Busulfan accord

Package leaflet: Information for the patient

Busulfan Accord, 6 mg/ml, concentrate for solution for infusion
Busulfanum
Please read this leaflet carefully before using this medicine because it contains important
information for you.

• Keep this leaflet so that you can read it again if necessary.
• If you have any questions, please consult your doctor.
• If you experience any adverse reactions, including any adverse reactions not listed in this leaflet, inform your doctor. See section 4.

Contents of the leaflet

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

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

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

2. Important information before using Busulfan Accord

When not to use Busulfan Accord

• 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 she may be pregnant.

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

• if the patient has liver, kidney, heart or lung disease,
• if the patient has had seizures in the past,
• if the patient is currently taking any other medicines.

Cases of small blood vessel clotting may occur after haematopoietic cell transplantation (HCT) following high-dose therapy in combination with other medicines.
Busulfan Accord and other medicines
Tell your doctor about all medicines the patient is currently taking or has recently taken, including medicines obtained without a prescription, as well as any medicines the patient plans to take.
In particular, inform your doctor or pharmacist if the patient is taking deferasirox (a medicine used to remove excess iron from the body). Busulfan Accord may interact with other medicines.
Particular caution is required when itraconazole and metronidazole (used in certain types of infections) or ketobemidone (used to treat pain) are administered concomitantly, as this may lead to increased adverse effects.
Caution should be exercised when using paracetamol within 72 hours before or during administration of Busulfan Accord.
Pregnancy, breastfeeding and effects on fertility
During pregnancy, while breastfeeding, if there is suspicion that the patient may be pregnant, or if pregnancy is planned, consult a doctor before using Busulfan Accord. Women must not become pregnant during treatment with Busulfan Accord and for 6 months after treatment has ended.
Women must stop breastfeeding before starting treatment with Busulfan Accord.
If either partner is being treated with Busulfan Accord, appropriate contraceptive measures must be used.
After treatment with Busulfan Accord, it may not be possible to conceive (infertility). If the patient is considering having children, this should be discussed with the doctor before starting treatment.
Busulfan Accord may also cause symptoms of menopause, and in girls before puberty, it may delay maturation.
Men undergoing treatment with Busulfan Accord are advised not to plan fatherhood during treatment and for 6 months after its completion.

3. How to use Busulfan Accord

Dosage and administration
The dose of Busulfan Accord is calculated based on the patient's body weight.

Adults
Busulfan Accord in combination with cyclophosphamide

• The recommended dose of Busulfan Accord is 0.8 mg/kg body weight.
• Each infusion lasts 2 hours.
• Busulfan Accord is administered every 6 hours for 4 consecutive days prior to transplantation.

Busulfan Accord in combination with fludarabine

• The recommended dose of Busulfan Accord is 3.2 mg/kg body weight.
• Each infusion lasts 3 hours.
• Busulfan Accord is administered once daily for 2 or 3 consecutive days prior to transplantation.

Newborns, children and adolescents (aged 0 to 17 years)
The recommended dose of Busulfan Accord in combination with cyclophosphamide or melphalan is based on body weight and ranges between 0.8 - 1.2 mg/kg body weight.

• Each infusion lasts 2 hours.
• Busulfan Accord is administered every 6 hours for 4 consecutive days prior to transplantation.

Medications administered prior to Busulfan Accord
Before administration of Busulfan Accord, patients receive:

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

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.

Serious adverse reactions
The most serious adverse reactions following administration of busulfan or transplantation procedure may include: reduction in circulating blood cells (an intended effect of the drug used to prepare for transplantation), infections, liver disorders including hepatic veno-occlusive disease, graft-versus-host disease (where the transplanted tissue attacks the patient's body), and pulmonary complications. Your doctor will regularly monitor blood cell counts and liver enzyme levels to detect and manage these complications.

