Busulfan zentiva

Patient Information Leaflet

Busulfan Zentiva, 6 mg/ml, concentrate for solution for infusion
Busulfanum
Please read all of this leaflet carefully before 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 further questions, please ask your doctor, pharmacist or nurse.
• If you experience any side effects, including any not listed in this leaflet, please tell your doctor, pharmacist or nurse. See section 4.

Leaflet Contents:

1. What Busulfan Zentiva is and what it is 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 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 existing bone marrow prior to transplantation.
Busulfan Zentiva is used in adults, newborns, infants, children and adolescents for treatment prior to transplantation procedures.
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 administered prior to receiving a bone marrow or haematopoietic stem cell transplant.

2. Important information before using Busulfan Zentiva

When not to use Busulfan Zentiva:

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

Warnings and precautions
Busulfan Zentiva is a potent cytotoxic medicine which causes a significant reduction in blood cells. This effect is intended at the recommended dose. Therefore, the patient must be closely monitored. There is a possibility that treatment with Busulfan Zentiva may increase the risk of developing another malignancy in the future. Inform your doctor:

• if there are existing liver, kidney, heart or lung diseases,
• if the patient has previously experienced seizures,
• if the patient is currently taking other medicines. Cases of blood clots in small blood vessels may occur after haematopoietic cell transplantation (HCT) following high-dose therapy in combination with other medicines.

Busulfan Zentiva and other medicines
Tell your doctor about all medicines you are currently taking or have recently taken, including medicines obtained without a prescription. Busulfan Zentiva may interact with other medicines.
In particular, inform your doctor or pharmacist if the patient is taking the following medicines:

• Deferasirox (a medicine used to remove excess iron from the body). Extreme caution is required when taking itraconazole and metronidazole (used in certain types of infections) or ketobemidone (used to treat pain), as they may exacerbate adverse effects. Paracetamol should be used with caution within 72 hours before or during administration of Busulfan Zentiva.

Pregnancy and breastfeeding
During pregnancy, while breastfeeding, or if pregnancy is suspected or planned, consult your doctor before using Busulfan Zentiva. Women must not become pregnant during treatment with Busulfan Zentiva and for 6 months after treatment has ended. Women must stop breastfeeding before starting treatment with Busulfan Zentiva.
If either partner is being treated with Busulfan Zentiva, effective contraception must be used.
After treatment with Busulfan Zentiva, it may not be possible to become pregnant (infertility). If you are considering having children, discuss this with your doctor before starting treatment.
Busulfan Zentiva may also cause symptoms of menopause, and in girls before puberty, it may delay 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

Dosage and method of administration:
The busulfan dose 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 over 4 consecutive days prior to transplantation.

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 daily over 2 or 3 consecutive days prior to transplantation.

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 and ranges between 0.8 and 1.2 mg/kg body weight.

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

Medications administered prior to Busulfan Zentiva:
Before administration of Busulfan Zentiva, the patient receives:

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

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everybody will experience them.
Serious adverse reactions:
The most serious adverse reactions following administration of busulfan or the transplantation procedure itself may include reduction in circulating blood cells (an intended effect of the medicine in order to prepare for transplantation), infections, liver disorders including hepatic veno-occlusive disease, graft-versus-host disease (where the transplant attacks the patient's body), and pulmonary complications. Your doctor will regularly monitor blood count and liver enzyme test results to detect and treat these complications.

Other adverse reactions may include:

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

• reduction in circulating blood cells (red and white cells) and platelets
• infections
• insomnia, anxiety, dizziness and depression
• loss of appetite, decreased levels of magnesium, calcium, potassium and phosphate and albumin in blood, and increased blood glucose levels
• increased heart rate, increased or decreased blood pressure, vasodilation (increase in diameter of blood vessels) and blood clots
• shortness of breath, nasal discharge (rhinitis), sore throat, cough, hiccups, nosebleeds, abnormal breath sounds
• nausea, inflammation of the mucous membrane of the mouth, vomiting, abdominal pain, diarrhoea, constipation, heartburn, discomfort in the anal area, fluid in the abdominal cavity
• enlarged liver, jaundice (yellowing of the skin or whites of the eyes), blockage of the liver vein
• rash, itching, hair loss
• back, muscle and joint pain
• increased excretion of metabolic products, creatinine, which passes through the kidneys to be filtered and eliminated in urine (creatinine clearance), discomfort during urination, decreased urine output and blood in urine
• fever, headache, fatigue, chills, pain, allergic reaction, swelling (fluid accumulation), pain or inflammation at the injection site, chest pain, inflammation of mucous membranes
• increased liver enzymes and increased body weight
• intestinal paralysis

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

• confusion, nervous system disorders
• low sodium levels in blood
• changes and disturbances in heart rhythm, presence of fluid in the pericardium or inflammation of the pericardium, reduced amount of blood pumped by the heart into the circulation (cardiac output)
• increased respiratory rate, respiratory failure, bleeding from air-filled sacs in the lungs called alveoli (alveolar haemorrhage), asthma, collapse of small areas of the lung, fluid in the pleura
• inflammation of the oesophageal mucosa, intestinal paralysis, vomiting blood (haematemesis)
• skin discoloration, redness of the skin, peeling skin (desquamation)
• increased levels of nitrogen compounds in blood, moderate kidney failure, kidney function disorders

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

• delirium (significant disorientation), nervousness, hallucinations (seeing things that are not really there), agitation (anxiety or restlessness), brain function disorders, haemorrhagic stroke, and seizures
• arterial thrombosis in the leg (femoral artery), additional heart contractions, slowing of heart function, severe loss of fluid from capillaries (small blood vessels)
• decreased oxygen content in blood
• bleeding from the stomach and/or intestine

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

• Dysfunction of sex glands
• Lens disorders, including clouding of the eye lens (cataract) and blurred vision (corneal thinning)
• Menopausal symptoms and infertility in women
• Brain abscess, skin inflammation, systemic infection
• Liver disorders
• Increased lactate dehydrogenase activity in blood
• Increased levels of uric acid and urea in blood
• Incomplete development of dentition
• Increased blood pressure in the blood vessels of the lungs (pulmonary hypertension)

Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor, pharmacist or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions 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
Adverse reactions can also be reported to the marketing authorisation holder.
Reporting adverse reactions helps provide more information on the safety of this medicine.

5. How to store Busulfan Zentiva

Keep this medicine out of sight and reach of children.
Do not use this medicine after the expiry date stated on the vial label and on the outer carton
after "Expiry date (EXP)". The expiry date refers to the last day of the stated month.
Closed 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 5% glucose solution or 9 mg/ml (0.9%) sodium chloride solution for injection, stored at 20°C ± 5°C, or for 6 hours after dilution with 9 mg/ml (0.9%) sodium chloride solution for injection, stored at 2°C-8°C, followed by storage for 3 hours at 20°C ± 5°C (including infusion time).
From a microbiological point of view, the medicine should be used immediately unless the dilution method excludes the risk of microbiological contamination. If not used immediately, the user is responsible for the storage duration and conditions.
Do not freeze.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. Doing so helps protect the environment.

6. Contents of the pack and other information

What Busulfan Zentiva contains

• The active substance is busulfan. One ml of concentrate contains 6 mg of busulfan (60 mg per vial). After dilution: one ml of solution contains approximately 0.5 mg of busulfan.
• The other components are: dimethylacetamide, polyethylene glycol 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 colourless glass vials, each containing 60 mg of busulfan.
Busulfan Zentiva is available in single packs of 1 vial or in multi-packs containing 8 vials. After dilution, Busulfan Zentiva is a clear, colourless solution.
Vials may (or may not) be covered with heat-shrink sleeves and may (or may not) have a plastic cap protector covering the bottom of the vial. This plastic protector does not come into direct contact with the medicinal product and is intended to provide additional protection during transport. This improves safety when handling the medicinal product for both healthcare professionals and pharmacy personnel.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation 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 authorised in the European Economic Area member states 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

The following information is intended exclusively for healthcare professionals.

PREPARATION GUIDELINES FOR THE SOLUTION
Busulfan Zentiva, 6 mg/ml, concentrate for solution for infusion
Please read the guidelines carefully before preparing and administering Busulfan Zentiva.

1. DESCRIPTION
Busulfan Zentiva is supplied as a clear, colourless solution in type I colourless glass vials. Busulfan Zentiva must be diluted before administration.

2. RECOMMENDATIONS FOR PREPARING THE MEDICINAL PRODUCT FOR ADMINISTRATION
Appropriate procedures for the preparation and disposal of cytotoxic medicinal products must be followed.
All preparation procedures must strictly adhere to aseptic techniques, preferably using a vertical laminar airflow cabinet.
As with other cytotoxic compounds, care must be taken when handling and preparing busulfan solution:

• It is recommended to wear gloves and protective clothing.
• In case of contact of the concentrate or diluted solution with skin or mucous membranes, the affected area should be immediately and thoroughly rinsed with water.

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

To prepare the final infusion solution, add (A) ml of Busulfan Zentiva to (B) ml of diluent [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 trained healthcare personnel.

• Using a non-polycarbonate syringe with a needle:
  • Withdraw the calculated volume of concentrate from the vial.
  • Inject the contents of the syringe into an infusion bag (or syringe) already containing the calculated volume of the selected diluent. Busulfan Zentiva must always be added to the diluent, not the diluent to the concentrate. Busulfan Zentiva must 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.
• After dilution, mix the solution thoroughly 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, colourless solution.

Instructions for administration
Before and after each infusion, flush the intravenous line with approximately 5 ml of 0.9% (9 mg/ml) sodium chloride solution for injection or 5% glucose solution for injection.
Residual drug remaining in the tubing must not be flushed through, as the effect of rapid infusion of busulfan solution has not been studied, and therefore this practice is not recommended.
The total prescribed dose of busulfan should be administered over two or three hours, depending on the conditioning regimen.
Small volumes may be administered over 2 hours using electric syringe pumps. In this case, infusion sets with minimal priming volume (i.e. 0.3–0.6 ml) should be used, pre-filled with the drug solution before starting the busulfan infusion and then flushed with 0.9% sodium chloride solution (9 mg/ml) for injection or 5% glucose solution for injection.
Busulfan solution must not be administered simultaneously with another intravenous solution.
Polycarbonate syringes must not be used for busulfan solution.
For single use only. Use only a clear solution free from cloudiness or particles.

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 in 5% glucose solution or 9 mg/ml (0.9%) sodium chloride solution for injection, when stored at 20°C ± 5°C, or for 6 hours after dilution in 9 mg/ml (0.9%) sodium chloride solution for injection, when stored at 2°C - 8°C, followed by 3 hours at 20°C ± 5°C (including infusion time).
From a microbiological standpoint, the product should be used immediately unless dilution procedures exclude the risk of microbiological contamination. If not used immediately, the user is responsible for the storage duration and conditions.

3. PROCEDURE FOR DISPOSAL OF UNUSED MEDICINAL PRODUCT OR WASTE
Any unused medicinal product or waste material must be disposed of in accordance with local regulations for cytotoxic medicinal products.