Busulfan TilloMed

Patient Information Leaflet

Busulfan Tillomed 6 mg/ml concentrate for solution for infusion

Busulfan
Generic medicine
Please read this leaflet carefully before using this medicine because it contains
important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any side effects not listed in this leaflet. See section 4.

Contents of this leaflet

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

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

Busulfan Tillomed contains the active substance busulfan, which belongs to a group of medicines called alkylating agents. Busulfan Tillomed destroys the original bone marrow prior to transplantation.
Busulfan Tillomed is used in adults, neonates, children and adolescents as a treatment prior to transplantation.
In adults, Busulfan Tillomed is used in combination with cyclophosphamide or fludarabine.
In neonates, children and adolescents, Busulfan Tillomed is used in combination with cyclophosphamide or melphalan.
This medicine will be administered to you before receiving a bone marrow transplant or hematopoietic progenitor cell transplant.

2. What you should know before using Busulfan Tillomed

Do not use Busulfan Tillomed

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

Warnings and precautions
Busulfan Tillomed is a potent cytotoxic drug that causes a profound reduction in blood cells. At the recommended dose, this is the intended effect. Therefore, careful monitoring will be carried out. The use of Busulfan Tillomed may increase the risk of developing another tumour in the future. You must inform your doctor:

• if you have problems with your liver, kidneys, heart or lungs,
• if you have a history of epileptic seizures,
• if you are currently taking other medicines.

Cases of blood clot formation in small blood vessels may occur after haematopoietic cell transplantation (HCT) with high-dose treatment in combination with other medicines.

Other medicines and Busulfan Tillomed
Tell your doctor if you are taking, have recently taken, or might take any other medicines, including those without a prescription. Busulfan Tillomed may interact with other drugs.
In particular, inform your doctor or pharmacist if you are taking any of the following medicines:

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

Special caution is required if you are using itraconazole and metronidazole (used for certain types of infections) or ketobemidone (used to treat pain), as these may increase the risk of adverse effects.
The use of paracetamol within the 72 hours prior to or during administration of Busulfan Tillomed must be carefully dosed.

Pregnancy and breastfeeding
If you are pregnant, think you might be pregnant, planning a pregnancy, or breastfeeding, consult your doctor before taking this medicine. Women must avoid pregnancy during treatment with Busulfan Tillomed and for six months after the end of treatment.
Women must stop breastfeeding before starting treatment with Busulfan Tillomed.
Adequate contraceptive precautions must be taken when either partner is receiving Busulfan Tillomed.
You may no longer be able to become pregnant (infertility) after treatment with Busulfan Tillomed. If you wish to have children, you should discuss this with your doctor before starting treatment. Busulfan Tillomed may also cause symptoms of menopause and, in pre-adolescent girls, may prevent the onset of puberty.
Men treated with Busulfan Tillomed are advised not to father a child during treatment and for up to 6 months after treatment ends.

3. How to use Busulfan Tillomed

Dosage and administration:
The dose of Busulfan Tillomed will be calculated based on your body weight.

In adults:
Busulfan Tillomed in combination with cyclophosphamide:

• The recommended dose of Busulfan Tillomed is 0.8 mg/kg.
• Each infusion will last 2 hours.
• Busulfan Tillomed will be administered every 6 hours for 4 consecutive days, prior to transplantation.

Busulfan Tillomed in combination with fludarabine:

• The recommended dose of Busulfan Tillomed is 3.2 mg/kg.
• Each infusion will last 3 hours.
• Busulfan Tillomed will be administered once daily for 2 or 3 consecutive days prior to transplantation.

In neonates, children and adolescents (from 0 to 17 years of age):
The recommended dose of Busulfan Tillomed, in combination with cyclophosphamide or melphalan, is based on body weight and ranges between 0.8 and 1.2 mg/kg.

• Each infusion will last 2 hours.
• Busulfan Tillomed will be administered every 6 hours for 4 consecutive days prior to transplantation.

