Busulfan (Page 5 of 6)

8.5 Geriatric Use

Clinical studies of busulfan did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

10 OVERDOSAGE

There is no known antidote to busulfan injection other than hematopoietic progenitor cell transplantation. In the absence of hematopoietic progenitor cell transplantation, the recommended dosage for busulfan would constitute an overdose of busulfan. The principal toxic effect is profound bone marrow hypoplasia/aplasia and pancytopenia, but the central nervous system, liver, lungs, and gastrointestinal tract may be affected. Monitor hematologic status closely and institute vigorous supportive measures as medically indicated. Survival after a single 140 mg dose of busulfan tablets in an 18 kg, 4-year old child has been reported. Inadvertent administration of a greater than normal dose of oral busulfan (2.1 mg per kg; total dose of 23.3 mg per kg) occurred in a 2-year old child prior to a scheduled bone marrow transplant without sequelae. An acute dose of 2.4 g was fatal in a 10-year old boy. There is one report that busulfan is dialyzable, thus dialysis should be considered in the case of overdose.

11 DESCRIPTION

Busulfan is a bifunctional alkylating agent known chemically as 1,4-butanediol, dimethanesulfonate. The molecular formula of busulfan is CH₃ SO₂ O(CH₂ )₄ OSO₂ CH₃ with a molecular weight of 246 g/mole. Busulfan has the following chemical structure:

Busulfan injection is supplied as a clear, colorless, sterile, solution in 10 mL single-dose vials for intravenous administration upon dilution. Each vial contains 60 mg of busulfan, USP in N,N-dimethylacetamide (DMA), 3.3 mL and Polyethylene Glycol 400, NF 6.7 mL. The solubility of busulfan in water is 0.1 g per L and the pH of busulfan injection diluted to approximately 0.5 mg per mL busulfan in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP as recommended for infusion reflects the pH of the diluent used and ranges from 3.51 to 4.7.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Busulfan is a bifunctional alkylating agent in which two labile methanesulfonate groups are attached to opposite ends of a four-carbon alkyl chain. In aqueous media, busulfan hydrolyzes to release the methanesulfonate groups. This produces reactive carbonium ions that can alkylate DNA. DNA damage is thought to be responsible for much of the cytotoxicity of busulfan.

12.3 Pharmacokinetics

The pharmacokinetics of busulfan were studied in 59 patients participating in a prospective trial of a busulfan-cyclophosphamide preparatory regimen prior to allogeneic hematopoietic progenitor stem cell transplantation. Patients received 0.8 mg/kg busulfan every six hours, for a total of 16 doses over four days. Fifty-five of fifty-nine patients (93%) administered busulfan maintained AUC values below the target value (less than 1500 μM•min).

Table 3: Steady State Pharmacokinetic Parameters Following Busulfan Infusion (0.8 mg per kg; N = 59)

* Clearance normalized to actual body weight for all patients.
	Mean	CV (%)	Range
Cmax (ng per mL)	1222	18	496 — 1684
AUC (μM•min)	1167	20	556 — 1673
CL (mL per min per kg)*	2.52	25	1.49 — 4.31

Busulfan pharmacokinetics showed consistency between dose 9 and dose 13 as demonstrated by reproducibility of steady state C_max and a low coefficient of variation for this parameter.

Distribution: Busulfan achieves concentrations in the cerebrospinal fluid approximately equal to those in plasma. Busulfan primarily binds to albumin (Mean ± standard deviation = 32.4 ± 2.2%).

Metabolism: Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis. This conjugate undergoes extensive oxidative metabolism in the liver.

Excretion: Following administration of ¹⁴ C-labeled busulfan to humans, approximately 30% of the radioactivity was excreted into the urine over 48 hours; negligible amounts were recovered in feces.

Specific Populations

Pediatric Patients: In a pharmacokinetic study of busulfan injection in 24 pediatric patients, the population pharmacokinetic (PPK) estimates of busulfan injection for clearance (CL) and volume of distribution (V) were determined. For actual body weight, PPK estimates of CL and V were 4.04 L/hr per 20 kg (3.37 mL per min per kg; interpatient variability 23%); and 12.8 L per 20 kg (0.64 L per kg; interpatient variability 11%).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Busulfan is a mutagen and a clastogen. In in vitro tests it caused mutations in Salmonella typhimurium and Drosophila melanogaster. Chromosomal aberrations induced by busulfan have been reported in vivo (rats, mice, hamsters, and humans) and in vitro (rodent and human cells). The intravenous administration of busulfan (48 mg/kg given as biweekly doses of 12 mg/kg, or 30% of the total busulfan dose on a mg/m² basis) has been shown to increase the incidence of thymic and ovarian tumors in mice.

Busulfan depleted oocytes of female rats and induced sterility in male rats and hamsters. The solvent DMA may also impair fertility. A DMA daily dose of 0.45 g/kg/day given to rats for nine days (equivalent to 44% of the daily dose of DMA contained in the recommended dose of busulfan on a mg/m² basis) significantly decreased spermatogenesis in rats. A single subcutaneous dose of 2.2 g/kg (27% of the total DMA dose contained in busulfan on a mg/m² basis) four days after insemination terminated pregnancy in 100% of tested hamsters [see Use in Specific Populations (8.3)].

14 CLINICAL STUDIES

Documentation of the safety and efficacy of busulfan as a component of a conditioning regimen prior to allogeneic hematopoietic progenitor cell reconstitution is derived from two sources:

i) analysis of a prospective clinical trial of busulfan that involved 61 patients diagnosed with various hematologic malignancies, and

ii) the published reports of randomized, controlled trials that employed high-dose oral busulfan as a component of a conditioning regimen for transplantation, which were identified in a literature review of five established commercial databases.

Prospective Clinical Trial of Busulfan: The prospective trial was a single-arm, open-label study in 61 patients who received busulfan as part of a conditioning regimen for allogeneic hematopoietic stem cell transplantation. The study included patients with acute leukemia past first remission (first or subsequent relapse), with high-risk first remission, or with induction failure; chronic myelogenous leukemia (CML) in chronic phase, accelerated phase, or blast crisis; primary refractory or resistant relapsed Hodgkin’s disease or non-Hodgkin’s lymphoma; and myelodysplastic syndrome. Forty-eight percent of patients (29/61) were heavily pretreated, defined as having at least one of the following: prior radiation, greater than or equal to 3 prior chemotherapeutic regimens, or prior hematopoietic stem cell transplant. Seventy-five percent of patients (46/61) were transplanted with active disease.

Patients received 16 busulfan doses of 0.8 mg per kg every 6 hours as a two-hour infusion for 4 days, followed by cyclophosphamide 60 mg per kg once per day for two days (BuCy2 regimen). All patients received 100% of their scheduled busulfan regimen. No dose adjustments were made. After one rest day, allogeneic hematopoietic progenitor cells were infused. The efficacy parameters in this study were myeloablation (defined as one or more of the following: absolute neutrophil count [ANC] less than 0.5×10⁹ /L, absolute lymphocyte count [ALC] less than 0.1×10⁹ /L, thrombocytopenia defined as a platelet count less than 20,000/mm³ or a platelet transfusion requirement) and engraftment (ANC greater than or equal to 0.5×10⁹ /L).

All patients (61/61) experienced myeloablation. The median time to neutropenia was 4 days. All evaluable patients (60/60) engrafted at a median of 13 days post-transplant (range 9 to 29 days); one patient was considered non-evaluable because he died of a fungal pneumonia 20 days after BMT and before engraftment occurred. All but 13 of the patients were treated with prophylactic G-CSF. Evidence of donor cell engraftment and chimerism was documented in all patients who had a chromosomal sex marker or leukemic marker (43/43), and no patient with chimeric evidence of allogeneic engraftment suffered a later loss of the allogeneic graft. There were no reports of graft failure in the overall study population. The median number of platelet transfusions per patient was 6, and the median number of red blood cell transfusions per patient was 4.

Twenty-three patients (38%) relapsed at a median of 183 days post-transplant (range 36 to 406 days). Sixty-two percent of patients (38/61) were free from disease with a median follow-up of 269 days post-transplant (range 20 to 583 days). Forty-three patients (70%) were alive with a median follow up of 288 days post-transplant (range 51 to 583 days). There were two deaths before BMT Day +28 and six additional patients died by BMT Day +100. Ten patients (16%) died after BMT Day +100, at a median of 199 days post-transplant (range 113 to 275 days).

Oral Busulfan Literature Review: Four publications of randomized, controlled trials that evaluated a high-dose oral busulfan-containing conditioning regimen (busulfan 4 mg/kg/d x4 days + cyclophosphamide 60 mg/kg/d x2 days) for allogeneic transplantation in the setting of CML were identified. Two of the studies (Clift and Devergie) had populations confined to CML in chronic phase that were randomized between conditioning with busulfan/cyclophosphamide (BU/CY) and cyclophosphamide/total body irradiation (CY/TBI). A total of 138 patients were treated with BU/CY in these studies. The populations of the two remaining studies (Ringden and Blume) included patients with CML, acute lymphoblastic leukemia (ALL), and acute myelogenous leukemia (AML). In the Nordic BMT Group study published by Ringden, et al., 57 patients had CML, and of those, 30 were treated with BU/CY. Patients with CML in chronic phase, accelerated phase, and blast crisis were eligible for this study. The participants with CML (34/122 patients) in a SWOG study published by Blume, et al., had disease beyond first chronic phase. Twenty of those CML patients were treated with BU/CY, and the TBI comparator arm utilized etoposide instead of cyclophosphamide.

Table 4 summarizes the efficacy analyses reported from these 4 studies.

Table 4: Summary of Efficacy Analyses from the Randomized, Controlled Trials Utilizing a High Dose Oral Busulfan-Containing Conditioning Regimen Identified in a Literature Review

BU = BusulfanCY = CyclophosphamideTBI = Total Body IrradiationDFS = Disease Free SurvivalANC = Absolute Neutrophil Count
* Eto = etoposide. TBI was combined with etoposide in the comparator arm of this study.
Clift, 1994 CML Chronic Phase;
3 year Overall Survival		3 Year DFS (p = 0.43)		Relapse		Time to Engraftment (ANC greater than or equal to 500)
BU/CY	CY/TBI	BU/CY	CY/TBI	BU/CY	CY/TBI	BU/CY	CY/TBI
80%	80%	71%	68%	13%	13%	22.6 days	22.3 days
Devergie, 1995 CML Chronic Phase;
5 year Overall Survival (p = 0.5)		5 Year DFS (p = 0.75)		Relapse (Relative Risk analysis BU/CY:CY/TBI) (p = 0.04)		Time to Engraftment (ANC greater than or equal to 500)
BU/CY	CY/TBI	BU/CY	CY/TBI	BU/CY	CY/TBI	BU/CY	CY/TBI
60.6% ± 11.7%	65.8% ± 12.5%	59.1% ± 11.8%	51.0% ± 14%	4.10 (95% CI = 1.00 — 20.28)		None Given	None Given
Ringden, 1994 CML, AML, ALL;
3 year Overall Survival (p < 0.03)		3 year Relapse Free Survival (p = 0.065)		Relapse (p = 0.9)		Time to Engraftment (ANC greater than 500)
BU/CY	CY/TBI	BU/CY	CY/TBI	BU/CY	CY/TBI	BU/CY	CY/TBI
62%	76%	56%	67%	22%	26%	20 days	20 days
Blume, 1993 * CML, AML, ALL; Relative Risk Analysis BU/CY: Etoposide/ TBI
RR of Mortality		DFS		RR of Relapse (Relative Risk analysis BU/CY: Eto/TBI)		Time to Engraftment
BU/CY	Eto/TBI	BU/CY	Eto/TBI	BU/CY	Eto/TBI	BU/CY	Eto/TBI
0.97 (95% CI = 0.64 — 1.48)		Not Given		1.02 (95% CI = 0.56 — 1.86)		Not Given