Bendamustine eugia

Package leaflet: Information for the user

Bendamustine Eugia, 2.5 mg/ml, powder for preparation of concentrate for infusion solution
Bendamustini hydrochloridum
Please read all of this leaflet carefully before using this medicine because it contains
important information for the patient.

• Keep this leaflet, as you may need to read it again.
• If you have any further questions, please ask your doctor, pharmacist or nurse.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. This medicine may harm others, even if their symptoms are the same.
• If you experience any side effects, including any not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Contents of the leaflet:

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

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

Bendamustine Eugia is a medicine used to treat certain types of cancer (a cytotoxic medicine).
Bendamustine Eugia is used alone (monotherapy) or in combination with other medicines to treat the following cancers:

• chronic lymphocytic leukemia when chemotherapy containing fludarabine is not suitable for the patient,
• non-Hodgkin's lymphomas that did not respond or responded only briefly to previous treatment with rituximab,
• multiple myeloma when treatment containing thalidomide or bortezomib is not suitable for the patient.

2. Important information before using Bendamustine Eugia

When not to use Bendamustine Eugia:

• if the patient is allergic to bendamustine hydrochloride or any of the other ingredients of this medicine (listed in section 6);
• during breastfeeding; if treatment with Bendamustine Eugia is necessary during lactation, breastfeeding must be discontinued (see section "Pregnancy, breastfeeding and fertility");
• if the patient has severe liver damage (hepatocellular damage);
• if the patient has yellowing of the skin or whites of the eyes caused by liver dysfunction or blood disorders (jaundice);
• if the patient has severe bone marrow dysfunction (bone marrow suppression) and significant changes in white blood cell and platelet counts;
• if the patient has undergone major surgical procedures within 30 days before starting treatment;
• if the patient has an infection, especially accompanied by a reduced number of white blood cells (leukopenia);
• if the patient has been vaccinated against yellow fever.

Warnings and precautions
Before starting treatment with Bendamustine Eugia, discuss the following with your doctor, pharmacist or nurse:

• in case of reduced ability of the bone marrow to produce blood cells. Before starting treatment with Bendamustine Eugia, and before each subsequent treatment cycle and during treatment breaks, white blood cell and platelet counts should be checked.
• in case of infection. Contact your doctor if signs of infection occur, including fever and pulmonary symptoms.
• if skin reactions occur during treatment with Bendamustine Eugia. These reactions may worsen.
• if painful, red or purple, spreading rash with blisters and (or) other mucosal changes (e.g. in the mouth and on the lips) develops, especially if the patient previously had photosensitivity, respiratory tract infection (e.g. bronchitis) and (or) fever.
• in case of coexisting heart disease (e.g. myocardial infarction, chest pain, severe cardiac arrhythmias).
• if the patient experiences pain in the side, blood in the urine or reduced urine output. In patients with advanced disease, the body may be unable to eliminate all waste products from dying tumor tissue. This phenomenon is known as tumor lysis syndrome and may lead to kidney failure and heart problems within 48 hours after the first dose of Bendamustine Eugia. The doctor should ensure adequate hydration and may administer other medications to prevent this condition.
• in case of severe allergic or hypersensitivity reactions. Be vigilant for infusion-related reactions, especially after the first treatment cycle.
• inform the doctor immediately at any time during or after treatment if the patient develops any of the following symptoms: memory loss, thinking difficulties, walking difficulties or vision loss – these may be caused by a very rare but serious brain infection (progressive multifocal leukoencephalopathy, PML), which can be fatal.
• if any suspicious skin changes are observed, contact the doctor due to increased risk of certain types of skin cancer (non-melanoma skin cancer) associated with this medicine.

Bendamustine Eugia and other medicines
Tell your doctor or pharmacist about all medicines the patient is currently taking, has recently taken or plans to take.
If Bendamustine Eugia is used in combination with other medicines that suppress bone marrow function, the effect on bone marrow may be enhanced.
If Bendamustine Eugia is used together with medicines that affect the immune response, the effect on bone marrow may be intensified.
Cytostatic medicines may reduce the effectiveness of vaccines containing live viruses. Moreover, cytostatic medicines additionally increase the risk of infection after vaccination with live vaccines (e.g. antiviral vaccines).

Pregnancy, breastfeeding and fertility
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult her doctor or pharmacist before using this medicine.

