Busulfan Fresenius Kabi

Package leaflet: Information for the user

Busulfan Fresenius Kabi 6 mg/ml concentrate for

solution for infusion
busulfan.
Please 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 questions, ask your doctor.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor. See section 4.

Contents of this leaflet:

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

1. What Busulfan Fresenius Kabi is and what it is used for

This medicinal product contains the active substance busulfan, which belongs to a group of medicines called alkylating agents. Busulfan Fresenius Kabi destroys the original bone marrow prior to transplantation.
Busulfan Fresenius Kabi is used in adults, neonates, children, and adolescents as a preparative treatment prior to transplant.
In adults, Busulfan Fresenius Kabi is used in combination with cyclophosphamide or fludarabine.
In neonates, children, and adolescents, this medicinal product is used in combination with cyclophosphamide or melphalan.
You will be given this preparative medicine before undergoing a bone marrow transplant or hematopoietic stem cell transplant.

2. What you need to know before using Busulfan Fresenius Kabi

Do not use Busulfan Fresenius Kabi:

• 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 Fresenius Kabi is a potent cytotoxic medicine that causes marked suppression of blood cells. At the recommended dose, this is the intended effect. Therefore, close monitoring will be carried out.
The use of Busulfan Fresenius Kabi 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 had epileptic seizures,
• if you are taking other medicines.

Blood clots in small blood vessels may occur following haematopoietic cell transplantation (HCT) when this treatment is given at high doses in combination with other medicines.
Other medicines and Busulfan Fresenius Kabi
Tell your doctor if you are taking, have recently taken, or might take any other medicines, including those without a prescription. Busulfan Fresenius Kabi may interact with other medicines.
Particular care is needed if you are taking itraconazole and metronidazole (used for certain types of infections) or ketobemidone (used for pain) or deferasirox (a medicine used to remove excess iron from the body), as this could increase side effects.
The use of paracetamol within 72 hours before or during administration of Busulfan Fresenius Kabi should be done with caution.
Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor before treatment with Busulfan Fresenius Kabi. Women must not become pregnant during treatment with busulfan and for 6 months after treatment ends.
Women must stop breastfeeding during treatment with Busulfan Fresenius Kabi.
Appropriate contraceptive precautions should be taken when your partner is being treated with Busulfan Fresenius Kabi.
You may no longer be able to have children (infertility) after treatment with Busulfan Fresenius Kabi. If you are interested in having children, discuss this with your doctor before starting treatment. Busulfan Fresenius Kabi may also cause symptoms of menopause and in pre-adolescent girls may prevent the onset of puberty.
Men treated with Busulfan Fresenius Kabi are advised not to father a child during treatment and for 6 months after treatment ends.

3. How to use Busulfan Fresenius Kabi

Dosage and administration:
The busulfan dose will be calculated based on body weight.

In adults
Busulfan Fresenius Kabi in combination with cyclophosphamide:

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

Busulfan Fresenius Kabi in combination with fludarabine

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

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

Therapies prior to treatment with Busulfan Fresenius Kabi:
Prior to treatment with Busulfan Fresenius Kabi, you will be given:

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

4. Possible side effects

Like all medicines, Busulfan Fresenius Kabi can cause side effects, although not everyone experiences
them.
Serious side effects:
The most serious side effects of busulfan therapy or following transplant procedures may include
reduction in circulating blood cell counts (the intended effect of the medicine to prepare you for transplant
infusion), infections, liver disorders including blockage of a liver vein, graft-versus-host disease (in which
the transplant attacks your body), and pulmonary complications. Contact your doctor immediately if you
experience any of the following symptoms. Your doctor will regularly monitor your blood cell counts and
liver enzymes to assess and manage these events.
Other side effects may include:
Very common (may affect more than 1 in 10 people):
Blood: reduction in circulating blood cells (red and white blood cells) and platelets. Infections.
Nervous system: insomnia, anxiety, dizziness, depression. Nutrition: loss of appetite, reduced levels
of magnesium, calcium, potassium, phosphate, albumin in the blood, and increased blood glucose.
Cardiac: increased heart rate, increased or decreased blood pressure, vasodilation (a condition in
which blood vessels widen), and blood clots. Respiratory: shortness of breath, nasal discharge (rhinitis),
pharyngitis, cough, hiccups, nosebleeds, abnormal breathing sounds. Gastrointestinal: nausea,
inflammation of the mucous lining of the mouth, vomiting, abdominal pain, diarrhoea, constipation,
heartburn, anal pain, fluid in the abdomen. Hepatic: enlarged liver, jaundice, blockage of a liver vein.
Skin: skin rashes, itching, hair loss.
Muscles and bones: back pain, muscle and joint pain. Renal: increased creatinine excretion,
difficulty urinating, decreased urine output, and blood in the urine. General disorders: fever, headache,
weakness, chills, pain, allergic reactions, oedema, generalized pain or inflammation at the injection site,
chest pain, inflammation of the mucous membranes. Clinical investigations: increased liver enzymes and
weight gain.
Common (may affect up to 1 in 10 people):
Nervous system: confusion, nervous system disorders. Nutrition: low sodium levels in the blood.
Cardiac: changes and abnormalities in heart rhythm, fluid retention or inflammation around the heart,
reduced cardiac output. Respiratory: increased respiratory rate, respiratory failure, alveolar haemorrhage,
asthma, collapse of small areas of the lung, fluid around the lung. Gastrointestinal: inflammation of the
oesophageal mucosa, intestinal paralysis, vomiting with blood. Skin: skin colour changes, skin
redness, skin peeling. Renal: increased levels of nitrogen-containing compounds in the blood, moderate
renal failure, kidney disorders.
Uncommon (may affect up to 1 in 100 people):
Nervous system: delirium, nervousness, hallucinations, agitation, abnormal brain function, cerebral
haemorrhage, and epileptic seizures. Cardiac: femoral arterial thrombosis, extrasystoles, decreased
heart rate, widespread leakage of fluid from capillaries (small blood vessels). Respiratory: decreased
levels of oxygen in the blood. Gastrointestinal: bleeding in the stomach and/or intestines.
Not known (frequency cannot be estimated from the available data):
Sex gland dysfunction.
Disorders of the lens, including clouding of the eye's lens (cataract) and blurred vision (corneal thinning).
Menopausal symptoms and female infertility.
Brain abscess, skin inflammation, generalized infection.
Liver disorders.
Increased lactate dehydrogenase in the blood.
Increased uric acid and urea in the blood.
Incomplete tooth development.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, consult your doctor, pharmacist,
or nurse. You may also report side effects directly via the national reporting system at the 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 Fresenius Kabi

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial label and on the box after Exp.
Unopened vials
Store in a refrigerator (2 °C–8 °C).
Reconstituted solution:
Chemical and physical stability after dilution in 5% glucose solution for injection or 9 mg/ml (0.9%) sodium chloride solution has been demonstrated for 8 hours (including infusion time) after dilution when stored at 25 °C ± 2 °C, or for 12 hours after dilution when stored at 2 °C–8 °C and subsequently kept at 25 °C ± 2 °C for 3 hours (including infusion time). Do not freeze.
Do not dispose of medicines 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 Fresenius Kabi 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 excipients are dimethylacetamide and macrogol 400.

Description of the appearance of Busulfan Fresenius Kabi and contents of the pack
Busulfan Fresenius Kabi is a concentrate for solution for infusion. Once diluted,
Busulfan Fresenius Kabi is a clear, colourless, viscous solution.
Busulfan Fresenius Kabi is supplied in clear glass vials; each vial contains 60 mg
of busulfan. Each vial is wrapped in a heat-shrink plastic film.
Each vial contains 10 ml of concentrate.
Packs
Pack containing 8 vials (8 boxes containing 1 vial each).
Marketing Authorisation Holder
Fresenius Kabi Deutschland GmbH
Else-Kröner-Straße 1,
61352 Bad Homburg v.d.Höhe
Germany
Manufacturer
Fresenius Kabi Deutschland GmbH
Pfingstweide 53
61169 Friedberg
Germany
For any information about this medicinal product, please contact the Marketing Authorisation Holder.
Other sources of information
Detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu
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The following information is intended exclusively for medical or healthcare personnel:
INSTRUCTIONS FOR PREPARATION
Busulfan Fresenius Kabi 6 mg/ml concentrate for solution for infusion
Busulfan
Read these instructions before preparing and administering Busulfan Fresenius Kabi.