Other adverse reactions 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, and depression. Nutritional status: loss of appetite, decreased levels of magnesium, calcium, potassium, phosphate, and albumin in blood, and increased blood glucose levels. Heart: increased heart rate, high or low blood pressure, vasodilation (increase in diameter of blood vessels), and thrombosis. Respiratory system: shortness of breath, nasal discharge (rhinitis), sore throat, cough, hiccups, nosebleeds, and abnormal respiratory sounds. Gastrointestinal tract: nausea, oral mucositis, vomiting, abdominal pain, diarrhoea, constipation, heartburn, discomfort around the anus, and fluid in the abdominal cavity. Liver: enlarged liver, jaundice. Skin: rash, itching, hair loss. Muscles and bones: back, muscle, and joint pain. Kidneys: increased creatinine excretion, discomfort during urination, reduced urine output, and haematuria. General: fever, headache, fatigue, chills, pain, allergic reaction, oedema, generalised pain or inflammation at the site of administration, chest pain, mucositis.

Diagnostic investigations: elevated liver enzyme activity, increased body weight.

Common (may affect up to 1 in 10 people):
Nervous system: confusion, nervous system disorders. Nutritional status: low blood sodium levels. Heart: changes and disturbances in heart rhythm, presence of fluid in the pericardium or pericarditis, reduced cardiac output. Respiratory system: increased respiratory rate, respiratory failure, alveolar haemorrhage, asthma, atelectasis (collapse of small areas of the lung), pleural effusion. Gastrointestinal tract: oesophagitis, intestinal paralysis, haematemesis (vomiting blood). Skin: skin discoloration, skin redness, skin peeling. Kidneys: increased blood nitrogen compounds, moderate kidney failure, kidney disorders.

Uncommon (may affect up to 1 in 100 people):
Nervous system: delirium, nervousness, hallucinations, agitation, brain dysfunction, intracranial haemorrhage, and seizures. Heart: femoral artery thrombosis, extrasystoles (extra heartbeats), bradycardia (slowed heart function), diffuse capillary leak (leakage from small blood vessels). Respiratory system: decreased oxygen levels in blood. Gastrointestinal tract: gastrointestinal bleeding from the stomach and/or intestine.

Frequency not known (cannot be estimated from available data):
Disorders of the sex glands.

Disorders of the lens, including lens opacity (cataract) and blurred vision (corneal thinning).

Increased blood pressure in the pulmonary blood vessels (pulmonary hypertension).

Symptoms of menopause and infertility in women.

Brain abscess, dermatitis, systemic infection.

Liver disorders.

Increased blood lactate dehydrogenase activity.

Increased blood levels of uric acid and urea.

Incomplete tooth development.

Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor or pharmacist. 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
Phone: +48 22 49 21 301
Fax: +48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Adverse reactions may also be reported to the marketing authorization holder.

Reporting adverse reactions helps to provide more information on the safety of this medicine.

5. How to store Busulfan Accord

Keep this medicine out of sight and reach of children.
Do not use this medicine after the expiry date stated on the vial and carton
after: EXP.
Closed vials:
Store in a refrigerator (2°C - 8°C).
Do not freeze the solution after dilution.
Diluted solution:
Chemical and physical stability after dilution with 5% glucose solution or
sodium chloride 0.9% (9 mg/ml) for injection has been demonstrated for the following periods:

• 4 hours (including infusion time) after dilution, when stored at 20°C - 25°C,
• 15 hours after dilution, when stored at 2°C - 8°C, followed by a period of 3 hours at 20°C - 25°C (including infusion time).

From a microbiological point of view, the product should be used immediately. If the product is not used immediately, the user is responsible for the storage conditions and duration prior to use.
Medicines must not be disposed of via the sewage system or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Contents of the package and other information

What Busulfan Accord 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 0,5 mg of busulfan.
• The other ingredients are: dimethylacetamide and macrogol 400.

