Busilvex 6 mg/ml concentrate for solution for infusion

Busilvex contains the substance busulfan, which belongs to a group of medicines called alkylating agents. Busilvex destroys the original bone marrow before the transplant.

Busilvex is used in adults, new-born infants, children and adolescents as a treatment prior to transplantation.
In adults Busilvex is used in combination with cyclophosphamide.
In new-born infants, children and adolescents, Busilvex is used in combination with cyclophosphamide or melphalan.
You will receive this preparative medicine before receiving a transplant of either bone marrow or haematopoietic progenitor cell.

Do not use Busilvex:

• if you are allergic (hypersensitive) to busulfan or any of the other ingredients of Busilvex
• if you are pregnant, or think you may be pregnant.

Take special care with Busilvex:

Busilvex is a potent cytotoxic medicine that results in profound decrease of blood cells. At the recommended dose, this is the desired effect. Therefore careful monitoring will be performed. It is possible that use of Busilvex may increase the risk of suffering another malignancy in the future. You should tell your doctor if:

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

It may no longer be possible for you to achieve a pregnancy (infertility) after treatment with busulfan. If you are concerned about having children, you should discuss this with your doctor before treatment. Busilvex can also produce symptoms of menopause and in pre-adolescent girls it can prevent the onset of puberty.

Men treated with Busilvex are advised not to father child during and up to 6 months after treatment.

Taking other medicines:

Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Busilvex may interact with other medicines.

Particular caution should be taken if you use itraconazol (used for certain types of infections) or ketobemidone (used to treat pain), because this may increase the side-effects.

The use of paracetamol during the 72 hours prior to or with Busilvex administration should be used with caution.

Pregnancy and breast-feeding

Tell your doctor if you are pregnant, think you may be pregnant or are breast-feeding, before you receive treatment with Busilvex. Women must not be pregnant during treatment with Busilvex and up to 6 months after treatment.
Women must stopbreast-feeding before starting their treatment with Busilvex.

Adequate contraceptive precautions should be used when either partner is receiving Busilvex.

Dosage:

In adults:The dose will be calculated according to your body weight.
The recommended dose of Busilvex is 0.8 mg per kg of body weight, in combination with cyclophosphamide.

In new-born infants, children and adolescents (0 to 17 years):
The recommended dose of Busilvex in combination with cyclophosphamide or melphalan is based on your body weight varying between 0.8 and 1.2 mg/kg.

Administration:

• Busilvex is administered by a qualified healthcare professional as a central intravenous infusion, after dilution of the individual vial. Each infusion will last 2 hours.
• Busilvex will be administered every 6 hours during 4 consecutive days prior to transplant.

Medicines before you receive Busilvex:

Before receiving Busilvex, you will be medicated with

• anticonvulsive medicines to prevent seizures (phenytoin or benzodiazepines) and
• antiemetic medicines to prevent vomiting.

Like all medicines, Busilvex can cause side effects, although not every body gets them.

Serious side effects:

The most serious side effects of Busilvex therapy or the transplant procedure may include decrease in circulating blood cell counts (intended effect of the medicine to prepare you for your transplant infusion), infection, liver disorders including blocking of a liver vein, graft versus host disease (the graft attacks your body) and pulmonary complications. Your doctor will monitor your blood counts and liver enzymes regularly to detect and manage these events.

Very common side effects (affects more than 1 user in 10):
Blood : decrease of blood circulating cells (red and white) and platelets. Nervous system: insomnia, anxiety, dizziness, and depression. Nutrition : loss of appetite, decrease in magnesium, calcium, potassium, phosphate in blood, and increase in blood sugar. Cardiac : increase in heart rate, increase or decrease of blood pressure, vasodilatation (a state of increased calibre of the blood vessels), and blood clots. Respiratory : shortness of breath, nasal secretion (rhinitis), sore throat, cough, hiccup, nosebleeds, abnormal breath sounds. Gastro-intestinal: nausea, inflammation of the mucosa of the mouth, vomiting, abdominal pain , diarrhoea, constipation, heart burn, anus discomfort, liquid in the abdomen. Hepatic : enlarged liver, jaundice,. Skin: rash, itching, loss of hairs. Muscleand bone: back, muscle and joint pain. Renal: increase in creatinine elimination, discomfort in urination, and decrease in urine output. General:, fever, headache, , weakness, chills, pain, allergic reaction, oedema, general pain or inflammation at injection site, chest pain, inflammation of the mucosa. Investigations: elevated liver enzymes, weight increased

Common side effects (affects 1 to 10 users in 100 patients):
Nervous system: confusion. Nutrition : low blood sodium. Cardiac : changes and abnormalities in heart rhythm, fluid retention or inflammation around the heart, decrease heart output. Respiratory : increase in breath rhythm, respiratory failure, alveolar haemorrhages, asthma, collapse of small portions of the lung, fluid around the lung. Gastro-intestinal: inflammation of the mucosa of oesophagus, paralysis of the gut, vomiting blood.. Skin: Skin colour disorder, redness of the skin, skin desquamation Renal: increase in the amount of nitrogen components in the blood stream, blood in urines, moderate renal insufficiency.

