Consumer medicine information

Myleran IV Concentrate for infusion

Busulfan

BRAND INFORMATION

Brand name

Myleran IV Concentrate for infusion

Active ingredient

Busulfan

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Myleran IV Concentrate for infusion.

What is this leaflet?

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

All medicines have risks and benefits. Your doctor has weighed the risks of you being given MYLERAN IV against the benefits they expect it will have for you.

If you have any concerns about being given MYLERAN IV, ask your doctor or pharmacist.

Keep this leaflet with your medicine.

You may need to read it again.

What MYLERAN IV is used for

MYLERAN IV 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.

MYLERAN IV contains the active ingredient, Busulfan. Busulfan belongs to a group of medicines called alkylating agents. MYLERAN IV destroys the original bone marrow before the transplant.

Your doctor may have prescribed this medicine for another use.

Ask your doctor if you have any questions about why MYLERAN IV has been prescribed for you.

Before you are given MYLERAN IV

MYLERAN IV injection is not suitable for everyone.

When you must not be given it

  • MYLERAN IV should not be given if you are allergic to busulfan or any of the other ingredients listed in this leaflet.
  • MYLERAN IV should not be given if you are pregnant, or you think you may be pregnant.

Before you are given it

MYLERAN IV is a powerful cytotoxic drug that results in a huge decrease of blood cells. At the recommended dose, this is the desired effect. Therefore careful monitoring will be performed. It is possible that use of MYLERAN IV may increase the risk of suffering another malignancy in the future.

Tell your doctor if you:

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

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. MYLERAN IV can also produce symptoms of menopause and in pre-adolescent girls it can prevent the onset of puberty.

Tell your doctor if you are pregnant, think you may be pregnant or are breast-feeding, before you receive treatment with MYLERAN IV.

Women should avoid becoming pregnant during treatment with MYLERAN IV and up to 6 months after treatment. Women should not breast-feed during their treatment with MYLERAN IV.

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

Taking other medicines

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

MYLERAN IV may interact with other drugs.

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

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

How MYLERAN IV is given

How much is given

In adults
The dose will be calculated according to your body weight.

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

In 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.

MYLERAN IV 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 MYLERAN IV in your blood.

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

Before receiving MYLERAN IV you will be given anticonvulsive drugs to prevent seizures (phenytoin or benzodiazepines) and antiemetic drugs to prevent vomiting.

Overdose

As MYLERAN IV 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 MYLERAN IV, tell your doctor immediately, or the Poisons Information Centre (telephone 13 1126), or go to Accident and Emergency at your nearest hospital.

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

Side Effects

Like all medicines, MYLERAN IV can have side effects. 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 pulmonary complications. Your doctor will monitor your blood counts and liver enzymes regularly to detect and manage these events.

Tell your doctor nurse or pharmacist if you notice any of the following and they worry you:

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

These side effects of MYLERAN IV are very common (reported in more than 1 patient out of 10).

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

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

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

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

Febrile neutropenia, tumor lysis syndrome, thrombotic micro-angiopathy (TMA), severe bacterial, viral and fungal infections, sepsis and tooth hypoplasia have also been observed during treatment.

If you are unsure of any of these side effects please ask your doctor.

If you notice any side effects either listed or not listed in this leaflet, please notify a member of the staff taking care of you.

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

After using MYLERAN IV

Disposal

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

Product description

What MYLERAN IV looks like

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

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

Ingredients

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

It also contains Dimethylacetamide and Macrogol 400.

Storage

MYLERAN IV injection will be stored at 2°C-8°C in a refrigerator (do not freeze).

Sponsor

MYLERAN IV is distributed in Australia by:

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos Street
St Leonards NSW 2065
Australia

Australian Registration Number:

MYLERAN IV 60 mg/10 mL:
AUST R 256212

Date of leaflet:
September 2017

BRAND INFORMATION

Brand name

Myleran IV Concentrate for infusion

Active ingredient

Busulfan

Schedule

S4

 

Name of the medicine

Busulfan.

Excipients.

Dimethylacetamide (DMA) and macrogol 400.

Description

Chemical name: 1,4-butanediol dimethanesulfonate. Molecular Formula: C6H14O6S2. Molecular Weight: 246.31. CAS Registry Number: 55-98-1.
Myleran IV 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 Myleran IV, is a white crystalline solid that is only very slightly soluble in water, sparingly soluble in acetone and slightly soluble in ethanol.
Each 10 mL vial of Myleran IV contains 60 mg (6 mg/mL) of busulfan and the ingredients dimethylacetamide (DMA) and macrogol 400. The drug product Myleran IV is intended for dilution with 0.9% sodium chloride solution for injection or 5% glucose solution for injection.

Pharmacology

Pharmacodynamic properties.

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.

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.

Elimination.

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 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.

Clinical Trials

Clinical trials in adults.

Documentation of the safety and efficacy of 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 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. Busulfan with cyclophosphamide was effective in inducing myeloablation and engraftment. Relapse-free and overall survival were similar in the two trials (Table 1).
Uncontrolled (Fernandez) and non-randomised controlled trials (Mamlouk) in adults with haematological malignancies showed comparable incidences of engraftment for once daily and twice daily 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 2). Reproducible busulfan pharmacokinetic parameters were demonstrated for once daily 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 busulfan with cyclophosphamide regimen. Two-year survival was 37-88% depending on risk (Table 3). Reproducible busulfan pharmacokinetic parameters were demonstrated for 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 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 busulfan-fludarabine conditioning regimen (Table 4). 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 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 busulfan ranged from 3.2-4.8 mg/kg/day depending on weight group. The busulfan dose was based on body weight as detailed in the Dosage and Administration section and given in four divided doses daily for 4 days.
In autologous HSCT, 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, 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 5).
Four uncontrolled trials in children (Table 6) with malignant and non-malignant conditions showed comparable incidences of engraftment for once daily busulfan 4 mg/kg/day for 4 days (Grigull) or with 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 busulfan with cyclophosphamide or melphalan. Lower incidences of engraftment were obtained for reduced intensity conditioning regimens using a reduced dose or reduced duration of busulfan (Kletzel, Horn, Jacobsohn). The reduced intensity conditioning was associated with lower incidences of treatment related toxicity.

Indications

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

Contraindications

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

Precautions

The consequence of treatment with 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 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 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 Adverse 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 busulfan clinical trials experienced cardiac tamponade or other specific cardiac toxicities related to busulfan. However cardiac function should be monitored regularly in patients receiving busulfan (see Adverse 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 Adverse Effects).

Seizures.

Seizures have been reported with high dose busulfan treatment. Special caution should be exercised when administering the recommended dose of busulfan to patients with a history of seizures. Patients should receive adequate anticonvulsant prophylaxis. In adults all data with 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 busulfan is necessary in these patients. Non-myeloablative conditioning regimens, with a reduced dose or reduced duration of 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 Clinical Trials).

Effects on fertility.

Busulfan can impair fertility. Impotence, sterility, azoospermia, and testicular atrophy have been reported in male patients. Therefore, men treated with 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 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 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.

Use in pregnancy.

Category D
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.

Use in lactation.

Patients who are taking 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.

Paediatric use.

Busulfan may be used in children (0-17 years).
Data on the use of busulfan in children are limited (see Clinical Trials) and there have been no studies in juvenile animals. The level of DMA in 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.

Use in the elderly.

Patients older than 50 years of age have been successfully treated with busulfan. See Clinical Trials section for information on the use of busulfan in elderly patients in non-myeloablative conditioning regimens. Only limited information is available for the safe use of busulfan in patients older than 60 years.

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. On the basis of human data, busulfan has been classified by IARC as a human carcinogen. WHO has concluded that there is a causal relationship between busulfan exposure and cancer. Leukaemia patients treated with busulfan developed many different cytological abnormalities, and some developed carcinomas. Busulfan is thought to be leukemogenic.

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).

Hepatic impairment.

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 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.

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 busulfan in combination with fludarabine gave a high incidence of regimen related toxicity.

Effects on ability to drive and use machines.

No relevant effects have been noted.

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 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 busulfan (see Adverse Effects).

Adverse 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 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 7. See Precautions 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 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.

Post-marketing experience.

The following adverse reactions (reported as MedDRA terms) have been identified during post- approval use of Busulfan (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.

Dosage and Administration

Myleran IV 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 follows.
The 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 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 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 busulfan dose.

Administration.

Myleran IV must be diluted prior to administration. A final concentration of approximately 0.5 mg/mL busulfan should be achieved. Myleran IV should be administered by intravenous infusion via central venous catheter.
Myleran IV 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 Myleran IV to 24 h after the last dose of Myleran IV. 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 Myleran IV 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 Myleran IV 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:
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 Myleran IV solution.
The use of gloves and protective clothing is recommended.
If Myleran IV or diluted Myleran IV solution contacts the skin or mucosa, wash them thoroughly with water immediately.

Calculation of the quantity of Myleran IV to be diluted and of the diluent.

Myleran IV 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 Myleran IV ensuring the final concentration of busulfan remains at approximately 0.5 mg/mL.
For example, the amount of Myleran IV and diluent to be administered would be calculated as follows for a patient with a Y kg body weight receiving Z mg/kg busulfan.
To prepare the final solution for infusion, add (A) mL of Myleran IV 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.

Do not use polycarbonate syringes with Myleran IV.
Using a non polycarbonate syringe fitted with a needle:
Remove the calculated volume of Myleran IV 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 Myleran IV to the diluent, not the diluent to Myleran IV. Do not put Myerlan IV 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 Myleran IV is a clear colourless solution.

Instructions for use.

Myleran IV 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.
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 Myleran IV has not been tested and is not recommended.
The entire prescribed Myleran IV 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 Myleran IV 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 Myleran IV is administered via an in-line filter or a filter fitted with an infusion set.
Do not infuse concomitantly with another intravenous solution.
Myleran IV 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, Myleran IV must not be mixed with other medicinal products except those mentioned in the Dosage and Administration section.

Overdosage

For advice on the management of overdosage, please contact the Poisons Information Centre (telephone 131 126).
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 other than haematopoietic stem cell transplantation. In the absence of haematopoietic progenitor cell transplantation, the recommended dosage of busulfanwould 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 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.

Presentation

Unopened vials of Myleran IV Injection must be stored at 2°-8°C in a refrigerator (do not freeze).
Myleran IV 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.
Myleran IV is provided in packages of eight vials.

Storage

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

Poison Schedule

S4.