Label: information for the user

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

Bendamustine hydrochloride

Read this label carefully before starting to use this medication, because it contains important information for you.

• Keep this label, as you may need to read it again.
• If you have any doubts, consult your doctor or pharmacist.
• This medication has been prescribed only to you, and you must not give it to other people even if they have the same symptoms as you, as it may harm them.
• If you experience any adverse effects, consult your doctor or pharmacist, even if they are not listed in this label. See section 4.

1. What Levact is and for what it is used

2. What you need to know before starting touse Levact

3. How to use Levact

4. Possible adverse effects

5. Storage of Levact

6. Contents of the package and additional information

Levact is a medication used for the treatment of certain types of cancer (it is a cytotoxic medication).

Levact is used alone (monotherapy) or in combination with other medications for the treatment of the following types of cancer:

-chronic lymphocytic leukemia, if combination chemotherapy with fludarabine is not suitable for you.

-non-Hodgkin lymphomas that have not responded, or have only responded for a short period of time, after previous treatment with rituximab

-multiple myeloma, if high doses of chemotherapy and autologous stem cell transplantation or treatments containing thalidomide or bortezomib are not suitable for you.

No use Levact

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

-during breastfeeding, if you need treatment with Levact during breastfeeding, you must discontinue it (see section Advertencias and precautions on breastfeeding);

-if you have severe liver dysfunction (liver cell functional damage);

-if you have yellowing of the skin or the white of the eyes caused by liver or blood problems (jaundice);

-if you have a severe bone marrow disorder (bone marrow depression) and severe alterations in the number of white blood cells and platelets in the blood;

-if you have undergone major surgery within 30 days of starting treatment;

-if you have had an infection, especially if it has been accompanied by a reduction in the number of white blood cells (leucocytopenia);

-in combination with yellow fever vaccines.

Advertencias and precautions

Consult your doctor or pharmacist before starting to use Levact

-in case your bone marrow has reduced ability to replace blood cells. You must have your white blood cell and platelet count measured in the blood before starting treatment with Levact, before each treatment cycle, and between cycles.

-in case of infections. If you experience signs of infection, such as fever or respiratory symptoms, you must contact your doctor.

-At any time during or after treatment, immediately inform your doctor 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 severe 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 the skin, as the use of this medication may increase the risk of developing certain types of skin cancer (non-melanoma skin cancer).

-in case of widespread painful red or purple rashes and blisters and/or other lesions that appear on the mucous membrane (e.g., mouth and lips), particularly if you have had previous sensitivity to light, respiratory infections (e.g., bronchitis), and/or fever.

-if you have a heart disease (e.g., heart attack, chest pain, severe heart rhythm disorders).

-if you experience pain in the side or if you notice blood in the urine or that you urinate less. If your disease is very severe, your body may not be able to eliminate all the waste products of dying cancer cells. This is called tumor lysis syndrome and can cause kidney failure and heart problems within 48 hours after the first dose of Levact. Your doctor will ensure that you are adequately hydrated and will give you other medications to prevent this from happening.

-in case of severe allergic or hypersensitivity reactions, you must be aware of reactions to infusion after your first treatment cycle.

Use of Levact with other medications

Inform your doctor or pharmacist if you are taking, have taken recently, or may need to take any other medication.

If Levact is used in combination with medications that inhibit blood cell formation in the bone marrow, the effect on the bone marrow may be intensified.

If Levact is used in combination with medications that alter your immune response, this effect may be intensified.

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

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medication.

Pregnancy

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

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

Breastfeeding

Levact should not be administered during breastfeeding. If you need treatment with Levact during breastfeeding, you must discontinue it.

Consult your doctor or pharmacist before using any medication.

Fertility

Men treated with Levact are advised not to father children during treatment or for 6 months after treatment. Before starting treatment, you must be advised on sperm conservation, as there is a possibility that it may cause permanent infertility.

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

Driving and operating machinery

Levact has a significant influence on your ability to drive and operate machinery. Do not drive or operate machinery if you experience adverse effects such as dizziness or lack of coordination.

Follow exactly the administration instructions of this medication indicated by your doctor or pharmacist. In case of doubt, consult your doctor or pharmacist again.

Levact is administered through a vein for 30 to 60 minutes in various doses, either alone (monotherapy) or combined with other medications.

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

Your doctor will measure these values periodically.

Chronic Lymphocytic Leukemia

Non-Hodgkin Lymphomas

Multiple Myeloma

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

Renal or Hepatic Insufficiency

Dose adjustment may be necessary based on the degree of liver function deterioration (initial reduction of 30% in case of moderate liver deterioration, in case of good tolerance, your doctor may consider returning to the normal dose).

No dose adjustment is necessary in case of renal function alteration. Your doctor will decide if a dose adjustment is necessary.

How to Administer

Levact can only be administered by experienced doctors in tumor treatment.

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

Your doctor will administer the prepared solution for infusion. The solution is administered through a vein as a brief infusion for 30 to 60 minutes.

Treatment Duration

No specific treatment duration with Levact has been defined. Treatment duration depends on the disease and response to treatment.

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

If You Forget to Use Levact

If you forget a dose of Levact, your doctor will usually proceed with the normal dosing schedule.

If You Interrupt Levact Treatment

Your doctor will decide if treatment should be interrupted or a different preparation used.

If you have any other doubts about the use of this medication, ask your doctor or pharmacist.

Like all medicines, Levact can cause side effects, although not everyone will experience them. Some of the results listed below may be found after tests performed by your doctor.

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

In very rare cases, tissue degradation (necrosis) has been observed after Levact extravasation in the tissue surrounding blood vessels (extravascular). If the product leaks out of a vein, there may be a burning sensation at the site of the needle insertion. Consequences may include pain and skin healing problems.

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

Very common:

Common:

Uncommon:

• Accumulation of fluid in the sac surrounding the heart (pericardial effusion)
• Ineffective production of all blood cells in the bone marrow (spongy tissue inside bones where blood cells are generated)
• Acute leukemia
• Myocardial infarction, chest pain (heart attack)
• Heart failure

Rare:

• Decreased potassium blood level (nutrient necessary for nerve and muscle cell function, including heart cells)
• Cardiac function alteration (disfunction)
• Cardiac rhythm alteration (arrhythmia)
• Increased or decreased blood pressure (hypotension or hypertension)
• Pulmonary function alteration
• Diarrhea
• Constipation
• Mouth ulcers (stomatitis)
• Loss of appetite

• Hair loss
• Cutaneous alterations
• Amenorrhea (absence of menstruation)
• Pain
• Insomnia
• Chills
• Dehydration
• Dizziness
• Urticaria (hives)

• Blood infection (sepsis)
• Severe allergic and hypersensitivity reactions (anaphylactic reactions)
• Decreased bone marrow function, which may cause you to feel unwell or appear in your blood test results

• Signs similar to anaphylactic reactions (anaphylactoid reactions)
• Somnolence
• Loss of voice (aphonia)
• Acute circulatory failure (circulatory failure primarily of cardiac origin with inability to maintain oxygen and nutrient supply to tissues and toxin removal)

• Redness of the skin (erythema)
• Skin inflammation (dermatitis)
• Itching (pruritus)
• Maculopapular rash (exanthema)
• Excessive sweating (hyperhidrosis)

Very rare:

Unknown frequency:

• Liver failure
• Renal failure
• Irregular and often rapid heartbeats (atrial fibrillation)
• Widespread painful red or purple rash and blisters and/or other lesions that appear on mucous membranes (e.g., mouth and lips), particularly if you have had previous sensitivity to light, respiratory infections (e.g., bronchitis), and/or fever
• Medication-induced rash in combination therapy with rituximab
• Pneumonitis
• Pulmonary bleeding
• Excessive urination, even at night, and excessive thirst, even after drinking liquids (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 immediate medical attention if you notice any of the following side effects (unknown frequency):

Severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. These may appear as red spots resembling a bullseye, or circular patches often with central blisters on the torso, skin peeling, mouth ulcers, throat, nose, genital, and eye involvement, 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 side effects you are experiencing to be severe or if you notice any side effects not mentioned in this prospectus, inform your doctor.

Reporting of adverse reactions

If you experience any type of adverse reaction, consult your doctoror pharmacist, even if it is a possible adverse reaction not listed in this prospectus. You can also report them directly through theSpanish System for Pharmacovigilance of Medicinal Products for Human Use:www.notificaRAM.es. By reporting adverse reactions, you can contribute to providing more information on the safety of this medication.

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

Do not use this medication after the expiration date that appears on the label and on the 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.

Solutions for infusions correctly prepared according to the instructions listed at the end of this leaflet 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 deadlines.

The user is responsible for maintaining aseptic conditions.

Medicines should not be disposed of through the drains or in the trash. Deposit the containers and medicines that you do not need in the SIGRE collection point at the pharmacy. If in doubt, ask your pharmacist how to dispose of the containers and medicines that you do not need. In this way, you will help protect the environment.

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 contents of the package

Glass vials of brown color with rubber stopper and aluminum flip-off 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 Responsible for Manufacturing

Marketing Authorization Holder

pharmaand GmbH

Taborstrasse 1

1020 Vienna, Austria

Responsible for Manufacturing

Magnalabs EOOD

Bogdana Street, Stopanski Dvor,

vlg. Bistrica 1443

District Sofia (capital)

Stolichna Municipality

Bulgaria

For more information about this medication, please contact the local representative of the marketing authorization holder:

Laboratorios Farmacéuticos ROVI, S.A.

Julián Camarillo, 35

28037 Madrid, Spain

This leaflet was approved in July 2022

For detailed and updated information about this medication, please visit the website of the Spanish Agency for Medicines and Medical Devices (AEMPS)

This information is intended solely for medical professionals:

As with all similar cytotoxics, healthcare personnel and doctors must exercise extreme caution due to the potential genotoxicity and carcinogenicity of the preparation. Avoid inhalation (respiration) and contact with the skin and mucous membranes while 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, work on a special safety workbench (laminar flow) with a disposable, impermeable to liquids, absorbent sheet. Contaminated items are cytostatic waste. Please follow national guidelines for the disposal of cytostatic material! Pregnant women should not work with cytotoxics.

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

1. Concentrate preparation

• First, dissolve a vial of Levact containing 25 mg of bendamustine hydrochloride in 10 ml, agitating it.
• First, dissolve a vial of Levact containing 100 mg of bendamustine hydrochloride in 40 ml, agitating it.

2. Preparation of the perfusion solution

Once a clear solution is obtained (usually within 5 to 10 minutes), 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 perfusion or injection solutions. Levact should not be mixed with other substances in perfusion.

3. Administration

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

The vials are for single use only.

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

If the product is accidentally injected into the tissue surrounding blood vessels (extravasation), stop the infusion immediately. Remove the needle after a brief aspiration. Then, cool the affected tissue area. Elevate the arm. It is unclear whether the use of additional treatments (such as corticosteroids) is beneficial (see section 4).