LEVACT 2.5 mg/ml POWDER FOR CONCENTRATE FOR INFUSION SOLUTION

Introduction

Package Leaflet: Information for the User

Levact 2.5mg/ml powder for concentrate for solution for infusion

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

1. What is Levact and what is it used for

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

Levact 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 suitable for you.
• non-Hodgkin's lymphoma, which has not responded, or has responded only for a short period, 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 Levact

Do not use Levact

• if you are allergic to bendamustine hydrochloride or any of the other ingredients of this medicine (listed in section 6);
• if you are breast-feeding, if you need to be treated with Levact during breast-feeding, you must stop breast-feeding (see section Warnings and precautions regarding breast-feeding);
• 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 (depression of the bone marrow) and severe alterations 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

Consult your doctor or pharmacist before starting treatment with Levact

• if your bone marrow's ability to produce blood cells is reduced. The number of white blood cells and platelets in your blood should be measured before starting treatment with Levact, before each treatment cycle, and in the intervals between cycles.
• if you have infections. If you have signs of infection, such as fever or respiratory symptoms, you should contact your doctor.
• At any time during or after treatment, inform 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).
• if you experience skin reactions during treatment with Levact. Skin reactions can increase in intensity.
• Contact your doctor if you detect 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).
• if you have widespread, painful, red or purple rashes and blisters and/or other lesions that start 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 heart disease (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 Levact. 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 be aware of infusion reactions after your first treatment cycle.

Using Levact with other medicines

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.

If Levact 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 Levact 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

Levact may cause genetic damage and has caused birth defects 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 your doctor to explain the risk of possible side effects of the treatment for your child. Genetic counseling is recommended.

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

Breast-feeding

Levact should not be administered during breast-feeding. If you need to be treated with Levact during breast-feeding, you must stop breast-feeding.

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

Fertility

Men treated with Levact 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 Levact may cause permanent infertility.

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

Driving and using machines

Levact has a major influence on the ability to drive and use machines. Do not drive or use machines if you experience side effects such as dizziness or lack of coordination.

3. How to use Levact

Follow exactly the instructions for administration of this medicine given by your doctor or pharmacist. If you are unsure, consult your doctor or pharmacist again.

Levact is administered 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 (leukocyte) and/or platelet count is below the determined levels.

Your doctor will measure these values periodically.

Chronic lymphocytic leukemia

Non-Hodgkin's lymphoma

Multiple myeloma

Treatment will be stopped if the white blood cell (leukocyte) and/or platelet count falls below the determined levels. Treatment can be resumed when the leukocyte and platelet count has increased.

Kidney or liver impairment

The dose may need to be adjusted according to the degree of liver function impairment (initial reduction of 30% in case of moderate liver impairment, in case of good tolerance your doctor may consider returning to the normal dose).

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

Levact can only be administered by doctors with experience in the treatment of tumors.

Your doctor will administer the exact dose of Levact and take the necessary precautions.

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

Duration of treatment

The duration of treatment with Levact has not been defined. The duration of treatment depends on the disease and the response to treatment.

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

If you miss a dose of Levact

If you miss a dose of Levact, your doctor will normally continue with the normal dosing schedule.

If you stop treatment with Levact

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, Levact can produce adverse effects, although not all people suffer from them. Some of the results listed below may be found after tests performed by your doctor.

To evaluate adverse effects, the following definitions are used, based on frequency:

In very rare cases, tissue degradation (necrosis) has been observed after extravasation of Levact in the tissue surrounding blood vessels (extravascular). If the product is extravasated outside a vessel, there may be a burning sensation at the needle insertion site. The consequences may be pain and skin healing problems.

The dose-limiting adverse effect of Levact is an alteration of bone marrow function, which usually normalizes. Suppression of bone marrow function may lead to a reduction in blood cell counts, which in turn may lead to an increased risk of infection, anemia, or an increased risk of bleeding.

Very frequent:

Frequent:

Rare:

Very rare:

Frequency not known:

• 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
• Medicamentous exanthema in combination therapy with rituximab
• Pneumonitis
• Bleeding from the lungs
• Excessive urination, even at night, and excessive thirst even after drinking fluids (nephrogenic diabetes insipidus)

There have been reports of tumors (myelodysplastic syndromes, acute myeloid leukemia, bronchial carcinoma) after treatment with Levact. A clear relationship with Levact could not be determined.

Consult your doctor or seek medical attention immediately if you notice any of the following adverse effects (frequency not known):

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

Widespread rash, high body temperature, swollen lymph nodes, and involvement of other body organs (drug reaction with eosinophilia and systemic symptoms, also known as DRESS or drug hypersensitivity syndrome).

If you consider any of the adverse effects you are experiencing to be serious or if you notice any adverse effect not mentioned in this prospectus, inform your doctor.

Reporting of Adverse Effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that does not appear in this prospectus. You can also report it directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Levact

Keep this medicine out of sight and reach of children.

Do not use this medicine after the expiration date shown on the label and packaging. The expiration date is the last day of the month indicated.

Store in the outer packaging to protect the contents from light

Check the validity period before opening or preparing the solution.

The correctly prepared infusion solutions according to the instructions listed at the end of this prospectus are stable in polyethylene bags at room temperature / 60% relative humidity for 3.5 hours and in the refrigerator for 2 days. Levact does not contain preservatives.

Therefore, the solution should not be used after these periods.

The user is responsible for maintaining aseptic conditions.

Medicines should not be thrown away through drains or into the trash. Deposit the packaging and medicines you no longer need at the SIGRE point in the pharmacy. If in doubt, ask your pharmacist how to dispose of packaging and medicines you no longer need. This will help protect the environment.

6. Package Contents and Additional Information

Composition of Levact

The active ingredient is bendamustine hydrochloride.

1 vial contains 25 mg of bendamustine hydrochloride

1 vial contains 100 mg of bendamustine hydrochloride

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

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

The powder is white and crystalline in appearance.

Levact is marketed in packages containing 5, 10, and 20 vials with 25 mg of bendamustine hydrochloride and 5 vials with 100 mg of bendamustine hydrochloride.

Only some package sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

pharmaand GmbH

Taborstrasse 1

1020 Vienna, Austria

Manufacturer

Magnalabs EOOD

Bogdana Street, Stopanski Dvor,

vlg. Bistrica 1443

District Sofia (capital)

Stolichna Municipality

Bulgaria

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

Laboratorios Farmacéuticos ROVI, S.A.

Julián Camarillo, 35

28037 Madrid, Spain

This prospectus was approved in July 2022

Detailed and updated information about this medicine is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS)

http://www.aemps.gob.es

This information is intended only for doctors or 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 (breathing) and contact with skin and mucous membranes when handling Levact (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% saline solution (isotonic). 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 should be prepared by dissolving the contents of a Levact vial exclusively in water for injections, as follows:

1. Preparation of the concentrate
   • First, dissolve a Levact vial containing 25 mg of bendamustine hydrochloride in 10 ml, shaking it.
   • First, dissolve a Levact vial 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 (after 5 to 10 minutes, usually), dissolve the total recommended dose of Levact in 0.9% saline solution (isotonic) to achieve a final volume of approximately 500 ml. Levact should not be dissolved with other infusion or injection solutions. Levact should not be mixed in infusion with other substances.

1. Administration

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

The vials are for single use.

Unused products or waste must be disposed of in accordance with local requirements.

If the product is unintentionally injected into the tissue surrounding blood vessels (extravascular injection), the infusion will be stopped immediately. The needle will be removed after brief aspiration. The affected tissue area will then be cooled. The arm will be elevated. It is not clear whether the use of additional treatments (such as corticosteroids) is beneficial (see section 4).