Consumer medicine information

Busulfan ARX Concentrated Injection

Busulfan

BRAND INFORMATION

Brand name

Busulfan APOTEX

Active ingredient

Busulfan

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Busulfan ARX Concentrated Injection.

What is in this leaflet

This leaflet answers some common questions about this medicine. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What this medicine is used for

Busulfan ARX Concentrated Injection 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.

Busulfan ARX Concentrated Injection contains the active ingredient busulfan and belongs to a group of medicines called alkylating agents. Busulfan destroys the original bone marrow before the transplant.

There is no evidence that this medicine is addictive.

Your doctor may have prescribed this medicine for another reason.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

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

Before you are given this medicine

When you must not be given it

Do not take this medicine if you have an allergy 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, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting or hay fever-like symptoms

Do not take this medicine if you are pregnant, think you may be pregnant or are breastfeeding. Busulfan may affect your developing baby if you are given it during pregnancy.

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

Women must not breastfeed during their treatment with busulfan. It may pass into human breast milk.

If you think you are having an allergic reaction, contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you are given it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • liver, kidney, heart or lung problem
  • history of seizures.

Tell your doctor if you are pregnant or plan to become pregnant. 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. Busulfan can also produce symptoms of menopause and in pre-adolescent girls it can prevent the onset of puberty.

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

If you have not told your doctor about any of the above, tell them before you start taking busulfan.

Taking other medicines

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

Some medicines and busulfan may interfere with each other. These include:

  • itraconazole/metronidazole (used for certain types of infections)
  • ketobemidone (used to treat pain)
  • cyclophosphamide and melphalan, often used in combination with busulfan, should not be taken for 24 hours after busulfan injection

Your doctor may ask you to stop taking medicines before receiving busulfan. 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 during busulfan administration.

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

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

How this medicine is given

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

How much is given

Your doctor will determine how much of this medicine you will be given. This will depend on your condition and whether you are taking any other medicines.

Adults
The dose will be calculated according to your body weight.

The recommended dose of busulfan is up to 3.2 mg per kg of body weight per day, in combination with cyclophosphamide, melphalan or fludarabine.

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

How it is given

Busulfan 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 busulfan in your blood.

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

Before receiving busulfan you will be given anticonvulsive drugs to prevent seizures (such as phenytoin or benzodiazepines) and antiemetic drugs to prevent vomiting

If you take too much (overdose)

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

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to the Accident and Emergency department at your nearest hospital.

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

While you are being given this medicine

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking busulfan.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking busulfan.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking busulfan. It may affect other medicines used during surgery.

If you become pregnant while taking busulfan, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking busulfan. It may interfere with the results of some tests.

Keep all your doctor's appointments so that your progress can be checked. Your doctor may occasionally do tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you.

Busulfan is a powerful cytotoxic drug (medicine to treat some cancers) that results in a huge decrease of blood cells. At the recommended dose, this is the desired effect. However, careful monitoring is needed as it is possible that use of busulfan may increase the risk of suffering another malignancy in the future.

Side effects

Tell your doctor as soon as possible if you do not feel well while you are being given busulfan or if you have any questions or concerns.

All medicines can have side effects. Sometimes they are serious but most of the time they are not.

The most serious side effects may include decrease in circulation 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.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

These side effects of busulfan are very common (reported in more than 1 patient out of 10):

  • decrease of blood circulating cells (red and white) and platelets.
  • infections, fever, chills.
  • insomnia, 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, vasodilation (a state of increased calibre of the blood vessels) and blood clots.
  • shortness of breath, nasal secretion (rhinitis), sore throat, cough, hiccup, nosebleeds, abnormal breath sounds.
  • nausea, inflammation of the mucosa of the mouth, vomiting, abdominal pain, diarrhoea, constipation, heart burn, anus discomfort, liquid in the abdomen.
  • enlarged liver, jaundice.
  • rash, itching, hair loss.
  • back, muscle and joint pain.
  • increase in creatinine elimination, discomfort in urination, and decrease in urine output.
  • fever, headache, weakness, chills, pain, swelling (oedema), general pain or inflammation at injection site, chest pain, inflammation of the mucosa.
  • elevated liver enzymes, increased weight.

Less common side effects (reported in 1 to 10 out of 100 patients) include:

  • 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 mucosa oesophagus, paralysis of the gut, vomiting blood.
  • skin colour disorder, redness of the skin, skin peeling.
  • increase in the amount of nitrogen components in the blood stream, blood in urines, moderate renal insufficiency.

