Busulfan Teva

Package leaflet: Information for the user

BUSULFAN TEVA 6 mg/ml concentrate for solution for infusion

busulfan
Equivalent medicine
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor. See section 4.

Contents of this leaflet:

1. What BUSULFAN TEVA is and what it is used for
2. What you need to know before taking BUSULFAN TEVA
3. How to take BUSULFAN TEVA
4. Possible side effects
5. How to store BUSULFAN TEVA
6. Contents of the pack and other information

1. What BUSULFANO TEVA is and what it is used for

BUSULFANO TEVA contains the active substance busulfan, which belongs to a group of medicines called alkylating agents. BUSULFANO TEVA destroys the original bone marrow prior to transplantation.
BUSULFANO TEVA is used in adults, neonates, children, and adolescents as a preparative treatment before transplant.
In adults, BUSULFANO TEVA is used in combination with cyclophosphamide or fludarabine.
In neonates, children, and adolescents, BUSULFANO TEVA is used in combination with cyclophosphamide or melphalan.
You will be given this preparatory medicine before undergoing a bone marrow transplant or hematopoietic stem cell transplant.

2. What you need to know before using BUSULFAN TEVA

Do not take BUSULFAN TEVA

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

Warnings and precautions
BUSULFAN TEVA is a potent cytotoxic medicine that causes marked suppression of blood cells. At the prescribed dose, this is the intended effect. Therefore, careful monitoring will be carried out.
The use of BUSULFAN TEVA may increase the risk of developing another tumour in the future. You must inform your doctor:

• if you have problems with your liver, kidneys, heart or lungs,
• if you have had epileptic seizures,
• if you are taking any other medicines. Blood clots may form in small blood vessels following haematopoietic cell transplantation (HCT) when high doses of your treatment are used in combination with other medicines.

Other medicines and BUSULFAN TEVA
Tell your doctor if you are taking, have recently taken, or might take any other medicines, including those without a prescription. BUSULFAN TEVA may interact with other medicines.
In particular, inform your doctor or pharmacist if you are taking any of the following medicines:

• Deferasirox (a medicine used to remove excess iron from the body).

Special caution is required if you are taking itraconazole and metronidazole (used for certain types of infections) or ketobemidone (used for pain), as this could increase unwanted effects.
The use of paracetamol within 72 hours before or during administration of BUSULFAN TEVA should be done with caution.

Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor before treatment with BUSULFAN TEVA. Women must not become pregnant during treatment with BUSULFAN TEVA and for 6 months after treatment has ended.
Women must stop breastfeeding during treatment with BUSULFAN TEVA.
Adequate contraceptive precautions must be taken when your partner is being treated with BUSULFAN TEVA.
You may no longer be able to become pregnant (infertility) after treatment with busulfan. If you are interested in having children, you should discuss this with your doctor before starting treatment.
BUSULFAN TEVA may also cause symptoms of menopause and, in pre-adolescent girls, may prevent the onset of puberty.
Men treated with BUSULFAN TEVA are advised not to father a child during treatment and for 6 months after treatment ends.

3. How to use BUSULFANO TEVA

Dosage and administration:
The dose of BUSULFANO TEVA will be calculated based on body weight.

In adults:
BUSULFANO TEVA in combination with cyclophosphamide:

• The recommended dose of BUSULFANO TEVA is 0.8 mg/kg.
• Each infusion will last 2 hours.
• BUSULFANO TEVA will be administered every 6 hours for 4 consecutive days prior to transplantation.

BUSULFANO TEVA in combination with fludarabine:

• The recommended dose of BUSULFANO TEVA is 3.2 mg/kg.
• Each infusion will last 3 hours.
• BUSULFANO TEVA will be administered once daily for 2 or 3 consecutive days prior to transplantation.

In neonates, children and adolescents (from 0 to 17 years of age):
The recommended dose of BUSULFANO TEVA in combination with cyclophosphamide or melphalan is based on body weight and ranges between 0.8 and 1.2 mg/kg.

• Each infusion will last 2 hours.
• BUSULFANO TEVA will be administered every 6 hours for 4 consecutive days before transplantation.

Therapies prior to treatment with BUSULFANO TEVA:
Before treatment with BUSULFANO TEVA, you will be given:

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

4. Possible side effects

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

Serious side effects:

The most serious side effects of treatment with BUSULFAN TEVA or following transplant procedures may include reduced blood cell counts (an intended effect of the medicine to prepare you for transplant infusion), infections, liver disorders including blockage of a vein in the liver, graft-versus-host disease (where the transplant attacks your body), and pulmonary complications. Your doctor will regularly monitor your blood cell counts and liver enzymes to assess and manage these events.

Other side effects may include:

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

Blood: reduced circulating blood cells (red and white blood cells) and platelets. Infections.
Nervous system: insomnia, anxiety, dizziness, and depression. Nutrition: loss of appetite, reduced levels of magnesium, calcium, potassium, phosphate, and albumin in the blood, and increased blood glucose.
Cardiac: increased heart rate, increased or decreased blood pressure, vasodilation (a condition in which blood vessels widen), and blood clots.
Respiratory: shortness of breath, nasal discharge (rhinitis), sore throat, cough, hiccups, nosebleeds, abnormal breathing sounds.
Gastrointestinal: nausea, inflammation of the mucous membranes in the mouth, vomiting, abdominal pain, diarrhoea, constipation, heartburn, anal pain, fluid in the abdomen.
Hepatic: enlarged liver, jaundice, blockage of a vein in the liver.
Skin: skin rashes, itching, hair loss.
Musculoskeletal: back pain, muscle and joint pain.
Renal: increased creatinine excretion, difficulty urinating, reduced urine volume, and blood in the urine.
General disorders: fever, headache, weakness, chills, pain, allergic reactions, oedema, generalised pain or inflammation at the injection site, chest pain, inflammation of mucous membranes.
Investigations: 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: changes and abnormalities in heart rhythm, fluid retention or inflammation around the heart, reduced cardiac output.
Respiratory: increased respiratory rate, respiratory failure, alveolar haemorrhage, asthma, collapse of small areas of the lung, fluid around the lung.
Gastrointestinal: inflammation of the oesophageal mucosa, intestinal paralysis, vomiting with blood.
Skin: skin colour changes, skin redness, skin peeling.
Renal: increased levels of nitrogen-containing compounds in the blood, moderate renal failure, kidney disorders.

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

Nervous system: delirium, nervousness, hallucinations, agitation, abnormal brain function, cerebral haemorrhage, and epileptic seizures.
Cardiac: femoral artery thrombosis, extrasystoles, decreased heart rate, widespread leakage of fluid from capillaries (small blood vessels).
Respiratory: decreased levels of oxygen in the blood.
Gastrointestinal: bleeding in the stomach and/or intestines.

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

Sex gland dysfunction.
Lens disorders, including clouding of the eye's lens (cataract) and blurred vision (corneal thinning).
Menopausal symptoms and female infertility.
Brain abscess, skin inflammation, systemic infection.
Liver disorders.
Increased lactate dehydrogenase in the blood. Increased uric acid and urea in the blood.
Incomplete tooth development.

Reporting of side effects

If you experience any side effects, including those not listed in this leaflet, talk to your doctor. You can also report side effects directly via the Italian national reporting system at www.aifa.gov.it/content/segnalazioni-reazioni-avverse.

By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store BUSULFANO TEVA

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and the carton after
EXP. The expiry date refers to the last day of that month.

Intact vials:
Store in the refrigerator (2°C–8°C).

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

From a microbiological standpoint, the product should be used immediately after dilution. If not used immediately, the in-use storage times and conditions prior to use are the responsibility of the user and normally should not exceed the above-mentioned conditions, provided that dilution is carried out under controlled and validated aseptic conditions.

Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What BUSULFANO TEVA contains

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

Description of the appearance of BUSULFANO TEVA and contents of the pack
BUSULFANO TEVA is a clear, colourless solution.
BUSULFANO TEVA is available in clear glass vials (type I) with a butyl rubber stopper, sealed with a Flurotec resin film and an aluminium cap with a polypropylene disc.
BUSULFANO TEVA is available in a multiple pack containing 8 vials (2 packs of 4).
Marketing Authorization Holder
Teva B.V.
Swensweg 5 - 2031GA Haarlem
The Netherlands
Manufacturer
S.C. SINDAN-PHARMA S.R.L.
11th Ion Mihalache Boulevard
Bucharest
011171 Romania
This medicinal product is authorised in the European Economic Area Member States under the following names:
Croatia: Busulfan TEVA 6 mg/ml koncentrat za otopinu za infuziju
Italy: Busulfano Teva
<--------------------------------------------------------------------------------------------------------------------------->
The following information is intended for healthcare professionals only:
PREPARATION GUIDE
BUSULFANO TEVA 6 mg/ml concentrate for solution for infusion
Busulfan
Read this guide before preparing and administering BUSULFANO TEVA

1. PRESENTATION

BUSULFANO TEVA is presented as a clear, colorless solution in 10 ml transparent glass vials (type I). BUSULFANO TEVA must be diluted before administration.

2. SAFETY HANDLING INSTRUCTIONS

Procedures for the safe handling and proper disposal of antineoplastic medicinal products must be observed.
All transfer procedures must be carried out under aseptic conditions, preferably within a laminar flow cabinet.
As with other cytotoxic products, caution must be exercised when handling and preparing the BUSULFAN TEVA solution:

• Use of gloves and protective clothing is recommended.
• If BUSULFAN TEVA or the solution in which BUSULFAN TEVA has been diluted comes into contact with skin or mucous membranes, wash immediately and thoroughly with water.

Calculation of the amount of BUSULFAN TEVA to be diluted and of the diluent
BUSULFAN TEVA must be diluted prior to use either in a 9 mg/ml (0.9%) sodium chloride injectable solution or in a 5% glucose injectable solution.
The volume of diluent must be 10 times the volume of BUSULFAN TEVA to ensure that the final concentration of busulfan is approximately 0.5 mg/ml.
The amount of BUSULFAN TEVA and diluent to be administered should be calculated as follows for a patient weighing Y kg:

• Amount of BUSULFAN TEVA:

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

• Amount of diluent (A ml BUSULFAN TEVA) x (10) = B ml of diluent
  To prepare the final infusion solution, add (A) ml of BUSULFAN TEVA to (B) ml of diluent (9 mg/ml (0.9%) sodium chloride injectable solution or 5% glucose injectable solution)

Preparation of the infusion solution
BUSULFAN TEVA must be prepared by qualified healthcare personnel using sterile transfer techniques.

• Use a syringe (not made of polycarbonate) with a needle.
• Withdraw the calculated volume of BUSULFAN TEVA from the vial.
• Transfer the contents of the syringe into an intravenous bag (or syringe) already containing the calculated amount of selected diluent. Always add BUSULFAN TEVA to the diluent; do not add diluent to BUSULFAN TEVA. Do not place BUSULFAN TEVA into an intravenous bag that does not already contain either a 9 mg/ml (0.9%) sodium chloride injectable solution or a 5% glucose injectable solution.
• Mix the diluted solution thoroughly by inverting several times.

After dilution, 1 ml of infusion solution contains 0.5 mg of busulfan.
Diluted BUSULFAN TEVA is a clear, colourless solution.

Instructions for use
Before and after each infusion, flush the indwelling catheter line thoroughly with approximately 5 ml of 9 mg/ml (0.9%) sodium chloride injectable solution or 5% glucose injectable solution.
Do not rapidly flush residual drug from the administration tubing, as rapid infusion of BUSULFAN TEVA has not been tested and is not recommended.
The entire prescribed dose of BUSULFAN TEVA must be administered over 2 or 3 hours, depending on the treatment regimen.
Small volumes may be administered using electric syringe pumps within 2 hours. In this case, an infusion set with minimal priming volume (0.3–0.6 ml) should be used, filled with the solution prior to the start of actual infusion with BUSULFAN TEVA, and then flushed with 9 mg/ml (0.9%) sodium chloride injectable solution or 5% glucose injectable solution.
Do not administer BUSULFAN TEVA infusion concomitantly with another intravenous solution.
Due to incompatibilities, do not use any infusion components containing polycarbonate with BUSULFAN TEVA.
For single use only. The product should only be used if the solution is clear and free from particles in suspension.

Storage conditions
Unopened vials:
Store in a refrigerator (2 °C – 8 °C)
Diluted solution:
Chemical and physical in-use stability after dilution in 5% glucose injectable solution or 9 mg/ml (0.9%) sodium chloride injectable solution has been demonstrated for 8 hours (including infusion time) when stored at 20 °C ± 5 °C, or for 12 hours after dilution when stored at 2 °C – 8 °C, followed by 3 hours at 20 °C ± 5 °C (including infusion time).
From a microbiological standpoint, the product should be used immediately.

3. DISPOSAL PROCEDURE

Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations applicable to cytotoxic medicinal products.