Pregnancy
Bendamustine Eugia may cause damage to genetic material and has been shown to cause developmental abnormalities in animal studies. Bendamustine Eugia must not be used during pregnancy unless the physician considers it absolutely necessary. If treatment must be initiated, consultation with the doctor regarding potential adverse effects on the unborn child is recommended, and genetic counseling should be sought.
Women of childbearing potential must use an effective method of contraception both before starting treatment with Bendamustine Eugia and during treatment. If a patient becomes pregnant during treatment with Bendamustine Eugia, she must inform her doctor immediately and seek genetic counseling.

Breastfeeding
Bendamustine Eugia must not be used during breastfeeding. If treatment with Bendamustine Eugia is necessary, the patient must discontinue breastfeeding.

Before taking any medicine, consult a doctor or pharmacist.

Fertility
Men should not father children during treatment with Bendamustine Eugia or for 6 months after the end of treatment. There is a risk that treatment with Bendamustine Eugia may cause infertility; therefore, men should consult their doctor about sperm preservation before starting treatment.

Driving and operating machinery
Bendamustine Eugia has a marked influence on the ability to drive vehicles and operate machinery. Patients should not drive or operate machinery if they experience adverse effects such as dizziness or lack of coordination.

3. How to use Bendamustine Eugia

This medicine should always be used exactly as prescribed by your doctor or pharmacist. If in doubt,
consult your doctor or pharmacist. Bendamustine Eugia is administered intravenously over a period of
30-60 minutes, at various doses, either as a single agent (monotherapy) or in combination with other
medicines.
Treatment should not be initiated if the white blood cell (leukocyte) and/or platelet count falls below
the level specified by the doctor.
Your doctor will monitor these parameters at regular intervals.
Chronic lymphocytic leukemia

Non-Hodgkin's lymphomas

Multiple myeloma

Treatment should be discontinued when the white blood cell (leukocyte) count and (or) platelet count
decreases to a level specified by the physician. Treatment may be continued once the white blood cell and platelet counts have increased.
Liver or kidney function disorders
Depending on the degree of liver function impairment, dose adjustment may be necessary (by 30% in
cases of moderate liver dysfunction). Dose adjustment is not necessary in patients with renal impairment. The treating physician will decide whether dose modification is required.
How the medicine is administered
Treatment with Bendamustine Eugia should only be initiated by physicians experienced in cancer therapy. The physician will administer the appropriate dose of Bendamustine Eugia and take necessary precautions.
The treating physician will administer the infusion solution after it has been prepared according to the instructions.
The solution is given intravenously as a short-term infusion over 30–60 minutes.
Duration of treatment
There is no generally applicable time limit for treatment with Bendamustine Eugia. The duration of treatment depends on the disease and how the patient responds to therapy.
If in doubt or if you have any questions regarding treatment with Bendamustine Eugia, consult your doctor or nurse.
Missed dose of Bendamustine Eugia
If a dose of Bendamustine Eugia is missed, the physician will usually continue treatment according to the established dosing schedule.
Discontinuation of Bendamustine Eugia
The treating physician will decide whether to discontinue treatment or switch to another medicine.
If you have any further doubts regarding the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone experiences them.
Some of the effects listed below may be detected during examinations performed by a doctor.
The following frequency definitions are used to assess adverse reactions:

Tissue changes (necrosis) have been observed very rarely after extravascular injection of Bendamustine Eugia (extravasation). A sign of extravasation may be a burning sensation at the site of needle insertion. Consequences of such administration may include pain and poorly healing skin lesions.

Dose-limiting adverse reactions of Bendamustine Eugia are bone marrow suppression, which usually resolve after completion of treatment. Bone marrow suppression may lead to decreased blood cell counts, thereby increasing the risk of infections, anemia, or bleeding.

Very common:

• Low number of white blood cells (cells that fight infections in the blood)
• Decreased level of hemoglobin (the red pigment in blood: a protein in red blood cells that carries oxygen throughout the body)
• Low platelet count (colorless components of blood that help in blood clotting)
• Infections
• Nausea
• Vomiting
• Mucositis (inflammation of the mucous membranes)
• Headache
• Increased blood creatinine levels (a waste product produced by muscles)
• Increased blood urea levels (a waste product generated in the body)
• Fever
• Fatigue

Common:

