Consumer medicine information

Busulfex

Busulfan

BRAND INFORMATION

Brand name

Busulfex

Active ingredient

Busulfan

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Busulfex.

SUMMARY CMI

BUSULFEX®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using BUSULFEX?

BUSULFEX contains the active ingredient busulfan. BUSULFEX is used as part of a conditioning regimen prior to transplantation of either bone marrow or blood stem cells. BUSULFEX destroys the original bone marrow before the transplant.

For more information, see Section 1. Why am I using BUSULFEX? in the full CMI.

2. What should I know before I am given BUSULFEX?

You must not be given if you have ever had an allergic reaction to BUSULFEX, busulfan or any of the ingredients listed at the end of the CMI.
Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I am given BUSULFEX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with BUSULFEX and affect how it works.
A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How is BUSULFEX given?

  • BUSULFEX is given by a qualified healthcare professional as a central intravenous infusion
  • For adults, the dose will be calculated according to your body weight
  • For new-born-infants, children and adolescents (0 to 17 years), the recommended dose is based on body weight and may be up to 4.8 mg/kg/day

More instructions can be found in Section 4. How is BUSULFEX given? in the full CMI.

5. What should I know while using BUSULFEX?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using BUSULFEX
Driving or using machines
  • BUSULFEX may cause dizziness in some people
Drinking alcohol
  • Tell your doctor if you drink alcohol
Looking after your medicine
  • BUSULFEX injection will be stored at 2°C - 8°C in a refrigerator (do not freeze) in the Pharmacy.

For more information, see Section 5. What should I know while using BUSULFEX? in the full CMI.

6. Are there any side effects?

Common side effects include: decrease of blood circulating cells (red and white) and platelets; infections, fever, chills; sleeplessness, anxiety, dizziness, and depression; loss of appetite, decrease in magnesium, calcium, potassium, phosphate in blood and increase in blood sugar; increase in heart rate, increase or decrease of blood pressure, widening of the blood vessels (vasodilation) and blood clots; shortness of breath, runny nose (rhinitis), sore throat, cough, hiccup, nosebleeds, abnormal breath sounds; nausea, inflammation of the mucosa of the mouth, vomiting, stomach pain or discomfort, diarrhoea, constipation, heart burn, anus discomfort, liquid in the stomach; enlarged liver, jaundice; rash, itching, hair loss; back, muscle and joint pain; increase in creatinine elimination, discomfort in urination, and decrease in urine output. Serious side effects include: decreased in circulating blood cell counts; infection; liver disorders; complication relating to the lung.
For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

BUSULFEX®

Active ingredient(s): busulfan

Consumer Medicine Information (CMI)

This leaflet provides important information about using BUSULFEX. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using BUSULFEX.

Where to find information in this leaflet:

1. Why am I using BUSULFEX?
2. What should I know before I am given BUSULFEX?
3. What if I am taking other medicines?
4. How is BUSULFEX given?
5. What should I know while using BUSULFEX?
6. Are there any side effects?
7. Product details

1. Why am I using BUSULFEX?

BUSULFEX contains the active ingredient busulfan.

BUSULFEX is used in adults, new-born infants, children and adolescents as a treatment prior to transplantation of either bone marrow or blood stem cells. It is used in combination with other chemotherapeutic drugs, namely cyclophosphamide, melphalan or fludarabine.

BUSULFEX destroys the original bone marrow before the transplant.

Your doctor may have prescribed this medicine for another use.

2. What should I know before I am given BUSULFEX?

Warnings

You must not be given BUSULFEX if:

  • you are allergic to busulfan, or any of the ingredients listed at the end of this leaflet.
  • some of the symptoms of an allergic reaction may include:
    - shortness of breath
    - wheezing or difficulty breathing
    - swelling of the face, lips, tongue or other parts of the body
    - rash, itching or hives on the skin
  • always check the ingredients to make sure you can use this medicine.
  • you are pregnant, or you think you may be pregnant or are breast feeding.

Check with your doctor if you:

  • have or had any of the following medical conditions
    - liver, kidney, heart or lung problem
    - history of seizures
  • take any medicines for any other condition
  • been taking other drugs

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Women should avoid becoming pregnant during treatment with BUSULFEX and up to 6 months after treatment.

Women must not breast-feed during their treatment with BUSULFEX.

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

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

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with BUSULFEX and affect how it works.

These include:

  • itraconazole/metronidazole (used for certain types of infections)
  • ketobemidone (used to treat pain) because this may increase the side-effects

Your doctor may ask you to stop taking medicines before receiving BUSULFEX. This may include iron chelating agents (medicines used to reduce iron levels).

Paracetamol should be used with caution during the 72 hours prior to being given, and while being given BUSULFEX.

These medicines may be affected by BUSULFEX, or may affect how well it works. Your doctor may need to adjust your dose of BUSULFEX or of the other medicine.

Your doctor or pharmacist may have more information on medicines to be careful with or avoid while taking BUSULFEX.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect BUSULFEX.

4. How is BUSULFEX given?

How much is given

Adults

  • The dose will be calculated according to your body weight.
  • The recommended dose of BUSULFEX is up to 3.2 mg per kg of body weight per day, in combination with cyclophosphamide, melphalan or fludarabine

When BUSULFEX is given

New-born infants, children and adolescents (0 to 17 years)

  • The recommended dose is based on body weight and may be up to 4.8 mg/kg/day.

