Bendamustine Hikma

Patient Information Leaflet

Bendamustina Hikma 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, 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. Do not give it to other people, even if they have the same symptoms as yours, because it may be harmful.
• If you experience any side effect, including any not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

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

Bendamustina Hikma is a medicine used to treat certain types of cancer (cytotoxic drug).
Bendamustina Hikma is used alone (monotherapy) or in combination with other anticancer 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, or have responded only briefly, to prior treatment with rituximab,
• multiple myeloma in cases where a therapy containing thalidomide or bortezomib is not suitable for you.

2. What you need to know before using Bendamustina Hikma

Do not use Bendamustina Hikma

• If you are allergic to bendamustine hydrochloride or to any of the other ingredients of Bendamustina Hikma (listed in section 6);
• During breastfeeding: if treatment with Bendamustina Hikma is necessary during breastfeeding,
  you must stop breastfeeding (see section on warnings and precautions during breastfeeding);
• if you have severe hepatic insufficiency (damage to the functional cells of the liver);
• if your skin or the whites of your eyes are yellow due to liver or blood problems (jaundice);
• if you have severe impairment of bone marrow function (bone marrow suppression) 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 or nurse before using Bendamustina Hikma:

• if you have reduced ability of the bone marrow to regenerate blood cells. You must monitor your white blood cell and platelet counts before starting treatment with Bendamustina Hikma, before each subsequent treatment cycle, and during the intervals between treatment cycles.
• if you have an infection. You must contact your doctor if you experience symptoms of infection, including fever or pulmonary symptoms.
• At any time, during or after treatment, immediately inform your doctor if you notice—or someone else notices in you—memory loss, difficulty thinking, difficulty walking, or loss of vision; these signs could be due to a very rare but serious brain infection that can be fatal (progressive multifocal leukoencephalopathy, or PML).
• if you experience skin reactions during treatment with Bendamustina Hikma. Skin reactions may worsen.
• 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).
• if you develop a painful red or purplish rash that spreads and blisters and/or other lesions start to appear on 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 conditions (e.g. heart attack, chest pain, severely disturbed heart rhythms).
• if you have flank pain, blood in the urine, or reduced urine output. When your illness is very severe, your body may be unable to eliminate waste products from dying tumor cells. This is called tumor lysis syndrome and can lead to kidney failure and heart problems within 48 hours of the first dose of Bendamustina Hikma. Your doctor may ensure you are adequately hydrated and may give you other medicines to help prevent this.
• in case of severe allergic reactions or hypersensitivity. You should be vigilant for infusion reactions after your first treatment cycle.

Other medicines and Bendamustina Hikma
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
If Bendamustina Hikma 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 Hikma is taken together with medicines that alter your 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 following vaccination with live vaccines (e.g. antiviral vaccination).

Pregnancy, breastfeeding and fertility
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, ask your doctor or pharmacist for advice before using this medicine.
Pregnancy
Bendamustina Hikma can cause genetic damage and has caused malformations in animal studies. You must not use Bendamustina Hikma during pregnancy unless clearly prescribed by your doctor. If you are treated, you should consult a doctor about the potential risk of adverse effects of your therapy on the unborn child, and genetic counseling 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 Hikma. If you become pregnant during treatment with Bendamustina Hikma, you must immediately inform your doctor and seek genetic counseling.

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

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

Fertility
Men undergoing treatment with Bendamustina Hikma are advised not to father children during treatment and for 6 months after treatment ends. Before starting treatment, you may wish to seek advice regarding sperm preservation, as there is a possibility of permanent infertility.
If you are a man, you must avoid fathering children during treatment with Bendamustina Hikma and for up to 6 months after the end of treatment. There is a risk that treatment with Bendamustina Hikma may lead to infertility, and you may benefit from counseling on sperm preservation before starting treatment.

Driving and using machines
Bendamustina Hikma 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 Hikma

Always use this medicine exactly as prescribed by your doctor or pharmacist. Consult your doctor or pharmacist if you have any doubts.
Bendamustina Hikma 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 (leukocyte) or platelet count has fallen below certain levels.
Your doctor will monitor these values at regular intervals.
Chronic lymphocytic leukemia

Non-Hodgkin Lymphomas

Multiple myeloma

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

Renal or hepatic impairment
Depending on the degree of impairment of your liver function, it may be necessary to adjust your
dose (by 30% in case of moderate hepatic dysfunction). No dose adjustment is required
in case of renal impairment. Your doctor will decide whether a dosage adjustment is necessary.

Method of administration
Treatment with Bendamustine Hikma must be administered only by physicians experienced in cancer therapy. Your doctor will give you the exact dose of Bendamustine Hikma, using the necessary precautions.
Your doctor 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 generally no predetermined time limit for treatment with Bendamustine Hikma. The duration of treatment depends on the disease and response to treatment. If you are concerned or have any questions regarding treatment with Bendamustine Hikma, speak with your doctor or nurse.

If you forget to use Bendamustine Hikma
If a dose of Bendamustine Hikma has been missed, your doctor will usually maintain the normal dosing schedule.

If you discontinue treatment with Bendamustine Hikma
Your doctor 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 Hikma can cause side effects, although not everyone experiences them. Some of the side effects listed below may be detected through tests performed by your doctor.

The following frequency definitions are used to classify the side effects:

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
Not known: frequency cannot be estimated from the available data

Tissue necrosis (necrosis) has been observed very rarely following leakage of bendamustine into surrounding tissue outside the blood vessels (extravasation). A burning sensation at the site where the infusion needle was inserted may indicate extravasation. This can lead to pain and skin damage due to poor healing.

The side effect of Bendamustina Hikma that limits its dosage is bone marrow suppression, which usually returns to normal after treatment. Suppression of bone marrow function may lead to a reduction in blood cells, which in turn could increase the risk of infection, anaemia, or bleeding.

Very common:

• low number of white blood cells (blood cells that fight disease)
• decrease in red blood pigment (haemoglobin: a protein in red blood cells that carries oxygen in the body)
• low number of platelets (colourless blood cells that help blood clotting)
• infections
• feeling unwell (nausea)
• vomiting
• inflammation of mucous membranes
• headache
• increased creatinine levels in the blood (a waste substance produced by muscles)
• increased urea levels in the blood (a waste chemical)
• fever
• fatigue

Common:

• 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 breathlessness (anaemia)
• low neutrophil count (a type of white blood cell important for fighting infections)
• hypersensitivity reactions such as allergic skin inflammation (dermatitis) and skin rash (urticaria)
• increased liver enzymes AST/ALT (indicating inflammation or damage to liver cells)
• increased alkaline phosphatase enzyme (an enzyme produced mainly by the liver and bones)
• increased bile pigment (a substance produced during 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)
• impaired heart function (cardiac dysfunction)
• heart rhythm disturbances (arrhythmia)
• low or high blood pressure (hypotension or hypertension)
• impaired lung function
• diarrhoea
• constipation
• mouth ulceration (stomatitis)
• loss of appetite
• hair loss
• skin changes
• loss of menstrual cycle (amenorrhoea)
• pain
• insomnia
• chills
• dehydration
• dizziness
• itching (urticaria)

Uncommon:

• fluid accumulation in the pericardial sac (fluid accumulation in the pericardial space)
• insufficient production of blood cells by the bone marrow (the spongy tissue inside your bones where blood cells are produced)
• Acute leukaemia
• heart attack, chest pain (myocardial infarction)
• heart failure

Rare:

• blood infection (sepsis)
• severe allergic hypersensitivity reactions (anaphylactic reactions)
• reduced bone marrow function, which may make you feel unwell or be detected in blood tests
• symptoms resembling severe allergic anaphylactic reactions (anaphylactoid reactions)
• drowsiness
• loss of voice (aphonia)
• acute circulatory collapse (acute circulatory failure, primarily of cardiac origin, with inability to deliver oxygen or other nutrients to tissues and remove toxins)
• skin redness (erythema)
• skin inflammation (dermatitis)
• itching
• skin rash (macular exanthema)
• excessive sweating (hyperhidrosis)

Very rare:

• atypical primary lung inflammation (pneumonitis)
• rupture of red blood cells
• rapid drop in blood pressure sometimes accompanied by a reaction and skin rash (anaphylactic shock)
• changes in taste sensation
• altered sensations (paraesthesia)
• weakness and limb pain (peripheral neuropathy)
• severe condition resulting from blockade of specific receptors in the nervous system (anticholinergic syndrome)
• nervous system disorders
• lack of coordination (ataxia)
• brain inflammation (encephalitis)
• increased heart rate (tachycardia)
• vein inflammation (phlebitis)
• tissue formation in the lungs (pulmonary fibrosis)
• inflammation of the oesophagus associated with bleeding (haemorrhagic oesophagitis)
• bleeding from the stomach or intestine
• infertility
• multiple organ failure

Not known:

• 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, initially appearing on mucous membranes (e.g. mouth and lips), particularly if you previously had light sensitivity, respiratory infections (e.g. bronchitis), and/or fever
• drug rash when used in combination therapy with rituximab
• pneumonitis
• bleeding from the lungs
• excessive urination, including at night, and excessive thirst even after drinking fluids (nephrogenic diabetes insipidus)

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

Contact your doctor or seek immediate medical help 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 or eye ulcers, and may be preceded by fever and flu-like symptoms.