1. PRESENTATION

Busulfan Fresenius Kabi is presented as a clear, colourless solution in 10 ml clear glass vials (type I). Busulfan Fresenius Kabi must be diluted before administration.

2. SAFETY HANDLING INSTRUCTIONS

Procedures for the proper handling and disposal of antineoplastic medicinal products must be observed.
All transfer procedures must be carried out under aseptic conditions, preferably in a laminar flow hood.
As with other cytotoxic agents, caution must be exercised when handling and preparing busulfan solution:

• The use of gloves and protective clothing is recommended.
• If concentrated or diluted busulfan solution comes into contact with skin or mucous membranes, immediately and thoroughly wash with water.

Calculation of the amount of Busulfan Fresenius Kabi to be diluted and of the diluent

Busulfan Fresenius Kabi must be diluted before use, either in an injectable solution based on sodium chloride 9 mg/ml (0.9%) or in 5% glucose injectable solution.
The volume of diluent must be 10 times the volume of the concentrate, to ensure that the final concentration of Busulfan Fresenius Kabi is approximately 0.5 mg/ml.
For a patient weighing Y kg, the amount of Busulfan Fresenius Kabi and diluent to be administered should be calculated as follows:

• Amount of Busulfan Fresenius Kabi

Y (kg) x D (mg/kg)
-------------------------- = A ml of Busulfan Fresenius Kabi to be diluted
6 (mg/ml)
Y: patient's body weight in kg
D: busulfan dose (see Summary of Product Characteristics, section 4.2)

• Amount of diluent (A ml of Busulfan Fresenius Kabi) x (10) = B ml of diluent

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

Preparation of the infusion solution
Busulfan Fresenius Kabi must be prepared by qualified healthcare personnel using sterile transfer techniques.

• Use a syringe (not made of polycarbonate) with a needle:
  • withdraw the calculated volume of concentrate from the vial.
  • transfer the contents of the syringe into an intravenous bag (or syringe) containing the calculated volume of selected diluent. Always add Busulfan Fresenius Kabi to the diluent; do not add diluent to the concentrate. Do not place Busulfan Fresenius Kabi into an intravenous bag that does not already contain sodium chloride 9 mg/ml (0.9%) injectable solution or 5% glucose injectable solution.
• Mix the diluted solution thoroughly by inverting several times.

After dilution, 1 ml of infusion solution contains 0.5 mg of busulfan.
Diluted Busulfan Fresenius Kabi is a clear, colourless solution.

Instructions for use
Before and after each infusion, flush the indwelling catheter line thoroughly with approximately 5 ml of sodium chloride 9 mg/ml (0.9%) injectable solution or 5% glucose injectable solution.
Do not rapidly flush residual drug from the administration tubing, as rapid infusion of busulfan has not been studied and is not recommended.
The entire prescribed dose of busulfan must be administered over two or three hours, depending on the treatment regimen.
Small volumes may be administered via electric syringe pumps within 2 hours. In this case, an infusion set with minimal priming volume (0.3–0.6 ml) should be used, filled with the solution prior to the start of actual busulfan infusion, and then flushed with sodium chloride 9 mg/ml (0.9%) injectable solution or 5% glucose injectable solution.
Do not administer busulfan infusion simultaneously with another intravenous solution.
Due to incompatibilities, do not use any infusion components containing polycarbonate with busulfan.
For single use only. The product should only be used if the solution is clear and free from particulate matter.

Storage conditions
Unopened vials:
Store in a refrigerator (2 °C – 8 °C).
Diluted solution:
Chemical and physical in-use stability after dilution in 5% glucose injectable solution or sodium chloride 9 mg/ml (0.9%) has been demonstrated for 8 hours (including infusion time) when stored at 25 °C ± 2 °C, or for 12 hours after dilution when stored at 2 °C – 8 °C, followed by 3 hours at 25 °C ± 2 °C (including infusion time).
From a microbiological standpoint, the product should be used immediately after dilution.
If not used immediately, in-use storage times and conditions are the responsibility of the user and normally should not exceed the conditions stated above, provided dilution is performed under controlled and validated aseptic conditions.
Do not freeze the diluted solution.

3. DISPOSAL INSTRUCTIONS

Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations for cytotoxic medicinal products.