BUSULFEX is given by a qualified healthcare professional as a central intravenous infusion, after dilution of the individual vial. Each infusion will last 2 to 3 hours. Blood samples may be taken for testing the levels of BUSULFEX in your blood.

BUSULFEX will be given 1 to 4 times a day for up to 4 days prior to transplant.

Before receiving BUSULFEX you will be given a medicine to prevent seizures (anticonvulsive drugs) (for example phenytoin and antiemetic drugs to prevent vomiting).

If you are given too much BUSULFEX

As BUSULFEX is given to you in hospital under the supervision of your doctor, it is unlikely that you will receive an overdose.

However, if you experience any side effects after being given BUSULFEX, you should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

Symptoms of a BUSULFEX overdose include the side effects listed below in the Side Effects section but are usually of a more severe nature.

5. What should I know while using BUSULFEX?

Things you should do

Remind any doctor, dentist or pharmacist you visit that you are using BUSULFEX.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how BUSULFEX affects you.

BUSULFEX may cause dizziness in some people

Drinking alcohol

Tell your doctor if you drink alcohol.

Storage

BUSULFEX injection will be stored at 2°C - 8°C in a refrigerator (do not freeze) in the Pharmacy.

Getting rid of any unwanted medicine

Any unused medicine must be disposed of appropriately by the medical staff.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Gastrointestinal related
  • vomiting
  • stomach pain or discomfort
  • diarrhoea
  • constipation
  • heart burn
  • liquid in the stomach
Allergy related:
  • rash, itching
Pain related
  • anus discomfort
  • headache
  • general pain or inflammation at injection site
  • chest pain
General well-being related:
  • sleeplessness, anxiety, dizziness, and depression
  • loss of appetite, decrease in magnesium, calcium, potassium, phosphate in blood and increase in blood sugar
  • increase in heart rate, increase or decrease of blood pressure, widening of the blood vessels (vasodilation) and blood clots
  • shortness of breath, runny nose (rhinitis), sore throat, cough, hiccup, nosebleeds, abnormal breath sounds
  • nausea
  • hair loss
  • back, muscle and joint pain
  • increase in creatinine elimination, discomfort in urination, and decrease in urine output
  • weakness, pain, allergic reaction, swelling (oedema), inflammation of the mucosa
  • elevated liver enzymes, increased weight
  • confusion
  • low blood sodium
  • changes and abnormalities in heart rhythm, fluid retention or inflammation around the heart, decrease heart output
  • increase in breath rhythm, respiratory failure, bleeding in the lungs (alveolar haemorrhages), asthma, collapse of small portions of the lung, fluid around the lung
  • inflammation of the food pipe, paralysis of the gut, vomiting blood
  • skin colour disorder, redness of the skin, peeling of the skin
  • increase in the amount of nitrogen components in the blood stream, blood in urines, moderate change in kidney function (renal insufficiency)
Liver related:
  • enlarged liver
  • jaundice
Infection related:
  • infections, fever, chills
Inflammation related:
  • inflammation of the mucosa of the mouth
Blood related:
  • decrease of blood circulating cells (red and white) and platelets
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Brain related:
  • severe confusion, nervousness, hallucination, agitation, abnormal brain function, brain haemorrhage, and seizure.
Liver related:
  • liver toxicity including blocking of a liver vein, graft versus host disease (the graft attacks your body)
Lung related:
  • complications relating to the lung
Infection related:
  • infection
Blood related:
  • decrease in circulating blood cell counts (intended effect of the drug to prepare you for your transplant infusion)
  • blood clots (thrombosis) in the femoral artery (a large artery in the thigh), extra heart beats, decrease in heart rate, diffuse leakage of fluid from the capillaries (small blood vessels)
  • decrease in blood oxygen
  • bleeding in the stomach and/or the gut
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

The most serious side effects may include decrease in circulating blood cell counts (intended effect of the drug 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 complications relating to the lung. Your doctor will monitor your blood counts and liver enzymes regularly to detect and manage these events.

Lack of white blood cells associated with high fever (febrile neutropenia), metabolic disturbances (tumor lysis syndrome), unusual bleeding or bruising under the skin (thrombotic micro-angiopathy (TMA)), severe bacterial, viral and fungal infections, sepsis and changes in tooth hardness (tooth hypoplasia) have also been observed during treatment.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What BUSULFEX contains

Active ingredient
(main ingredient)
  • Busulfan
Other ingredients
(inactive ingredients)
  • Dimethylacetamide
  • Macrogol 400
Potential allergensNot applicable

Each vial contains 10mL for a single injection. Each mL of suspension contains 6 mg busulfan.

Do not take this medicine if you are allergic to any of these ingredients.

What BUSULFEX looks like

BUSULFEX appears as a clear colourless solution. It is a sterile solution that contains no antimicrobial agent. BUSULFEX is for single use in one patient only.

BUSULFEX is supplied in cartons each containing 8 single-dose 10 mL clear glass vials (type I).

(Aust R 150612).

Who distributes BUSULFEX

Otsuka Australia Pharmaceutical Pty Ltd
Suite 2.03, Level 2, 9 Help Street
Chatswood NSW 2067
Australia

Under licence from Otsuka Pharmaceutical Co., Ltd.

www.otsuka.com.au

This leaflet was prepared in June 2022.

Published by MIMS August 2022

BRAND INFORMATION

Brand name

Busulfex

Active ingredient

Busulfan

Schedule

S4

 

1 Name of Medicine

Busulfan.

