Busulfan

Busulfan is a potent cytotoxic, bifunctional alkylating agent of the alkyl sulfonate class (ATC L01AB01). At the high intravenous doses used for conditioning it causes profound myelosuppression and immunosuppression, which the SmPC describes as the desired therapeutic effects of the regimen. The oral tablets are dosed against the blood counts for chronic granulocytic leukaemia and related disorders.

Mechanism of Action

• DNA alkylation: in aqueous media busulfan releases its two methanesulfonate groups, producing carbonium ions that alkylate DNA. This is thought to be the main biological mechanism of its cytotoxic effect.
• Cross-linking: with a reactive group at each end of a four-carbon chain, busulfan forms cross-links between guanine bases in DNA that cells cannot easily repair. DNA replication and RNA transcription are disrupted and the cell undergoes apoptosis (DrugBank).
• Cell cycle: alkylating agents act on cells in any phase of the cycle (DrugBank).

Pharmacokinetics

• Absorption: after a 2-hour intravenous infusion the dose is immediately and completely available. Exposure was similar with oral 1 mg/kg and intravenous 0.8 mg/kg in adults, and variability was low between patients (CV 21%) and within a patient (CV 12%). Oral busulfan is reported to be completely absorbed from the gut (DrugBank).
• Distribution: the terminal volume of distribution is 0.62–0.85 L/kg. Cerebrospinal fluid concentrations are comparable to plasma, although probably too low for antineoplastic activity. Reversible binding to plasma proteins is about 7%; irreversible binding, mainly to albumin, is about 32%.
• Metabolism: mainly conjugation with glutathione (spontaneous and glutathione-S-transferase mediated), followed by oxidation in the liver. None of the metabolites is thought to contribute significantly to efficacy or toxicity. The SmPC bases its biotransformation and elimination data on oral busulfan.
• Elimination: total plasma clearance is 2.25–2.74 mL/min/kg and the terminal half-life 2.8–3.9 hours. About 30% of the dose is excreted in the urine over 48 hours, 1% as unchanged busulfan; faecal elimination is negligible. Irreversible protein binding may explain the incomplete recovery.
• Special populations: renal and hepatic impairment have not been studied. In children under 9 kg, therapeutic drug monitoring may be justified case by case.

Intravenous concentrate (conditioning before transplantation)

• Busulfan followed by cyclophosphamide (BuCy2): conditioning treatment before conventional haematopoietic progenitor cell transplantation (HPCT) in adults, when the combination is considered the best available option.
• Busulfan following fludarabine (FB): conditioning treatment before HPCT in adults who are candidates for a reduced-intensity conditioning (RIC) regimen.
• Busulfan followed by cyclophosphamide (BuCy4) or melphalan (BuMel): conditioning treatment before conventional HPCT in paediatric patients.

Oral tablets (2 mg)

• Chronic granulocytic leukaemia: palliative treatment of the chronic phase.
• Polycythaemia vera: effective in achieving prolonged remission, especially when thrombocytosis is marked.
• Essential thrombocythaemia and myelofibrosis: may be very useful in certain cases.

• Hypersensitivity to busulfan or to any of the excipients.
• Pregnancy (intravenous concentrate): HPCT is contraindicated in pregnant women, and so is busulfan.
• The tablet SmPC extract lists hypersensitivity as its only contraindication.

At conditioning doses, profound myelosuppression occurs in every patient and is the intended effect of the regimen, so it is not counted as an undesirable effect. Serious toxicity of the blood, liver and lungs is an expected consequence of conditioning and transplantation; infection and graft-versus-host disease (GVHD) were the main causes of illness and death, especially after allogeneic transplantation.

• Adults (busulfan with cyclophosphamide or melphalan, 103 patients): leucopenia 96%, thrombocytopenia 94%, anaemia 88%; one or more infections 39%; fever 87%; chills 47%. Hepatic veno-occlusive disease (VOD) occurred in 6% (8.2% after allogeneic transplant, fatal in 2 patients, and 2.5% after autologous). Acute GVHD affected 18% of allogeneic patients (grade III–IV 5%).
• Children (55 patients): infections (including febrile neutropenia) 89%; grade 3 raised transaminases 24%; VOD 15% after autologous and 7% after allogeneic transplant, never fatal or severe and resolved in all cases; acute GVHD 50% of allogeneic patients (grade III–IV 3.6%).
• Fludarabine regimen (1,574 patients in published trials): CMV reactivation 30.7–80.0%, EBV reactivation 2.3–61%, bacterial infections 32.0–38.9%, nausea and vomiting up to 59.1%, stomatitis up to 11%, haemorrhagic cystitis 16–18.1% and VOD 3.9–15.4%. The most frequent causes of non-relapse death to day 100 were infection or sepsis, GVHD, pulmonary disorders and organ failure.

Intravenous Busulfan with Cyclophosphamide or Melphalan (Adults and Children)

Very common (≥1/10): rhinitis, pharyngitis; neutropenia, thrombocytopenia, febrile neutropenia, anaemia; allergic reaction; anorexia, hyperglycaemia, hypocalcaemia, hypokalaemia, hypomagnesaemia, hypophosphataemia; anxiety, depression, insomnia; headache, dizziness; tachycardia; hypertension, hypotension, thrombosis, vasodilatation; dyspnoea, epistaxis, cough, hiccup; stomatitis, diarrhoea, abdominal pain, nausea, vomiting, dyspepsia, ascites, constipation, anal discomfort; hepatomegaly, jaundice; rash, pruritus, alopecia; myalgia, back pain, arthralgia; dysuria, oliguria; asthenia, chills, fever, chest pain, oedema (including generalised oedema), pain, pain or inflammation at the injection site, mucositis; raised transaminases, bilirubin, GGT, alkaline phosphatase and creatinine; weight gain; abnormal breath sounds.

Common (≥1/100 to <1/10): hyponatraemia; confusion; arrhythmia, atrial fibrillation, cardiomegaly, pericardial effusion, pericarditis; hyperventilation, respiratory failure, alveolar haemorrhage, asthma, atelectasis, pleural effusion; haematemesis, ileus, oesophagitis; hepatic veno-occlusive disease (more frequent in children); skin desquamation, erythema, pigmentation disorder; haematuria, moderate renal insufficiency; raised blood urea nitrogen, decreased ejection fraction.

Uncommon (≥1/1,000 to <1/100): delirium, nervousness, hallucination, agitation, seizure, encephalopathy, cerebral haemorrhage; ventricular extrasystoles, bradycardia, femoral artery thrombosis; capillary leak; hypoxia; gastrointestinal haemorrhage.

Not known (post-marketing reports): hypogonadism, premature menopause and ovarian failure; interstitial lung disease, pulmonary hypertension; tooth hypoplasia; cataract, corneal thinning and lens disorders (reported with oral busulfan).

Intravenous Busulfan with Fludarabine (FB, Adults)

Very common (≥1/10): viral infection, CMV and EBV reactivation, bacterial infection; hypoalbuminaemia, electrolyte disturbance, hyperglycaemia; nausea, vomiting, diarrhoea, stomatitis, mucositis; hepatic veno-occlusive disease; haemorrhagic cystitis (including virus-induced); raised transaminases, bilirubin and alkaline phosphatase.

Common (≥1/100 to <1/10): invasive fungal infection, pulmonary infection; headache and other nervous system disorders; hypertension; pulmonary haemorrhage; rash; renal disorder; raised creatinine.

Not known (post-marketing): brain abscess, cellulitis, sepsis; febrile neutropenia; anorexia; agitation, confusional state, hallucination; cerebral haemorrhage, encephalopathy; atrial fibrillation; respiratory failure; gastrointestinal haemorrhage; tooth hypoplasia; jaundice, liver disorders; oliguria; asthenia, oedema, pain; raised lactate dehydrogenase, uric acid, urea and GGT; weight gain.

Oral Tablets

The tablet SmPC states that there is no up-to-date clinical documentation on which to base frequencies, which vary with the dose and with combined treatments. Its table, which continues beyond the rows below, lists:

Very common (≥1/10): dose-related bone marrow depression showing as leucopenia and especially thrombocytopenia; at high doses idiopathic pneumonia syndrome, nausea, vomiting, diarrhoea, mouth ulcers, and hyperbilirubinaemia, jaundice, hepatic veno-occlusive disease with biliary fibrosis, hepatic atrophy and necrosis.

Common (≥1/100 to <1/10): secondary leukaemia after cancer chemotherapy; interstitial lung disease after long-term conventional-dose treatment; skin hyperpigmentation; at high doses alopecia and, in patients with thalassaemia, cardiac tamponade.

Rare (≥1/10,000 to <1/1,000): aplastic anaemia; at high doses convulsions; lens changes and cataracts (possibly bilateral) and corneal thinning (reported after a marrow transplant preceded by high-dose busulfan); at conventional doses nausea, vomiting, diarrhoea and mouth ulcers (which may improve with divided doses), dry mouth, jaundice and abnormal liver function, biliary fibrosis, alopecia and skin reactions (urticaria, erythema multiforme, erythema nodosum, non-acute porphyria, rashes, dry skin, skin fragility with complete anhidrotic cheilosis).

Very rare (<1/10,000): myasthenia gravis.

Not known: pulmonary hypertension; dental hypoplasia.

• Itraconazole: published studies in adults show reduced busulfan clearance with high-dose busulfan (about 20% in the tablet SmPC), raising busulfan levels. Monitor closely for busulfan toxicity; with the tablets, check blood counts weekly.
• Metronidazole: increased plasma busulfan levels have been reported (about 80% higher with 1,200 mg a day, given as 400 mg three times daily). Monitor closely for toxicity.
• Fluconazole: no interaction observed.
• Ketobemidone (an analgesic): published studies suggest it may be associated with high plasma busulfan; special care is recommended.
• Deferasirox: busulfan exposure is increased by a mechanism that is not fully elucidated. In patients who are or have recently been treated with deferasirox, monitor busulfan plasma concentrations regularly and adjust the dose if necessary.
• Paracetamol: described to lower glutathione in blood and tissues, so it may decrease busulfan clearance. Use with caution before (within 72 hours) or together with busulfan.
• Anticonvulsants: phenytoin or benzodiazepines were used for seizure prophylaxis in the trials. With high-dose oral busulfan, phenytoin has been reported to increase busulfan clearance (induction of glutathione-S-transferase), and the tablet SmPC notes it may reduce the myeloablative effect. No interaction was reported with benzodiazepines (diazepam, clonazepam, lorazepam), and in a phase II trial intravenous busulfan clearance was the same with clonazepam as with phenytoin.
• Timing of cyclophosphamide or melphalan: in the BuCy2 regimen, fewer VOD and other regimen-related toxicities were seen when more than 24 hours separated the last busulfan dose and the first cyclophosphamide dose. In children, giving melphalan less than 24 hours after the last busulfan dose may influence toxicity.
• Fludarabine, 5-HT3 antiemetics: busulfan and fludarabine share no metabolic pathway and no mutual interaction was reported; none was observed with ondansetron or granisetron.
• Other cytotoxics with lung toxicity: their effects may add to those of busulfan (tablet SmPC).
• Live vaccines: vaccination with live organisms is not recommended in immunocompromised patients.
• Food and herbal products: DrugBank advises drinking plenty of fluids, taking oral doses at the same time every day, and caution with grapefruit products and St John’s wort.

The intravenous concentrate is given before the transplant, and its administration should be supervised by a physician experienced in conditioning treatment before HPCT. The Spanish 6 mg/mL concentrate has the same indications and regimens. The tablets are used only under the direction of physicians experienced in cytotoxic agents.

Intravenous Concentrate in Adults (BuCy2)

• Busulfan: 0.8 mg/kg body weight as a 2-hour infusion every 6 hours for 4 consecutive days, 16 doses in total.
• Then cyclophosphamide: 60 mg/kg a day for 2 days, started at least 24 hours after the 16th busulfan dose.

Intravenous Concentrate in Children, 0 to 17 Years (BuCy4 or BuMel)

• Busulfan: the same infusion schedule (2 hours, every 6 hours, 4 consecutive days, 16 doses), with the dose set by actual body weight: under 9 kg, 1.0 mg/kg; 9 kg to under 16 kg, 1.2 mg/kg; 16 to 23 kg, 1.1 mg/kg; above 23 kg to 34 kg, 0.95 mg/kg; above 34 kg, 0.8 mg/kg.
• Then: four cycles of cyclophosphamide 50 mg/kg (BuCy4) or one administration of melphalan 140 mg/m² (BuMel), started at least 24 hours after the 16th busulfan dose.

Intravenous Concentrate with Fludarabine (FB, Adults)

• Fludarabine: a single daily 1-hour infusion of 30 mg/m² for 5 consecutive days, or 40 mg/m² for 4 consecutive days.
• Busulfan: 3.2 mg/kg as a single daily 3-hour infusion immediately after fludarabine, for 2 or 3 consecutive days.
• The safety and efficacy of FB in children have not been established.

Method of Administration and Premedication

• Intravenous use only. The concentrate must be diluted to a final concentration of about 0.5 mg/mL and given through a central venous catheter; it must not be given as a rapid intravenous, bolus or peripheral injection. Dilution instructions are in section 6.6 of the SmPC.
• All patients should receive anticonvulsant premedication to prevent seizures, from 12 hours before busulfan until 24 hours after the last dose. Phenytoin or benzodiazepines were used in the studies.
• Antiemetics should be given before the first dose and continued on a fixed schedule according to local practice.

Special Populations (Intravenous Concentrate)

• Elderly: patients over 50 years (23 patients) were treated successfully without dose adjustment, with limited information over 60; the adult dose is used. For FB, more than 500 patients aged 55 or over appear in publications with similar efficacy, and no adjustment was deemed necessary.
• Obese: in adults, dosing on adjusted ideal body weight (AIBW) should be considered. Ideal body weight (IBW) is 50 + 0.91 × (height in cm − 152) kg for men and 45 + 0.91 × (height in cm − 152) kg for women; AIBW = IBW + 0.25 × (actual body weight − IBW). The medicinal product is not recommended in obese children and adolescents with a body mass index above 30 kg/m² until further data become available.
• Renal impairment: not studied; no dose modification is recommended as busulfan is moderately excreted in urine, but caution is advised.
• Hepatic impairment: not studied; caution, particularly in severe impairment.

Tablets (2 mg)

• General: given in cycles or continuously, with the dose set individually under strict clinical and haematological control. Tablets must not be divided; if less than one tablet a day is needed on average, leave one or more days between treatment days. Use lower doses when busulfan is combined with other cytotoxic agents. In obese patients, consider dosing by body surface area or adjusted ideal body weight.
• Chronic granulocytic leukaemia, induction in adults: 0.06 mg/kg a day with an initial daily maximum of 4 mg, which can be a single dose. Check blood counts at least weekly during induction, and raise the dose only if the response is inadequate after three weeks. Continue until the total white-cell count has fallen to 15–25 × 10⁹/L (usually 12 to 20 weeks), then stop; the count may fall further over the next two weeks. Continuing the induction dose beyond this point, or after the platelet count falls below 100 × 10⁹/L, risks prolonged and possibly irreversible marrow aplasia.
• Chronic granulocytic leukaemia, maintenance in adults: control may last long without further busulfan, and extra courses are usually given when the white-cell count rises to 50 × 10⁹/L or symptoms return. Some physicians prefer continuous maintenance, aiming for a white-cell count of 10–15 × 10⁹/L with blood counts at least every 4 weeks; the usual dose is 0.5–2 mg a day, though individual needs may be much lower.
• Children: the disease rarely occurs in children. Busulfan can treat Philadelphia chromosome-positive disease, but the juvenile Philadelphia-negative form hardly responds.
• Polycythaemia vera: usually 4–6 mg a day continuously for 4 to 6 weeks, watching blood counts closely, especially platelets. Give further courses on relapse, or maintenance at about half the induction dose. If the disease was first controlled by venesection, short courses can be used only to control the platelet count.
• Myelofibrosis: the usual starting dose is 2–4 mg a day, with careful haematological monitoring because the marrow is extremely sensitive in this condition.
• Essential thrombocythaemia: usually 2–4 mg a day. Stop treatment if the total white-cell count falls below 5 × 10⁹/L or the platelet count below 500 × 10⁹/L.

Myelosuppression and Infection

• Profound myelosuppression occurs in all patients at the recommended dose and schedule, and severe granulocytopenia, thrombocytopenia, anaemia or any combination may develop. Frequent complete blood counts, including differential white-cell and platelet counts, are needed during treatment and until recovery.
• Prophylactic or empirical anti-infectives (antibacterial, antifungal, antiviral) should be considered during the neutropenic period. Platelet and red-cell support, and growth factors such as G-CSF, should be used as medically indicated.
• In adults, neutrophils fell below 0.5 × 10⁹/L at a median of 4 days after transplant in all patients, recovering at a median of day 10 (autologous) and day 13 (allogeneic); thrombocytopenia occurred in 98% and anaemia (haemoglobin below 8.0 g/dL) in 69%. In children, all patients had neutropenia (lasting 5 and 18.5 days after autologous and allogeneic transplant), thrombocytopenia and anaemia.
• Fanconi anaemia cells are hypersensitive to cross-linking agents, and experience of busulfan conditioning in children with Fanconi anaemia is limited, so use it with caution.

Hepatic Toxicity and Veno-Occlusive Disease

• Busulfan is mainly metabolised in the liver: use caution in pre-existing hepatic impairment, especially severe. Serum transaminases, alkaline phosphatase and bilirubin should be monitored regularly for 28 days after transplant to detect hepatotoxicity early.
• Hepatic veno-occlusive disease is a major complication. The risk may be higher after prior radiotherapy, three or more cycles of chemotherapy, or a previous progenitor cell transplant.

Seizures

Seizures have been reported with high-dose busulfan. Use special caution at the recommended dose in patients with a history of seizures, and give adequate anticonvulsant prophylaxis (see Administration and Dosage).

Lungs, Heart and Kidneys

• A fatal case of acute respiratory distress syndrome with respiratory failure and interstitial pulmonary fibrosis occurred in the busulfan studies. Busulfan may cause pulmonary toxicity that adds to that of other cytotoxic agents, so take care in patients with previous mediastinal or lung radiation.
• Cardiac function should be monitored regularly; no cardiac tamponade or other specific cardiac toxicity occurred in the studies.
• Consider periodic monitoring of renal function.
• Thrombotic microangiopathy after haematopoietic cell transplantation, including fatal cases, has been reported with high-dose conditioning regimens that combined busulfan with another conditioning treatment.

Second Malignancy

The raised risk of a second malignancy should be explained to the patient. The International Agency for Research on Cancer (IARC) classifies busulfan as a human carcinogen, and the World Health Organization has concluded that there is a causal relationship between busulfan exposure and cancer. Busulfan is thought to be leukaemogenic.

Additional Precautions for the Tablets

• Use only under the direction of physicians experienced in cytotoxic agents.
• Stop treatment if pulmonary toxicity develops. If anaesthesia is needed in a patient with possible lung toxicity, keep the inspired oxygen concentration as low as is safe and watch breathing closely afterwards.
• Immunisation with live vaccines is not recommended, because it can cause infection in immunocompromised patients.
• Busulfan should generally not be given together with or shortly after radiotherapy, and it is ineffective once blast transformation has occurred.
• Patients with chronic granulocytic leukaemia may have hyperuricaemia or hyperuricosuria, which should be corrected before starting. During treatment, prevent hyperuricaemia and uric acid nephropathy with adequate hydration and allopurinol.
• Renal impairment has not been studied; no dose change is recommended since busulfan is moderately excreted in urine, but take caution. Take caution in hepatic impairment as well. With itraconazole or metronidazole, watch for busulfan toxicity and check blood counts weekly.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use effective contraception during treatment and for up to 6 months after it.
• Pregnancy: contraindicated for the intravenous concentrate. Animal studies show reproductive toxicity (embryo-foetal lethality and malformations). A few congenital abnormalities have been reported with low-dose oral busulfan, not necessarily due to the active substance, and exposure in the third trimester may be associated with impaired intrauterine growth.
• Breastfeeding: it is unknown whether busulfan or dimethylacetamide (DMA) pass into breast milk. Because of the tumourigenic potential shown in human and animal studies, breastfeeding should be discontinued during treatment.
• Fertility: busulfan can impair fertility in men and women. Men are advised not to father a child during treatment and for up to 6 months after it, and to seek advice on sperm cryopreservation because infertility may be irreversible. Ovarian suppression and amenorrhoea with menopausal symptoms commonly occur in premenopausal patients, and treatment of a pre-adolescent girl prevented the onset of puberty because of ovarian failure. Impotence, sterility, azoospermia and testicular atrophy have been reported in men. The solvent DMA may also impair fertility; it reduced fertility in male and female rodents.

Excipients

The centrally authorised concentrate contains dimethylacetamide and macrogol 400. Each 2 mg tablet contains 92.5 mg of anhydrous lactose, an excipient with known effect.

Effect on Driving

The SmPC of the centrally authorised concentrate states that busulfan has no influence on the ability to drive and use machines.

• Concentrate for infusion: store in a refrigerator at 2–8 °C. Do not freeze the diluted solution. As a refrigerated product, it must stay in the cold chain during transport and storage. The central product comes in clear colourless type I glass vials with a Teflon-faced rubber stopper and an aluminium flip-off seal, containing 10 mL or 40 mL; packs hold either eight 10 mL vials or one 40 mL vial.
• Tablets: do not store above 25 °C.

• Central concentrate: unopened vials 2 years. After first opening and before dilution, the 240 mg/40 mL vial is stable for 28 days at 5 ± 3 °C after multiple needle entries and product withdrawal; other in-use times and conditions are the user’s responsibility. Diluted in 5% glucose or 0.9% sodium chloride, the solution is stable for 8 hours at 25 ± 2 °C (including infusion time), or 12 hours at 2–8 °C followed by 3 hours at 25 ± 2 °C (including infusion time). From a microbiological point of view it should be used immediately after dilution.
• Spanish 6 mg/mL concentrate: vials 18 months. Diluted solution: 4 hours at 20–25 °C, or 15 hours at 2–8 °C followed by 3 hours at 20–25 °C (including infusion time); if not used immediately, in-use times are the user’s responsibility.
• Tablets: 3 years.

Prescription only (Rx). The intravenous concentrate is supervised by a physician experienced in conditioning treatment before HPCT. It is diluted and infused in hospital through a central venous catheter, so it is supplied to the hospital or clinic that administers it, under cold-chain conditions (2–8 °C). The 2 mg tablets are a cytotoxic taken orally under the direction of physicians experienced in cytotoxic agents; they are supplied to the patient or the treating clinic on prescription and are stored at room temperature (not above 25 °C).