BUSULFAN ZENTIVA 6 mg/ml CONCENTRATE FOR INFUSION SOLUTION

Introduction

Package Leaflet: Information for the User

Busulfan Zentiva 6 mg/ml concentrate for solution for infusion EFG

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, pharmacist, or nurse.
• If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. See section 4.

Contents of the pack

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

1. What Busulfan Zentiva is and what it is used for

Busulfan Zentiva contains the active substance busulfan, which belongs to a group of medicines called alkylating agents. Busulfan Zentiva destroys the original bone marrow before the transplant.

Busulfan Zentiva is used in adults, newborns, children, and adolescents as pre-treatment before transplant.

In adults, Busulfan Zentiva is used in combination with cyclophosphamide or fludarabine.

In newborns, children, and adolescents, Busulfan Zentiva is used in combination with cyclophosphamide or melphalan.

This medicine will be given to you to prepare you before receiving a bone marrow or hematopoietic stem cell transplant.

2. What you need to know before you use Busulfan Zentiva

Do not use Busulfan Zentiva:

• if you are allergic to busulfan or any of the other ingredients of this medicine (listed in section 6),
• if you are pregnant or think you may be pregnant.

Warnings and precautions

Busulfan Zentiva is a potent cytotoxic medicine that causes a significant decrease in blood cell counts. At the recommended dose, this is the desired effect. For this reason, strict monitoring is required. There is a possibility that the use of Busulfan Zentiva may increase the risk of developing another malignant tumor in the future. You should inform your doctor:

• if you have a liver, kidney, heart, or lung problem,
• if you have a history of seizures,
• if you are currently taking other medicines.

Blood clots may form in small blood vessels after hematopoietic stem cell transplantation (HSCT) with high doses of your treatment in combination with other medicines.

Other medicines and Busulfan Zentiva

Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines, including those obtained without a prescription. Busulfan Zentiva may interact with other medicines.

Especially, inform your doctor or pharmacist if you are taking one of these medicines:

• Deferasirox (a medicine used to remove excess iron from the body).

You should be careful if you are using itraconazole and metronidazole (used to treat certain types of infections) or cetobemidone (used to treat pain), as it may increase the occurrence of side effects.

The use of paracetamol during the 72 hours prior to or during the administration of Busulfan Zentiva should be done with caution.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor before receiving treatment with Busulfan Zentiva. Women should not be pregnant during treatment with Busulfan Zentiva or in the 6 months following treatment.

Women should stop breastfeeding before starting treatment with Busulfan Zentiva.

Effective contraceptive methods should be used when one of the partners is being treated with Busulfan Zentiva.

It is possible that you may not be able to become pregnant (infertility) after treatment with Busulfan Zentiva. If you wish to have children, you should consult your doctor before treatment. Busulfan Zentiva may also cause symptoms of menopause and in pre-adolescent girls may prevent the onset of puberty.

Men treated with Busulfan Zentiva should not father children during and up to 6 months after completing treatment.

3. How to use Busulfan Zentiva

Dose and administration:

The dose of Busulfan Zentiva will be calculated based on your body weight.

In adults:

Busulfan Zentiva in combination with cyclophosphamide:

• The recommended dose of Busulfan Zentiva is 0.8 mg/kg
• Each infusion will last 2 hours
• Busulfan Zentiva will be administered every 6 hours for 4 consecutive days before the transplant.

Busulfan Zentiva in combination with fludarabine:

• The recommended dose of Busulfan Zentiva is 3.2 mg/kg
• Each infusion will last 3 hours
• Busulfan Zentiva will be administered once a day for 2 or 3 consecutive days before the transplant.

In newborns, children, and adolescents (from 0 to 17 years):

The recommended dose of Busulfan Zentiva in combination with cyclophosphamide or melphalan depends on your body weight and ranges from 0.8 to 1.2 mg/kg.

• Each infusion will last 2 hours.
• Busulfan Zentiva will be administered every 6 hours for 4 consecutive days before the transplant.

Medicines before administration of Busulfan Zentiva:

Before receiving Busulfan Zentiva, you will be treated with:

• anticonvulsant medicines to prevent seizures (phenytoin or benzodiazepines) and
• antiemetic medicines to prevent vomiting.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Serious side effects

The most serious side effects associated with treatment with Busulfan Zentiva or the transplant procedure may include a decrease in the number of circulating blood cells (an effect that is intended with the medicine to prepare you for the transplant), infections, liver disorders such as obstruction of a liver vein, graft-versus-host disease (the graft reacts against your body), and pulmonary complications. Your doctor will regularly monitor your blood counts and liver enzymes to detect and treat these effects.

Other side effects may include:

Very common (may affect more than 1 in 10 people):

• decrease in the number of blood cells (red and white) and platelets,
• infections,
• insomnia, anxiety, dizziness, and depression,
• loss of appetite, decrease in magnesium, calcium, potassium, phosphate, and albumin levels in the blood, and increase in blood sugar levels,
• increased heart rate, increased or decreased blood pressure, vasodilation (widening of blood vessels), blood clot formation,
• difficulty breathing, nasal secretion (rhinitis), sore throat, cough, hiccups, nosebleeds, abnormal breathing sounds,
• nausea, inflammation of the mouth mucosa, vomiting, abdominal pain, diarrhea, constipation, chest burning, anal discomfort, fluid in the abdomen,
• enlargement of the liver, jaundice (yellowing of the skin or whites of the eyes), obstruction of a liver vein,
• rash, itching, hair loss,
• back pain, muscle and jaw pain,
• increase in the elimination of a chemical waste product, creatinine, which passes through the kidneys to be filtered and eliminated in the urine (creatinine clearance), discomfort while urinating, and decrease in urine production and blood in urine,
• fever, headache, weakness, chills, pain, allergic reactions, edema (fluid retention), pain or inflammation at the injection site, chest pain, mucosal inflammation,
• elevated liver enzymes and weight gain,
• intestinal paralysis.

Common (may affect up to 1 in 10 people):

• confusion, nervous system disorders,
• low sodium levels in the blood,
• changes and abnormalities in heart rhythm, fluid retention or inflammation around the heart, decrease in the amount of blood pumped by the heart into the circulatory system (cardiac output),
• increased respiratory rate, respiratory failure, bleeding from the air sacs in the lungs (alveolar hemorrhage), asthma, collapse of small areas of the lung, fluid around the lung,
• inflammation of the esophagus mucosa, intestinal paralysis (no intestinal movement), vomiting blood,
• skin discoloration disorders, skin redness, skin peeling,
• increase in the amount of nitrogenous components in the blood, moderate kidney failure, kidney disorder.

Uncommon (may affect up to 1 in 100 people):

• delirium (severe confusion), nervousness, hallucinations (seeing things that are not real), agitation (anxiety or nervousness), abnormal brain function, cerebral hemorrhage, and seizures,
• clots in the thigh artery (femoral artery), extra heartbeats, decreased heart rate, diffuse dripping of fluid from the capillaries (small blood vessels),
• decrease in oxygen levels in the blood,
• bleeding from the stomach and/or intestine.

Frequency not known (cannot be estimated from the available data)

• sexual dysfunction,
• eye disorders including cataract (clouding of the lens) and blurred vision (corneal thinning),
• symptoms of menopause and female infertility.
• brain abscesses, skin inflammation, generalized infection,
• liver disorders,
• increase in lactate dehydrogenase enzyme in the blood,
• increase in uric acid and urea in the blood,
• incomplete dental development,
• increase in blood pressure in the pulmonary blood vessels (pulmonary hypertension).

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist, even if they are not listed in this leaflet. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Busulfan Zentiva

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

Do not use this medicine after the expiry date which is stated on the carton and label of the vial after EXP. The expiry date is the last day of the month stated.

Unopened vial:

Store in a refrigerator (2 °C - 8 °C).

Diluted solution:

The chemical and physical stability during use after dilution with a 5% glucose solution or 9 mg/ml (0.9%) sodium chloride solution is 8 hours (including infusion time) if stored at 20 °C ± 5 °C or 6 hours after dilution in a 9 mg/ml (0.9%) sodium chloride solution if the solution is stored between 2 °C and 8 °C followed by 3 additional hours of storage at 20 °C ± 5 °C (including infusion time).

Do not freeze.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Container Content and Additional Information

Composition of Busulfan Zentiva

• The active ingredient is busulfan. One ml of concentrate contains 6 mg of busulfan (60 mg of busulfan in the vial). After dissolution: one ml of solution contains approximately 0.5 mg of busulfan
• The other components are N,N-dimethylacetamide, macrogol 400, and anhydrous citric acid.

Appearance of the Product and Container Content

Busulfan Zentiva is a concentrate for solution for infusion that is supplied in transparent glass vials. Each vial contains 60 mg of busulfan.

Busulfan Zentiva is available in individual packaging with 1 vial or in multiple packaging containing 8 vials.

When diluted, Busulfan Zentiva yields a clear and colorless solution.

Vials with or without a retractable plastic wrapper with a protective base (disk). The retractable wrapper does not come into contact with the product and provides additional protection during transport. Additionally, it improves the safe handling of the product by healthcare professionals.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Zentiva k.s.,

U kabelovny 130,

Prague 10 – Dolní Mecholupy,

102 37 Czech Republic

Manufacturer

SGS Pharma Magyarorszag Kft.

Derkovits Gyula Utca 53,

Budapest XIX,1193,

Hungary

Tillomed Malta Limited

Malta Life Sciences Park,

LS2.01.06 Industrial Estate,

San Gwann, SGN 3000, Malta

You can request more information about this medication by contacting the local representative of the Marketing Authorization Holder:

Zentiva Spain S.L.U.

Avenida de Europa, 19, Edificio 3, Planta 1.

28224 Pozuelo de Alarcón, Madrid

Spain

This medication is authorized in the Member States of the European Economic Area and the United Kingdom (Northern Ireland) with the following names:

United Kingdom (Northern Ireland): Busulfan Tillomed 6mg/ml concentrate for Solution for Infusion

France: Busulfan Tillomed 6mg/ml solution à diluer pour perfusion

Italy: Busulfan Tillomed

Germany: Busulfan Tillomed 6mg/ml Konzentrat zur Herstellung einer Infusionslösung

Spain: Busulfano Zentiva 6mg/ml concentrado para solución para perfusión EFG

Poland: Busulfan Zentiva

Date of the Last Revision of this Prospectus:July 2025

Other Sources of Information

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

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This information is intended only for healthcare professionals:

PREPARATION GUIDE

Busulfan Zentiva 6 mg/ml concentrate for solution for infusion EFG

Busulfan

Read this guide before preparing and administering Busulfan Zentiva.

1. PRESENTATION

Busulfan Zentiva is presented as a clear and colorless solution in 10 ml type I glass vials.

Busulfan Zentiva must be diluted before administration.

1. RECOMMENDATIONS FOR SAFE HANDLING

Adequate handling and disposal procedures for anticancer medications must be taken into account.

All transfer procedures require strict compliance with aseptic techniques; preferably, a safety cabinet with vertical laminar flow should be used.

As with other cytotoxic compounds, caution should be exercised when handling or preparing the Busulfan Zentiva solution:

• It is recommended to use gloves and protective clothing.
• If the product (Busulfan Zentiva or a solution of it) comes into contact with the skin or mucous membranes, wash the area immediately and abundantly with water.

Calculation of the amount of Busulfan Zentiva and diluent for the solution

Before using the Busulfan Zentiva specialty, it is necessary to dilute the product with injectable sodium chloride solution 9 mg/ml (0.9%) or with injectable glucose solution 5%.

The amount of diluent must be equal to 10 times the volume of Busulfan Zentiva, ensuring that the final concentration of busulfan is approximately 0.5 mg/ml.

The amount of Busulfan Zentiva and diluent for administration will be calculated as follows:

For a patient with a body weight of Y kg:

• Amount of Busulfan Zentiva:

Y: patient's body weight (in kg)

D: dose of Busulfan Zentiva (see section 4.2)

• Amount of diluent:

To prepare the final infusion solution, (A) ml of Busulfan Zentiva are added to (B) ml of diluent (injectable sodium chloride solution 9 mg/ml (0.9%) or injectable glucose solution 5%).

Preparation of the infusion solution

Busulfan Zentiva must be prepared by healthcare professionals using sterile transfer techniques.

• A non-polycarbonate syringe with a needle should be used:

• the calculated volume of Busulfan Zentiva should be withdrawn from the vial.

• the contents of the syringe should be introduced into a bag (or syringe) for injection that already contains the calculated amount of the chosen diluent. Busulfan Zentiva should always be added to the diluent, not the other way around. Busulfan Zentiva should not be introduced into an infusion bag that does not contain the injectable sodium chloride solution 9 mg/ml (0.9%) or the injectable glucose solution 5%.

• The diluted solution should be carefully mixed by several inversions.

After dilution, 1 ml of infusion solution contains 0.5 mg of busulfan.

After dilution, Busulfan Zentiva is a clear and colorless solution.

Instructions for use

Before and after each infusion, the catheterization circuit should be flushed with approximately 5 ml of injectable sodium chloride solution 9 mg/ml (0.9%) or glucose solution (5%).

Residual medication should not be administered through the administration system, as rapid injection of busulfan has not been studied and is not recommended.

The total dose of Busulfan Zentiva prescribed should be administered over a period of two or three hours, depending on the conditioning regimen.

Small volumes should be administered over 2 hours using an electronic syringe pump. In this case, it is recommended to use an infusion device with a minimum dead space (e.g., 0.3-0.6 ml). Flush with the medication solution before infusing Busulfan Zentiva and then wash with injectable sodium chloride solution 9 mg/ml (0.9%) or injectable glucose solution (5%).

No other intravenous solution should be administered concomitantly with this infusion.

Polycarbonate syringes should not be used with Busulfan Zentiva.

Single-use product. Only clear, particle-free solutions should be used.

Storage Conditions

Closed vials:

Store in a refrigerator (2°C - 8°C).

Diluted solution:

It has been confirmed that the chemical and physical stability during use after dilution with a 5% glucose solution or 9 mg/ml (0.9%) sodium chloride solution is 8 hours (including infusion time) if stored at 20 °C ± 5 °C or 6 hours after dilution in 9 mg/ml (0.9%) sodium chloride solution if the solution is stored between 2 °C and 8 °C plus an additional 3 hours at 20 °C ± 5 °C (including infusion time).

From a microbiological point of view, the product should be used immediately after dilution. If not used immediately, the storage times during use and the conditions prior to use are the responsibility of the user.

1. PROCEDURE FOR PROPER DISPOSAL

Disposal of unused medication and all materials that have come into contact with it will be carried out in accordance with local regulations regarding the disposal of cytotoxic medications.