What Busulfan Accord looks like and contents of the pack
Busulfan Accord is a concentrate for solution for infusion, available in colourless glass vials: each vial contains 60 mg of busulfan.
Busulfan Accord is a clear, colourless solution without visible solid particles, supplied in packs containing 1 vial or 8 vials of 10 ml concentrate for solution for infusion.
Not all pack sizes may be marketed.
After dilution, the medicine Busulfan Accord is a clear, colourless solution.
Marketing Authorisation Holder:
Accord Healthcare Polska Sp. z o.o.
ul. Taśmowa 7
02-677 Warsaw
Tel: +4 822 577 28 00
Manufacturer/Importer:
Accord Healthcare Polska Sp. z o.o.
ul. Lutomierska 50
95-200 Pabianice
Poland
Accord Healthcare Single Member S.A.
64th Km National Road Athens, Lamia,
32009 Schimatari
Greece
This medicinal product is authorised in the Member States of the European Economic Area under the following names:

The following information is intended for healthcare professionals only.
PREPARATION INSTRUCTIONS
Busulfan Accord, 6 mg/ml, concentrate for solution for infusion
Please read these instructions before preparing and administering Busulfan Accord.

1. DESCRIPTION
Busulfan Accord is available as a clear, colourless solution in 10 ml transparent glass vials (Type I).
Busulfan Accord must be diluted before administration.

2. SAFETY HANDLING RECOMMENDATIONS
Appropriate procedures for the preparation and disposal of cytotoxic medicinal products must be followed.
All transfer procedures must strictly adhere to aseptic techniques, preferably using a vertical laminar airflow cabinet.
As with other cytotoxic agents, caution must be taken during the preparation and administration of busulfan solution:

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

Calculation of the amount of Busulfan Accord and diluent to be used
Before administration, Busulfan Accord must be diluted using 0.9% (9 mg/ml) sodium chloride injection solution or 5% glucose injection solution.
The volume of diluent must be 10 times greater than the volume of Busulfan Accord to achieve a final busulfan concentration of approximately 0.5 mg/ml.

The required amounts of Busulfan Accord and diluent should be calculated as follows:
For a patient with body weight Y kg:

• Amount of Busulfan Accord:

Y (kg) x D (mg/kg) = A ml of Busulfan Accord to be diluted
6 (mg/ml)
Y: patient's body weight in kg
D: busulfan dose (see SmPC, section 4.2)

• Amount of diluent:

(A ml of Busulfan Accord) x (10) = B ml of diluent

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

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

• Using a non-polycarbonate syringe with a needle:
  • Withdraw the calculated volume of Busulfan Accord from the vial;
  • Inject the syringe contents into an infusion bag (or syringe) already containing the calculated volume of the selected diluent. Busulfan Accord must always be added to the diluent, not the diluent to the drug. Busulfan Accord must not be injected into an infusion bag that does not contain 0.9% sodium chloride injection solution (9 mg/ml) or 5% glucose injection solution.
• After dilution, gently mix the solution by inverting several times.

After dilution, 1 ml of the infusion solution contains 0.5 mg of busulfan.
After dilution, Busulfan Accord is a clear, colourless solution.

Instructions for use
Before and after each infusion, flush the intravenous line with approximately 5 ml of 0.9% sodium chloride injection solution (9 mg/ml) or 5% glucose injection solution.
The residual drug remaining in the tubing must not be flushed out, as rapid infusion of busulfan has not been studied and is not recommended.
The entire prescribed dose of Busulfan Accord should be administered over two or three hours, depending on the conditioning regimen.
Small volumes may be administered over 2 hours using an electric syringe pump. In such cases, infusion sets with minimal priming volume (i.e. 0.3–0.6 ml) should be used. The sets must be pre-filled with the drug solution before starting the actual infusion of Busulfan Accord, then flushed with 0.9% sodium chloride injection solution (9 mg/ml) or 5% glucose injection solution.
Busulfan Accord must not be administered simultaneously with any other intravenous solution.
Polycarbonate syringes must not be used for the administration of Busulfan Accord.
For single use only. Use only clear, particle-free solutions.

Storage conditions
Closed vials:
Store in a refrigerator (2°C – 8°C).

Diluted solution:
Chemical and physical in-use stability has been demonstrated for 4 hours after dilution (including infusion time) when stored at 20°C – 25°C, or for 15 hours after dilution when stored at 2°C – 8°C followed by 3 hours at 20°C – 25°C (including infusion time), using either 5% glucose solution or 0.9% sodium chloride injection solution (9 mg/ml).
From a microbiological standpoint, the diluted solution should be used immediately.

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