Label: Information for the User

Busulfan Accord 6 mg/ml Concentrate for Solution for Infusion EFG

busulfan

Read this label carefully before starting to use this medicine, because it contains important information for you.

• Keep this label, as you may need to read it again.
• If you have any questions, consult your doctor or pharmacist.
• If you experience any adverse effects, consult your doctor or pharmacist, even if they are not listed in this label.

1. What is Busulfan Accord and how is it used

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

3. How to use Busulfan Accord

4. Possible adverse effects

5. Storage of Busulfan Accord

6. Contents of the package and additional informationl

Busulfan Accord contains the active ingredient busulfan, which belongs to a group of medicines called alkylating agents. Busulfan Accord destroys the original bone marrow before transplantation.

Busulfan Accord is used in adults, newborns, children, and adolescents aspre-transplant treatment.

In adults, Busulfan Accord is used in combination with cyclophosphamide or fludarabine.

In newborns, children, and adolescents, Busulfan Accord is used in combination with cyclophosphamide or melphalan.

This medication will be administered to prepare you before receiving a bone marrow or hematopoietic progenitor cell transplant.

No use BusulfanoAccord:

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

Warnings and Precautions

Busulfan Accord is a potent cytotoxic medication that causes a significant decrease in blood cells. At the recommended dose, this is the desired effect. Therefore, strict control 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 another medication.

After a hematopoietic cell transplant (HCT) at high doses of your treatment in combination with other medications, cases of blood clot formation in small blood vessels may occur.

Use of Busulfan Accord with other medications

Inform your doctor or pharmacist if you are using, have used recently, or may need to use any other medication, including those purchased without a prescription; especially, inform your doctor or pharmacist if you are taking Deferasirox (a medication used to remove excess iron from the body). Busulfan Accord may interact with other medications.

You should exercise special caution if you are using itraconazole and metronidazole (used in the treatment of certain types of infections) or cetobemidone (used in the treatment of pain), as it may increase the occurrence of adverse 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 intend 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 should discontinue breastfeeding before starting treatment with Busulfan Accord.

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

It may not be possible to conceive (infertility) after treatment with busulfan. If you wish to have children, you should consult with your doctor before treatment. Busulfan Accord may produce menopausal symptoms and in preadolescent girls may prevent the onset of puberty.

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

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 (0 to 17 years):

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

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

Medications before Busulfan Administration:

Before receiving Busulfan Accord, you will be treated with:

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

antiemetic medications to prevent vomiting.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

Severe side effects

The most severe side effects associated with treatment with busulfan or the transplant procedure may include a decrease in circulating blood cell count (an effect intended by the medication to prepare you for the transplant), infections, liver disorders such as bile duct obstruction, graft-versus-host disease (the transplant reacts against your body), and respiratory complications. Your doctor will regularly monitor your blood counts and liver enzymes to detect and treat these side effects.

Other side effects may include:

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

Blood:decrease in the number of circulating 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 (widening of blood vessels), and blood clot formation.Respiratory:difficulty breathing, nasal secretion (rhinitis), sore throat, cough, hiccups, nasal bleeding, and abnormal breathing sounds.Gastrointestinal:nausea, inflammation of the oral mucosa, vomiting, abdominal pain, diarrhea, constipation, chest burning, anal discomfort, and fluid in the abdomen.Hepatic:enlargement of the liver, jaundice, bile duct obstruction.Skin:eruption, itching, hair loss.Musculoskeletal and skeletal:back pain, muscle pain, and mandibular pain.Renal:increased creatinine excretion, urinary discomfort, and decreased urine production and hematuria.General:fever, headache, weakness, chills, pain, allergic reactions, edema, chest pain, and mucosal inflammation.Complementary examinations: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:change and abnormalities in heart rhythm, fluid retention or inflammation around the heart, decreased ejection fraction.Respiratory:increased respiratory rate, respiratory insufficiency, alveolar hemorrhage, asthma, pulmonary collapse, fluid around the lung.Gastrointestinal:inflammation of the esophageal mucosa, intestinal paralysis, hematemesis.Skin:skin color disorders, skin redness, skin peeling.Renal:increased nitrogenous components in the blood, moderate renal insufficiency, renal disorder.

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

Nervous system:delirium, nervousness, hallucinations, agitation, abnormal brain function,intracerebral hemorrhage, and convulsions.Cardiac:thrombi in the femoral artery, additional heartbeats, decreased heart rate, diffuse capillary fluid leakage.Respiratory:decreased oxygen in the blood.Gastrointestinal:gastric and/or intestinal bleeding.

