BUSULFAN Fresenius Kabi 6 mg/ml concentrate for infusion solution

Introduction

Package Leaflet: Information for the User

Busulfan Fresenius Kabi 6mg/ml Concentrate for Solution for Infusion

busulfan

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 further questions, ask your doctor.
• If you experience any side effects, talk to your doctor or pharmacist, even if they are not listed in this leaflet. See section 4.

Contents of the pack:

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

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

This medicine contains the active substance busulfan, which belongs to a group of medicines called alkylating agents. Busulfan Fresenius Kabi destroys the original bone marrow before the transplant.

Busulfan Fresenius Kabi is used in adults, newborns, children, and adolescents as pre-treatment before transplant.

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

In newborns, children, and adolescents, the medicine is used in combination with cyclophosphamide or melphalan.

This medicine will be given to you to prepare you before receiving a bone marrow or hematopoietic stem cell transplant.

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

Do not use Busulfan Fresenius Kabi:

• 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 Fresenius Kabi 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 is required.

There is a possibility that the use of Busulfan Fresenius Kabi may increase the risk of developing another malignant tumor in the future. You should inform your doctor:

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

Blood clots may form in small blood vessels after hematopoietic stem cell transplantation (HSCT) with high doses of your treatment in combination with other medicines.

Using Busulfan Fresenius Kabi with other medicines

Tell your doctor or pharmacist if you are using, have recently used, or might use other medicines, including those obtained without a prescription. Busulfan Fresenius Kabi may interact with other medicines.

You should be especially careful if you are using itraconazole and metronidazole (used to treat certain types of infections) or cetobemidone (used to treat pain) or deferasirox (a medicine used to remove excess iron from the body), as this may increase the risk of side effects.

The use of paracetamol during the 72 hours prior to or during the administration of Busulfan Fresenius Kabi 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 Fresenius Kabi. Women should not be pregnant during treatment with Busulfan Fresenius Kabi or for 6 months after the end of treatment.

Women should stop breastfeeding before starting treatment with Busulfan Fresenius Kabi.

Effective contraceptive methods should be used when one partner is being treated with Busulfan Fresenius Kabi.

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

Men treated with Busulfan Fresenius Kabi should not father children during and up to 6 months after the end of treatment.

3. How to use Busulfan Fresenius Kabi Dose and administration:

Dose and administration:

The dose of busulfan will be calculated based on your 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 before the transplant.

Busulfan Fresenius Kabi in combination with fludarabine:

• The recommended dose of busulfan is 3.2 mg/kg.
• Each infusion will last 3 hours.
• Busulfan Fresenius Kabi 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 Fresenius Kabi in combination with cyclophosphamide or melphalan depends on body weight and ranges from 0.8 to 1.2 mg/kg.

Medicines before administration of Busulfan Fresenius Kabi:

Before receiving Busulfan Fresenius Kabi, 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. Contact your doctor or nurse immediately if you have any of the following symptoms. 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 blood cells (red and white) 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, heartburn, anal discomfort, and fluid in the abdomen. Hepatic:increased liver size, jaundice, obstruction of a liver vein. Skin:rash, itching, hair loss.

Musculoskeletal and bone:back pain, muscle and joint pain. Renal:increased creatinine clearance, discomfort while urinating, and decreased 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 enzyme levels 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:increased nitrogenous component levels in the blood, moderate renal insufficiency, and renal disorder.

Rare (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 capillary bleeding (small blood vessels). Respiratory:decreased oxygen levels in the blood. Gastrointestinal:stomach and/or intestinal bleeding.

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

Sexual gland dysfunction.

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

Menopausal symptoms and female infertility.

Brain abscess. Skin inflammation, generalized infection. Liver disorders.

Increased lactate dehydrogenase levels in the blood. Increased uric acid and urea levels in the blood.

Incomplete dental development.

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

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. You can also report side effects directly through the national reporting system included in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Busulfan Fresenius Kabi

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.

Sealed vial:

Store in a refrigerator (2°C-8°C).

Diluted solution:

Chemical and physical stability has been demonstrated after dilution in 5% glucose solution or 9 mg/ml (0.9%) sodium chloride solution for 8 hours (including infusion time) when stored at 25°C ± 2°C or 12 hours when stored at 2°C and 8°C followed by 3 hours stored at 25°C ± 2°C (including infusion time). Do not freeze.

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 Contents and Additional Information

Composition of Busulfan Fresenius Kabi

• The active ingredient is busulfan. One ml of concentrate contains 6 mg of busulfan (60 mg in a 10 ml vial) and (240 mg in a 40 ml 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 Contents

This medication is a concentrate for solution for infusion. When diluted, Busulfan Fresenius Kabi is a clear, colorless, and viscous solution.

Busulfan Fresenius Kabi is supplied in transparent glass vials. Each vial is wrapped with a retractable plastic film.

Each vial contains either 10 ml or 40 ml of concentrate.

A pack contains 8 vials of 10 ml each or one vial of 40 ml.

Marketing Authorization 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

You can request more information about this medication from the marketing authorization holder.

Date of the Last Revision of this Leaflet:05/2025

Other Sources of Information

Detailed information about this medication is available on the European Medicines Agency website http://www.ema.europa.eu.

This information is intended only for healthcare professionals:

PREPARATION GUIDE

Busulfan Fresenius Kabi 6 mg/ml Concentrate for Solution for Infusion

Busulfan

Read this guide before preparing and administering busulfan.

1. Presentation

Busulfan is presented as a clear, colorless, and viscous solution in transparent glass vials of 10 ml and 40 ml. Busulfan must be diluted before administration.

1. Recommendations for Safe Handling

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

All transfer procedures require strict adherence to aseptic techniques; a safety cabinet with vertical laminar flow is preferred.

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 medication, busulfan, or a solution of it comes into contact with the skin or mucous membranes, wash the area immediately and thoroughly with water.

After multiple needle entries and medication withdrawal, the 40 ml vials maintain microbial, chemical, and physical stability for a maximum of 28 days at 5°C ± 3°C. Other use times and storage conditions are the responsibility of the user.

Calculation of the amount of busulfan to dilute and diluent

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

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

The amount of concentrate and diluent for administration will be calculated as follows for a patient with a body weight of Y kg:

• Amount of busulfan:

Y (kg) x D (mg/kg)

= A ml of busulfan to dilute

6 (mg/ml)

Y: patient's body weight in kg

D: busulfan dose (see section 4.2.)

• Amount of diluent:

(A ml of busulfan) x (10) = B ml of diluent

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

Preparation of the Infusion Solution

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

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

• the calculated volume of concentrate should be withdrawn from the vial.

• the contents of the syringe should be introduced into a bag (or syringe) for injection that already contains the calculated amount of the chosen diluent. Busulfan should always be added to the diluent, not the other way around. Busulfan should not be introduced into an infusion bag that does not contain the injectable sodium chloride solution 9 mg/ml (0.9%) or the injectable glucose solution 5%.

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

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

The diluted concentrate is a clear, colorless solution.

Instructions for Use

Before and after each infusion, the catheterization circuit should be flushed with about 5 ml of injectable sodium chloride solution 9 mg/ml (0.9%) or injectable glucose solution (5%).

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

The total dose of busulfan 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 set with a minimum dead space (e.g., 0.3-0.6 ml). Flush with the medication solution before busulfan infusion and wash afterwards with injectable sodium chloride solution 9 mg/ml (0.9%) or injectable glucose solution (5%).

Busulfan should not be infused concomitantly with another intravenous solution.

Due to incompatibility, infusion components containing polycarbonate should not be used with busulfan.

Medication for single use. Only clear, particle-free solutions should be used.

Storage Conditions

Closed Vials:

Store in a refrigerator (2°C-8°C).

Diluted Solution:

Chemical and physical stability has been demonstrated after dilution with injectable glucose solution 5% or sodium chloride solution 9 mg/ml (0.9%) for 8 hours (including infusion time) when stored at 25°C ± 2°C or 12 hours when stored at 2°C-8°C followed by 3 hours stored at 25°C ± 2°C (including infusion time).

From a microbiological point of view, the product should be used immediately after dilution. If not used immediately, the storage times and conditions during use are the responsibility of the user and normally would not be longer than those mentioned above, although the dilution has taken place in controlled and validated aseptic conditions.

Do not freeze the diluted solution.

It is recommended that healthcare professionals and end-users follow best practices, such as perforating perpendicular to the surface of the stopper and within the target ring to avoid hitting the stopper legs, perforating at adequate speeds, and limiting the reuse of needles to help reduce the risks of perforation and fragmentation of the stopper.

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.