Uncommon side effects (affects 1 to 10 users in 1,000 patients):
Nervous system: delirium, nervousness, hallucination, agitation, abnormal brain function, cerebral haemorrhage, and seizure. Cardiac : clotting offemoral artery, thrombosis, extra heart beats, decrease in heart rate, diffuse leak of fluid from the capillaries (small blood vessels). Respiratory : decrease in blood oxygen. Gastro-intestinal: bleeding in the stomach and/or the gut.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

5. STORING BUSILVEX

Keep out of the reach and sight of children.
Do not use Busilvex after the expiry date which is stated on the carton.

• Store in a refrigerator (2°C ? 8°C). ? .

Diluted solution:

Chemical and physical in-use stability after dilution in glucose 5% or sodium chloride 9 mg/ml (0.9%) solution for injection has been demonstrated for 8 hours (including infusion time) after dilution when stored at 20 °C ± 5 °C or 12 hours after dilution when stored at 2 °C-8 °C followed by 3 hours stored at 20 °C ± 5 °C (including infusion time).
Do not freeze

What Busilvex contains

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

What Busilvex looks like and contents of the pack

Busilvex consists of a concentrate for solution for infusion and is supplied in colourless glass vials, each vial containing 60 mg of busulfan.
When diluted Busilvex is a clear colourless solution.

Busilvex is available in a box containing 8 vials.

Marketing Authorisation Holder
Pierre Fabre Médicament
45, place Abel Gance
F-92654 Boulogne-Billancourt cedex
France

Manufacturer
Pierre Fabre Médicament Production, site Aquitaine Pharm International
Avenue du béarn
F-64320 Idron
France

This leaflet was last approved on:

<------------------------------------------------------------------------------------------------------------------------------ The following information is intended for medical or healthcare professionals only

PREPARATION GUIDE

Busilvex 6 mg/ml concentrate for solution for infusion

Busulfan

Read this guide prior to the preparation and administration of Busilvex.

1. PRESENTATION

Busilvex is supplied as a clear colourless solution in 10 ml clear glass vials (type I). Busilvex must be diluted prior to administration.

2. RECOMMENDATION FOR SAFE HANDLING

Procedures for proper handling and disposal of anticancer medicinal products should be considered.

All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical laminar flow safety hood

As with other cytotoxic compounds, caution should be exercised in handling and preparing the Busilvex solution:

• The use of gloves and protective clothing is recommended.
• If Busilvex or diluted Busilvex solution contacts the skin or mucosa, wash them thoroughly with water immediately.

Calculation of the quantity of Busilvex to be diluted and of the diluent
Busilvex must be diluted prior to use with either sodium chloride 9 mg/ml (0.9%) solution for injection or glucose solution for injection 5% .
The quantity of the diluent must be 10 times the volume of Busilvex ensuring the final concentration of busulfan remains at approximately 0.5 mg/ml.

The amount of Busilvex and diluent to be administered would be calculated as follows: for a patient with a Y kg body weight:

• Quantity of Busilvex:

Y (kg) x D (mg/kg)

= A ml of Busilvex to be diluted

6 (mg/ml)

Y: body weight of the patient in kg
D: dose of Busilvex (see SPC section 4.2)

• Quantity of diluent:

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

To prepare the final solution for infusion, add (A) ml of Busilvex to (B) ml of diluent (sodium chloride 9 mg/ml (0.9%) solution for injection or glucose solution for injection 5%)

Preparation of the solution for infusion
Busilvex must be prepared by a healthcare professional using sterile transfer techniques.

• Using a non polycarbonate syringe fitted with a needle:
• the calculated volume of Busilvex must be removed from the vial.
• the contents of the syringe must be dispensed into an intravenous bag (or syringe) which already contains the calculated amount of the selected diluent. Busilvex must always be added to the diluent, not the diluent to Busilvex. Busilvex must not be put into an intravenous bag that does not contain sodium chloride 9 mg/ml (0.9%) solution for injection or glucose solution for injection 5%.
• The diluted solution must be mixed thoroughly by inverting several times

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

Diluted Busilvex is a clear colourless solution

Instructions for use
Prior to and following each infusion, flush the indwelling catheter line with approximately 5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection or glucose (5%) solution for injection.

The residual medicinal product must be flushed in the administration tubing as rapid infusion of Busilvex has not been tested and is not recommended.