Uncommon side effects (reported in 1 to 10 out of 1000 patients) include:

  • severe confusion (delirium), nervousness, hallucination, agitation, abnormal brain function, cerebral haemorrhage, and seizure.
  • clotting of femoral artery, thrombosis, extra heart beats, decrease in heart rate, diffuse leak of fluid from the capillaries (small blood vessels).
  • decrease in blood oxygen.
  • bleeding in the stomach and/or the gut.

Lack of white blood cells associated with high fever (febrile neutropenia), metabolic disturbances (tumour 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 that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it. If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 2-8°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor stops giving you this medicine or it has passed its expiry date, the medical staff will dispose of the remaining medicine safely.

Product description

What Busulfan ARX Concentrated Injection looks like

Busulfan ARX Concentrated Injection 60 mg/10 mL appears as a clear colourless solution. It is a sterile solution that contains no antimicrobial agent.

Busulfan ARX Concentrated Injection is for single use in one patient only and is supplied in cartons each containing 8 single-dose 10 mL clear glass vials (type I).

Ingredients

Each vial contains 60 mg of busulfan as the active ingredient.

It also contains the following inactive ingredients:

  • dimethylacetamide (DMA)
  • macrogol 400

This medicine is gluten-free, lactose-free, sucrose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

Busulfan ARX Concentrated Injection 60 mg/10 (pack of 8 glass vials): AUST R 210228

Sponsor

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel St,
Cremorne VIC 3121

This leaflet was last updated in:
March 2023.

Published by MIMS April 2023

BRAND INFORMATION

Brand name

Busulfan APOTEX

Active ingredient

Busulfan

Schedule

S4

 

1 Name of Medicine

Busulfan.

2 Qualitative and Quantitative Composition

Each 10 mL vial of concentrated injection contains 60 mg of busulfan.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

The concentrated injection is a clear and colorless solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Busulfan concentrated injection 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

IV busulfan administration should be supervised by a physician experienced in conditioning treatment prior to HSCT.
It is intended for dilution with 0.9% sodium chloride solution for injection or 5% glucose solution for injection.

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 in Table 1.
The IV busulfan 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 IV busulfan 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 IV busulfan 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 IV busulfan dose.

Administration.

Busulfan concentrated injection must be diluted prior to administration. A final concentration of approximately 0.5 mg/mL busulfan should be achieved. Busulfan concentrated injection should be administered by intravenous infusion via central venous catheter.
Busulfan concentrated injection 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 Busulfan concentrated injection to 24 h after the last dose of Busulfan concentrated injection. 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 Busulfan concentrated injection 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 Busulfan concentrated injection is recommended. The formula for adjustment of subsequent doses to achieve the desired target exposure (AUC), is provided below.
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 follows.
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 bodyweight (AIBW) is calculated as follows:
AIBW = IBW + 0.25 x (actual bodyweight - 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 busulfan solution.
The use of gloves and protective clothing is recommended.
If Busulfan concentrated injection or diluted Busulfan concentrated injection solution contacts the skin or mucosa, wash them thoroughly with water immediately.

Calculation of the quantity of busulfan concentrated injection to be diluted and of the diluent.

Busulfan concentrated injection 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 Busulfan concentrated injection ensuring the final concentration of busulfan remains at approximately 0.5 mg/mL.
For example, the amount of Busulfan concentrated injection 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 Busulfan concentrated injection.
Quantity of diluent.
(A mL busulfan) x (10) = B mL of diluent.
To prepare the final solution for infusion, add (A) mL of Busulfan concentrated injection 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 Busulfan concentrated injection.
Using a nonpolycarbonate syringe fitted with a needle:
Remove the calculated volume of Busulfan concentrated injection 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 Busulfan concentrated injection to the diluent, not the diluent to Busulfan concentrated injection. Do not put Busulfan concentrated injection 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 Busulfan concentrated injection 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 Busulfan concentrated injection has not been tested and is not recommended.
The entire prescribed Busulfan concentrated injection 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 Busulfan concentrated injection 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 Busulfan concentrated injection is administered via an in-line filter or a filter fitted with an infusion set.
Do not infuse concomitantly with another intravenous solution.
Busulfan concentrated injection 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.
Any unused product or waste should be disposed of in accordance with local requirements for cytotoxic drugs.

Incompatibilities.

In the absence of compatibility studies, Busulfan concentrated injection must not be mixed with other medicinal products except those mentioned in this section.

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

The consequence of treatment with IV busulfan 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 IV busulfan 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 life-threatening 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 IV busulfan 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 OMC-BUS-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 post-transplant.

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 IV busulfan clinical trials experienced cardiac tamponade or other specific cardiac toxicities related to busulfan. However cardiac function should be monitored regularly in patients receiving IV busulfan (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 (see Section 4.8 Adverse Effects (Undesirable 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 IV busulfan to patients with a history of seizures. Patients should receive adequate anticonvulsant prophylaxis. In adults all data with IV busulfan 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 IV busulfan is necessary in these patients. Non-myeloablative conditioning regimens, with a reduced dose or reduced duration of IV busulfan, 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.

IV busulfan 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 IV busulfan 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 IV busulfan 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 IV busulfan. See Section 5.1 Pharmacodynamic Properties, Clinical trials for information on the use of IV busulfan in elderly patients in nonmyeloablative conditioning regimens. Only limited information is available for the safe use of IV busulfan in patients older than 60 years.

Paediatric use.

IV busulfan may be used in children (0-17 years).
Data on the use of IV busulfan 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 IV busulfan 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 toxicity 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 IV busulfan 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 glutathion-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 IV busulfan (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 IV busulfan are advised not to father a child during and up to 6 months after treatment and to seek advice on cryo-conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with IV busulfan. Ovarian suppression and amenorrhoea with menopausal symptoms commonly occur in pre-menopausal patients. Busulfan treatment in a pre-adolescent 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)
IV busulfan is contraindicated during pregnancy. Busulfan and DMA reduced fetal weight and caused embryofetal lethality and malformations in various animal species in pre-clinical 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 IV busulfan must be advised not to breast-feed. It is not known whether busulfan and DMA are excreted in human milk. Because of the potential for severe adverse effects, including tumourigenicity, breast-feeding 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 IV busulfan 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 IV busulfan 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.

Postmarketing experience.

The following adverse reactions (reported as MedDRA terms) have been identified during post-approval use of IV busulfan: febrile neutropenia, tumor lysis syndrome, thrombotic micro-angiopathy (TMA), severe bacterial, viral (eg, 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 effects.

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 www.tga.gov.au/reporting-problems and contact Arrotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

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 Busulfan concentrated injection other than haematopoietic stem cell transplantation. In the absence of haematopoietic progenitor cell transplantation, the recommended dosage of busulfan 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 dialyzable, thus dialysis should be considered in the case of an overdose. Since, busulfan is metabolized through conjugation with glutathione, administration of glutathione might be considered.
It must be considered that overdose of Busulfan concentrated injection will also increase exposure to DMA. In human 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.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pharmacotherapeutic group: Cytotoxic agents (alkylating agents). ATC Code: L01AB01.
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 IV busulfan 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 IV busulfan 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. IV busulfan 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 IV busulfan 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 IV busulfan.
Two uncontrolled trials in adults with haematological malignancies (Russell, de Lima) showed comparable incidences of engraftment for once daily busulfan 3.2-3.3 mg/kg in combination with fludarabine compared with the four times daily IV busulfan with cyclophosphamide regimen. Two-year survival was 37-88% depending on risk (Table 5). Reproducible busulfan pharmacokinetic parameters were demonstrated for IV busulfan.
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 IV busulfan 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 IV busulfan-fludarabine conditioning regimen (Table 6). Although the cumulative incidence of disease relapse was higher in patients receiving the non-myeloablative 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 IV busulfan 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 IV busulfan ranged from 3.2-4.8 mg/kg/day depending on weight group. The IV busulfan dose was based on body weight as detailed (see Section 4.2 Dose and Method of Administration) and given in four divided doses daily for 4 days.
In autologous HSCT, IV busulfan 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, IV busulfan 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 IV busulfan 4 mg/kg/day for 4 days (Grigull) or with IV busulfan 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 IV busulfan with cyclophosphamide or melphalan. Lower incidences of engraftment were obtained for reduced intensity conditioning regimens using a reduced dose or reduced duration of IV busulfan (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 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 busulfan 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

Dimethylacetamide (DMA), macrogol 400.

6.2 Incompatibilities

Due to incompatibility, do not use any infusion components containing polycarbonate with Busulfan concentrated injection.
In the absence of compatibility studies, Busulfan concentrated injection 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.

6.4 Special Precautions for Storage

Unopened vials must be stored at 2°-8°C in a refrigerator. (Do not freeze).
Busulfan ARX injection 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.

6.5 Nature and Contents of Container

Type I clear glass vials with bromobutyl rubber stoppers and blue aluminium flip-off seals in cartons of 8 vials (AUST R number 210228).

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Busulfan concentrated injection is an intravenous form of busulfan, a chemotherapeutic agent commonly used as part of a conditioning regimen prior to haematopoietic stem cell transplantation.
Busulfan, the active ingredient of busulfan concentrated injection, is a white crystalline solid that is only very slightly soluble in water, sparingly soluble in acetone and slightly soluble in ethanol.
Chemical Name: Busulfan, 1,4-butanediol dimethanesulfonate.
Molecular Formula: C6H14O6S2.
Molecular Weight: 246.31.

Chemical structure.


CAS number.

55-98-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes