Bendamustine Aurobindo

Package leaflet: Information for the user

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

Generic medicine
Please read all of this leaflet carefully before you start taking 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, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not 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, pharmacist, or nurse. See section 4.

Contents of this leaflet:

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

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

Bendamustina Aurobindo is a medicine used to treat certain types of cancer (cytotoxic medicine).
Bendamustina Aurobindo is used alone (monotherapy) or in combination with other medicines to treat the following types 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 a thalidomide- or bortezomib-based treatment regimen is not suitable for you.

2. What you should know before taking Bendamustina Aurobindo

Do not take Bendamustina Aurobindo:

• 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 Aurobindo is necessary during breastfeeding, you must stop breastfeeding (see section ‘Pregnancy, breastfeeding and fertility’);
• if you have severe hepatic insufficiency (damage to the functional liver cells);
• if your skin or the whites of your eyes are yellow due to liver or blood problems (jaundice);
• if you have a severe disorder of bone marrow function (bone marrow suppression) with significant changes in the number of white blood cells and platelets in the blood;
• if you have undergone major surgical procedures within 30 days prior to starting treatment;
• if you have an infection, especially if 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 taking Bendamustina Aurobindo

• If you have reduced ability of the bone marrow to regenerate blood cells. You must have your white blood cell and platelet counts checked before starting treatment with Bendamustina Aurobindo, before each subsequent treatment cycle, and during the intervals between treatment cycles.
• If you have an infection. You should contact your doctor if you experience symptoms of infection, including fever or respiratory symptoms.
• If you experience skin reactions during treatment with Bendamustina Aurobindo. The severity of skin reactions may increase.
• If you develop a painful red or purple 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 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 flank pain, blood in the urine, or reduced urine output. When your disease is very advanced, your body may be unable to eliminate waste products from destroyed tumor cells. This condition is called tumor lysis syndrome and may lead to kidney failure and heart problems within 48 hours after the first dose of Bendamustina Aurobindo. Your doctor may ensure you are adequately hydrated and may give you other medications to help prevent this condition.
• If you experience a severe allergic reaction or hypersensitivity reactions. Be alert for infusion-related reactions that occurred after your first treatment cycle.
• At any time during or after treatment, inform your doctor immediately if you or someone else notices: memory loss, difficulty thinking, difficulty walking, or loss of vision—these may be due to a very rare but serious brain infection that can be fatal (progressive multifocal leukoencephalopathy or PML).
• Contact your doctor if you notice any suspicious skin changes, as there may be an increased risk of certain types of skin cancer (non-melanoma skin cancer) with the use of this medicine.

Other medicines and Bendamustina Aurobindo
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
If Bendamustina Aurobindo is taken together with medicines that inhibit blood cell formation in the bone marrow, the effect on the bone marrow may be intensified.
If Bendamustina Aurobindo 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. In addition, cytostatic medicines increase the risk of infection after vaccination with live vaccines (e.g., antiviral vaccination).

Pregnancy, breastfeeding and fertility
If you are pregnant, think you may be pregnant, planning to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.

Pregnancy
Bendamustina Aurobindo can cause genetic damage and has caused malformations in animal studies. You must not use Bendamustina Aurobindo during pregnancy unless clearly indicated by your doctor. If treatment is necessary, you should discuss with your doctor the potential risk of adverse effects of your 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 Aurobindo. If you become pregnant during treatment with Bendamustina Aurobindo, you must inform your doctor immediately and seek genetic counselling.

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

Consult your doctor or pharmacist before taking any medicine.

Fertility
If you are a man, you should avoid fathering a child during treatment with Bendamustina Aurobindo and for up to 6 months after the end of treatment. There is a risk that treatment with Bendamustina Aurobindo may lead to infertility, and prior to starting treatment, you may benefit from counselling regarding sperm preservation.

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

3. How to take Bendamustina Aurobindo

Use this medicine exactly as instructed by your doctor or pharmacist. If you have
any doubts, consult your doctor or pharmacist.
Bendamustina Aurobindo 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 dropped 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 fall to certain levels. Treatment may be continued once white blood cell and platelet counts have recovered.

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

How it is administered
Treatment with Bendamustina Aurobindo must be performed only by physicians experienced in cancer therapy. Your doctor will administer the exact dose of Bendamustina Aurobindo, taking all necessary precautions.

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

Duration of treatment
There is generally no predefined time limit for treatment with Bendamustina Aurobindo. 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 Aurobindo, speak with your doctor or nurse.

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

If you stop treatment with Bendamustina Aurobindo
Your treating physician will usually 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 adverse reactions

Like all medicines, Bendamustina Aurobindo can cause adverse reactions, although not everybody gets them. Some of the effects listed below may be detected through tests performed by your doctor.
The following frequency definitions are used in evaluating adverse reactions:

Necrotic tissue (necrosis) has been very rarely observed following leakage of Bendamustina Aurobindo into surrounding tissue outside the blood vessels (extravasation). A burning sensation at the site where the infusion needle was inserted may be a sign of leakage from the blood vessels. As a result, pain and skin defects due to poor healing may occur.

The side effect of Bendamustina Aurobindo that limits its dosage is worsening of bone marrow function, which generally returns to normal after treatment. Suppression of bone marrow function may lead to a reduced blood cell count, which in turn could increase the risk of infections, anaemia, or an increased risk of bleeding.

Very common:

• Low number of white blood cells (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.
• Headache.
• Increased level of creatinine in the blood (a waste substance produced by your muscles).
• Increased level of urea 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 common type of white blood cell important for fighting infections).
• Hypersensitivity reactions such as skin allergic reactions (dermatitis), 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 breakdown of red blood cells).
• Low potassium levels in the blood (a nutrient necessary for nerve and muscle cell function, including those of your heart).
• Reduced heart function (dysfunction).
• Heart rhythm disturbances (arrhythmia).
• Low or high blood pressure (hypotension or hypertension).
• Lung function disorders.
• Diarrhoea.
• Constipation.
• Mouth pain (stomatitis).
• Loss of appetite.
• Hair loss.
• Skin changes.
• Absence of menstrual cycle (amenorrhoea).
• Pain.
• Insomnia.
• Chills.
• Dehydration.
• Dizziness.
• Itchy rash (urticaria).

Uncommon:

• Fluid accumulation in the pericardial sac (fluid leakage into the pericardial space).
• Reduced production of 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:

• Blood infection (sepsis).
• Severe allergic hypersensitivity reactions (anaphylactic reactions).
• Reduced bone marrow function, which may cause general malaise or show up in blood tests.
• Symptoms similar to anaphylactic reaction (anaphylactoid reactions).
• Drowsiness.
• Loss of voice (aphonia).
• Acute circulatory collapse (circulatory failure, primarily of cardiac origin, with inability to supply oxygen and other nutrients to tissues and remove toxins).
• Skin redness (erythema).
• Skin inflammation (dermatitis).
• Itching (pruritus).
• 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 with skin reaction and rash (anaphylactic shock).
• Taste disturbances.
• Changes in touch sensation (paraesthesia).
• Malaise and pain in limbs (peripheral neuropathy).
• Severe condition due to blockade of specific receptors in the nervous system.
• Disorders of the nervous system.
• Lack of coordination (ataxia).
• Brain inflammation (encephalitis).
• Increased heart rate (tachycardia).
• Vein inflammation (phlebitis).
• Tissue formation in the lungs (lung fibrosis).
• Haemorrhagic inflammation of the oesophagus (haemorrhagic oesophagitis).
• Bleeding from the stomach or intestine.
• Infertility.
• Multi-organ failure.

Not known:

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

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

Contact your doctor or seek immediate medical attention if you experience any of the following adverse effects (frequency not known):
Serious skin reactions including Stevens-Johnson Syndrome and toxic epidermal necrolysis. These may appear as reddish spots, 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 other organ involvement (drug reaction with eosinophilia and systemic symptoms, also known as DRESS or drug hypersensitivity syndrome).

Reporting of adverse reactions
If you experience any adverse reaction, including those not listed in this leaflet, consult your doctor or pharmacist. You may also report adverse reactions directly via the national reporting system at www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting adverse reactions, you can help provide more information on the safety of this medicine.

5. How to store Bendamustina Aurobindo

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 that month.
The vials may or may not be packaged in a protective plastic overwrap.
Notes on expiry date after opening or preparation of the solution
Chemical and physical in-use stability has been demonstrated for 3.5 hours at 25°C and up to 48 hours at 2–8°C in polyethylene bags.
From a microbiological standpoint, the solution should be used immediately.
If not used immediately, the storage times during use and the conditions prior to use are the responsibility of the user and normally should not exceed 24 hours at a temperature of 2–8°C, unless reconstitution/dilution 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 you no longer use. This will help protect the environment.

6. Package contents and other information

What Bendamustina Aurobindo 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.

Description of the appearance of Bendamustina Aurobindo and contents of the pack
Concentrate for solution for infusion (lyophilized powder).
White to off-white lyophilized powder.
Bendamustina Aurobindo is available in packs containing:
1, 5, 10 and 20 vials of 25 mg bendamustine hydrochloride.
1, 5 and 10 vials of 100 mg bendamustine hydrochloride.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Eugia Pharma (Malta) Limited
Vault 14, Level 2, Valletta Waterfront,
Floriana FRN 1914, Malta

Manufacturer
APL Swift Services (Malta) Ltd
HF26, Hal Far Industrial Estate,
Hal Far, Birzebbugia, BBG 3000
Malta
Generis Farmacêutica SA
Rua João de Deus, 19,
2700-487 Amadora
Portugal
Arrow Generiques
26 Avenue Tony Garnier, Lyon
France

This medicinal product is authorised in the European Economic Area (EEA) Member States under the following names:
Belgium: Bendamustine AB 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 Aurovitas
Portugal: Bendamustina Generis
Spain: Bendamustina Aurovitas 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 substances, strict safety precautions must be observed by nursing staff and physicians 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 Aurobindo (wear gloves, protective clothing, and possibly a face mask). If any part of the body becomes contaminated, wash thoroughly with soap and water, and rinse eyes with 0.9% saline (isotonic) solution. If possible, work should be performed on a suitable work surface (laminar flow hood) using a liquid-impermeable, disposable absorbent sheet. Contaminated materials are cytostatic waste. Please follow national guidelines for the disposal of cytostatic materials! Pregnant personnel must be excluded from working with cytotoxic agents.

The ready-to-use solution must be prepared by dissolving the contents of one vial of Bendamustina Aurobindo exclusively in water for injections, as follows:

1. Preparation of the concentrate

   • A vial of Bendamustina Aurobindo containing 25 mg of bendamustine hydrochloride is first dissolved in 10 ml, with gentle agitation of the solution.
   • A vial of Bendamustina Aurobindo containing 100 mg of bendamustine hydrochloride is first dissolved in 40 ml, with gentle agitation of the solution.

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

3. Administration
   The solution is administered by intravenous infusion over 30–60 minutes. Vials are for single use only. Unused product and waste material must be disposed of in accordance with local regulations.

Any accidental injection into tissue outside the blood vessels (extravascular injection) must be stopped immediately. 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 the use of corticosteroids, have not been shown to provide clear benefits (see section 4).