The entire prescribed Busilvex dose should be delivered over two hours.

Small volumes may be administered over 2 hours using electric syringes. In that case infusion sets with minimal priming space should be used (i.e 0.3-0.6 ml), primed with medicinal product solution prior to beginning the actual Busilvex infusion and then flushed with sodium chloride 9 mg/ml (0.9%) solution for injection or glucose (5%) solution for injection.

Busilvex must not be infused concomitantly with another intravenous solution.

Polycarbonate syringes must not be used with Busilvex.

For single use only. Only a clear solution without particles should be used.

3. PROCEDURE FOR PROPER DISPOSAL

Any unused product or waste should be disposed of in accordance with local requirements for cytotoxic medicinal products.

What Busilvex contains

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

What Busilvex looks like and contents of the pack

Busilvex consists of a concentrate for solution for infusion and is supplied in colourless glass vials, each vial containing 60 mg of busulfan.
When diluted Busilvex is a clear colourless solution.

Busilvex is available in a box containing 8 vials.

Marketing Authorisation Holder
Pierre Fabre Médicament
45, place Abel Gance
F-92654 Boulogne-Billancourt cedex
France

Manufacturer
Pierre Fabre Médicament Production, site Aquitaine Pharm International
Avenue du béarn
F-64320 Idron
France

This leaflet was last approved on:

<------------------------------------------------------------------------------------------------------------------------------ The following information is intended for medical or healthcare professionals only

PREPARATION GUIDE

Busilvex 6 mg/ml concentrate for solution for infusion

Busulfan

Read this guide prior to the preparation and administration of Busilvex.

1. PRESENTATION

Busilvex is supplied as a clear colourless solution in 10 ml clear glass vials (type I). Busilvex must be diluted prior to administration.

2. RECOMMENDATION FOR SAFE HANDLING

Procedures for proper handling and disposal of anticancer medicinal products should be considered.

All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical laminar flow safety hood

As with other cytotoxic compounds, caution should be exercised in handling and preparing the Busilvex solution:

• The use of gloves and protective clothing is recommended.
• If Busilvex or diluted Busilvex solution contacts the skin or mucosa, wash them thoroughly with water immediately.

Calculation of the quantity of Busilvex to be diluted and of the diluent
Busilvex must be diluted prior to use with either sodium chloride 9 mg/ml (0.9%) solution for injection or glucose solution for injection 5% .
The quantity of the diluent must be 10 times the volume of Busilvex ensuring the final concentration of busulfan remains at approximately 0.5 mg/ml.

The amount of Busilvex and diluent to be administered would be calculated as follows: for a patient with a Y kg body weight:

• Quantity of Busilvex:

Y (kg) x D (mg/kg)

= A ml of Busilvex to be diluted

6 (mg/ml)

Y: body weight of the patient in kg
D: dose of Busilvex (see SPC section 4.2)

• Quantity of diluent:

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

To prepare the final solution for infusion, add (A) ml of Busilvex to (B) ml of diluent (sodium chloride 9 mg/ml (0.9%) solution for injection or glucose solution for injection 5%)

Preparation of the solution for infusion
Busilvex must be prepared by a healthcare professional using sterile transfer techniques.

• Using a non polycarbonate syringe fitted with a needle:
• the calculated volume of Busilvex must be removed from the vial.
• the contents of the syringe must be dispensed into an intravenous bag (or syringe) which already contains the calculated amount of the selected diluent. Busilvex must always be added to the diluent, not the diluent to Busilvex. Busilvex must not be put into an intravenous bag that does not contain sodium chloride 9 mg/ml (0.9%) solution for injection or glucose solution for injection 5%.
• The diluted solution must be mixed thoroughly by inverting several times

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

Diluted Busilvex is a clear colourless solution

Instructions for use
Prior to and following each infusion, flush the indwelling catheter line with approximately 5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection or glucose (5%) solution for injection.

The residual medicinal product must be flushed in the administration tubing as rapid infusion of Busilvex has not been tested and is not recommended.

The entire prescribed Busilvex dose should be delivered over two hours.

Small volumes may be administered over 2 hours using electric syringes. In that case infusion sets with minimal priming space should be used (i.e 0.3-0.6 ml), primed with medicinal product solution prior to beginning the actual Busilvex infusion and then flushed with sodium chloride 9 mg/ml (0.9%) solution for injection or glucose (5%) solution for injection.

Busilvex must not be infused concomitantly with another intravenous solution.

Polycarbonate syringes must not be used with Busilvex.

For single use only. Only a clear solution without particles should be used.

3. PROCEDURE FOR PROPER DISPOSAL

Any unused product or waste should be disposed of in accordance with local requirements for cytotoxic medicinal products.