Unknown frequency (cannot be estimated from available data)

Sexual gland dysfunction.

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

Menopausal symptoms and female infertility.

Cerebral abscesses. Generalized skin inflammation, generalized infection.

Liver disorders.

Increased lactate dehydrogenase in the blood.

Increased uric acid and urea in the blood.

Incomplete tooth development.

Reporting side effects

If you experience any type of side effect, consult your doctor or pharmacist, even if it is a side effect that does not appear in this prospectus. You can also report them directly through theSpanish System for Pharmacovigilance of Medicines for Human Use:https://www.notificaram.es. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

Do not use this medication after the expiration date that appears on the vial label and on the box after CAD.

Sealed vial:

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

Diluted solution:

Chemical and physical stability has been confirmed for use after dilution with a 5% glucose solution or 0.9% sodium chloride solution (9 mg/ml) for:

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

Do not freeze.

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

Medications should not be disposed of through the drains or trash. Ask your pharmacist how to dispose of the containers and medication that you no longer need. This will help protect the environment.

Busulfan CompositionAccord

• 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 contents of the container

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 transparent and colorless solution free of visible particles and is available in containers containing 1 vial or 8 vials of 10 ml of concentrate for solution for infusion.

Only some container sizes may be marketed.

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

Marketing Authorization Holder

Accord Healthcare S.L.U.

World Trade Center

Moll de Barcelona, s/n

Edifici Est, 6th floor

08039 Barcelona

Spain

Responsible for manufacturing

Accord Healthcare Polska Sp.z o.o.,

ul. Lutomierska, 50, 95-200

Pabianice,

Poland

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

Last review date of this leaflet: August 2020

The detailed and updated information on this medicine is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS) http://www.aemps.es/

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This information is intended solely for healthcare professionals:

PREPARATION GUIDE

BusulfanAccord6 mg/ml concentrate for solution for infusion

Busulfan

Read this guide before preparation and administration of Busulfan.

1. PRESENTATION

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

Busulfan Accord must be diluted before administration.

2. RECOMMENDATIONS FOR SAFE HANDLING

Proper handling and disposal procedures for anticancer medications should be followed.

All transfer procedures require strict adherence to aseptic techniques; preferably, a laminar flow hood with vertical airflow 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 the same) comes into contact with the skin or mucous membranes, wash the area immediately and abundantly with water.

Calculation of the amount of BusulfanAccordand diluent for the solution

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

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

The amount of BusulfanAccordand diluent for administration will be calculated as follows:

for a patient with a body weight of Y kg:

• Amount of BusulfanAccord:

Y: patient's body weight in kg

D: busulfan dose (see Technical Dossier section 4.2.)

• Amount of diluent:

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

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

Preparation of the infusion solution

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

• A syringe that is not made of polycarbonate, equipped with a needle, should be used:

• The calculated volume of Busulfan Accord should be withdrawn from the vial.
• The contents of the syringe should be introduced into an injection bag (or syringe) that already contains the calculated amount of the chosen diluent. Busulfan Accord should always be added on top of the diluent, not the other way around. Busulfan Accord should not be introduced into an infusion bag that does not contain sodium chloride 9 mg/ml (0.9%) injection solution or 5% glucose injection solution.

• The diluted solution should be mixed carefully by inverting several times.

After dilution, 1 ml of 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 circuit should be washed with 5 ml of sodium chloride 9 mg/ml (0.9%) injection solution or glucose injection solution.

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

The total dose of BusulfanAccordprescribed should be administered within 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 system with a minimum dead space (e.g., 0.3-0.6 ml). Purgation with the medication solution before infusion of BusulfanAccordand washing afterwards with sodium chloride 9 mg/ml (0.9%) injection solution or glucose injection solution.

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

Polycarbonate syringes should not be used with BusulfanAccord.

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

Storage conditions

Sealed vials:

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

Diluted solution:

It has been confirmed that the chemical and physical stability during use after dilution with 5% glucose solution or sodium chloride 9 mg/ml (0.9%) injection solution is 4 hours (including infusion time) after dilution if stored at 20°C -25°Cor 15 hours after dilution if stored between 2 °C-8 °C plus 3 additional hours at 20°C -25°C(including infusion time).

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

3. PROCEDURE FOR PROPER DISPOSAL

The 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.