Busulfan

246.3

246.30

200-250-2

G1LN9045DK

755916|750

2811

DTXSID3020910

C321

White needles|Crystals

L01AB01|L - Antineoplastic and immunomodulating agents

2942000000

104

-0.5

Pale Brown Crystalline Powder

1.56 g/cm³

114-118 °C

464ºC at 760 mmHg

9℃

1.471

Decomposes in water

Hygroscopic, Refrigerator, Under Inert Atmosphere

6.56X10-6 mm Hg at 25 deg C (est)

Peritoneal-rat LD50: 22 mg/kg; oral-mouse LD50: 110 mg/kg

Thermal decomposition to emit toxic sulfur oxide fumes

Henry's Law constant = 5.16X10-10 atm-cu m/mol at 25 °C (est)

Hydroxyl radical reaction rate constant = 4.70X10-12 cu cm/molec-sec at 25 °C (est)

This compound is an alkylating agent which hydrolyzes in water. (NTP, 1992).

Esters, Sulfate Esters, Phosphate Esters, Thiophosphate Esters, and Borate Esters

MYLERAN is an alkylating agent which hydrolyzes in water. (NTP, 1992). Strong reducers may yield hydrogen sulfide.

Ⅲ

6.1(b)

UN 2811 6.1/PG 1

3

45-26/27/28-63-46-36/37/38-23/24/25-39/23/24/25-11

53-36/37/39-45-28A-36/37-16-7

EK1750000

T+,T,F

Storehouse ventilated at low temperature and dry; stored separately from oxidants and acids; not easy to store for a long time to prevent polymerization

Moisture Sensitive

P210-P260-P280-P301 + P310-P311

H225-H301 + H311 + H331-H370

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be removed, bagged in thick plastic and prepared for disposal in a hazardous waste dump site or incinerator licensed by the Environmental Protection Agency (EPA). /Antineoplastic agents/|For more Disposal Methods (Complete) data for BUSULFAN (8 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl busulfan, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

National Toxicology Program. Eleventh Report on Carcinogens (2005). The Report on Carcinogens is an informational scientific and public health document that identifies and discusses substances (including agents, mixtures, or exposure circumstances) that may pose a carcinogenic hazard to human health. 1,4-Butanediol Dimethanesulfonate (Myleran) (55-98-1) is listed as known to be a human carcinogen.[Available from, as of July 31, 2009: http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s026buta.pdf]

Flash point data for this chemical are not available. It is probably combustible. (NTP, 1992)

|Danger|H300 (18%): Fatal if swallowed [Danger Acute toxicity, oral]|P201, P202, P260, P261, P262, P264, P270, P271, P280, P281, P284, P301+P310, P302+P350, P302+P352, P304+P340, P305+P351+P338, P308+P313, P310, P312, P314, P320, P321, P322, P330, P332+P313, P337+P313, P361, P362, P363, P403+P233, P405, and P501|Aggregated GHS information provided by 50 companies from 9 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H301: Toxic if swallowed [Danger Acute toxicity, oral]|P201, P202, P260, P264, P270, P281, P301+P310, P308+P313, P309+P311, P314, P321, P330, P405, and P501

Fires involving this material should be controlled using a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]: As an immediate precautionary measure, isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids. SPILL: Increase, in the downwind direction, as necessary, the isolation distance shown above. FIRE: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2016)

SMALL SPILLS AND LEAKAGE: If a spill of this chemical occurs, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with acetone and transfer the dampened material to a suitable container. Use absorbent paper dampened with acetone to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with acetone followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should store this material at ambient temperatures and protect from moisture. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with a combination filter cartridge, i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid gas, SO2 and a high efficiency particulate filter). (NTP, 1992)|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lots; therefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/|For more Preventive Measures (Complete) data for BUSULFAN (20 total), please visit the HSDB record page.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Methods for transporting hazardous drugs to the health-care setting should be consistent with environmental protection and national or local regulations for transporting hazardous substances. When hazardous drugs are being transported to the home-care setting, appropriate containers (eg, lined cardboard boxes) and procedures should be used to prevent breakage and contain leakage. ... The drugs must be securely capped or sealed and properly packaged and protected during transport to reduce further the chance of breakage and spillage in a public area such as a corridor or elevator. /Antineoplastic agents/