2 Qualitative and Quantitative Composition

Each 10 mL vial of Busulfex contains 60 mg (6 mg/mL) of busulfan.
Busulfan, the active ingredient of Busulfex, is a white crystalline solid that is only very slightly soluble in water, sparingly soluble in acetone and slightly soluble in ethanol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Busulfex is an intravenous form of busulfan, a chemotherapeutic agent commonly used as part of a conditioning regimen prior to haematopoietic stem cell transplantation.
Busulfex is supplied as a sterile solution in 10 mL single-use clear glass vials each containing 60 mg of busulfan at a concentration of 6 mg/mL for intravenous use.

4 Clinical Particulars

4.1 Therapeutic Indications

Busulfex is indicated for use in combination with cyclophosphamide, melphalan or fludarabine in conditioning prior to haematopoietic stem cell transplantation.

4.2 Dose and Method of Administration

Busulfex administration should be supervised by a physician experienced in conditioning treatment prior to HSCT.

Dosage.

In adult patients eligible for myeloablative HSCT the proposed dosage recommendation is 3.2 mg/kg body weight/day for four days, giving a total dose of 12.8 mg/kg.
In new-born infants, children and adolescents (0 to 17 years) eligible for myeloablative HSCT it is recommended that dosing is based on a patient’s body weight as shown in Table 1.
The Busulfex daily dose may be given as a single three-hour infusion once daily (od) over 4 consecutive days for a total of 4 doses. Alternatively the daily dose may be divided and given as a two to three hour infusion every 12 hours (bd) for four days, giving a total of 8 doses, or every 6 hours (qid) for four days, giving a total of 16 doses.
In a non-myeloablative conditioning regimen (also known as a reduced-intensity conditioning regimen) a lower Busulfex daily dose may be administered and/or the dose may be administered for less than four days, resulting in a lower total dose. In clinical trials Busulfex total doses ranging from 0.8 mg/kg to 6.4 mg/kg in reduced intensity conditioning regimens have been typically used, administered in divided doses over two to four days.
When used in combination with cyclophosphamide or melphalan, dosing of these chemotherapeutic agents should not be initiated for at least 24 hours following the final Busulfex dose.

Administration.

Busulfex must be diluted prior to administration. A final concentration of approximately 0.5 mg/mL busulfan should be achieved. Busulfex should be administered by intravenous infusion via central venous catheter.
Busulfex should not be given by rapid intravenous, bolus or peripheral injection.
All patients should be pre-medicated with anticonvulsant medication to prevent seizures reported with the use of high dose busulfan. It is recommended to administer anticonvulsants 12 h prior to Busulfex to 24 h after the last dose of Busulfex. In adults all studied patients received phenytoin. There is no experience with other anticonvulsant agents such as benzodiazepines. In paediatric studies patients received either phenytoin or benzodiazepines.
Antiemetics should be administered prior to the first dose of Busulfex and continued on a fixed schedule according to local practice through its administration.

Therapeutic drug monitoring.

Therapeutic drug monitoring and dose adjustment following the first dose of Busulfex is recommended. The formula for adjustment of subsequent doses to achieve the desired target exposure (AUC), is provided in Figure 1.
For example, if a patient received a dose of 50 mg busulfan and if the corresponding AUC measured was 800 microMol-minute, for a target AUC of 1125 microMol-minute, the target mg dose would be as in Figure 2.
A minimum of four blood samples should be taken to ensure accurate AUC determinations with the first sample taken at the completion of the infusion (time 0), and subsequent samples 1, 2 and 4 hours after the infusion is completed.
To avoid contamination with infusing drug blood samples for busulfan estimation should be taken either from the other lumen of a double lumen central venous line (after adequate flushing) or from a peripheral IV line.
Obese patients.

Adults.

For obese patients, dosing based on adjusted ideal body weight (AIBW) should be considered.
Ideal body weight (IBW) is calculated as follows:
IBW men (kg) = 50 + 0.91 x (height in cm-152);
IBW women (kg) = 45 + 0.91 x (height in cm-152).
Adjusted ideal body weight (AIBW) is calculated as follows:
AIBW= IBW + 0.25 x (actual body weight - IBW).

New-born infants, children and adolescents.

There is no experience in obese children and adolescents with body mass index Weight (kg)/(m)2 > 30 kg/m2.

Instruction for handling and disposal.

Procedures for proper handling and disposal of anticancer drugs 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 Busulfex solution:
The use of gloves and protective clothing is recommended.
If Busulfex or diluted Busulfex solution contacts the skin or mucosa, wash them thoroughly with water immediately.

Calculation of the quantity of Busulfex to be diluted and of the diluent.

Busulfex must be diluted prior to use with either sodium chloride (0.9%) solution for injection or glucose (5%) solution for injection. The quantity of the diluent must be 10 times the volume of Busulfex ensuring the final concentration of busulfan remains at approximately 0.5 mg/mL.
For example, the amount of Busulfex and diluent to be administered would be calculated as follows for a patient with a Y kg body weight receiving Z mg/kg busulfan.
Quantity of Busulfex (see Figure 3).
Quantity of diluent:
(A mL Busulfex) x (10) = B mL of diluent.
To prepare the final solution for infusion, add (A) mL of Busulfex 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.

Due to incompatibility, do not use any infusion components containing polycarbonate with Busulfex.
Using a non polycarbonate syringe fitted with a needle:
Remove the calculated volume of Busulfex from the vial.
Dispense the contents of the syringe into an intravenous bag (or syringe) which already contains the calculated amount of the selected diluent. Always add Busulfex to the diluent, not the diluent to Busulfex. Do not put Busulfex into an intravenous bag that does not contain sodium chloride (0.9%) solution for injection or glucose (5%) solution for injection.
Mix thoroughly by inverting several times.
After dilution, 1 mL of solution for infusion contains 0.5 mg of busulfan. Diluted Busulfex 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 (0.9%) solution for injection or glucose (5%) solution for injection.
Do not flush residual drug in the administration tubing as rapid infusion of Busulfex has not been tested and is not recommended.
The entire prescribed Busulfex dose should be delivered over two or three hours (depending on frequency of dose).
Small volumes may be administered over 2 or 3 hours using electric syringes. In this case infusion sets with minimal priming space should be used (i.e. 0.3-0.6 mL), primed with drug solution prior to beginning the actual Busulfex infusion and then flushed with sodium chloride (0.9%) solution for injection or glucose (5%) solution for injection.
A nylon or polyester filter should be used if Busulfex is administered via an in-line filter or a filter fitted with an infusion set.
Do not infuse concomitantly with another intravenous solution.
Busulfex contains no antimicrobial agent. Product is for single use in one patient only. Only a clear solution without any particles should be used. Opened vials should be used immediately to assure sterility. Discard any residue.

4.3 Contraindications

Busulfex is contraindicated in patients with hypersensitivity to the active substance busulfan or to any of the excipients.
Busulfan is contraindicated in women who are pregnant and/or lactating.

4.4 Special Warnings and Precautions for Use

The consequence of treatment with Busulfex at the recommended dose and schedule is profound myelosuppression, occurring in all patients. Severe granulocytopenia, thrombocytopenia, anaemia, or any combination thereof may develop. Frequent complete blood counts, including differential white blood cell counts, and platelet counts should be monitored during the treatment and until recovery is achieved. To detect hepatotoxicity, which may herald the onset of hepatic veno-occlusive disease, serum transaminases, alkaline phosphatase and bilirubin should be evaluated daily until transplant day 28. Prophylactic or empiric use of anti-infectives (bacterial, fungal, viral) should be considered for the prevention and management of infections during the neutropenic period. Platelet and red blood cell support, as well as the use of growth factors such as G-CSF, should be employed as medically indicated. Documentation on Precautions with Busulfex use is derived from two uncontrolled clinical trials in adults (trials OMC-BUS-3 and 4) and one uncontrolled clinical trial in children (trial F60002 IN 1 01 G0).

Myelosuppression.

In adults, absolute neutrophil counts < 0.5 x 109/L at a median of 4 days post transplant occurred in 100% of patients and recovered at median day 10 and 13 days following autologous and allogeneic transplant respectively (median neutropenic period of 6 and 9 days respectively). Thrombocytopenia (< 25 x 109/L or requiring platelet transfusion) occurred at a median of 5-6 days in 98% of patients. Anaemia (haemoglobin < 80 g/L) occurred in 69% of patients.
In children, absolute neutrophil counts < 0.5 x 109/L at a median of 3 days post transplant occurred in 100% of patients and lasted 5 and 18.5 days in autologous and allogeneic transplant respectively. In children, thrombocytopenia (< 25 x 109/L or requiring platelet transfusion) occurred in 100% of patients. Anaemia (haemoglobin < 80 g/L) occurred in 100% of patients.

Infection.

In adults, 39% of patients (40/103) experienced one or more episodes of infection, of which 83% (33/40) were rated as mild or moderate. Pneumonia was fatal in 1% (1/103) and lifethreatening in 3% of patients. Other infections were considered severe in 3% of patients. Fever was reported in 87% of patients and graded as mild/moderate in 84% and severe in 3%. 47% of patients experienced chills which were mild/moderate in 46% and severe in 1%.
In children, infections (documented and non documented febrile neutropenia) were experienced in 89% of patients (49/55). Mild/moderate fever was reported in 76% of patients.

Fanconi anaemia.

The Fanconi anaemia cells have hypersensitivity to cross-linking agents. There is limited clinical experience of the use of busulfan as component of conditioning regimen prior to HSCT in children with Fanconi anaemia. Therefore Busulfex should be used with caution in this type of patients.

Graft versus host disease.

In adults, the incidence of acute graft versus host disease (a-GVHD) data was collected in OMCBUS-4 study (allogeneic) (n=61). A total of 11 patients (18%) experienced a- GVHD. The incidence of a-GVHD grades I-II was 13% (8/61), while the incidence of grade III-IV was 5% (3/61). Acute GVHD was rated as serious in 3 patients. Chronic GVHD (c-GVHD) was reported if serious or the cause of death, and was reported as the cause of death in 3 patients.
In children, the incidence of acute graft versus host disease (a-GVHD) data was collected in allogeneic patients (n=28). A total of 14 patients (50%) experienced a-GVHD. The incidence of a-GVHD grades I-II was 46.4% (13/28), while the incidence of grade III-IV was 3.6% (1/28). Chronic GVHD was reported only if it is the cause of death: one patient died 13 months posttransplant.

Liver toxicity.

In adults, 15% of serious adverse events involved liver toxicity. HVOD is a recognized potential complication of conditioning therapy post-transplant. Six of 103 patients (6%) experienced HVOD. HVOD occurred in: 8.2% (5/61) allogeneic patients (fatal in 2 patients) and 2.5% (1/42) of autologous patients. Elevated bilirubin (n=3) and elevated AST (n=1) were also observed. Two of the above four patients with serious serum hepatotoxicity were among patients with diagnosed HVOD. Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or prior stem cell transplant may be at an increased risk (see Section 4.8 Adverse Effects (Undesirable Effects)).
In children grade 3 elevated transaminases were reported in 24% of patients. HVOD was reported in 15% (4/27) and 7% (2/28) of the autologous and allogenic transplant respectively. HVOD observed were neither fatal nor severe and resolved in all cases.
Repeated doses of the solvent, DMA, produced signs of liver toxicity, the first being increases in serum clinical enzymes followed by histopathological changes in the hepatocytes. Higher doses can produce hepatic necrosis and liver damage can be seen following single high exposures.

Cardiac toxicity.

Cardiac tamponade has been reported in children with thalassemia (8/400 or 2% in one series) who received high doses of oral busulfan and cyclophosphamide as the preparatory regimen for hematopoietic progenitor cell transplantation. Six of the eight children died and two were saved by rapid pericardiocentesis. Abdominal pain and vomiting preceded the tamponade in most patients. No patients treated in the Busulfex clinical trials experienced cardiac tamponade or other specific cardiac toxicities related to Busulfex. However cardiac function should be monitored regularly in patients receiving Busulfex (see Section 4.8 Adverse Effects (Undesirable Effects)).

Pulmonary toxicity.

Occurrence of acute respiratory distress syndrome with subsequent respiratory failure associated with interstitial pulmonary fibrosis was reported in Adverse Effects studies in one patient who died, although, no clear etiology was identified. In addition, busulfan might induce pulmonary toxicity that may be additive to the effects produced by other cytotoxic agents. Therefore, attention should be paid to this pulmonary issue in patients with prior history of mediastinal or pulmonary radiation (see Section 4.8 Adverse Effects (Undesirable Effects)).

Seizures.

Seizures have been reported with high dose busulfan treatment. Special caution should be exercised when administering the recommended dose of Busulfex to patients with a history of seizures. Patients should receive adequate anticonvulsant prophylaxis. In adults all data with Busulfex have been obtained using phenytoin. There are no data available on the use of other anticonvulsant agents such as benzodiazepines, therefore the effect of other agents on busulfan pharmacokinetics is not known. In paediatric patients data have been obtained using benzodiazepines and phenytoin.

High-risk patients.

HSCT is generally not recommended in high-risk patients because of poorer outcomes. High-risk patients include those of age > 50 years and those with prior myeloablative transplants, organ dysfunction, poor performance status or extensive prior chemotherapy. Careful consideration of the risks and benefits of Busulfex is necessary in these patients. Non-myeloablative conditioning regimens, with a reduced dose or reduced duration of Busulfex, have demonstrated a low rate of regimen related toxicity in high-risk patients but can lead to an increase in the incidence of disease relapse (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Use in hepatic impairment.

Busulfex as well as busulfan has not been studied in patients with hepatic impairment. Since busulfan is mainly metabolized through the liver, caution should be observed when Busulfex is used in patients with pre-existing impairment of liver function, especially in those with severe hepatic impairment. It is recommended when treating these patients that serum transaminase, alkaline phosphatase, and bilirubin should be monitored regularly 28 days following transplant for early detection of hepatotoxicity.

Use in renal impairment.

Studies in renally impaired patients have not been conducted, however, as busulfan is moderately excreted in the urine, dose modification is not recommended in these patients.
Caution is recommended. In a Phase I study conducted in patients with metastatic renal carcinoma, all of whom had only one functioning kidney, a conditioning regimen of once- daily Busulfex in combination with fludarabine gave a high incidence of regimen related toxicity.

Use in the elderly.

Patients older than 50 years of age have been successfully treated with Busulfex. See Section 5.1 Pharmacodynamic Properties, Clinical trials, for information on the use of Busulfex in elderly patients in non-myeloablative conditioning regimens. Only limited information is available for the safe use of Busulfex in patients older than 60 years.

Paediatric use.

Busulfex may be used in children (0-17 years).
Data on the use of Busulfex in children are limited (see Section 5.1 Pharmacodynamic Properties, Clinical trials) and there have been no studies in juvenile animals. The level of DMA in Busulfex is higher than in other products and this may represent a particular risk to children. Pulmonary thrombosis and vasculitis were seen with DMA alone in clinical trials in adults and hepatoxicity and neurotoxic effects have been reported with DMA in the literature.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No specific clinical trial was carried out to assess drug-drug interaction between IV busulfan and antifungal agents. From published studies in adults, administration of itraconazole to patients receiving high dose busulfan may result in reduced busulfan clearance. Patients should be monitored for signs of busulfan toxicity when itraconazole is used as an antifungal prophylaxis with IV busulfan.
No interaction was observed when busulfan was combined with fluconazole (antifungal agent) or 5-HT3 antiemetics such as ondansetron or granisetron.
Metronidazole increases plasma levels of busulfan, which may lead to treatment related toxicities.
Published studies in adults have described that ketobemidone (analgesic) might be associated with high levels of plasma busulfan; therefore, special care is recommended when combining these two drugs.
It has been reported that when using the BuCy2 regimen in adults the time interval between the last oral busulfan administration and the first cyclophosphamide administration may influence the development of toxicities. A reduced incidence of hepatic veno-occlusive disease (HVOD) and other regimen related toxicities have been observed in patients when the lag time between the last dose of oral busulfan and the first dose of cyclophosphamide is > 24 hours.
It has also been reported that when using the BuMel regimen in paediatric patients the administration of melphalan less than 24 hours after the last oral busulfan administration may influence the development of toxicities.
Paracetamol is described to decrease glutathione levels in blood and tissues and may, therefore, decrease busulfan clearance when used in combination. Caution should be exercised when using paracetamol prior to (less than 72 hours) or concurrently with Busulfex due to a possible decrease in the metabolism of busulfan.
Phenytoin or benzodiazepines were administered for seizure prophylaxis in all patients in the clinical trials conducted with IV busulfan. The concomitant systemic administration of phenytoin to patients receiving high dose busulfan has been reported to increase busulfan clearance, due to induction of glutathione-S-transferase. However, no evidence of this effect has been seen in IV data.
No interaction has been reported when benzodiazepines such as diazepam, clonazepam or lorazepam have been used to prevent seizures with high dose busulfan. Periodic monitoring of renal function should be considered during therapy with Busulfex (see Section 4.8 Adverse Effects (Undesirable Effects)).

Iron chelating agents.

Decreased clearance of busulfan has been observed with deferasirox. The mechanism of this interaction is not fully elucidated. Iron chelating agents should be discontinued well in advance of administration of busulfan to avoid increased exposure to busulfan.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Busulfan can impair fertility. Impotence, sterility, azoospermia, and testicular atrophy have been reported in male patients. Therefore, men treated with Busulfex are advised not to father a child during and up to 6 months after treatment and to seek advice on cryoconservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with Busulfex. Ovarian suppression and amenorrhoea with menopausal symptoms commonly occur in pre-menopausal patients. Busulfan treatment in a preadolescent girl prevented the onset of puberty due to ovarian failure. Busulfan may cause temporary or permanent infertility in females.
Busulfan disrupted spermatogenesis in rats, guinea pigs, rabbits and monkeys, depleted oocytes and impaired fertility in female mice, and induced sterility in male rats and male hamsters. The solvent dimethylacetamide (DMA) was found to impair fertility in studies with male and female rodents.
(Category D)
Busulfex is contraindicated during pregnancy. Busulfan and DMA reduced fetal weight and caused embryofetal lethality and malformations in various animal species in preclinical studies. For busulfan, terata were observed in the musculoskeletal system of mice, rats and rabbits, while DMA induced malformations occurred in the heart, major vessels and oral cavity in the rat. Administration of busulfan to pregnant rats caused sterility in male and female offspring due to the destruction of germinal cells in the testes and ovaries.
There are no adequate and well controlled studies of either busulfan or DMA in pregnant women. A few cases of congenital abnormalities have been reported with low dose oral busulfan, not necessarily attributable to the drug, and third trimester exposure may be associated with impaired intrauterine growth.
Women of childbearing potential must use effective contraception during and up to 6 months after treatment.
 Patients who are taking Busulfex must be advised not to breastfeed. It is not known whether busulfan and DMA are excreted in human milk. Because of the potential for severe adverse effects, including tumorigenicity, breastfeeding should be discontinued at the start of therapy.

4.7 Effects on Ability to Drive and Use Machines

No relevant effects have been noted.

4.8 Adverse Effects (Undesirable Effects)

Adverse event information is derived from two trials in adults in 103 patients (OMC-BUS 3 and 4) and one trial in children in 55 patients (F60002 IN 1 01) in which Busulfex was used in a four times daily regimen for 4 days in combination with cyclophosphamide or melphalan. Adverse reactions reported as more than an isolated case are listed in Table 2. See Section 4.4 Special Warnings and Precautions for Use, for more information on serious adverse reactions. Serious toxicities involving the haematological, hepatic and respiratory systems were considered as expected consequences of the conditioning regimen and transplant process. These include infection and graft-versus-host disease which were the major causes of morbidity and mortality. The safety profile for Busulfex in once daily and twice daily regimens and in combination with fludarabine appears similar to four times daily in combination with cyclophosphamide or melphalan; however the data are very limited and in small numbers of patients.

Post-marketing experience.

The following adverse reactions (reported as MedDRA terms) have been identified during postapproval use of Busulfex (busulfan) Injection: febrile neutropenia, tumor lysis syndrome, thrombotic micro-angiopathy (TMA), severe bacterial, viral (e.g. cytomegalovirus viraemia) and fungal infections, sepsis and tooth hypoplasia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

For advice on the management of overdosage, please contact the Poisons Information Centre (telephone 13 11 26).
The principal toxic effect is profound myeloablation and pancytopenia but the central nervous system, liver, lungs and gastrointestinal tract may also be affected.
There is no known antidote to Busulfex other than haematopoietic stem cell transplantation. In the absence of haematopoietic progenitor cell transplantation, the recommended dosage of Busulfex would constitute an overdose of busulfan. The haematologic status should be closely monitored and vigorous supportive measures instituted as medically indicated.
There have been two reports that busulfan is dialysable, thus dialysis should be considered in the case of an overdose. Since busulfan is metabolised through conjugation with glutathione, administration of glutathione might be considered.
It must be considered that overdose of Busulfex will also increase exposure to DMA. In humans, the principal toxic effects were hepatotoxicity and central nervous system effects. CNS changes precede any of the more severe side effects. No specific antidote for DMA overdose is known. In case of overdose, management would include general supportive care.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Cytotoxic agents (alkylating agents). ATC Code: L01AB01.

Mechanism of action.

Busulfan is a potent cytotoxic agent and a bifunctional alkylating agent. In aqueous media, release of the methanesulphonate groups produces carbonium ions which can alkylate DNA, thought to be an important biological mechanism for its cytotoxic effect.

Clinical trials.

Clinical trials in adults.

Documentation of the safety and efficacy of Busulfex in combination with cyclophosphamide in myeloablation prior to autologous or allogeneic haematopoietic stem cell transplantation (HSCT) in adults is derived from two uncontrolled clinical trials (trials OMC-BUS 3 and 4 respectively).
The trials were conducted in patients with haematological disease, the majority of whom had advanced disease. Diseases included were acute leukaemia past first remission, in first or subsequent relapse, in first remission (high risk), or induction failures; chronic myelogenous leukaemia in chronic or advanced phase; primary refractory or resistant relapsed Hodgkin’s disease or non-Hodgkin’s lymphoma, and myelodysplastic syndrome. The age of patients was 18-63 years and 60% were male. Patients received 0.8 mg/kg Busulfex every 6 hours by intravenous (IV) infusion for 4 days from day 7 to day 4 before HSCT. Cyclophosphamide 60 mg/kg/day once daily IV was given for 2 days from day 3 to 2 before HSCT (BuCy2 regimen).
The primary efficacy parameters in these studies were myeloablation, engraftment, relapse, and survival. Busulfex with cyclophosphamide was effective in inducing myeloablation and engraftment. Relapse-free and overall survival were similar in the two trials (Table 3).
Uncontrolled (Fernandez) and non-randomised controlled trials (Mamlouk) in adults with haematological malignancies showed comparable incidences of engraftment for once daily and twice daily Busulfex 3.2 mg/kg/day regimens in combination with cyclophosphamide 60 mg/kg/day compared with the four times daily regimen. Short-term survival was above 80% (Table 4). Reproducible busulfan pharmacokinetic parameters were demonstrated for once daily Busulfex.
Two uncontrolled trials in adults with haematological malignancies (Russell, de Lima) showed comparable incidences of engraftment for once daily Busulfex 3.2-3.3 mg/kg in combination with fludarabine compared with the four times daily Busulfex with cyclophosphamide regimen. Two-year survival was 37-88% depending on risk (Table 5). Reproducible busulfan pharmacokinetic parameters were demonstrated for Busulfex.
In a retrospective analysis (Alyea) comparing the outcomes of allogeneic transplant in patients aged > 50 years with haematological malignancies, who received either a non- myeloablative conditioning regimen of once-daily Busulfex 0.8 mg/kg for 4 days in combination with fludarabine 30 mg/m2 for 4 days or a myeloablative conditioning regimen of total body irradiation (TBI)/cyclophosphamide or oral busulfan/cyclophosphamide, improved 100-day treatment-related mortality rates and non-relapse mortality rates were noted in patients receiving the non-myeloablative Busulfex-fludarabine conditioning regimen (Table 6). Although the cumulative incidence of disease relapse was higher in patients receiving the nonmyeloablative conditioning regimen, overall survival and progression-free survival were not adversely affected by the reduction in intensity of the conditioning regimen.

Clinical trials in children.

Documentation of the safety and efficacy of Busulfex in combination with cyclophosphamide or melphalan in myeloablation prior to autologous or allogeneic HSCT in children is derived from one uncontrolled clinical trial (trial F60002 IN 1 01 G0). The age of patients was 0.3-17.2 years and 53% were male. The dose of Busulfex ranged from 3.2-4.8 mg/kg/day depending on weight group. The Busulfex dose was based on body weight (see Section 4.2 Dose and Method of Administration) and given in four divided doses daily for 4 days.
In autologous HSCT, Busulfex was given from day 6 to day 3 before HSCT and melphalan 140 mg/m2 IV on the day before HSCT (BuMel regimen). In allogeneic HSCT, Busulfex was given from day 9 to day 6 before HSCT and cyclophosphamide 50 mg/kg IV for 4 days from day 5 to 2 before HSCT (BuCy4 regimen). All patients achieved myeloablation and engraftment. The estimated 2-year survival was almost 80% (Table 7).
Four uncontrolled trials in children (Table 8) with malignant and non-malignant conditions showed comparable incidences of engraftment for once daily Busulfex 4 mg/kg/day for 4 days (Grigull) or with Busulfex targeted to a steady-state concentration of 900 nanogram/mL four times daily (approx 3.2 mg/kg/day) for 4 days (Horn) in combination with fludarabine 30- 40 mg/m2/day, compared with four times daily Busulfex with cyclophosphamide or melphalan. Lower incidences of engraftment were obtained for reduced intensity conditioning regimens using a reduced dose or reduced duration of Busulfex (Kletzel, Horn, Jacobsohn). The reduced intensity conditioning was associated with lower incidences of treatment related toxicity.

5.2 Pharmacokinetic Properties

Absorption and distribution pharmacokinetics of IV busulfan has been investigated. The information presented on metabolism and elimination is based on oral busulfan.

Absorption.

The pharmacokinetics of IV busulfan was studied in 124 evaluable patients following a 2-hour intravenous infusion for a total of 16 doses over four days. Immediate and complete availability of the dose is obtained after intravenous infusion of busulfan. Similar blood exposure was observed when comparing plasma concentrations in patients receiving 1 mg/kg oral and 0.8 mg/kg IV busulfan. Low inter (CV=21%) and intra (CV=12%) patient variability on drug exposure was demonstrated through a population pharmacokinetic analysis with IV busulfan, performed on 102 patients.

