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Busulfan

(British Approved Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Synonyms: Bussulfam; Busulfaani; Busulfan; Busulfanas; Busulfano; Busulfanum; Busulphan; Buszulfán; CB-2041; GT-41; Myelosan; NSC-750; WR-19508
BAN: Busulfan
INN: Busulfan [rINN (en)]
INN: Busulfano [rINN (es)]
INN: Busulfan [rINN (fr)]
INN: Busulfanum [rINN (la)]
INN: Бусульфан [rINN (ru)]
Chemical name: Tetramethylene di(methanesulphonate); Butane-1,4-diol di(methanesulphonate)
Molecular formula: C6H14O6S2 =246.3
CAS: 55-98-1
ATC code: L01AB01
Read code: y02jB

Pharmacopoeias. In China, Europe, International, Japan, and US.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Busulfan). A white or almost white, crystalline powder. Very slightly soluble in water and in alcohol; freely soluble in acetone and in acetonitrile. Store in airtight containers. Protect from light.

The United States Pharmacopeia 31, 2008 (Busulfan). A white, crystalline powder. Very slightly soluble in water; slightly soluble in alcohol; soluble 1 in 45 of acetone. Store in airtight containers.

Adverse Effects and Treatment

For a general outline see Antineoplastics.

The major adverse effect of busulfan with standard doses is bone-marrow depression, manifest as leucopenia, thrombocytopenia, and sometimes, anaemia. The nadir of the granulocyte count usually occurs after about 10 to 30 days with recovery occurring over up to 5 months, but busulfan has sometimes caused irreversible or extremely-prolonged bone-marrow depression. Hyperpigmentation is common, and in a few cases after long-term therapy may be part of a syndrome simulating Addison’s disease.

Rarely, progressive interstitial pulmonary fibrosis, known as ‘busulfan lung’, can occur on prolonged treatment. Gastrointestinal disturbances are rare at usual therapeutic doses but may be dose-limiting where high doses are given before bone marrow transplantation. Other rare adverse effects include dry skin and other skin reactions, liver damage, gynaecomastia, cataract formation, and, at high doses, CNS effects including convulsions.

Busulfan may result in impaired fertility and gonadal function. As with other alkylating agents, it is potentially carcinogenic, mutagenic, and teratogenic.

Effects on the bladder. Haemorrhagic cystitis occurred in a patient who had received prolonged therapy with busulfan. High-dose busulfan used in conditioning regimens for haematopoietic stem cell transplantation may increase the risk of lateonset haemorrhagic cystitis.

Effects on the liver. Jaundice in the terminal phase of chronic myeloid leukaemia in a 31 -year-old man was attributed to busulfan which had been taken for 6 years. Busulfan toxicity involving the liver was also reported in a patient who had taken busulfan for 54 months, while hepatitis possibly associated with busulfan therapy has also been described. Dose-dependent veno-occlusive disease (VOD) has been reported in 20 to 40% of patients receiving high-dose busulfan before bone marrow transplantation. Licensed product information from 1 manufacturer (Pierre Fabre, UK) states that previous radiotherapy, progenitor cell transplantation, or three cycles of chemotherapy or more, can increase the risk of hepatic VOD; another (GSK) lists concurrent use of multiple alkylating agents, or total doses of busulfan in excess of 16 mg/kg, as possible risk factors. A reduced incidence of hepatic VOD has been seen in those patients given high-dose busulfan and cyclophosphamide when the first dose of cyclophosphamide has been delayed for more than 24 hours after the last dose of busulfan.

Effects on the nervous system. High-dose busulfan, used in conditioning regimens for bone marrow transplantation, has been associated with the development of convulsions, both generalised and myoclonic. As a result, the use of prophylactic antiepileptic therapy has been suggested as a component of such regimens. However, some do not consider the routine use of prophylactic antiepileptics justified, and the potential for phenytointo increase the metabolism of busulfan, thereby possibly decreasing its myeloablative efficacy, has been pointed out. In addition, phenytoin plasma concentrations have been found to be subtherapeutic in patients who developed convulsions despite a standard prophylactic dose, and the regimen was subsequently adjusted to take account of plasma concentrations. Clobazam has been suggested as an alternative to phenytoin for prophylaxis of busulfan-induced seizures. Licensed product information from one manufacturer (GSK, UK) recommends the use of prophylactic antic onvulsants, and prefers a benzodiazepine to phenytoin. However, other manufacturers suggest use with phenytoin; Otsuka in the United States of America state that the recommended dose of their parenteral product is based on studies in which phenytoin was given, and that if other anticonvulsants are used exposure should be monitored, as a 15% increase in plasma-busulfan may be expected, with increased risk of toxicity.

Effects on the skin and hair. For the effect of radiotherapy in activating skin lesions in busulfan-treated patients, see under Precautions, below.

Precautions

For reference to the precautions necessary with antineoplastics. Careful attention should be given to monitoring blood counts during therapy. This should be done at least weekly at the start of standard dose therapy. With high dose therapy blood counts should be monitored daily, as should liver function. Prophy lactic anticonvulsants should be used during high dose therapy (see Effects on the Nervous System, above). Busulfan should be stopped if lung toxicity develops. The use of oxygen may exacerbate possible lung toxicity; if anaesthesia is required the concentration of oxygen should be minimised.

Handling. Busulfan is irritant; avoid contact with skin and mucous membranes.

Porphyria. Busulfan is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in animals.

Radiotherapy. Severe cutaneous reactions occurred in patients given radiotherapy at least 30 days after combined chemotherapy with high-dose busulfan.

It is possible that radiotherapy could worsen subclinical lung injury caused by busulfan.

Interactions

For a general outline of antineoplastic drug interactions. Phenytoin increases the clearance of busulfan (see Effects on the Nervous System, above).

Antifungals. Giving itraconazole with busulfan resulted in a decrease in the clearance of busulfan; fluconazole had no such effect. Busulfan doses may need to be decreased if itraconazole is also given.

Antineoplastics. When tioguanine was given with busulfan for chronic myeloid leukaemia, a number of cases of hepatic nodular regenerative hyperplasia, with abnormal liver function tests, portal hypertension, and oesophageal varices were noted. There were no cases in patients treated with busulfan alone, and the mechanism of this possible interaction is unclear.

Antiprotozoals. In a study of patients who received high-dose busulfan as part of a myeloablative regimen before stem cell transplantation, the use of metronidazole significantly increased plasma concentrations of busulfan and the degree of associated toxicity, including elevation of liver function tests, veno-occlusive disease, and mucositis.

Pharmacokinetics

Busulfan is readily absorbed from the gastrointestinal tract and rapidly disappears from the blood with a half-life of 2 to 3 hours. It is extensively metabolised, and excreted in the urine almost entirely as sulfur-containing metabolites. It crosses the blood-brain barrier.

Metabolism. In a study of the pharmacokinetics of high-dose busulfan in 5 patients receiving 1 mg/kg orally every six hours for 4 days, the mean elimination half-life decreased from about 3.4 hours after the first dose to about 2.3 hours after the final dose, suggesting that busulfan may induce its own metabolism.

Therapeutic drug monitoring. A review concluded that therapeutic drug monitoring of busulfan would maximise en-graftment and minimise toxicity and relapse in haematopoietic stem cell transplantation. In regimens using busulfan with cyclophosphamide, steady-state plasma concentrations of busulfan above 600 micrograms/litre appeared to favour engraftment. A pharmacokinetic analysis found that in patients with graft rejections, busulfan trough concentrations were below 150 nanograms/mL; steady state concentrations also tended to be lower in this group but not significantly so. The bioavailability of oral busulfan is variable, particularly in children; intravenous conditioning regimens, adjusted on the basis of first-dose pharmacokinetics and therapeutic drug monitoring, have been used to overcome this problem. A study found a significant correlation between busulfan concentration in plasma and saliva after oral dosing in children; busulfan saliva analysis may therefore be a useful, non-invasive alternative to plasma analysis.

Uses and Administration

Busulfan is an antineoplastic with a cell-cycle non-specific alkylating action unlike that of the nitrogen mustards, and having a selective depressant action on bone marrow. In small doses, it depresses granulocytopoiesis and to a lesser extent thrombocytopoiesis but has little effect on lymphocytes. With larger doses, severe bone-marrow depression eventually ensues. Because of its selective action, busulfan has been used in the palliative treatment of chronic myeloid leukaemia. It provides symptomatic relief with a reduction in spleen size and a general feeling of well-being. The fall in leucocyte count is usually accompanied by a rise in the haemoglobin concentration. Permanent remission is not induced and resistance to its beneficial effects gradually develops.

Busulfan may be used in patients with polycythaemia vera and in some patients with myelofibrosis and primary thrombocythaemia. It is also used at high doses as part of a conditioning regimen to prepare patients for bone marrow transplantation, a procedure discussed on site under Haematopoietic Stem Cell Transplantation.

The licensed initial oral dosage ofbusulfan in chronic myeloid leukaemia is 60 micrograms/kg daily, with a usual maximum single daily dose of 4 mg. This is continued until the white cell count has fallen to between 15 000 and 25 000 cells/mm (typically 12 to 20 weeks). It should be stopped earlier if the platelet count falls below 100 000 cells/mm. Higher doses may be given if the response after 3 weeks is inadequate but this increases the risk of irreversible damage to the bone marrow and calls for special vigilance. Complete blood counts should be made at least every week and the trends followed closely; if haemorrhagic tendencies occur or there is a steep fall in the white cell count indicating severe bone-marrow depression, busulfan should be withdrawn until marrow function has returned.

Once an initial remission has been attained treatment is stopped and not resumed until the white cell count returns to 50 000 cells/mm. If this occurs within 3 months continuous maintenance treatment with a usual dose of 0.5 to 2 mg daily may be given. In patients with polycythaemia vera the usual oral dose is 4 to 6 mg daily, continued for 4 to 6 weeks with careful monitoring of blood counts. Further courses are given when relapse occurs; alternatively, maintenance therapy may be given at half the dose required for induction. Doses of 2 to 4 mg daily have been given for essential thrombocythaemia or myelofibrosis. In conditioning regimens for bone marrow transplantation busulfan has been given in usual doses of 3.5 to 4mg/kg daily in divided doses for 4 days orally (total dose 14 to 16 mg/kg), with cyclo-phosphamide, for ablation of the recipient’s bone marrow. When given by intravenous infusion in a regimen with phenytoin (see Effects on the Nervous System, above), a recommended dose is 3.2 mg/kg ideal body-weight daily for 4 days (total dose 12.8 mg/kg); actual body-weight is used for the calculation if it is less than the ideal weight. The daily dose is given as 4 infusions of 800 micrograms/kg at intervals of 6 hours; each dose should be diluted in sodium chloride 0.9% or glucose 5% to a final concentration of about 500 micrograms/mL, and given over 2 hours through a central venous catheter using an infusion pump. UK licensed product information states that cyclophosphamide dosing should not be started for at least 24 hours after the last dose ofbusulfan; US information permits use no sooner than 6 hours after the last busulfan dose.

In the UK, busulfan is licensed for use with cyclophosphamide or melphalan as a conditioning regimen prior to haematopoietic stem cell transplantation in children. The recommended dose for children up to 17 years of age is weight-based as follows: • less than 9 kg: busulfan 1 mg/kg

• 9 to 16 kg: busulfan 1.2 mg/kg

• 16 to 23 kg: busulfan 1.1 mg/kg

• 23 to 34 kg: busulfan 950 micrograms/kg

• greater than 34 kg: busulfan 800 micrograms/kg This dose is given every 6 hours over 4 days to a total of 16 doses, diluted and infused as for adults. Cyclophosphamide or melphalan should not be started for at least 24 hours after the last dose ofbusulfan.

Preparations

British Pharmacopoeia 2008: Busulfan Tablets;

The United States Pharmacopeia 31, 2008: Busulfan Tablets.

Proprietary Preparations

Argentina: Myleran;

Australia: Myleran;

Austria: Myleran;

Belgium: Myleran;

Brazil: Myleran;

Canada: Busulfex; Myleran;

Chile: Myleran;

Czech Republic: Busilvex; Myleran;

Denmark: Busilvex;

France: Busilvex; Myleran;

Germany: Busilvex; Myleran;

Greece: Busilvex; Myleran;

Hong Kong: Busulfex; Myleran;

India: Myleran;

Ireland: Myleran;

Israel: Busulfex; Myleran;

Italy: Busilvex; Myleran;

Malaysia: Myleran;

Mexico: Myleran;

The Netherlands: Busilvex; Myleran;

Norway: Busilvex;

New Zealand: Myleran;

Poland: Busilvex; Myleran;

Portugal: Busilvex; Myleran;

Russia: Myleran;

South Africa: Myleran;

Singapore: Myleran;

Spain: Busilvex;

Sweden: Busilvex; Myleran;

Switzerland: Busilvex; Myleran ;

Thailand: Myleran;

Turkey: Busulfex; Myleran;

United Kingdom (UK): Busilvex; Myleran;

United States of America (US and USA): Busulfex; Myleran

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