Busulfan Zentiva

Leaflet accompanying the packaging: patient information

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

Busulfan

Read the leaflet carefully before using the medicine, as it contains important information for the patient.

• Keep this leaflet, you may need to read it again.
• In case of any doubts, consult a doctor, pharmacist, or nurse.
• If the patient experiences any side effects, including those not listed in this leaflet, inform the doctor, pharmacist, or nurse. See section 4.

Table of contents of the leaflet:

• 1. What is Busulfan Zentiva and what is it used for
• 2. Important information before using Busulfan Zentiva
• 3. How to use Busulfan Zentiva
• 4. Possible side effects
• 5. How to store Busulfan Zentiva
• 6. Contents of the packaging and other information

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

Busulfan Zentiva contains the active substance busulfan, which belongs to a group of medicines called alkylating agents. Busulfan Zentiva destroys existing bone marrow before receiving a transplant.
Busulfan Zentiva is used in adults, newborns, infants, children, and adolescents for pre-transplant treatment.
In adults, Busulfan Zentiva is used in combination with cyclophosphamide or fludarabine.
In newborns, infants, children, and adolescents, Busulfan Zentiva is used in combination with cyclophosphamide or melphalan.
This medicine is given before receiving a bone marrow or stem cell transplant.

2. Important information before using Busulfan Zentiva

When not to use Busulfan Zentiva:

• if the patient is allergic to busulfan or any of the other ingredients of this medicine (listed in section 6),
• if the patient is pregnant or suspects pregnancy.

Warnings and precautions

Busulfan Zentiva is a strong cytotoxic medicine that can cause a significant decrease in the number of blood cells. At the recommended dose, this is a desired effect. Therefore, the patient is under close observation. There is a possibility that the use of Busulfan Zentiva may increase the risk of developing another cancer in the future. Inform the doctor:

• if there are liver, kidney, heart, or lung diseases,
• if there have been seizures in the past,
• if the patient is taking other medicines at the moment.

Cases of thrombosis in small blood vessels may occur after hematopoietic cell transplantation (HCT) after the use of high therapeutic doses in combination with other medicines.

Busulfan Zentiva and other medicines

Tell the doctor about all medicines being taken currently or recently and about medicines that the patient plans to use, including those available without a prescription. Busulfan Zentiva may interact with other medicines.
In particular, inform the doctor or pharmacist if the patient is taking the following medicines:

• Deferasirox (a medicine used to remove excess iron from the body). Particular caution is advised if itraconazole and metronidazole (used in some types of infections) or ketobemidone (used in pain treatment) are used, as they may enhance the side effects. Paracetamol should be used with caution within 72 hours before or at the same time as the administration of Busulfan Zentiva.

Pregnancy and breastfeeding

In pregnancy and during breastfeeding, or if pregnancy is suspected, or if the patient plans to become pregnant, consult a doctor before using Busulfan Zentiva. Women must not become pregnant during treatment with Busulfan Zentiva and for 6 months after its completion.
Women must stop breastfeeding before starting treatment with Busulfan Zentiva.
If either partner is treated with Busulfan Zentiva, appropriate contraceptive measures should be used.
After treatment with Busulfan Zentiva, it may not be possible to become pregnant (infertility). If having children is considered, discuss this with the doctor before starting treatment.
Busulfan Zentiva may also cause symptoms of menopause, and in girls before puberty, it may inhibit maturation.
Men treated with Busulfan Zentiva are advised not to plan fatherhood during treatment and for 6 months after its completion.

3. How to use Busulfan Zentiva

Dose and method of administration:

The dose of busulfan is calculated based on the patient's body weight.
Adults:
Busulfan Zentiva in combination with cyclophosphamide:

• The recommended dose of Busulfan Zentiva is 0.8 mg/kg body weight.
• Each infusion lasts 2 hours.
• Busulfan Zentiva is 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 body weight.
• Each infusion lasts 3 hours.
• Busulfan is administered once a day for 2 or 3 consecutive days before the transplant.

Newborns, infants, children, and adolescents (0-17 years):
The recommended dose of Busulfan Zentiva in combination with cyclophosphamide or melphalan is calculated based on body weight; it is within the range of 0.8 - 1.2 mg/kg body weight.

• Each infusion lasts 2 hours.
• Busulfan Zentiva is administered every 6 hours for 4 consecutive days before the transplant.

Medicines given before Busulfan Zentiva administration:

Before administering Busulfan Zentiva, the patient receives:

• anti-seizure medicines to prevent seizures (phenytoin or benzodiazepines) and
• anti-emetic medicines to prevent nausea (vomiting).

4. Possible side effects

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

Severe side effects:

The most severe side effects after using busulfan or the transplant itself may include a decrease in the number of circulating blood cells (an intended effect of the medicine to prepare for the transplant), infection, liver disorders, including blockage of liver veins, graft-versus-host disease (the transplant attacks the patient's body), and pulmonary complications. The doctor will regularly monitor blood morphology and liver enzyme test results to detect and treat these complications.

Other side effects may include:

Very common (may occur in more than 1 in 10 patients):

• decrease in the number of circulating blood cells (red and white) and platelets
• infections
• insomnia, anxiety, dizziness, and depression
• loss of appetite, decreased magnesium, calcium, potassium, and phosphate levels in the blood, and increased blood sugar levels
• rapid heart rate, increased or decreased blood pressure, vasodilation (increased diameter of blood vessels), and blood clots
• shortness of breath, nasal discharge (rhinitis), sore throat, cough, hiccups, nosebleeds, abnormal breathing sounds
• nausea, oral mucositis, vomiting, abdominal pain, diarrhea, constipation, heartburn, discomfort in the anal area, ascites.
• liver enlargement, jaundice (yellowing of the skin or whites of the eyes), hepatic veno-occlusive disease
• rash, itching, hair loss
• back pain, muscle and joint pain
• increased creatinine clearance, which passes through the kidneys to filter and eliminate in urine, (creatinine clearance), discomfort during urination, decreased urine output, and hematuria
• fever, headache, weakness, chills, pain, allergic reaction, edema (fluid accumulation), pain or inflammation at the injection site, chest pain, mucositis
• increased liver enzyme levels and weight gain
• paralytic ileus

Common (may occur in up to 1 in 10 patients):

• confusion, neurological disorders
• low sodium levels in the blood
• changes and disorders of heart rhythm, presence of fluid in the pericardium or pericarditis, decreased cardiac output
• increased respiratory rate, respiratory failure, bleeding from air-filled sacs in the lungs called alveoli (alveolar hemorrhages), asthma, atelectasis, pleural effusion
• esophageal inflammation, paralytic ileus, hematemesis (vomiting blood),
• skin discoloration, skin redness, peeling skin (desquamation)
• increased levels of nitrogen compounds in the blood, moderate kidney failure, kidney dysfunction

Uncommon (may occur in up to 1 in 100 patients):

• delirium (severe disorientation), nervousness, hallucinations (seeing things that are not there), agitation (anxiety or nervousness), brain disorders, hemorrhagic stroke, and seizures
• thrombosis of the femoral artery (femoral artery), extra heartbeats, slowed heart rate, significant loss of fluid from capillaries (small blood vessels)
• decreased oxygen levels in the blood
• bleeding from the stomach and/or intestines

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

• Endocrine disorders
• Lens disorders, including cataracts and blurred vision (corneal clouding)
• Menopausal symptoms and infertility in women
• Brain abscess, skin inflammation, generalized infection
• Liver disorders
• Increased lactate dehydrogenase activity in the blood
• Increased uric acid and urea levels in the blood
• Impaired dental development

Reporting side effects

If any side effects occur, including those not listed in the leaflet, inform the doctor, pharmacist, or nurse. Side effects can be reported directly to the Department of Monitoring of Adverse Reactions to Medicinal Products of the Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products: Al. Jerozolimskie 181C, 02-222 Warsaw, tel.: +48 22 49 21 301, fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl.
Side effects can also be reported to the marketing authorization holder.
Reporting side effects will help to gather more information on the safety of the medicine.

5. How to store Busulfan Zentiva

The medicine should be stored out of sight and reach of children.
Do not use this medicine after the expiry date stated on the label of the vial and on the carton after "Expiry Date" (EXP). The expiry date refers to the last day of the month stated.
Unopened vials:
Store in a refrigerator (2°C - 8°C).
Diluted solution:
Chemical and physical stability of the solution has been demonstrated for 8 hours (including infusion time) after dilution with glucose 5% solution or sodium chloride 9 mg/ml (0.9%) solution for injection, at a temperature of 20°C ± 5°C, or for 6 hours after dilution with sodium chloride 9 mg/ml (0.9%) solution for injection, stored at a temperature of 2°C-8°C, and then stored for 3 hours at a temperature of 20°C ± 5°C (including infusion time).
From a microbiological point of view, the product should be used immediately, unless the method of dilution precludes the risk of microbial contamination. If not used immediately, the user is responsible for the storage time and conditions of the product.
Do not freeze.
Medicines should not be disposed of via wastewater or household waste. Ask the pharmacist how to dispose of medicines that are no longer needed. This will help protect the environment.

6. Contents of the packaging and other information

What Busulfan Zentiva contains

• The active substance of the medicine is busulfan. One ml of the concentrate contains 6 mg of busulfan (60 mg in a vial). After dilution: one ml of the solution contains approximately 0.5 mg of busulfan.
• Other ingredients are: dimethylacetamide, macrogol 400, and anhydrous citric acid.

What Busulfan Zentiva looks like and contents of the pack

Busulfan Zentiva contains a concentrate for solution for infusion and is supplied in vials of clear glass, each vial contains 60 mg of busulfan.
Busulfan Zentiva is available in single packs of 1 vial or multipacks containing 8 vials. After dilution, Busulfan Zentiva is a clear, colorless solution.
The vials may (or may not) be covered with shrink-wrap sleeves, as well as have a plastic protective cap. This plastic cap does not come into contact with the medicinal product and serves as additional protection during transport. This improves safety when handling the medicinal product by healthcare professionals and pharmacy staff.

Marketing authorization holder and manufacturer

Marketing authorization holder

Zentiva, k.s.
U kabelovny 130
Dolní Měcholupy
102 37, Prague 10
Czech Republic

Manufacturer/Importer:

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

This medicinal product is authorized in the Member States of the European Economic Area under the following names:

France: Busulfan Tillomed 6mg/ml solution à diluer pour perfusion
Italy: Busulfan Tillomed
Germany: Busulfan Zentiva 6mg/ml Konzentrat zur Herstellung einer Infusionslösung
Spain: Busulfano Zentiva 6mg/ml concentrado para solución para perfusion EFG
Poland: Busulfan Zentiva
Date of last revision of the leaflet:November 2023
The following information is intended for healthcare professionals only.

GUIDELINES FOR PREPARATION OF THE SOLUTION

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

Busulfan
Read the guidelines before preparing and administering Busulfan Zentiva.

1. DESCRIPTION

Busulfan Zentiva is available as a clear, colorless solution in clear glass vials of type I. Busulfan Zentiva must be diluted before administration.

2. RECOMMENDATIONS FOR PREPARATION OF THE MEDICINE FOR USE

Follow the procedures for proper preparation and disposal of cytotoxic medicines.
All preparation procedures require strict adherence to aseptic techniques, preferably using a vertical laminar flow extractor.
As with other cytotoxic compounds, busulfan solution should be handled with care:

• it is recommended to wear gloves and protective clothing.
• in case of contact of the concentrate or diluted solution with the skin or mucous membrane, the area should be rinsed immediately with water.

Calculation of the amount of Busulfan Zentiva to be diluted and the amount of solvent
Busulfan Zentiva should be diluted before administration using 0.9% (9 mg/ml) sodium chloride solution for injection or 5% glucose solution for injection.
The amount of solvent must be 10 times greater than the volume of Busulfan Zentiva, so that the final concentration of busulfan is approximately 0.5 mg/ml.
The amount of Busulfan Zentiva and solvent should be calculated as follows:
for a patient with a body weight of Y kg:

• Amount of Busulfan Zentiva: Y (kg) x D (mg/kg) -------------------------- = A ml of Busulfan Zentiva to be diluted 6 (mg/ml) Y: patient's body weight in kg D: dose of Busulfan Zentiva (see SmPC section 4.2)
• Amount of solvent: (A ml of Busulfan Zentiva) x (10) = B ml of solvent To prepare the final infusion solution, add (A) ml of Busulfan Zentiva to (B) ml of solvent [0.9% (9 mg/ml) sodium chloride solution for injection or 5% glucose solution for injection].

Preparation of the infusion solution
Busulfan Zentiva must be prepared using sterile equipment by healthcare professionals.

• Using a non-poly carbonate syringe with a needle:
• Draw up the calculated volume of the concentrate from the vial.
• Inject the contents of the syringe into an infusion bag (or syringe), which already contains the calculated volume of the chosen solvent. Busulfan Zentiva must always be added to the solvent, not the solvent to the concentrate. Busulfan Zentiva should not be injected into an infusion bag that does not contain 0.9% (9 mg/ml) sodium chloride solution for injection or 5% glucose solution for injection.

The diluted solution should be thoroughly mixed by inverting several times. After dilution, 1 ml of the infusion solution contains 0.5 mg of busulfan. After dilution, Busulfan Zentiva is a clear, colorless solution.

Instructions for use
Before and after each infusion, flush the inserted venous catheter using approximately 5 ml of 0.9% (9 mg/ml) sodium chloride solution for injection or 5% glucose solution for injection.
The medicine remaining in the lines cannot be flushed, as the effect of rapid infusion of busulfan solution has not been studied, and therefore, such a procedure is not recommended.
The total prescribed dose of busulfan should be administered within two or three hours, depending on the conditioning regimen.
Small volumes can be administered over 2 hours using electric syringes. In this case, use infusion sets with a minimum priming volume before use (i.e., 0.3-0.6 ml), filled with the medicine solution before starting the busulfan infusion, and then flushed with 0.9% sodium chloride (9 mg/ml) solution for injection or 5% glucose solution for injection.
Busulfan solution should not be administered simultaneously with another intravenous solution.
Do not use poly carbonate syringes for busulfan solution.
For single use only. Use only a clear solution without turbidity.
Storage conditions
Unopened vials:
Store in a refrigerator (2°C - 8°C).
Diluted solution:
Chemical and physical stability has been demonstrated for 8 hours (including infusion time) after dilution with 5% glucose solution or 9 mg/ml (0.9%) sodium chloride solution for injection, at a temperature of 20°C ± 5°C, or for 6 hours after dilution with 9 mg/ml (0.9%) sodium chloride solution for injection, stored at a temperature of 2°C-8°C, and then stored for 3 hours at a temperature of 20°C ± 5°C (including infusion time).
From a microbiological point of view, the product should be used immediately, unless the method of dilution precludes the risk of microbial contamination. If not used immediately, the user is responsible for the storage time and conditions of the product.

3. PROCEDURE FOR DISPOSAL OF UNUSED MEDICINE

Any unused medicine or waste material should be disposed of in accordance with local regulations for cytotoxic medicines.