Distribution.

Terminal volume of distribution Vz ranged between 0.62 and 0.85 L/kg. Busulfan concentrations in the cerebrospinal fluid are comparable to those in plasma although these concentrations are probably insufficient for anti-neoplastic activity. Reversible binding to plasma proteins was around 7% while irreversible binding, primarily to albumin, was about 32%.

Metabolism.

Busulfan is metabolised mainly through conjugation with glutathione (spontaneous and glutathione-S-transferase mediated). The glutathione conjugate is then further metabolised in the liver by oxidation. None of the metabolites is thought to contribute significantly to either efficacy or toxicity.

Excretion.

Total clearance in plasma ranged 2.25 - 2.74 mL/minute/kg. The terminal half-life ranged from 2.8 to 3.9 hours. Approximately 30% of the administered dose is excreted into the urine over 48 hours with 1% as unchanged drug. Elimination in faeces is negligible. Irreversible protein binding may explain the incomplete recovery. Contribution of long- lasting metabolites is not excluded.

Pharmacokinetic linearity.

The dose proportional increase of drug exposure was demonstrated following intravenous busulfan up to 1 mg/kg.

Pharmacokinetic/ pharmacodynamics relationships.

The literature on oral busulfan when used in myeloablative conditioning regimens every six hours for four days suggests a therapeutic window between 900 and 1500 microMol-minute for AUC. During clinical trials with IV busulfan administered in this way, 90% of patients AUCs were below the upper AUC limit (1500 microMol-minute) and at least 80% were within the targeted therapeutic window (900 - 1500 microMol-minute).

Special populations.

The effects of renal dysfunction on IV busulfan disposition have not been thoroughly assessed. However Busulfex was not well tolerated in a Phase I study conducted in patients with metastatic renal carcinoma where all patients had only one functioning kidney.
The effects of hepatic dysfunction on IV busulfan disposition have not been assessed. Nevertheless the risk of liver toxicity may be increased in this population.
No age effect on busulfan clearance was evidenced from available IV busulfan data in patients over 60 years.

Pharmacokinetics in children.

A continuous variation of clearance ranging from 2.49 to 3.92 mL/minute/kg was established in children from < 6 months up to 17 years old. The terminal half life ranged from 2.26 to 2.52 h. The described dosing based on body weight allows achievement of a similar targeted AUC whatever the child’s age, comparable with adult plasma exposure. Inter and intra patient variabilities in plasma exposure were lower than 20% and lower than 10%, respectively.
The successful engraftment achieved in all paediatric patients during the phase II clinical trial suggests the appropriateness of the targeted AUCs of 900 to 1500 microMol-minute. Occurrence of hepatic veno-occlusive disease (HVOD) was not related to overexposure. A pharmacokinetic/pharmacodynamic relationship was observed between stomatitis and AUCs in autologous patients and between bilirubin increase and AUCs in a combined autologous and allogeneic patient analysis.

5.3 Preclinical Safety Data

Genotoxicity.

Busulfan was mutagenic in bacterial (Salmonella typhimurium and E. coli), insect (Drosophila melanogaster) and mammalian (mouse, hamster and human) cells. Busulfan induced chromosomal aberrations in vitro (mouse, hamster and human cells) and in vivo (mouse, rat, hamster and human).

Carcinogenicity.

Busulfan belongs to a class of substances which are potentially carcinogenic based on their mechanism of action. On the basis of human data, busulfan has been classified by the International Agency for Research on Cancer (IARC) as a human carcinogen. The World Health Organisation (WHO) has concluded that there is a causal relationship between busulfan exposure and cancer. The available data in animals support the carcinogenic potential of busulfan. Intravenous administration of busulfan to mice significantly increased the incidences of thymic and ovarian tumours.
The increased risk of a second malignancy should be explained to the patient. Leukaemia patients treated with busulfan developed many different cytological abnormalities, and some developed carcinomas. Busulfan is thought to be leukemogenic.

6 Pharmaceutical Particulars

6.1 List of Excipients

The excipients are dimethylacetamide (DMA) and macrogol 400.
The drug product Busulfex is intended for dilution with 0.9% sodium chloride solution for injection or 5% glucose solution for injection.

6.2 Incompatibilities

In the absence of compatibility studies, Busulfex must not be mixed with other medicinal products except those mentioned (see Section 4.2 Dose and Method of Administration).

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
Busulfex must be diluted in sodium chloride 9 mg/mL (0.9%) solution for injection or 5% glucose prior to use. To reduce microbiological hazard, use as soon as practicable after preparation. If storage is necessary, hold at 2°-8°C for not more than 15 hours.
The chemical and physical stability of the diluted solution has been demonstrated for 8 hours at 20 ± 5°C.

6.4 Special Precautions for Storage

Unopened vials of Busulfex Injection must be stored at 2°-8°C in a refrigerator (Do not freeze).

6.5 Nature and Contents of Container

Busulfex is provided in packages of eight clear Type I glass vials.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Busulfan, 1,4-butanediol dimethanesulfonate. Molecular Formula: C6H14O6S2. Molecular Weight: 246.31.

Chemical structure.


CAS number.

CAS Registry Number: 55-98-1.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes