.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Bendamustina Accord contains
The active substance is bendamustine hydrochloride.
One vial contains 25 mg of bendamustine hydrochloride (as monohydrate bendamustine hydrochloride).
One vial contains 100 mg of bendamustine hydrochloride (as monohydrate bendamustine hydrochloride).
After reconstitution, 1 ml of concentrate contains 2.5 mg of bendamustine hydrochloride (as monohydrate
bendamustine hydrochloride).
The other component is mannitol.

Description of the appearance of Bendamustina Accord and contents of the pack
Amber glass vials with bromobutyl rubber stoppers and aluminium seals.
Bendamustina Accord is available in packs containing 5, 10 and 20 vials of 25 mg bendamustine hydrochloride, and 1 and 5 vials containing 100 mg of bendamustine hydrochloride.
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 6ª planta,
08039 Barcelona,
Spain

Manufacturer
Accord Healthcare Polska Sp.z o.o.,
ul. Lutomierska 50,
95-200 Pabianice,
Poland
Accord Healthcare single
member S.A.
64th Km National Road
Athens, Lamia,
Schimatari, 32009,
Greece

This medicinal product is authorized in the European Economic Area countries under the following names:

The following information is intended exclusively for physicians or healthcare professionals:
As with all similar cytotoxic substances, strict safety precautions must be applied for nursing and medical personnel due to the potential carcinogenic and genotoxic effects of the preparation. Avoid inhalation (aerosols) and contact with skin and mucous membranes when handling Bendamustina Accord (wear gloves, protective clothing, and, if possible, a face mask!). If any part of the body becomes contaminated, clean thoroughly with soap and water, and rinse eyes with 0.9% saline solution (isotonic). If available, work should be performed on a suitable workbench (laminar flow hood) using a liquid-proof, disposable absorbent pad. Contaminated materials are considered cytotoxic waste. Please follow national guidelines for the disposal of cytotoxic material. Pregnant personnel must be excluded from working with cytostatic agents.

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

1. Preparation of the concentrate

   • A vial of Bendamustina Accord containing 25 mg of bendamustine hydrochloride is first dissolved in 10 ml of solvent, gently agitating the solution.
   • A vial of Bendamustina Accord containing 100 mg of bendamustine hydrochloride is first dissolved in 40 ml of solvent, gently agitating the solution.

2. Preparation of the infusion solution
   Immediately after obtaining a clear solution (usually within 5–10 minutes), the recommended total dose of Bendamustina Accord must be diluted with 0.9% saline solution (isotonic) to achieve a final volume of approximately 500 ml. Bendamustina Accord must not be diluted with other infusion or injectable solutions. Bendamustina Accord must not be mixed in infusions containing other substances.

3. Administration
   The solution is administered as an intravenous infusion over 30–60 minutes. Vials are for single use only. Any unused product and waste material must be disposed of in accordance with local regulations. In case of accidental extravasation (injection into tissues outside the blood vessel), the injection must be immediately stopped. The needle should be removed after gentle aspiration. The affected skin area should then be cooled and the limb elevated. Additional treatments, such as corticosteroids, have not been shown to provide certain benefit (see section 4).