• Bleeding (hemorrhage)
• Metabolic disturbances associated with the release of tumor cell contents into the bloodstream
• Decreased number of red blood cells, which may cause paleness, weakness, or shortness of breath (anemia)
• Low neutrophil count (a common type of white blood cell important in fighting infections)
• Hypersensitivity reactions, such as allergic dermatitis (skin inflammation), rash (urticaria)
• Increased activity of liver enzymes AspAT/AlAT (which may indicate inflammation or damage to liver cells)
• Increased activity of alkaline phosphatase enzyme (an enzyme mainly produced in the liver and bones)
• Increased levels of bilirubin (a substance formed during normal breakdown of red blood cells)
• Decreased potassium levels in blood (a nutrient essential for nerve and muscle cell function, including in the heart)
• Impaired heart function (cardiac dysfunction)
• Heart rhythm disorders (arrhythmia)
• Low or high blood pressure (hypotension or hypertension)
• Lung function disorders
• Diarrhea
• Constipation
• Mouth pain (oral mucositis)
• Loss of appetite
• Excessive hair loss
• Skin changes
• Absence of menstruation (amenorrhea)
• Pain
• Insomnia
• Chills
• Dehydration
• Dizziness
• Itchy rash (urticaria)

Uncommon:

• Fluid accumulation in the pericardial sac (pericardial effusion)
• Ineffective production of all types of blood cells (bone marrow aplasia – spongy material inside bones where blood cells are produced)
• Acute leukemia
• Heart attack, chest pain (myocardial infarction)
• Heart failure

Rare:

• Blood infection (sepsis)
• Severe hypersensitivity reactions (anaphylactic reactions)
• Bone marrow suppression, which may cause worsening general condition or be evident in blood test results
• Symptoms resembling anaphylactic reactions (anaphylactoid reactions)
• Somnolence (drowsiness)
• Loss of voice (aphonia)
• Acute circulatory collapse (circulatory failure, mainly of cardiac origin, resulting in inadequate oxygen and nutrient supply to tissues and impaired toxin removal)
• Skin redness (erythema)
• Dermatitis (skin inflammation)
• Itching (pruritus)
• Skin rash (maculopapular rash)
• Excessive sweating (hyperhidrosis)

Very rare:

• Primary atypical pneumonia (pneumonia)
• Hemolysis (destruction of red blood cells)
• Sudden drop in blood pressure, sometimes with skin reactions or rash (anaphylactic shock)
• Disturbance of taste
• Altered sensation (paresthesia)
• Poor general condition and limb pain (peripheral neuropathy)
• Severe condition leading to blockade of a specific receptor in the nervous system
• Neurological disorders
• Lack of motor coordination (ataxia)
• Encephalitis (inflammation of the brain)
• Rapid heartbeat (tachycardia)
• Phlebitis (inflammation of veins)
• Tissue formation in the lungs (pulmonary fibrosis)
• Hemorrhagic esophagitis (bleeding inflammatory condition of the esophagus)
• Bleeding from stomach or intestines
• Infertility
• Multi-organ failure

Frequency unknown:

• Liver failure
• Kidney failure
• Irregular or rapid heartbeat (atrial fibrillation)
• Painful red or purple spreading rash with blisters and (or) other mucosal changes (e.g., in the mouth and lips), especially if the patient previously had photosensitivity, respiratory tract infection (e.g., bronchitis), and (or) fever
• Drug rash associated with combination therapy including rituximab
• Pneumonia
• Pulmonary hemorrhage
• Excessive urination, including at night, and excessive thirst even after drinking fluids (nephrogenic diabetes insipidus)

There have been reports of tumors (myelodysplastic syndrome, acute myeloid leukemia, bronchial carcinoma) following treatment with Bendamustine Eugia. A definitive association with Bendamustine Eugia could not be established.

Patients should contact their doctor immediately if any of the following adverse reactions occur (frequency unknown):

Severe skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis. These may present as red or round spots on the skin, often with central blisters on the trunk, skin peeling, oral, throat, nasal, genital, and ocular mucosal ulcers, and may be preceded by fever and flu-like symptoms.

Widespread rash, high body temperature, enlarged lymph nodes, and multi-organ involvement (drug reaction with eosinophilia and systemic symptoms, also known as DRESS syndrome or drug hypersensitivity syndrome).

Reporting of adverse reactions

If any adverse effects occur, including those not listed in this leaflet, patients should inform their doctor or pharmacist. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions, Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw, phone: +48 22 49 21 301, fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl

Adverse reactions can also be reported to the marketing authorization holder.

Reporting adverse reactions helps to increase knowledge about the safety of the medicinal product.

5. How to store Bendamustine Eugia

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and carton after:
EXP. The expiry date refers to the last day of the stated month.
Vials may, but do not have to, be packed in a protective plastic overwrap.
Note regarding shelf life after opening or reconstitution of the solution.
Chemical and physical in-use stability has been demonstrated for 3.5 hours at 25°C and for up to 48
hours at 2°C - 8°C in polyethylene bags.
From a microbiological point of view, the medicine should be used immediately.
If not used immediately, the user is responsible for the storage time and conditions prior to use, and
these should usually not exceed 24 hours at 2°C - 8°C, unless reconstitution/dilution was carried out
under controlled and validated aseptic conditions.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. This will help protect the environment.

6. Contents of the pack and other information

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

What Bendamustine Eugia looks like and contents of the pack
Powder for solution for infusion concentrate.
White to off-white lyophilized cake or powder.
20 ml vials with 20 mm neck made of tubular orange glass type I, with grey bromobutyl rubber stoppers of 20 mm diameter, sealed with an aluminium seal and a polypropylene cap.
50 ml vials with 20 mm neck made of tubular orange glass type I, with grey bromobutyl rubber stoppers of 20 mm diameter, sealed with an aluminium seal and a polypropylene cap.
Bendamustine Eugia is available in packs containing
1, 5, 10 or 20 vials containing 25 mg of bendamustine hydrochloride
and
1, 5 or 10 vials containing 100 mg of bendamustine hydrochloride.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer/Importer
Marketing Authorisation Holder:
Eugia Pharma (Malta) Ltd.
Vault 14, level 2
Valletta Waterfront
Floriana, FRN1914
Malta
e-mail: [email protected]

Manufacturer/Importer:
APL Swift Services (Malta) Ltd.
HF26, Hal Far Industrial Estate, Hal Far
Birzebbugia, BBG 3000
Malta
Generis Farmacêutica, S.A.
Rua João de Deus 19, Venda Nova
2700-487 Amadora
Portugal
Arrow Génériques
26 Avenue Tony Garnier
69007 Lyon
France

This medicinal product is authorised for marketing in the European Economic Area under the following names:
Belgium: Bendamustine Eugia 2.5 mg/ml powder for concentrate for solution for infusion / poudre pour solution à diluer pour perfusion / Pulver für ein Konzentrat zur Herstellung einer Infusionslösung
France: BENDAMUSTINE ARROW 2.5 mg/ml, poudre pour solution à diluer pour perfusion
Germany: Bendamustin PUREN 2.5 mg/ml Pulver für ein Konzentrat zur Herstellung einer Infusionslösung
Italy: Bendamustina Aurobindo
Poland: Bendamustine Eugia
Portugal: Bendamustina Generis
Spain: Bendamustina Aurovitas 2.5 mg/ml polvo para concentrado para solución para perfusión EFG

Information intended exclusively for medical professionals:

As with all similar cytotoxic substances, due to the potential of the drug to cause genetic damage and neoplastic diseases, nursing and medical personnel must take more stringent precautions than usual. When handling Bendamustine Eugia, inhalation (breathing in) of the drug and contact with skin or mucous membranes must be avoided (wear gloves, protective clothing, and possibly a face mask!). If any part of the body becomes contaminated with the product, it should be thoroughly washed with soap and water, and the eyes should be rinsed with 0.9% (isotonic) saline solution. Whenever possible, work should be carried out in specially protected work areas (under a laminar flow hood), with the work surface covered by a single-use, fluid-proof absorbent pad. Contaminated materials are cytostatic waste. National guidelines for the disposal of cytostatic materials must be followed. Pregnant women must not handle cytostatic products.

The ready-to-use solution should be prepared by dissolving the contents of the vial of Bendamustine Eugia exclusively in Water for Injections, as follows:

1. Preparation of the concentrate

   • One vial of Bendamustine Eugia containing 25 mg of bendamustine hydrochloride should first be dissolved in 10 ml of Water for Injections by shaking.
   • One vial of Bendamustine Eugia containing 100 mg of bendamustine hydrochloride should first be dissolved in 40 ml of Water for Injections by shaking.

2. Preparation of the infusion solution
   After obtaining a clear solution (usually within 5–10 minutes), the total recommended dose of Bendamustine Eugia should be immediately diluted with 0.9% (isotonic) saline solution to achieve a final volume of approximately 500 ml. Bendamustine Eugia must not be dissolved in other infusion or injection solutions. Bendamustine Eugia must not be mixed in the same infusion with other substances.

3. Administration of the drug
   The solution should be administered as a 30–60 minute intravenous infusion. Vials are for single use only. Any unused product or waste material should be disposed of in accordance with local regulations.

Any accidental extravasation (injection into tissues outside blood vessels) must be immediately stopped. The needle should be removed after brief aspiration. The affected tissue area should then be cooled. The arm should be elevated. Additional treatments, such as the use of corticosteroids, do not provide clear benefits (see section 4).