Busulfex

BUSULFEX- busulfan injection
ESP Pharma, Inc.

Caution: Must be diluted prior to use.

Rx only

WARNING

BUSULFEX® (busulfan) Injection is a potent cytotoxic drug that causes profound myelosuppression at the recommended dosage. It should be administered under the supervision of a qualified physician who is experienced in allogeneic hematopoietic stem cell transplantation, the use of cancer chemotherapeutic drugs and the management of patients with severe pancytopenia. Appropriate management of therapy and complications is only possible when adequate diagnostic and treatment facilities are readily available. SEE “WARNINGS” SECTION FOR INFORMATION REGARDING BUSULFAN-INDUCED PANCYTOPENIA IN HUMANS.

DESCRIPTION

Busulfan is a bifunctional alkylating agent known chemically as 1,4- butanediol, dimethanesulfonate. BUSULFEX® (busulfan) Injection is intended for intravenous administration. It is supplied as a clear, colorless, sterile, solution in 10 mL single use vials.

Each vial of BUSULFEX contains 60 mg (6 mg/mL) of busulfan, the active ingredient, a white crystalline powder with a molecular formula of CH3 SO2 O(CH2 )4 OSO2 CH3 and a molecular weight of 246 g/mole. Busulfan is dissolved in N,N-dimethylacetamide (DMA) 33% vol/vol and Polyethylene Glycol 400, 67% vol/vol. The solubility of busulfan in water is 0.1 g/L and the pH of BUSULFEX diluted to approximately 0.5 mg/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 3.4 to 3.9.

BUSULFEX is intended for dilution with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP prior to intravenous infusion.

CLINICAL PHARMACOLOGY

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.

Pharmacokinetics

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

Table 1: Steady State Pharmacokinetic Parameters Following Busulfex ® (busulfan) Infusion (0.8 mg/kg; N=59)
Mean CV (%) Range
* Clearance normalized to actual body weight for all patients.
Cmax (ng/mL) 1222 18 496-1684
AUC (μM•min) 1167 20 556-1673
CL (ml/min/kg)* 2.52 25 1.49-4.31

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

In a pharmacokinetic study of BUSULFEX in 24 pediatric patients, the population pharmacokinetic (PPK) estimates of BUSULFEX 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/20 kg (3.37 ml/min/kg; interpatient variability 23%); and 12.8 L/20 kg (0.64 L/kg; interpatient variability 11%).

Distribution, Metabolism, Excretion:

Studies of distribution, metabolism, and elimination of BUSULFEX have not been done; however, the literature on oral busulfan is relevant. Additionally, for modulating effects on pharmacodynamic parameters see Drug Interactions.

Distribution: Busulfan achieves concentrations in the cerebrospinal fluid approximately equal to those in plasma. Irreversible binding to plasma elements, primarily albumin, has been estimated to be 32.4 ± 2.2% which is consistent with the reactive electrophilic properties of busulfan.

Metabolism: Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis. This conjugate undergoes further 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. The incomplete recovery of radioactivity may be due to the formation of long-lived metabolites or due to nonspecific alkylation of macromolecules.

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 BUSULFEX 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.

The prospective trial was a single-arm, open-label study in 61 patients who received BUSULFEX 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, ≥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 BUSULFEX doses of 0.8 mg/kg every 6 hours as a two-hour infusion for 4 days, followed by cyclophosphamide 60 mg/kg once per day for two days (BuCy2 regimen). All patients received 100% of their scheduled BUSULFEX 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≥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 x 4 days + cyclophosphamide 60 mg/kg/d x 2 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 2 below summarizes the efficacy analyses reported from these 4 studies.

Table 2: Summary of efficacy analyses from the randomized, controlled trials utilizing a high dose oral busulfan-containing conditioning regimen identified in a literature review.

*Eto = etoposide. TBI was combined with etoposide in the comparator arm of this study.

BU = Busulfan

CY = Cyclophosphamide

TBI = Total Body Irradiation

DFS = Disease Free Survival

ANC = Absolute Neutrophil Count

Clift, 1994
CML Chronic Phase;
3 year Overall 3 year DFS Relapse Time to Engraftment
Survival (p=0.43) (ANC ≥ 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 5 year DFS (p=0.75) Relapse (Relative Risk analysis Time to Engraftment (ANC ≥ 500)
(p=0.5) BU/CY:CY/TBI)
(p=0.04)
BU/CY CY/TBI BU/CY CY/TBI BU/CY CY/TBI BU/CY CY/TBI
60.6% 65.8% 59.1% 51.0% 4.10 None None
±11.7% ±12.5% ±11.8% ±14% (95%CI =1.00-20.28) Given Given
Ringden, 1994
CML, AML, ALL;
3 year Overall 3 year Relapse Free Relapse Time to Engraftment
Survival Survival (p=0.9) (ANC >500)
(p<0.03) (p=0.065)
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 Time to Engraftment
(Relative Risk analysis
BU/CY:Eto/TBI)
BU/CY Eto/TBI BU/CY Eto/TBI BU/CY Eto/TBI BU/CY Eto/TBI
0.97 Not Given 1.02 Not Given
(95% CI=0.64-1.48) (95% CI=0.56-1.86)

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