Medicines before receiving Busulfan Tillomed:
Before receiving Busulfan Tillomed, you will be treated with:

• anticonvulsant medicines to prevent seizures (phenytoin or benzodiazepines), and
• antiemetic medicines to prevent nausea and 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 adverse reactions associated with Busulfan Tillomed therapy, or following the transplant procedure, may include a decrease in circulating blood cell counts (an expected effect of the medicine to prepare you for transplant infusion), infections, liver disorders including blockage of a liver vein, graft-versus-host disease (where the transplant attacks your body), and pulmonary complications. Your doctor will regularly monitor your blood counts and liver enzymes to detect and manage these events.

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, decreased levels of magnesium, calcium, potassium, phosphate, and albumin in the blood, and increased blood glucose
• increased heart rate, increased or decreased blood pressure, vasodilation (widening of blood vessels), and blood clots
• shortness of breath, nasal discharge (rhinitis), sore throat, cough, hiccups, nosebleeds, abnormal breathing
• nausea, inflammation of the mucous membrane of the mouth (mucositis), vomiting, abdominal pain, diarrhea, constipation, heartburn, discomfort around the anal sphincter, fluid in the abdomen
• liver enlargement, jaundice (yellowing of the skin or whites of the eyes), blockage of a liver vein
• rash, itching, hair loss
• back pain, muscle pain, joint pain
• increased excretion of creatinine (a waste chemical filtered by the kidneys and eliminated in urine), difficulty urinating, decreased urine output, and blood in the urine
• fever, headache, weakness, chills, pain, allergic reaction, edema (fluid accumulation), pain or inflammation at the injection site, chest pain, inflammation of the membrane lining internal organs
• elevated liver enzymes and weight gain
• intestinal paralysis

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

• confusion, nervous system disorders
• low levels of sodium in the blood (hyponatremia)
• changes and abnormalities in heart rhythm, fluid retention or inflammation around the heart, reduced 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 called alveoli (alveolar hemorrhage), asthma, collapse of small areas of the lung, fluid around the lungs
• inflammation of the esophageal membrane, paralysis (loss of movement) of the intestine, vomiting with blood
• changes in skin color, skin redness, skin peeling
• increased levels of nitrogen in the bloodstream, moderate kidney failure, kidney disorders

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

• delirium (severe confusion), restlessness, hallucinations (seeing things that are not real), agitation (anxiety or nervousness), abnormal brain function, brain hemorrhage, and seizures
• clotting of the artery in the thigh (femoral artery), increased heart rate, decreased heart rate, fluid leakage from capillaries (small blood vessels)
• decreased levels of oxygen in the blood
• bleeding in the stomach and/or intestines

Not known (frequency cannot be estimated from the available data):

• dysfunction of the sex glands
• eye disorders, including clouding of the eye lens (cataract) and blurred vision (corneal thinning)
• menopausal symptoms and female infertility
• brain abscess, skin inflammation, systemic infection
• liver disorders
• increased levels of the enzyme lactate dehydrogenase
• increased levels of uric acid and urea in the blood
• incomplete dental development
• increased pressure in the blood vessels of the lungs (pulmonary hypertension)

Reporting of side effects

If you get any side effects, including those not listed in this leaflet, talk to your doctor. You can also report side effects through the national reporting system at the following website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Busulfan Tillomed

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

6. Package contents and other information

What Busulfan Tillomed concentrate for infusion solution contains

• The active substance is busulfan. One ml of concentrate contains 6 mg of busulfan (60 mg of busulfan per vial). After dilution: one ml of solution contains approximately 0.5 mg of busulfan.
• The other components are N,N-dimethylacetamide, Macrogol 400 and anhydrous citric acid.

Description of the appearance of Busulfan Tillomed and package contents
Busulfan Tillomed consists of a concentrate for solution for infusion and is supplied in
colourless glass vials, each vial containing 60 mg of busulfan.
Busulfan Tillomed is available in single packs containing 1 vial or multipacks containing 8
vials. When diluted, Busulfan Tillomed is a clear, colourless solution.
The vials may or may not be equipped with a plastic anti-breakage and anti-spill coating / plastic base (disc). This plastic coating does not come into contact with the medicinal product and provides additional protection during transport. This improves safe handling of the medicine both by healthcare professionals and pharmacy personnel.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Tillomed Italia S.r.l.
viale Richard 1, Torre A, 20143, Milan, Italy
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

This medicinal product is authorised in the EEA Member States under the following names:
France: Busulfan Tillomed 6mg/ml solution to be diluted for infusion
Italy: Busulfan Tillomed
Germany: Busulfan Tillomed 6mg/ml concentrate for solution for infusion
Spain: Busulfano Zentiva 6mg/ml concentrate for infusion solution
EFG
Poland: Busulfan Zentiva

The following information is intended exclusively for physicians or healthcare professionals.
PREPARATION INSTRUCTIONS
Busulfan Tillomed 6 mg / ml concentrate for infusion solution
Busulfan
Read this guide before preparing and administering Busulfan Tillomed.