Widespread rash, high body temperature, swollen lymph nodes, and involvement of other 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 experience any side effects not listed in this leaflet, please contact your doctor.

Reporting of side effects

If you experience any side effects, 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. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Bendamustine Hikma

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and label.
The expiry date refers to the last day of that month.
Store below 25°C. Keep the vial in the original packaging to protect it from light.

Notes on shelf life after opening or preparation of the solution
Infusion 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 a temperature between 2°C and 8°C in polyethylene bags.
From a microbiological standpoint, the diluted solution should be used immediately. If not used immediately, the storage times and conditions prior to use are the responsibility of the user and should normally not exceed 24 hours at a temperature between 2°C and 8°C, unless reconstitution/dilution has taken place under controlled and validated aseptic conditions.
It is the responsibility of the user to maintain aseptic conditions.

Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

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

What Bendamustina Hikma looks like and contents of the pack
Amber glass vials with rubber stoppers and aluminium flip-off caps.
The powder is white and crystalline.
Bendamustina Hikma is available in packs containing 1 or 5 vials.
Not all pack sizes may be marketed.

Marketing Authorization Holder
Hikma Farmacêutica (Portugal), S.A.
Estrada do Rio da Mó, 8, 8A and 8B, Fervença
2705-906 Terrugem SNT
Portugal

Manufacturer
Thymoorgan Pharmazie GmbH, Schiffgraben 23, D-38690 Goslar, Germany

Sales Licensee for Italy
Hikma Italia SpA
Viale Certosa 10, 27100 Pavia

This medicinal product is authorized in the European Economic Area Member States under the following names:
Austria   Bendamustin Hikma 2.5 mg/ml Powder for a concentrate for solution for infusion
France    BENDAMUSTINE HIKMA 2.5 mg/mL, poudre pour solution à diluer
Germany   Bendamustin Hikma 2.5 mg/ml Pulver für ein Konzentrat zur Herstellung einer Infusionslösung
Italy      Bendamustina Hikma 2.5 mg/ml powder for concentrate for solution for infusion
Portugal   Bendamustina Hikma
United Kingdom Bendamustine 2.5 mg/ml Powder for concentrate for solution for infusion
Spain     Bendamustina Hikma 2.5 mg/ml Polvo para concentrado para solución para perfusión EFG

The following information is intended exclusively for physicians or healthcare professionals:
As with all similar cytotoxic agents, more stringent safety measures must be adopted for medical and nursing personnel due to the potential carcinogenic and genotoxic effects of this preparation. Avoid inhalation (by aspiration) and contact with skin and mucous membranes when handling Bendamustina Hikma (wear gloves, protective clothing, and possibly a face mask!). If any part of the body becomes contaminated, wash thoroughly with water and soap, and rinse eyes with 0.9% isotonic saline solution. Whenever possible, it is recommended to work on a suitable workbench (laminar flow hood) with a liquid-impermeable disposable absorbent pad. Contaminated materials must be 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 one vial of Bendamustina Hikma exclusively in water for injections, as follows:

1. Preparation of the concentrate

   • A vial of Bendamustina Hikma containing 25 mg of bendamustine hydrochloride is first dissolved in 10 ml by agitation.
   • A vial of Bendamustina Hikma containing 100 mg of bendamustine hydrochloride is first dissolved in 40 ml by agitation.

2. Preparation of the infusion solution
   As soon as a clear solution is obtained (usually within 5–10 minutes), the recommended total dose of bendamustine must be immediately diluted with 0.9% isotonic saline solution to obtain a final volume of approximately 500 ml. Bendamustina Hikma must not be diluted with other infusion or injection solutions. Bendamustina Hikma must not be mixed with other substances in the same infusion.

3. Administration
   The solution is administered by intravenous infusion over 30–60 minutes. The vials are for single use only.

Any unused medicine and waste material derived from this medicine must be disposed of in accordance with local regulations.
In case of accidental injection into tissue outside blood vessels (extravascular injection), the procedure must be immediately stopped. The needle must be removed after brief aspiration. The affected tissue area should then be cooled. The arm should be elevated. Additional treatments such as corticosteroids do not clearly provide benefits (see section 4).