Leaflet: information for the user

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

Read this leaflet carefully before you start using this medicine, because it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, consult your doctor, pharmacist or nurse.
• If you experience any side effects, consult your doctor, pharmacist or nurse, even if they are not listed in this leaflet. See section 4.

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

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

3. How to use Busulfan Zentiva

4. Possible side effects

5. Storage of Busulfan Zentiva

6. Contents of the pack and additional information

Busulfano Zentiva contains the active ingredient busulfan, which belongs to a group of medicines called alkylating agents. Busulfano Zentiva destroys the original bone marrow before transplantation.

Busulfano Zentiva is used in adults, newborns, children, and adolescents aspre-transplant treatment.

Busulfano Zentiva is used in adults in combination with cyclophosphamide or fludarabine.

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

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

Do not use Busulfano Zentiva:

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

Warnings and precautions

Busulfano Zentiva is a powerful cytotoxic medication that causes a significant decrease in blood cells. At the recommended dose, this is the desired effect. For this reason, strict control should be carried out. There is a possibility that the use of Busulfano 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 another medication.

Thrombosis in small blood vessels may occur after hematopoietic stem cell transplantation (HSCT) with high doses of your treatment in combination with other medications.

Use of Busulfano Zentiva with other medications

Inform your doctor or pharmacist if you are using, have used recently, or may need to use any other medication, including those obtained without a prescription. Busulfano Zentiva may interact with other medications.

Especially, inform your doctor or pharmacist if you are taking one of the following medications:

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

You should exercise special caution if you are using itraconazole and metronidazole (used in the treatment of certain types of infections) or cetobemidone (used in the treatment of pain), as it may increase the risk of adverse effects.

The use of paracetamol during the 72 hours prior to or during the administration of Busulfano Zentiva should be carried out with caution.

Pregnancy and lactation

If you are pregnant or breastfeeding, or think you may be pregnant, consult your doctor before receiving treatment with Busulfano Zentiva.

Women should not be pregnant during treatment with Busulfano Zentiva or in the 6 months following treatment.

Women should discontinue breastfeeding before starting treatment with Busulfano Zentiva.

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

It may not be possible to conceive after treatment with Busulfano Zentiva. If you wish to have children, you should consult with your doctor before treatment. Busulfano Zentiva may also produce menopausal symptoms and in preadolescent girls may prevent the onset of puberty.

Men treated with Busulfano Zentiva are advised not to father children during and up to 6 months after completing treatment.

Dose and Administration:

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

For Adults:

Busulfano Zentiva in combination with cyclophosphamide:

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

Busulfano Zentiva in combination with fludarabine:

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

For Newborns, Children, and Adolescents (0 to 17 years):

The recommended dose of Busulfano Zentiva in combination with cyclophosphamide or melphalan depends on your body weight, and varies between 0.8 and 1.2 mg/kg.

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

Medications before Busulfano Zentiva Administration:

Before receiving Busulfano Zentiva, you will be treated with:

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

.

Like all medicines, this medicine may cause side effects, although not everyone will experience them.

Severe side effects

The most severe side effects associated with treatment with Busulfano Zentiva or the transplant procedure may include a decrease in circulating blood cell count (an effect intended by the medication to prepare you for the transplant), infections, liver disorders such as bile duct obstruction, graft-versus-host disease (the transplant reacts against your body), and respiratory complications. Your doctor will regularly monitor your blood counts and liver enzymes to detect and treat these side effects.

Other side effects may include:

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

• decrease in the number of circulating blood cells (red and white blood cells, 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, nasal bleeding, abnormal breathing sounds,
• nausea, inflammation of the mucous membranes of the mouth, vomiting, abdominal pain, diarrhea, constipation, burning sensation in the chest, anal discomfort, fluid in the abdomen,
• enlargement of the liver, jaundice (yellowing of the skin or white of the eyes), bile duct obstruction,
• eruption, 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 elimination), urinary discomfort, and decrease in urine production and blood in urine,
• fever, headache, weakness, chills, pain, allergic reactions, edema (fluid retention), general pain or inflammation at the injection site, chest pain, mucous membrane inflammation,
• high levels of 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,
• change 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 insufficiency, alveolar hemorrhage (bleeding from the air sacs of the lungs), asthma, pulmonary collapse, fluid around the lung,
• inflammation of the esophageal mucosa, intestinal paralysis (no intestinal movements), vomiting of blood,
• skin discoloration disorders, skin redness, skin peeling,
• increase in nitrogenous components in the blood fluid, moderate renal insufficiency, renal disorder.

Rare (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 convulsions,
• thrombi in the femoral artery, additional heartbeats, decreased heart rate, diffuse capillary fluid leakage (small blood vessels),
• decrease in blood oxygen levels,
• bleeding from the stomach and/or intestine.

Unknown frequency (cannot be estimated from available data)

• sexual gland dysfunction,
• ocular alterations including cataract formation and blurred vision (corneal thinning),
• menopausal symptoms 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.

Reporting side effects

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

Keepthis medicationout of the sight and reach of children.

Do not usethis medicationafter the expiration date that appears onthe packaging and vial labelafter CAD. The expiration date is the last day of the month indicated.

Sealed vial:

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

Diluted solution:

Chemical and physical stability has been confirmed for 8 hours (including infusion time) when stored at 20 °C±5 °C after dilution with a 5% glucose injectable solution or 0.9% sodium chloride solution, and for 6 hours after dilution in a 0.9% sodium chloride solution when stored between 2 °C and 8 °C, followed by an additional 3 hours of storage at 20 °C ±5 °C (including infusion time).

Do not freeze.

Medicines should not be disposed of through drains or in the trash. Ask your pharmacisthow to dispose ofthe packaging and medication that is no longerneeded.This will help protect the environment.

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.

Aspect of the product and content of the packaging

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 inindividual packaging with 1 vial or in multiple packagingcontaining 8 vials.

When Busulfan Zentiva is diluted, a transparent and colorless solution is obtained.

Vials with or without a retractable plastic wrapper with a protective base (disc). The retractable wrapper is not in contact with the product and provides additional protection during transport. It also improves safe handling of the product by healthcare professionals.

Holder of the marketing authorization and responsible for manufacturing

Holder of the marketing authorization

Zentiva k.s.,

U kabelovny 130,

Prague 10 – Dolní Mecholupy,

102 37 Czech Republic

Responsible for manufacturing1

MIAS Pharma Limited

Suite 2, Stafford House, Strand Road

Portmarnock, Co. Dublin

Ireland

Tillomed Malta Limited

Malta Life Sciences Park,

LS2.01.06 Industrial Estate,

San Gwann, SGN 3000, Malta

[1]Only the corresponding manufacturing responsible will appear on the marketed product

Further information about this medicinal product can be obtained 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 medicinal product 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 concentrate for solution for infusion EFG

Poland:Busulfan Zentiva

Last review date of this leaflet:July 2020

Other sources of information

The detailed information about this medicinal product is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS) (http://www.aemps.gob.es/).

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This information is intended solely for healthcare professionals:

PREPARATION GUIDE

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

Busulfan

Read this guide before preparation and administration of Busulfan Zentiva.

1. PRESENTATION

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

Busulfan Zentiva must be diluted before administration.

2. RECOMMENDATIONS FOR SAFE HANDLING

Proper procedures for handling and disposal of anticancer drugs must be taken into account.

All transfer procedures require strict compliance with aseptic techniques; preferably, a laminar flow hood with vertical 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 the same) 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 specialty Busulfan Zentiva, it is necessary to dilute the product with sodium chloride 9 mg/ml (0.9%) injection solution or with 5% glucose injection solution.

The amount of diluent must be equal to 10 times the volume of Busulfan Zentiva, which ensures 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: Busulfan Zentiva dose (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 (sodium chloride 9 mg/ml (0.9%) injection solution or 5% glucose injection solution).

Preparation of the infusion solution

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

• A syringe that is not made of polycarbonate, equipped with a needle:

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

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

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

Instructions for use

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

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

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

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

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

Polycarbonate syringes should not be used with Busulfan Zentiva.

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

Storage conditions

Sealed vials:

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

Diluted solution:

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

3. PROCEDURE FOR PROPER DISPOSAL

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