Bendamustine medac

Package leaflet: Information for the user

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

bendamustine hydrochloride
Generic medicine
Please read all of this leaflet carefully before you start using this medicine, because 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.
• If you get any side effects, talk to your doctor or pharmacist. This includes any side effects not listed in this leaflet. See section 4.

Contents of this leaflet:

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

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

Bendamustina medac is a medicine containing the active substance bendamustine hydrochloride (hereinafter referred to as bendamustine).
Bendamustine is a medicine used to treat certain types of cancer (cytotoxic medicine).
Bendamustine is used alone (monotherapy) or in combination with other medicines for the treatment of the following types of cancer:

• chronic lymphocytic leukaemia, in cases where combination chemotherapy with fludarabine is not suitable for you;
• non-Hodgkin’s lymphomas that have not responded to previous treatment with rituximab or that responded only for a short period of time;
• multiple myeloma, in cases where high-dose chemotherapy associated with autologous stem cell transplantation and therapy based on thalidomide or bortezomib are not suitable for you.

2. What you need to know before using Bendamustina medac

Do not use Bendamustina medac

• 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 bendamustine is necessary during breastfeeding, you must stop breastfeeding (see section on pregnancy, breastfeeding and fertility)
• if you have severe hepatic 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 severe bone marrow dysfunction (bone marrow suppression) with severe abnormalities in white blood cell and platelet counts
• if you have undergone major surgery less than 30 days before starting treatment
• if you have an infection, particularly if accompanied by a reduction in white blood cells (leucopenia)
• in combination with yellow fever vaccines.

Warnings and precautions
Talk to your doctor or nurse before using Bendamustina medac

• if you have reduced bone marrow capacity to regenerate blood cells. You must undergo blood tests to determine your white blood cell and platelet counts before starting treatment with Bendamustina medac, before each subsequent treatment cycle, and at intervals between treatment cycles;
• if you have infections. Contact your doctor if you experience signs of infection, including fever or lung symptoms;
• if you have pre-existing heart disease (e.g. heart attack, chest pain, severe heart rhythm disturbances).

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 that may be fatal (progressive multifocal leukoencephalopathy, or PML).
Contact your doctor if you notice any suspicious skin changes, as use of this medicine may increase the risk of certain types of skin cancer (non-melanoma skin cancer).
Talk to your doctor or nurse during treatment with Bendamustina medac

• if you experience nausea and vomiting. Your doctor may prescribe an antiemetic medicine to reduce nausea;
• if you experience pain in one side, blood in the urine, or reduced urine output. If your condition is very severe, your body may be unable to eliminate waste products from dying tumor cells. This condition is known as "tumor lysis syndrome" and may cause kidney failure and heart problems within 48 hours of the first dose of Bendamustina medac. Your doctor may ensure you are adequately hydrated and give you additional medicines to help prevent this;
• if you develop skin reactions during treatment with Bendamustina medac. The severity of these 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 experience severe allergic reactions or hypersensitivity. You should be alert for infusion-related reactions after the first treatment cycle.

Men treated with Bendamustina medac are advised not to father a child during treatment and for 6 months after treatment ends. Before starting treatment, you should seek information about sperm preservation due to the possibility of permanent infertility (see section on pregnancy, breastfeeding and fertility).
Children and adolescents
There is no experience with bendamustine hydrochloride in children and adolescents.
Other medicines and Bendamustina medac
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
Bendamustine hydrochloride may affect other medicines, which in turn may interfere with the action of bendamustine hydrochloride. Bendamustine hydrochloride may interact with:
If Bendamustina medac is used in combination with medicines that suppress bone marrow blood cell formation, the intensity of the effect on the bone marrow may increase.
If Bendamustina medac is used in combination with medicines that alter the immune response, the intensity of this effect may increase.
Cytostatic medicines may reduce the effectiveness of vaccination with live viruses. In addition, cytostatic medicines increase the risk of infection following vaccination with live vaccines (e.g. antiviral vaccination).
Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor or pharmacist before using this medicine.
Women of childbearing potential must use effective contraception during treatment with bendamustine and for 6 months after completion of treatment.
Men must use effective contraception and must not father a child during treatment with bendamustine and for 3 months after completion of treatment.
Pregnancy
Bendamustine may cause genetic damage and has caused malformations in animal studies. You must not use this medicine during pregnancy unless clearly prescribed by your doctor. If you are treated, you should seek medical advice regarding the risk of potential adverse effects of your therapy on the unborn child, and genetic counselling is recommended.
Breastfeeding
Bendamustine must not be administered during breastfeeding. If treatment with this medicine is necessary during breastfeeding, you must stop breastfeeding.
Fertility
If you are a man, there is a risk that treatment with bendamustine may lead to infertility, and you should seek counselling on sperm preservation before starting treatment.
Talk to your doctor or pharmacist before using any medicine.
Driving and using machines
Bendamustine hydrochloride may impair the ability to drive vehicles and use machinery. You must not drive or operate machinery if you experience adverse effects such as dizziness or lack of coordination.

3. How to use Bendamustina medac

Bendamustina medac is administered intravenously over a period of 30 – 60 minutes at various dosage levels, either alone (monotherapy) or in combination with other medicinal products.
Treatment must not be initiated if your white blood cells (leukocytes) and/or platelets have dropped below certain levels.
Your doctor will determine these values at regular intervals.

Chronic lymphocytic leukemia

• Bendamustina medac 100 mg per square meter of body surface area (based on your height and body weight): days 1 + 2
• Repeat cycle after 4 weeks, up to 6 times

Non-Hodgkin’s lymphoma

• Bendamustina medac 120 mg per square meter of body surface area (based on your height and body weight): days 1 + 2
• Repeat cycle after 3 weeks, at least 6 times

Multiple myeloma

• Bendamustina medac 120 - 150 mg per square meter of body surface area (based on your height and body weight): days 1 + 2
• Prednisone 60 mg per square meter of body surface area (based on your height and body weight) by injection or orally: days 1 - 4
• Repeat cycle after 4 weeks, at least 3 times

Treatment must be discontinued if your white blood cells (leukocytes) and/or platelets have dropped to certain levels. Treatment may continue once white blood cell and platelet counts have increased.

Renal or hepatic impairment
Depending on the degree of hepatic impairment, dose adjustment may be required (by 30% in case of moderate hepatic impairment). Bendamustina medac must not be used if you have severe hepatic impairment. No dose adjustment is necessary in case of renal impairment. The responsible physician will decide whether dose adjustment is needed.

How it is administered
Treatment with Bendamustina medac must be performed only by physicians experienced in cancer therapy. Your doctor will give you the exact dose of Bendamustina medac using the necessary precautions.
The responsible physician will administer the infusion solution after preparation as prescribed. The solution is administered intravenously as a short infusion lasting 30 – 60 minutes.

Duration of treatment
There is no predefined time limit for treatment with Bendamustina medac in general. The duration of treatment depends on the disease and the response to therapy.
If you are concerned or have any doubts about treatment with Bendamustina medac, consult your doctor or nurse.

If you forget to use Bendamustina medac
If a dose of Bendamustina medac is missed, your doctor will usually maintain the normal dosing schedule.

If you stop treatment with Bendamustina medac
Your treating physician will decide whether to discontinue treatment or switch to a different preparation.
If you have any doubts about using this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
Contact your doctor or seek immediate medical help if you notice any of the following side effects (frequency not known):
Severe skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis.
These may appear as red, target-like spots or circular patches, often with central blisters on the trunk, skin peeling, mouth, throat, nose, genital or eye ulcers, and may be preceded by fever and flu-like symptoms.
Widespread skin rashes, high body temperature, swollen lymph nodes, and involvement of multiple organs (drug reaction with eosinophilia and systemic symptoms, also known as DRESS or drug hypersensitivity syndrome).
Tissue damage (necrosis) has very rarely been observed following accidental injection into tissue outside the blood vessels (extravascular). A burning sensation at the infusion site may indicate administration of the medicine outside the blood vessels. The consequence of such administration may be pain and skin defects due to poor healing. The dose-limiting side effect of Bendamustina medac is bone marrow function impairment, which usually returns to normal after treatment. Suppressed bone marrow function may lead to low blood cell counts, which in turn may increase the risk of infection, anaemia, or increased risk of bleeding.

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

• decrease in the number of white blood cells (leucopenia)
• decrease in the red pigment of the blood (haemoglobin)
• decrease in the number of platelets (thrombocytopenia)
• infections
• nausea
• vomiting
• inflammation of the mucous membranes
• increased creatinine levels in the blood
• increased urea levels in the blood
• 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 (tumour lysis syndrome)
• reduction in red blood cells, which may cause paleness and lead to weakness or breathlessness (anaemia)
• decrease in neutrophil count (neutropenia)
• hypersensitivity reactions such as allergic skin inflammation (dermatitis), urticaria
• increased liver enzymes AST/ALT
• increased alkaline phosphatase enzyme
• increased bile pigment
• low potassium levels in the blood
• impaired heart function (dysfunction) (palpitations, angina pectoris)
• heart rhythm disorders (arrhythmia)
• low or high blood pressure (hypotension and hypertension)
• impaired lung function
• diarrhoea
• constipation
• mouth inflammation (stomatitis)
• loss of appetite
• hair loss
• skin changes
• absence of menstrual periods (amenorrhoea)
• pain
• insomnia
• chills
• dehydration
• dizziness
• rash, itching (urticaria)

Uncommon (may affect up to 1 in 100 people)

• fluid accumulation in the heart sac (fluid collection in the pericardial space)
• reduced production of all blood cells (myelodysplastic syndrome)
• 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 resembling anaphylactic reactions (anaphylactoid reactions)
• drowsiness
• loss of voice (aphonia)
• acute circulatory collapse
• skin redness (erythema)
• skin inflammation (dermatitis)
• itching
• skin rash (macular exanthema)
• excessive sweating (hyperhidrosis)
• reduced bone marrow function, possibly causing general malaise or detectable through blood tests

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

• atypical primary lung inflammation (pneumonia)
• destruction of red blood cells
• rapid drop in blood pressure, sometimes associated with skin reactions or rash (anaphylactic shock)
• altered sense of taste
• altered sensation (paraesthesia)
• discomfort and pain in limbs (peripheral neuropathy)
• nervous system disorder (anticholinergic syndrome)
• neurological disorders
• lack of coordination (ataxia)
• brain inflammation (encephalitis)
• increased heart rate (tachycardia)
• vein inflammation (phlebitis)
• formation of tissue in the lungs (pulmonary fibrosis)
• haemorrhagic oesophagitis
• bleeding from the stomach or intestine
• infertility
• multi-organ failure

Not known (frequency cannot be estimated from the available data)

• liver failure
• kidney failure
• irregular and often rapid heart rate (atrial fibrillation)
• painful red or purplish rash that spreads and forms blisters and/or other lesions starting in the mucous membrane (e.g. mouth and lips), especially if you previously had light sensitivity, respiratory tract infections (e.g. bronchitis) and/or fever
• drug rash during combination therapy with rituximab
• pneumonia
• bleeding from the lungs
• excessive urination, even at night, and excessive thirst even after drinking fluids (nephrogenic diabetes insipidus)

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, please inform your doctor 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 helps provide more information on the safety of this medicine.

5. How to store Bendamustina medac

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton after
Exp. The first two digits indicate the month and the last four digits indicate the year. The expiry date refers to the last day of that month.
Store the container in the outer packaging to protect the medicine from light.
Note on the shelf-life after opening or preparation of the solution
After reconstitution and dilution, chemical and physical stability has been demonstrated for 3.5 hours at
25°C/60% RH and for 2 days at 2 - 8°C in polyethylene bags.
From a microbiological standpoint, the product should be used immediately. If not used immediately, storage times and conditions prior to use are the responsibility of the user and normally should not exceed 24 hours at 2 - 8°C, unless reconstitution/dilution (etc.) has been carried out under controlled and validated aseptic conditions.
Do not dispose of any medicine 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 medac contains

• The active substance is bendamustine hydrochloride. One vial contains 25 mg of bendamustine hydrochloride. One vial contains 100 mg of bendamustine hydrochloride. After reconstitution, 1 ml of concentrate contains 2.5 mg of bendamustine hydrochloride.
• The other ingredient is mannitol.

Description of the appearance of Bendamustina medac and contents of the pack
White to off-white lyophilized powder in an amber glass vial with a stopper and an aluminum cap with a flip-off seal.
Type I 25 ml glass vials.
Type I 50 ml glass vials.
Bendamustina medac is available in packs of 1, 5 and 10 vials for injection containing 25 mg of bendamustine hydrochloride, and packs of 1 and 5 vials for injection containing 100 mg of bendamustine hydrochloride.
Not all pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer
medac Gesellschaft für klinische Spezialpräparate mbH
Theaterstr. 6
22880 Wedel
Germany

This medicinal product is authorized in the European Economic Area countries under the following names:
Denmark Bendamedac 2.5 mg/ml
France Bendamustine medac 2.5 mg/ml powder for solution for infusion
Germany Bendamustin medac 2.5 mg/ml Pulver für ein Konzentrat zur Herstellung einer Infusionslösung
Iceland Bendamustine medac 2.5 mg/ml
Italy Bendamustina medac
Lithuania Bendamustine medac 2.5 mg/ml milteliai infuzinio tirpalo koncentratui
Netherlands Bendamustine HCl medac 2.5 mg/ml, poeder voor concentraat voor oplossing voor infusie
Sweden Bendamustine medac 2.5 mg/ml

The following information is intended exclusively for physicians or healthcare professionals:
As with all similar cytotoxic agents, strict safety precautions must be observed for medical and nursing personnel, since preparation involves potential carcinogenic and genotoxic risks.
Avoid inhalation (breathing in) and contact with skin and mucous membranes during handling of bendamustine (wear gloves, protective clothing, and, if possible, a face mask!). In case of contamination of any body area, wash thoroughly with water and soap, and rinse eyes with 0.9% isotonic saline solution. Whenever possible, it is recommended to work on special safety workbenches (laminar flow hoods) using a disposable, liquid-proof absorbent pad. Contaminated materials are cytotoxic waste. Follow national guidelines for the disposal of cytotoxic materials! Pregnant personnel must not handle cytotoxic agents.

The ready-to-use solution must be prepared by dissolving the contents of one vial of Bendamustina medac exclusively in Water for Injections, as described below.

1. Preparation of the concentrate

   • A vial of Bendamustina medac containing 25 mg of bendamustine hydrochloride is first dissolved in 10 ml, with agitation of the solution.
   • A vial of Bendamustina medac containing 100 mg of bendamustine hydrochloride is first dissolved in 40 ml, with agitation of 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 medac must be diluted immediately with 0.9% sodium chloride solution (isotonic saline) to achieve a final volume of approximately 500 ml. Bendamustina medac must not be diluted with other infusion or injection solutions. Bendamustina medac must not be mixed in an infusion with other substances.