BUSULFAN ACCORD 6 mg/ml CONCENTRATE FOR INFUSION SOLUTION

2. What you need to know before you use Busulfan Accord

Do not use Busulfan Accord:

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

Warnings and precautions

Busulfan Accord is a potent cytotoxic medicine that causes a significant decrease in blood cell counts. At the recommended dose, this is the desired effect. For this reason, strict monitoring should be performed.

There is a possibility that the use of Busulfan Accord may increase the risk of developing another malignant tumor in the future.

You should inform your doctor:

• if you have a liver, kidney, heart, or lung problem,
• if you have a history of seizures,
• if you are taking other medicines.

After a hematopoietic stem cell transplant (HCT) in high doses of your treatment in combination with other medicines, there may be cases of blood clot formation in small blood vessels.

Using Busulfan Accord with other medicines

Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines, including those bought without a prescription; especially, tell your doctor or pharmacist if you are taking Deferasirox (a medicine used to remove excess iron from the body). Busulfan Accord may interact with other medicines.

You should be careful if you are using itraconazole and metronidazole (used to treat certain types of infections) or cetobemidone (used to treat pain), as it may increase the occurrence of side effects.

The use of paracetamol during the 72 hours prior to or during the administration of Busulfan Accord should be done with caution.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor before receiving treatment with Busulfan Accord. Women should not be pregnant during treatment with Busulfan Accord or in the 6 months following its completion.

Women must stop breastfeeding before starting treatment with Busulfan Accord.

Effective contraceptive methods should be used when one member of the couple is being treated with Busulfan Accord.

It is possible that you may not be able to become pregnant (infertility) after treatment with busulfan. If you wish to have children, you should consult your doctor before treatment. Busulfan Accord may cause symptoms of menopause and in pre-adolescent girls may prevent the onset of puberty.

Men treated with Busulfan Accord should not father children during and up to 6 months after completing treatment.

3. How to use Busulfan Accord

Dose and administration:

The dose of Busulfan Accord will be calculated based on your body weight.

In adults:

Busulfan in combination with cyclophosphamide:

• The recommended dose of Busulfan Accord is 0.8 mg/kg
• Each infusion will last 2 hours
• Busulfan Accord will be administered every 6 hours for 4 consecutive days before the transplant.

Busulfan in combination with fludarabine:

• The recommended dose of Busulfan Accord is 3.2 mg/kg
• Each infusion will last 3 hours
• Busulfan Accord will be administered once a day for 2 or 3 consecutive days before the transplant.

In newborns, children, and adolescents (from 0 to 17 years):

The recommended dose of Busulfan Accord in combination with cyclophosphamide or melphalan depends on your body weight and ranges from 0.8 to 1.2 mg/kg.

• Each infusion lasts 2 hours.
• Busulfan Accord will be administered every 6 hours for 4 consecutive days before the transplant.

Medicines before administration of Busulfan:

Before receiving Busulfan Accord, you will be treated with:

• anticonvulsant medicines to prevent seizures (phenytoin or benzodiazepines) and

antiemetic medicines to prevent 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 side effects associated with busulfan treatment or the transplant procedure may include a decrease in the number of circulating blood cells (an effect that is intended with the medicine to prepare you for the transplant), infections, liver disorders such as obstruction of a liver vein, graft-versus-host disease (the graft reacts against your body), and pulmonary complications. Your doctor will regularly monitor your blood counts and liver enzymes to detect and treat these effects.

Other side effects may include:

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

Blood:decrease in the number of red and white blood cells and platelets. Infections. Nervous system:insomnia, anxiety, dizziness, and depression. Nutrition:loss of appetite, decrease in magnesium, calcium, potassium, phosphate, and albumin levels in the blood, and increase in blood sugar levels. Cardiac:increased heart rate, increased or decreased blood pressure, vasodilation (increase in blood vessel diameter), and blood clot formation. Respiratory:difficulty breathing, nasal secretion (rhinitis), sore throat, cough, hiccups, nosebleeds, and abnormal breathing sounds. Gastrointestinal:nausea, inflammation of the mouth mucosa, vomiting, abdominal pain, diarrhea, constipation, chest burning, anal discomfort, and fluid in the abdomen. Hepatic:increase in liver size, jaundice, obstruction of a liver vein. Skin:rash, itching, hair loss. Musculoskeletal and bone:back pain, muscle and jaw pain. Renal:increase in creatinine elimination, discomfort while urinating, and decrease in urine production and blood in urine. General:fever, headache, weakness, chills, pain, allergic reactions, edema, pain or inflammation at the injection site, chest pain, and mucosal inflammation. Investigations:elevated 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, and decreased ejection fraction. Respiratory:increased respiratory rate, respiratory failure, alveolar hemorrhage, asthma, collapse of small areas of the lung, and fluid around the lung. Gastrointestinal:esophageal mucosa inflammation, intestinal paralysis, and vomiting blood. Skin:skin color disorders, skin redness, and skin peeling. Renal:increase in nitrogenous components in the blood, moderate renal failure, and renal disorder.

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

Nervous system:delirium, nervousness, hallucinations, agitation, abnormal brain function, cerebral hemorrhage, and seizures. Cardiac:femoral artery thrombosis, extra heartbeats, decreased heart rate, and diffuse bleeding from capillaries (small blood vessels). Respiratory:decrease in blood oxygen levels. Gastrointestinal:stomach and/or intestinal bleeding.

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

Sexual gland dysfunction.

Eye disorders including cataract (lens opacity) and blurred vision (corneal thinning).

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

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 development of teeth.

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist, even if they are not listed in this leaflet. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Conservation of Busulfan Accord

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the vial label and carton after EXP.

Closed vial:

Store in a refrigerator (2 °C - 8 °C).

Solution for infusion:

It has been confirmed that the chemical and physical stability during use after dilution with a 5% glucose solution or 9 mg/ml (0.9%) sodium chloride is:

• 4 hours (including infusion time) after dilution if stored at 20 °C - 25 °C.
• 15 hours after dilution when stored at 2 °C - 8 °C plus 3 additional hours stored at 20 °C - 25 °C (including infusion time).
• .

Do not freeze.

From a microbiological point of view, the product should be used immediately after dilution. If not used immediately, the storage conditions during use and before use are the responsibility of the user.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Container Content and Additional Information

Composition of Busulfan Accord

• The active ingredient is busulfan. One ml of concentrate contains 6 mg of busulfan (60 mg in the vial). After dissolution: one ml of solution contains approximately 0.5 mg of busulfan.
• The other components are dimethylacetamide and macrogol 400.

Appearance of the Product and Container Content

Busulfan Accord is a concentrate for solution for infusion that is supplied in transparent glass vials. Each vial contains 60 mg of busulfan.

Busulfan Accord is a clear and colorless solution free of visible particles and available in packs containing 1 vial or 8 vials of 10 ml of concentrate for solution for infusion.

Only some pack sizes may be marketed.

When Busulfan Accord is diluted, a clear and colorless solution is obtained.

Marketing Authorization Holder

Accord Healthcare S.L.U.

World Trade Center

Moll de Barcelona, s/n

Edifici Est, 6ª planta

08039 Barcelona

Spain

Manufacturer

Accord Healthcare Polska Sp.z o.o.,

ul. Lutomierska, 50, 95-200

Pabianice,

Poland

This pharmaceutical product is authorized in the EEA Member States under the following names:

Date of the Last Revision of this Leaflet: July 2025

Detailed and updated information on this medicinal product is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.es/

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This information is intended only for healthcare professionals:

PREPARATION GUIDE

Busulfan Accord 6 mg/ml concentrate for solution for infusion

Busulfan

Read this guide before preparing and administering Busulfan.

1. Presentation

Busulfan Accord is presented as a clear and colorless solution in 10 ml transparent glass vials of type I.

Busulfan Accord must be diluted before administration.

1. Recommendations for Safe Handling

Adequate handling and disposal procedures for anticancer drugs should be taken into account.

All transfer procedures require strict compliance with aseptic techniques; preferably, a safety cabinet with vertical laminar flow should be used.

As with other cytotoxic compounds, caution should be exercised when handling or preparing the busulfan solution:

• It is recommended to use gloves and protective clothing.
• If the product (busulfan or a solution of it) comes into contact with the skin or mucous membranes, wash the area immediately and abundantly with water.

Calculation of the amount of Busulfan Accord and diluent for the solution

Before using the Busulfan Accord specialty, it is necessary to dilute the product with a 9 mg/ml (0.9%) sodium chloride injectable solution or a 5% glucose injectable solution.

The amount of diluent should be equal to 10 times the volume of Busulfan Accord, ensuring that the final concentration of busulfan is approximately 0.5 mg/ml.

The amount of Busulfan Accord and diluent for administration will be calculated as follows:

for a patient with a body weight of Y kg:

• Amount of Busulfan Accord:

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 Accord) x (10) = B ml of diluent

To prepare the final solution for infusion, add (A) ml of Busulfan Accord to (B) ml of diluent (0.9% sodium chloride injectable solution or 5% glucose injectable solution).

Preparation of the solution for infusion

Busulfan Accord should be prepared by healthcare professionals using sterile transfer techniques.

• A non-polycarbonate syringe with a needle should be used:

• extract the calculated volume of Busulfan Accord from the vial.
• introduce the contents of the syringe into a bag (or syringe) for injection that already contains the calculated amount of the chosen diluent. Always add Busulfan Accord to the diluent, not the other way around. Do not introduce Busulfan Accord into an infusion bag that does not contain the 0.9% sodium chloride injectable solution or the 5% glucose injectable solution.

• The diluted solution should be carefully mixed by several inversions.

After dilution, 1 ml of the infusion solution contains 0.5 mg of busulfan.

After dilution, Busulfan Accord is a clear and colorless solution.

Instructions for use

Before and after each infusion, the catheterization circuit should be flushed with approximately 5 ml of 0.9% sodium chloride injectable solution or 5% glucose solution.

Residual medication should not be administered through the administration system, as rapid injection of busulfan has not been studied and is not recommended.

The total dose of Busulfan Accord prescribed should be administered over a period of two or three hours, depending on the conditioning regimen.

Small volumes should be administered over 2 hours using an electronic syringe pump. In this case, it is recommended to use an infusion device with a minimum dead space (e.g., 0.3-0.6 ml). Flush with the medication solution before infusing Busulfan Accord and then flush with 0.9% sodium chloride injectable solution or 5% glucose solution.

No other intravenous solution should be administered concomitantly with this infusion.

Polycarbonate syringes should not be used with Busulfan Accord.

Single-use product. Only clear solutions free of particles should be used.

Storage Conditions

Closed vials:

Store in a refrigerator (2°C - 8°C).

Diluted solution:

Chemical and physical stability after dilution with a 5% glucose solution or 0.9% sodium chloride solution has been confirmed for 4 hours (including infusion time) after dilution if stored at 20°C - 25°C or for 15 hours after dilution if stored at 2°C-8°C plus an additional 3 hours at 20°C - 25°C (including infusion time).

From a microbiological point of view, the diluted solution should be used immediately.

1. PROCEDURE FOR PROPER DISPOSAL

Disposal of unused medication and all materials that have come into contact with it should be carried out in accordance with local regulations regarding the disposal of cytotoxic medications.