highly toxic

Signs of overdose include allergic reaction, unusual bleeding or bruising, sudden weakness or unusual fatigue, persistent cough, congestion, or shortness of breath; flank, stomach or joint pain; pronounced nausea, vomiting, diarrhea, dizziness, confusion, or darkening of the skin, chills, fever, collapse, and loss of consciousness.

Oral busulfan therapy is associated with a low rate of serum enzyme elevations that are typically transient, mild and usually do not require dose adjustment. Rare instances of clinically apparent acute liver disease have been described in patients taking oral busulfan long term. The onset of injury is usually after years of therapy, and the pattern of serum enzyme elevations is usually cholestatic (Case 1). At least one case of cholestatic injury was reported to lead to hepatic failure.

Itraconazole reduced busulfan clearance by up to 25% in patients receiving itraconazole compared to patients who did not receive itraconazole. Higher busulfan exposure due to concomitant itraconazole could lead to toxic plasma levels in some patients. Fluconazole had no effect on the clearance of busulfan. Patients treated with concomitant cyclophosphamide and busulfan with phenytoin pretreatment have increased cyclophosphamide and busulfan clearance, which may lead to decreased concentrations of both cyclophosphamide and busulfan. However, busulfan clearance may be reduced in the presence of cyclophosphamide alone, presumably due to competition for glutathione.|Busulfan-induced pulmonary toxicity may be additive to the effects produced by other cytotoxic agents.|In one study, 12 of approximately 330 patients receiving continuous busulfan and thioguanine therapy for treatment of chronic myelogenous leukemia were found to have portal hypertension and esophageal varices associated with abnormal liver function tests. Subsequent liver biopsies were performed in 4 of these patients, all of which showed evidence of nodular regenerative hyperplasia. Duration of combination therapy prior to the appearance of esophageal varices ranged from 6 to 45 months. With the present analysis of the data, no cases of hepatotoxicity have appeared in the busulfan-alone arm of the study. Long-term continuous therapy with thioguanine and busulfan should be used with caution.|Busulfan may cause additive myelosuppression when used with other myelosuppressive drugs.|For more Interactions (Complete) data for BUSULFAN (8 total), please visit the HSDB record page.

LD50 Rat iv 14-25 mg/kg|LD50 Mouse oral 120 mg/kg

/AQUATIC SPECIES/ Tilapia mossambica (Peters) Teleostei, Cichlidae, is of commercial importance being farmed for human consumption. An effective means of sterilization would be of value since prolific breeding under farming conditions reduces growth rate. The possibility of using the antileukemic drug myleran as a chemosterilant has been investigated previously, however the present study indicated that it can induce dominant lethal mutations in this species.

Cardiac tamponade, often fatal, has been reported in a small number of pediatric patients with thalassemia who received oral busulfan and cyclophosphamide as the preparatory regimen for bone marrow transplantation; abdominal pain and vomiting preceded the tamponade in most cases. Cardiac tamponade was not reported in a clinical study of patients receiving IV busulfan.

32% bound to plasma proteins and 47% bound to red blood cells.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ ... exposure may be through inadvertent ingestion of the drug on foodstuffs (eg, workers' lunches), inhalation of drug dusts or droplets or direct skin contact. /Antineoplastic agents/

For use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous (myeloid, myelocytic, granulocytic) leukemia (FDA has designated busulfan as an orphan drug for this use). It is also used as a component of pretransplant conditioning regimens in patients undergoing bone marrow transplantation for acute myeloid leukemia and nonmalignant diseases.|FDA Label|Busulfan Fresenius Kabi followed by cyclophosphamide (BuCy2) is indicated as conditioning treatment prior to conventional haematopoietic progenitor cell transplantation (HPCT) in adult patients when the combination is considered the best available option.Busulfan Fresenius Kabi followed by cyclophosphamide (BuCy4) or melphalan (BuMel) is indicated as conditioning treatment prior to conventional haematopoietic progenitor cell transplantation in paediatric patients.|Busilvex followed by cyclophosphamide (BuCy2) is indicated as conditioning treatment prior to conventional haematopoietic progenitor cell transplantation (HPCT) in adult patients when the combination is considered the best available option.Busilvex following fludarabine (FB) is indicated as conditioning treatment prior to haematopoietic progenitor cell transplantation (HPCT) in adult patients who are candidates for a reduced-intensity conditioning (RIC) regimen.Busilvex followed by cyclophosphamide (BuCy4) or melphalan (BuMel) is indicated as conditioning treatment prior to conventional haematopoietic progenitor cell transplantation in paediatric patients.|Drug: Bumel|Drug: Busulfan

Busulfan is an orally administered anticancer alkylating agent used in the treatment of chronic myelogenous leukemia, as well as a parenterally administered myeloablative agent used in preparation of hematopoietic cell transplantation (HCT). Busulfan has been linked to transient serum enzyme elevations during therapy, to rare cases of cholestatic hepatitis, instances of nodular regenerative hyperplasia and, when given in high doses, to sinusoidal obstruction syndrome which can be severe and fatal.

Antineoplastic Agents, Alkylating Agents

Busulfan is used in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation in patients with chronic myelogenous leukemia (CML) and is designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this disease.|/VET/ Antineoplastic agent used in adjunct therapy of acute granulocytic leukemias in small animals.|Busulfan is an alkylating agent with myeloablative properties and activity against non-dividing marrow cells and, possibly, non-dividing malignant cells. Its use has been well established in the treatment of hematological malignancies, particularly in patients with chronic myeloid leukemia and other myeloproliferative syndromes.|Busilvex followed by cyclophosphamide (BuCy4) or melphalan (BuMel) is indicated as conditioning treatment prior to conventional hematopoietic progenitor cell transplantation in pediatric patients.

Myleran is a potent drug. It should not be used unless a diagnosis of chronic myelogenous leukemia has been adequately established and the responsible physician is knowledgeable in assessing response to chemotherapy. Myleran can induce severe bone marrow hypoplasia. Reduce or discontinue the dosage immediately at the first sign of any unusual depression of bone marrow function as reflected by an abnormal decrease in any of the formed elements of the blood. A bone marrow examination should be performed if the bone marrow status is uncertain.|Life-threatening hepatic veno-occlusive disease has occurred in patients receiving busulfan (usually in combination with cyclophosphamide or other antineoplastic agents as a component of marrow-ablative therapy prior to bone marrow transplantation). The manufacturer states that a clear causal relationship to busulfan has not been demonstrated. Hepatic veno-occlusive disease diagnosed by clinical examination and laboratory findings occurred in 8% (5/61) of patients receiving IV busulfan in the allogeneic transplant clinical trial and was fatal in 40% (2/5) of cases. Overall mortality from hepatic veno-occlusive disease was 3% for the entire study population. Retrospectively, 3 of the 5 patients diagnosed with hepatic veno-occlusive disease were found to meet the Jones' criteria for this condition. In patients receiving high-dose oral busulfan as a component of a conditioning regimen prior to bone marrow transplant in randomized, controlled studies, the incidence of hepatic veno-occlusive disease was 7.7-12%.|Interstitial pneumonitis and pulmonary fibrosis, which rarely were fatal, also have been reported in patients receiving high oral doses of busulfan as a component of a conditioning regimen prior to allogeneic bone marrow transplantation. Nonspecific interstitial fibrosis was diagnosed by lung biopsy in one patient receiving IV busulfan who subsequently died from respiratory failure.|In patients receiving oral busulfan, pancytopenia generally occurs with failure to adequately monitor hematologic status and promptly discontinue the drug in response to a large or rapid decrease in leukocyte or platelet counts. Although individual variation in response to the drug does not appear to be an important contributing factor, some patients may be especially sensitive to busulfan and experience abrupt onset of neutropenia or thrombocytopenia. Busulfan-induced pancytopenia may be more prolonged than that induced by other alkylating agents; although recovery may take 1 month to 2 years, the toxicity is potentially reversible and patients should be vigorously supported through any period of severe pancytopenia. Some patients develop bone marrow fibrosis or chronic aplasia which is probably due to busulfan toxicity. Aplastic anemia, sometimes irreversible, has been reported rarely in patients receiving oral busulfan; aplastic anemia usually has occurred following high doses of the drug or long-term administration of conventional doses.|For more Drug Warnings (Complete) data for BUSULFAN (42 total), please visit the HSDB record page.

Busulfan is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn leads to a miscoding of DNA. Alkylating agents are cell cycle-nonspecific and work by three different mechanisms, all of which achieve the same end result - disruption of DNA function and cell death. Overexpression of MGST2, a glutathione s-transferase, is thought to confer resistance to busulfan. The role of MGST2 in the metabolism of busulfan is unknown however.

A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to cross-link cellular macromolecules. Among their common properties are a requirement for metabolic activation to intermediates with antitumor efficacy and the presence in their chemical structures of N-methyl groups, that after metabolism, can covalently modify cellular DNA. The precise mechanisms by which each of these drugs acts to kill tumor cells are not completely understood. (From AMA, Drug Evaluations Annual, 1994, p2026) (See all compounds classified as Antineoplastic Agents, Alkylating.)|Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging. (See all compounds classified as Immunosuppressive Agents.)|Agents that destroy bone marrow activity. They are used to prepare patients for BONE MARROW TRANSPLANTATION or STEM CELL TRANSPLANTATION. (See all compounds classified as Myeloablative Agonists.)|Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. (See all compounds classified as Alkylating Agents.)

Completely absorbed from the gastrointestinal tract. Busulfan is a small, highly lipophilic molecule that crosses the blood-brain-barrier. The absolute bioavailability, if a single 2 mg IV bolus injection is given to adult patients, is 80% ± 20%. In children (1.5 - 6 years old), the absolute bioavailability was 68% ± 31%. When a single oral dose is given to patients, the area under the curve (AUC) was 130 ng•hr/mL. The peak plasma concentration when given orally is 30 ng/mL (after dose normalization to 2 mg). It takes 0.9 hours to reach peak plasma concentration after dose normalization to 4 mg.|Following administration of 14C- labeled busulfan to humans, approximately 30% of the radioactivity was excreted into the urine over 48 hours; negligible amounts were recovered in feces. Less than 2% of the administered dose is excreted in the urine unchanged within 24 hours. Elimination of busulfan is independent of renal function.|2.52 ml/min/kg [Following an infusion of dose of 0.8 mg/kg every six hours, for a total of 16 doses over four days]|The pharmacokinetic disposition of busulfan differs in children versus adults. The mean bioavailability of busulfan is lower in children than in adults; the interindividual variation in bioavailability for oral busulfan is large, particularly in children. In a pharmacokinetic study in children receiving IV busulfan (0.8 or 1 mg/kg based on actual body weight), an estimated volume of distribution of 0.64 L/kg (with an interpatient variability of 11%) was reported.|Busulfan, a small and highly lipophilic molecule, easily crosses the blood-brain barrier. Busulfan concentrations in the cerebrospinal fluid (CSF) are approximately equal to concurrent busulfan plasma concentrations. It is not known whether the drug is distributed into milk.|For adults receiving busulfan 2, 4, or 6 mg orally as a single dose on consecutive days, the drug exhibits linear kinetics for both the maximum plasma concentration and the area under the concentration-time curve (AUC); a mean peak plasma concentration (normalized to a dose of 2 mg) of about 30 ng/mL was observed. In a study of 12 patients receiving single oral busulfan doses of 4-8 mg, a mean peak plasma concentration (normalized to a dose of 4 mg) of about 68 ng/mL was reported; the time to peak plasma concentration was about 0.9 hours.|Busulfan is rapidly and completely absorbed from the GI tract after oral administration of the drug. The effect of food on the bioavailability of busulfan is not known.|For more Absorption, Distribution and Excretion (Complete) data for BUSULFAN (11 total), please visit the HSDB record page.

Busulfan is extensively metabolizes in the hepatic. Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis. GSTA1 is the primary GST isoform that facilitates the the metabolism of busulfan. Other GST isoforms that are also involved are GSTM1 and GSTP1. At least 12 metabolites have been identified among which tetrahydrothiophene, tetrahydrothiophene 12-oxide, sulfolane, and 3-hydroxysulfolane were identified. These metabolites do not have cytotoxic activity.|After IP injections of 2:3-(14)C-Myleran in the rat, rabbit and mouse, 60% of the urinary radioactivity was found to be in the form of the 3-hydroxy tetrahydrothiophene-1,1-dioxide, a sulphone. It is suggested that in vivo Myleran undergoes a reaction with cysteine or a cysteinyl moiety to form a cyclic sulphonium ion, which in turn undergoes cleavage to the tetrahydrothiophene, oxidation to the 1,1-dioxide and biological hydroxylation to the 3-hydroxy compound.|In the rat and mouse 50-60% of a single dose of Myleran-(35)S (10 mg/kg bw) injected intraperitoneally in arachis oil was excreted within 24 to 48 hours, mainly as methane sulphonic acid; a small amount of unchanged Myleran and two unidentified components were present. In the rabbit, methane sulphonic acid was the only metabolite found in the urine.|The metabolic fate of busulfan has been studied in rats and humans using (14)C- and (35)S-labeled materials. In humans, as in the rat, almost all of the radioactivity in (35)S-labeled busulfan is excreted in the urine in the form of (35)S-methanesulfonic acid. /It was/ demonstrated that the formation of methanesulfonic acid in vivo in the rat is not due to a simple hydrolysis of busulfan to 1,4-butanediol, since only about 4% of 2,3-(14)C-busulfan was excreted as carbon dioxide, whereas 2,3-(14)C-1,4-butanediol was converted almost exclusively to carbon dioxide. The predominant reaction of busulfan in the rat is the alkylation of sulfhydryl groups (particularly cysteine and cysteine-containing compounds) to produce a cyclic sulfonium compound which is the precursor of the major urinary metabolite of the 4-carbon portion of the molecule, 3-hydroxytetrahydrothiophene-1,1-dioxide. This has been termed a "sulfur-stripping" action of busulfan and it may modify the function of certain sulfur-containing amino acids, polypeptides, and proteins; whether this action makes an important contribution to the cytotoxicity of busulfan is unknown.|(14)C busulfan was administered ip (15 mg/kg) to 5 male Sprague-Dawley rats. For 72 hours, the urinary recovery of (14)C was approximately 70% of the total dose, while the fecal excretion was within the range 1.5-2%. The pattern of the urinary metabolites of busulfan was studied by HPLC in combination with radioactivity detection of the pooled urine. At least eight radioactive fractions could be separated. Three major metabolite peaks were identified by GC/MS and NMR spectroscopy: 3-hydroxysulfolane (39% of total urine radioactivity), tetrahydrothiophene 1- oxide (20%), and sulfolane (13%). Busulfan (6%) and tetrahydrofuran (2%) were also identified. A sulfonium ion glutathione conjugate was hypothesised as another metabolite, but was not isolated because it was very unstable. However, another compound was observed. This metabolite co-eluted with the sulfonium ion obtained of the reaction of busulfan with N-acetyl-L-cysteine and produced tetrahydrothiophene when hydrolyzed. Finally, busulfan and the three main metabolites were tested for cytotoxicity on Chinese V79 hamster cells in vitro. Cell toxicity was induced only by busulfan, which indicates that the cytotoxicity in vivo is mediated by the parent compound, as expected.

2.6 hours|The terminal half life /in children from < 6 months up to 17 years old/ ranged from 2.26 to 2.52 hr.|The elimination half-life is about 2.6 hours in adults receiving oral busulfan.|Following intravenous administration, the mean half life of busulfan ranged from 2.83 hours to 3.90 hours ... . Oral busulfan had a mean half life of 3.87 hours.

Busulfan is an alkylating agent that contains 2 labile methanesulfonate groups attached to opposite ends of a 4-carbon alkyl chain. Once busulfan is hydrolyzed, the methanesulfonate groups are released and carbonium ions are produced. These carbonium ions alkylate DNA, which results in the interference of DNA replication and RNA transcription, ultimately leading to the disruption of nucleic acid function. Specifically, its mechanism of action through alkylation produces guanine-adenine intrastrand crosslinks. These crosslinks occur through a SN2 reaction guanine N7 nucleophilically attacks the carbon adjacent to the mesylate leaving group. This kind of damage cannot be repaired by cellular machinery and thus the cell undergoes apoptosis.|The primary molecular action of busulfan is alkylation of intracellular nucleophiles. Both proteins and nucleic acids are affected. With regard to DNA, busulfan reacts with guanine residues to form a fourcarbon di-guanine DNA cross-linkage with release of methylsulfonate. The DNA cross-linkage causes misreading of the DNA code and single-strand breakage. The degree of DNA cross-linkage has been shown to be proportional to the dose and cytotoxicity of the compound. Busulfan-induced crosslinkages of DNA to nuclear proteins may also occur and is considered a cytotoxic mechanism. Busulfan has also been reported to esterify phosphate groups of chromosomal DNA, accounting for the fragmentation of chromosomes seen in various cell types after treatment. Chromosomal damage further contributes to the overall cytotoxic effect.|Studies of cloned tumour and normal cells indicate that busulfan interrupts certain parts of the cell mitotic cycle. While busulfan can act on cells at any stage of mitosis, similar to other alkylating agents, in vitro studies with tumour cell lines indicate that replicating cells are most sensitive to busulfan in the late G1 phase and that progression through the cell cycle is blocked in the G2 phase. Cultured cells in the S-phase, which involves DNA synthesis, are not as affected because the DNA repair systems are active at this stage. Clinically, busulfan is cytotoxic to proliferating tissues, especially granulopoietic cells in the bone marrow.

SYMPTOMS: Symptoms of exposure to this compound may include nausea, vomiting, diarrhea, impotence, sterility, amenorrhea, fetal malformation, depression of erythropoiesis leading to aplastic anemia, diffuse pulmonary fibrosis, precipitation of uric acid in kidney tubules and hemorrhages. ACUTE/CHRONIC HAZARDS: When heated to decomposition this compound emits toxic fumes of SOx. It is an experimental carcinogen. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. IMMEDIATELY call a physician and be prepared to transport the victim to a hospital even if no symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Generally, the induction of vomiting is NOT recommended outside of a physician's care due to the risk of aspirating the chemical into the victim's lungs. However, if the victim is conscious and not convulsing and if medical help is not readily available, consider the risk of inducing vomiting because of the high toxicity of the chemical ingested. Ipecac syrup or salt water may be used in such an emergency. IMMEDIATELY transport the victim to a hospital. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. OTHER: Since this chemical is a known or suspected carcinogen you should contact a physician for advice regarding the possible long term health effects and potential recommendation for medical monitoring. Recommendations from the physician will depend upon the specific compound, its chemical, physical and toxicity properties, the exposure level, length of exposure, and the route of exposure. (NTP, 1992)

Emergency and supportive measures. Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. /Antineoplastic agents/|Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. /Antineoplastic agents/|Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. /Antineoplastic agents/|Enhanced elimination. Because of the rapid intracellular incorporation of most of these agents, dialysis and other extracorporeal removal procedures are generally not effective. /Antineoplastic agents/

/SIGNS AND SYMPTOMS/ Hepatic veno-occlusive disease is a major complication that can occur during treatment with Busilvex. Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or prior progenitor cell transplant may be at an increased risk.|/CASE REPORTS/ ... Busulfan treatment in a pre-adolescent girl prevented the onset of puberty due to ovarian failure. ...|/CASE REPORTS/ A case of severe hemorrhagic cystitis induced by prolonged busulfan therapy /is reported/. The clinical course and pathological results were similar to irradiation and cyclophosphamide cystitis. ... Although hemorrhagic cystitis induced by busulfan is a rare complication it should be considered in the differential diagnosis and busulfan should be discontinued immediately.|/CASE REPORTS/ A 42-year-old Japanese woman given high doses of busulfan for a short time was referred to us because of decreased visual acuity and blurred vision in both eyes. She received 212 mg/day of busulfan for only 4 days. Ophthalmoscopic examination demonstrated a posterior polar subcapsular opacity of the lens in both eyes. Although the occurrence of cataract due to busulfan has been reported after long-term administration of busulfan, this is the first clinical case of cataract caused by high doses of busulfan for a short period. It is necessary to pay more attention to busulfan cataract.|For more Human Toxicity Excerpts (Complete) data for BUSULFAN (16 total), please visit the HSDB record page.

Busulfan

Parenteral: For injection concentrate, for IV infusion only: 6 mg/mL (60 mg) Busulfex (with dimethylacetamide 33% v/v and polyethylene glycol 67% v/v) ESP Pharma|Oral: Tablets, film-coated: 2 mg Myleran (GlaxoSmithKline)

... listed as known human carcinogen: Report on Carcingens, Eleventh Edition (PB2005-104914, 2004) p III-39.

Analyte: busulfan; matrix: chemical identification; procedure: reaction with potassium nitrate and potassium hydroxide; acidification with hydrochloric acid; addition of barium chloride; formation of a white precipitate|Analyte: busulfan; matrix: chemical identification; procedure: reaction with sodium hydroxide; heat to a clear solution; perception of a characteristic methanesulfonic acid odor|Analyte: busulfan; matrix: chemical identification; procedure: reaction with sodium hydroxide; addition of potassium permanganate; the purple color changes to violet then blue then emerald-green; or acidification with sulfuric acid and addition of potassium permanganate; permanganate color is not discharged|Analyte: busulfan; matrix: chemical purity; procedure: addition of water and phenolphthalein; neutralization with sodium hydroxide; addition of phenolphthalein indicator; titration with sodium hydroxide|For more Analytic Laboratory Methods (Complete) data for BUSULFAN (12 total), please visit the HSDB record page.

Analyte: busulfan; matrix: blood (plasma); procedure: high-performance liquid chromatography with ultraviolet detection at 251 nm; limit of detection: 200 nM|Analyte: busulfan; matrix: blood (plasma); procedure: high-performance liquid chromatography with ultraviolet detection at 226 nm following postcolumn photolysis; limit of detection: 20 ng/mL|Analyte: busulfan; matrix: blood (plasma); procedure: high-performance liquid chromatography with ultraviolet detection at 278 nm; limit of detection: 0.4 ng/mL|Analyte: busulfan; matrix: blood (serum); procedure: high-performance liquid chromatography with ultraviolet detection at 278 nm; limit of detection: 10 ng/mL|For more Clinical Laboratory Methods (Complete) data for BUSULFAN (6 total), please visit the HSDB record page.

Human drugs -> Busulfan Fresenius Kabi -> EMA Drug Category|Alkyl sulfonates -> Human pharmacotherapeutic group|Human drugs -> Busilvex -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human drugs -> Rare disease (orphan)|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients