BENDAMUSTINE HIKMA 2.5 mg/ml POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the User

Bendamustina Hikma 2.5 mg/ml powder for concentrate for solution for infusion EFG

Bendamustine hydrochloride

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 further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

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

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

Bendamustina Hikma is a medicine used to treat certain types of cancer (it is a cytotoxic medicine).

This medicine is used alone (monotherapy) or in combination with other medicines to treat the following types of cancer:

• chronic lymphocytic leukemia, if combination chemotherapy with fludarabine is not appropriate for you,
• non-Hodgkin lymphomas, which have not responded or have responded for only a short period of time to previous treatment with rituximab,
• multiple myeloma, if high-dose chemotherapy and autologous stem cell transplantation or treatments containing thalidomide or bortezomib are not suitable for you

2. What you need to know before you use Bendamustina Hikma

Do not use Bendamustina Hikma

if you are allergic to bendamustine hydrochloride or any of the other ingredients of this medicine (listed in section 6).

• during breast-feeding; if treatment with this medicine is necessary during breast-feeding, breast-feeding must be discontinued (see section pregnancy, breast-feeding and fertility).
• if you have severe liver dysfunction (damage to the functional cells of the liver).
• if you have yellowing of the skin or the whites of the eyes, caused by liver or blood problems (jaundice).
• if you have a severe disorder of bone marrow function (bone marrow depression) and severe changes in the number of white blood cells and platelets in the blood.
• if you have undergone major surgery in the 30 days prior to the start of treatment.
• if you have had any infection, especially if it has been accompanied by a reduction in the number of white blood cells (leucopenia).
• in combination with yellow fever vaccines.

Warnings and precautions

At any time during or after treatment, tell your doctor immediately if you notice or someone notices in you: memory loss, cognitive difficulties, difficulty walking or vision loss. These symptoms may be due to a rare but serious brain infection that can be fatal (progressive multifocal leukoencephalopathy or PML).

Contact your doctor if you notice any suspicious changes in your skin, as the use of this medicine may increase the risk of certain types of skin cancer (non-melanoma skin cancer).

Consult your doctor or nurse before starting treatment with this medicine

• if your bone marrow's ability to produce blood cells has been reduced. The number of white blood cells and platelets in your blood must be measured before starting treatment with this medicine, before each treatment cycle, and in the intervals between cycles.

• in case of infections. If you have signs of infection, such as fever or respiratory symptoms, you should contact your doctor.
• if you experience skin reactions during treatment with bendamustine. Reactions can increase in intensity.
• in case of widespread painful red or purple rashes and blisters and/or other lesions that begin to appear on the mucous membranes (e.g. mouth and lips), particularly if you have previously had sensitivity to light, respiratory infections (e.g. bronchitis) and/or fever.
• if you have a heart condition (e.g. heart attack, chest pain, severe heart rhythm disorders).
• if you experience pain in your side or if you notice blood in your urine or that you urinate less. If your disease is very severe, it is possible that your body may not be able to eliminate all the waste products of the dying cancer cells. This is called tumor lysis syndrome and can cause kidney failure and heart problems in the 48 hours following the administration of the first dose of this medicine. Your doctor will ensure that you are adequately hydrated and will give you other medicines to prevent this from happening.
• in case of severe allergic or hypersensitivity reactions. You should pay attention to infusion reactions after your first cycle of treatment.

Using Bendamustina Hikma with other medicines

Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines.

If this medicine is used in combination with medicines that inhibit blood cell production in the bone marrow, the effect on the bone marrow may be increased.

If this medicine is used in combination with medicines that alter your immune response, this effect may be increased.

Cytostatics may reduce the effectiveness of live virus vaccines. Additionally, cytostatics increase the risk of infection after vaccination with live virus vaccines (e.g. viral vaccination).

Pregnancy, breast-feeding, and fertility

If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

Pregnancy

This medicine may cause genetic damage and has caused malformations in animal studies. It should not be used during pregnancy unless your doctor considers it clearly necessary. If you receive this treatment, you should ask a doctor to explain the risk of possible side effects of the treatment for your child, and genetic counseling is recommended.

If you are a woman of childbearing age, you must use effective contraceptive measures before and during treatment with this medicine. If you become pregnant during treatment with this medicine, you should inform your doctor immediately and seek genetic counseling.

Breast-feeding

This medicine must not be used during breast-feeding. If treatment with bendamustine is necessary during breast-feeding, breast-feeding must be discontinued.

Consult your doctor before starting to use any medicine .

Fertility

Men treated with this medicine are advised not to father a child during treatment and for up to 6 months after treatment. Before starting treatment, you should be advised on the conservation of sperm, as there is a possibility that it may cause permanent infertility.

If you are a man, you should not father a child during treatment with this medicine and for up to 6 months after treatment. There is a risk that treatment with this medicine may cause infertility; you may want to seek advice on the conservation of sperm before starting treatment.

Driving and using machines

The influence of this medicine on the ability to drive and use machines is important. Do not drive or use machines if you experience side effects such as dizziness or lack of coordination.

3. How to use Bendamustina Hikma

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

This medicine is given into a vein over 30 to 60 minutes in various doses, either alone (monotherapy) or in combination with other medicines.

You will not be able to start treatment if your white blood cell count (leukocytes) and/or platelet count is below certain levels.

Your doctor will measure these values periodically.

Chronic lymphocytic leukemia

Non-Hodgkin lymphoma

Multiple myeloma

Treatment will be stopped if the white blood cell count (leukocytes) and/or platelet count is below certain levels. Treatment may be restarted when the white blood cell and platelet counts have increased.

Kidney or liver impairment

The dose may need to be adjusted according to the degree of liver function impairment (by 30% in case of moderate liver impairment). No dose adjustment is necessary in case of kidney function impairment. Your doctor will decide if a dose adjustment is necessary.

How it is administered

This medicine can only be administered by doctors with experience in the treatment of tumors. Your doctor will administer the exact dose of bendamustine and take the necessary precautions.

Your doctor will administer the solution for infusion after preparation as prescribed. The solution is administered into a vein as a short infusion over 30 to 60 minutes.

Duration of treatment

No specific duration of treatment with this medicine has been defined. The duration of treatment depends on the disease and response to treatment.

If you are concerned about anything or have any questions about treatment with this medicine, talk to your doctor or nurse.

If you miss a dose of Bendamustina Hikma

If you miss a dose of this medicine, your doctor will normally continue with the normal dosage regimen.

If you stop treatment with Bendamustina Hikma

Your doctor will decide whether to stop treatment or use a different preparation.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them. Some of the results listed below may be found after tests performed by your doctor:

The following frequencies are used to evaluate adverse reactions:

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

Unknown: the frequency cannot be estimated from the available data

In very rare cases, tissue alterations (necrosis) have been observed after unintentional injection into the tissue surrounding blood vessels (extravascular). A burning sensation at the needle insertion site may be a sign of administration outside the vessel. The consequences of administration in this way can be pain and skin defects with poor healing.

The dose-limiting adverse effect of this medicine is an alteration of bone marrow function, which usually normalizes once treatment is completed. Bone marrow function suppression can cause low blood cell counts, which in turn can increase the risk of infection, anemia, or a higher risk of bleeding.

Very common adverse effects

• reduction of white blood cell count (blood defenses)
• reduction of red blood cell pigment (hemoglobin: a protein in red blood cells that transports oxygen throughout the body)
• reduction of platelet count (colorless blood cells that collaborate in blood coagulation)
• infections
• nausea
• vomiting
• mucosal inflammation
• headache
• increase in blood creatinine concentration (a chemical waste product produced by your muscles)
• increase in blood urea concentration (a waste chemical product)
• fever
• fatigue

Common adverse effects

• bleeding (hemorrhage)
• metabolic disorder caused by the release of the contents of dying cancer cells into the bloodstream
• decrease in red blood cells, which can cause pale skin and weakness or difficulty breathing (anemia)
• reduction of neutrophil count (a type of white blood cell important for defending against infections)
• hypersensitivity reactions, such as allergic skin inflammation (dermatitis) or hives
• elevation of liver enzymes AST/ALT (which can indicate inflammation or damage to liver cells)
• increase in alkaline phosphatase enzyme (an enzyme mainly produced in the liver and bones)
• increase in bile pigment (a substance generated during the normal degradation of red blood cells)
• decrease in blood potassium level (a nutrient necessary for the functioning of nerve and muscle cells, including those of the heart)
• cardiac function disorder
• heart rhythm disorder (arrhythmia)
• elevation or decrease in blood pressure (hypotension or hypertension)
• pulmonary function disorder
• diarrhea
• constipation
• mouth ulcers (stomatitis)
• loss of appetite
• hair loss
• skin disorders
• absence of menstruation (amenorrhea)
• pain
• insomnia
• chills
• dehydration
• dizziness
• skin rash with itching (urticaria)

Uncommon adverse effects

• fluid accumulation in the sac surrounding the heart (fluid leak into the pericardial space)

• ineffective production of all blood cells (myelodysplastic syndrome)
• acute leukemia

• heart attack, chest pain (myocardial infarction)
• heart failure

Rare adverse effects

• blood infection (sepsis)
• severe allergic and hypersensitivity reactions (anaphylactic reactions)
• signs similar to anaphylactic reactions (anaphylactoid reactions)
• drowsiness
• loss of voice (aphonia)
• acute circulatory failure (failure of blood circulation mainly of cardiac origin with failure to maintain oxygen and nutrient supply to tissues and elimination of toxins)
• skin redness (erythema)
• skin inflammation (dermatitis)
• itching (pruritus)
• skin rash (maculopapular exanthema)
• excessive sweating (hyperhidrosis)

Very rare adverse effects

• atypical primary inflammation of the lungs (pneumonia)
• destruction of red blood cells
• rapid drop in blood pressure, sometimes with skin reactions or rashes (anaphylactic shock)
• alteration of taste
• alteration of sensitivity (paresthesias)
• weakness and pain in the limbs (peripheral neuropathy)
• inhibition of the physiological action of acetylcholine, especially as a neurotransmitter (Anticholinergic Syndrome)
• nervous system diseases
• neurological disorders
• lack of coordination (ataxia)
• brain inflammation (encephalitis)
• increase in heart rate (tachycardia)
• vein inflammation (phlebitis)
• tissue formation in the lungs (pulmonary fibrosis)
• hemorrhagic inflammation of the esophagus (hemorrhagic esophagitis)
• gastric or intestinal bleeding
• infertility
• multi-organ failure

Adverse effects of unknown frequency

• liver failure

• kidney failure
• irregular and often rapid heartbeats (atrial fibrillation)

• widespread painful red or purple rashes and blisters and/or other lesions that begin to appear on the mucous membrane (e.g., mouth and lips), particularly if there has been previous sensitivity to light, respiratory infections (e.g., bronchitis), and/or fever
• drug rash in combination therapy with rituximab
• pneumonitis
• bleeding from the lungs

There have been reports of secondary tumors (myelodysplastic syndromes, AML, bronchial carcinoma) after treatment with this medicine. A clear relationship with this medicine could not be determined.

Contact your doctor or seek medical attention immediately if you experience any of the following adverse effects (unknown frequency):

Severe skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis. These can appear as red, target-like patches or spots, often with central blisters on the trunk, peeling, mouth ulcers, throat, nose, genitals, and eyes, which can be preceded by fever and flu-like symptoms.

Widespread rash, high body temperature, enlarged lymph nodes, and other organ disorders (Drug Reaction with Eosinophilia and Systemic Symptoms, also known as DRESS or drug hypersensitivity syndrome).

If any of the adverse effects worsen, or if you notice any adverse effect not included in this prospectus, please inform your doctor.

Reporting of adverse effects

If you experience any other type of adverse effect, consult your doctor or nurse, even if it is a possible adverse effect that does not appear in this prospectus. You can also report them directly to www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Bendamustina Hikma

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiration date that appears on the label and on the box after CAD. The expiration date is the last day of the month indicated.

Store below 25 °C. Keep the vial in the outer packaging to protect the contents from light.

Note on the validity period after opening or preparation of the solution

Infusion solution

After reconstitution and dilution, the chemical and physical stability has been demonstrated for 3.5 hours at 25°/60% HR and 2 days at 2°C to 8°C in polyethylene bags.

From a microbiological point of view, the solution must be used immediately. Otherwise, the storage times and conditions before use are the responsibility of the user and will not normally exceed 24 hours at 2 °C – 8 °C, unless the reconstitution/dilution takes place in validated and controlled aseptic conditions.

The user is responsible for maintaining aseptic conditions.

6. Package Contents and Additional Information

Composition of Bendamustina Hikma

The active ingredient is bendamustine hydrochloride.

1 vial contains 25 mg or 100 mg of bendamustine hydrochloride (as bendamustine hydrochloride monohydrate).

After reconstitution, 1 ml of concentrate contains 2.5 mg of bendamustine hydrochloride.

The other component is mannitol.

Appearance of the Product and Package Contents

Ambber glass vials with rubber stopper and aluminum flip-off cap.

White and crystalline powder.

This medicine is available in packages containing 1 or 5 vials.

Only some package sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Hikma Farmacêutica (Portugal), S.A.

Estrada do Rio da Mó, 8 - Terrugem

2705-906 Sintra

Portugal

Manufacturer

Thymoorgan GmbH Pharmazie

Schiffgraben, 23

38690 Goslar

Germany

You can request more information about this medicine by contacting the local representative of the marketing authorization holder:

Hikma España, S.L.U.

Calle Anabel Segura nº11, Edificio A, planta 1ª, oficina 2

28108 - Alcobendas, Madrid

Spain

Date of the last revision of this prospectus: December 2020.

Detailed information about this medicine is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) www.aemps.gob.es

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This information is intended only for healthcare professionals:

As with all similar cytotoxics, nursing staff and doctors must take extreme safety precautions due to the potential genotoxic and carcinogenic effects of the preparation. Avoid inhalation (inhalation) and contact with the skin and mucous membranes when handling this medicine (wear gloves, protective clothing, and, if possible, a mask!). If any part of the body is contaminated, clean it carefully with water and soap, and rinse the eyes with 0.9% isotonic saline solution. If possible, it is recommended to work on a special safety bench (laminar flow) with a disposable, liquid-impermeable absorbent sheet. Contaminated items are cytostatic waste. Please follow national guidelines for the disposal of cytostatic material! Pregnant women on the staff should not work with cytostatics.

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

1. Preparation of the concentrate
   • First, dissolve a vial of this medicine containing 25 mg of bendamustine hydrochloride in 10 ml, shaking it.
   • First, dissolve a vial of this medicine containing 100 mg of bendamustine hydrochloride in 40 ml, shaking it.

1. Preparation of the infusion solution

As soon as a clear solution is obtained, dissolve the total recommended dose of this medicine in 0.9% isotonic saline solution to achieve a final volume of approximately 500 ml. This medicine should not be dissolved with other infusion or injection solutions. This medicine should not be mixed in infusion with other substances.

1. Administration

The solution will be administered by intravenous infusion for 30-60 minutes.

The vials are for single use.

Any remaining product in the vial or material must be discarded according to local regulations.

If extravasation occurs, the injection should be stopped immediately. The needle will be removed after brief aspiration. Then, the affected tissue area will be cooled. The arm will be elevated. It is not clear whether additional treatment, such as the use of corticosteroids, is beneficial (see section 4).