1. PRESENTATION

Busulfan Tillomed is supplied as a clear and colorless solution in transparent glass vials (Type I). Busulfan Tillomed must be diluted before administration.

2. RECOMMENDATION FOR SAFE HANDLING

Procedures for proper handling and disposal of antineoplastic medicinal products should be considered.
All transfer procedures require strict adherence to aseptic techniques, preferably using a vertical laminar flow safety cabinet.
As with other cytotoxic compounds, care must be taken when handling and preparing Busulfan Tillomed solution:

• Use of gloves and protective clothing is recommended.
• If Busulfan Tillomed or diluted Busulfan Tillomed solution comes into contact with skin or mucous membranes, wash immediately with water.

Calculation of the amount of Busulfan Tillomed to be diluted and of the diluent
Busulfan Tillomed must be diluted prior to use with either an injectable solution of sodium chloride 9 mg/ml (0.9%) or 5% glucose for injection.
The volume of diluent must be 10 times the volume of Busulfan Tillomed, ensuring that the final busulfan concentration remains at approximately 0.5 mg/ml.
The amount of Busulfan Tillomed and diluent to be administered is calculated as follows:
For a patient with a body weight of Y kg:

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

Preparation of the infusion solution
Busulfan Tillomed must be prepared by a healthcare professional using sterile transfer techniques.

• Using a syringe not made of polycarbonate and equipped with a needle:

  • The calculated volume of Busulfan Tillomed must be withdrawn from the vial.
  • The contents of the syringe must be dispensed into an intravenous infusion bag (or syringe) already containing the calculated amount of selected diluent.
    Busulfan Tillomed must always be added to the diluent, not the diluent to Busulfan Tillomed.
    Busulfan Tillomed must not be added to an intravenous bag that does not contain sodium chloride 9 mg/ml (0.9%) for injection or 5% glucose solution for injection.

• The diluted solution must be mixed thoroughly by inverting several times. After dilution, 1 ml of infusion solution contains 0.5 mg of busulfan. Diluted Busulfan Tillomed is a clear, colourless solution.

Instructions for use
Before and after each infusion, flush the indwelling catheter line with approximately 5 ml of sodium chloride 9 mg/ml (0.9%) for injection or 5% glucose for injection.

The residual medicine must not be flushed through the administration lines, as rapid infusion of busulfan has not been tested and is not recommended.
The entire prescribed Busulfan dose should be administered over two or three hours, depending on the administration regimen.
Small volumes may be administered over more than 2 hours using electric syringe pumps. In such cases, infusion sets with a minimal priming volume (i.e. 0.3–0.6 ml) should be used, before starting the actual Busulfan Tillomed infusion, and then flushed with sodium chloride 9 mg/ml (0.9%) for injection or 5% glucose solution for injection.
Busulfan Tillomed must not be infused simultaneously with another intravenous solution.
Polycarbonate syringes must not be used with Busulfan Tillomed.
For single use only. Only clear, particle-free solutions should be used.

Storage conditions
Unopened vials:
Store in the refrigerator (2 °C – 8 °C).
Diluted solution:
Chemical and physical in-use stability has been demonstrated for 8 hours (including infusion time) after dilution in 5% glucose or sodium chloride 9 mg/ml (0.9%) for injection, when stored at 20 °C ± 5 °C, or for 6 hours after dilution in sodium chloride 9 mg/ml (0.9%) 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, unless the dilution method excludes the risk of microbial contamination, the product should be used immediately. If not used immediately, the user is responsible for the duration and conditions of in-use storage.

3. PROCEDURE FOR PROPER DISPOSAL

Any unused or waste medicinal product should be disposed of in accordance with local requirements
for cytotoxic medicinal products.