busulfan
Dosage Form: injection
Busulfex®
(busulfan) Injection
Caution: Must be diluted prior to use.
Rx only
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.
Busulfex 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 CH3SO2O(CH2)4OSO2CH3 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.
Busulfex - 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).
| Mean | CV (%) | Range | |
|---|---|---|---|
| |||
| 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 14C‑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 ×4 days + cyclophosphamide 60 mg/kg/d ×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 summarizes the efficacy analyses reported from these 4 studies.
| Clift, 1994 CML Chronic Phase; | |||||||
|---|---|---|---|---|---|---|---|
| BU = Busulfan | |||||||
| CY = Cyclophosphamide | |||||||
| TBI = Total Body Irradiation | |||||||
| DFS = Disease Free Survival | |||||||
| ANC = Absolute Neutrophil Count | |||||||
| |||||||
| 3 year Overall Survival | 3 year DFS (p=0.43) | Relapse | Time to Engraftment (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 (p=0.5) | 5 year DFS (p=0.75) | Relapse (Relative Risk analysis BU/CY:CY/TBI) (p=0.04) | Time to Engraftment (ANC ≥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 >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 | ||||
Indications and Usage for Busulfex
Busulfex® (busulfan) Injection is indicated for use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia.
Contraindications
Busulfex is contraindicated in patients with a history of hypersensitivity to any of its components.
Warnings
Busulfex should be administered under the supervision of a qualified physician experienced in hematopoietic stem cell transplantation. Appropriate management of complications arising from its administration is possible only when adequate diagnostic and treatment facilities are readily available.
The following warnings pertain to different physiologic effects of Busulfex in the setting of allogeneic transplantation.
Hematologic
The most frequent serious consequence of treatment with Busulfex at the recommended dose and schedule is profound myelosuppression, occurring in all patients. Severe granulocytopenia, thrombocytopenia, anemia, or any combination thereof may develop. Frequent complete blood counts, including white blood cell differentials, and quantitative platelet counts should be monitored during treatment and until recovery is achieved. Absolute neutrophil counts dropped below 0.5×109/L at a median of 4 days post-transplant in 100% of patients treated in the Busulfex clinical trial. The absolute neutrophil count recovered at a median of 13 days following allogeneic transplantation when prophylactic G-CSF was used in the majority of patients. Thrombocytopenia (<25,000/mm3 or requiring platelet transfusion) occurred at a median of 5-6 days in 98% of patients. Anemia (hemoglobin <8.0 g/dL) occurred in 69% of patients. Antibiotic therapy and platelet and red blood cell support should be used when medically indicated.
Neurological
Seizures have been reported in patients receiving high-dose oral busulfan at doses producing plasma drug levels similar to those achieved following the recommended dosage of Busulfex. Despite prophylactic therapy with phenytoin, one seizure (1/42 patients) was reported during an autologous transplantation clinical trial of Busulfex. This episode occurred during the cyclophosphamide portion of the conditioning regimen, 36 hours after the last Busulfex dose. Anti-convulsant prophylactic therapy should be initiated prior to Busulfex treatment. Caution should be exercised when administering the recommended dose of Busulfex to patients with a history of a seizure disorder or head trauma or who are receiving other potentially epileptogenic drugs.
Hepatic
Current literature suggests that high busulfan area under the plasma concentration verses time curve (AUC) values (>1,500 µM∙min) may be associated with an increased risk of developing hepatic veno-occlusive disease (HVOD). Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or a prior progenitor cell transplant may be at an increased risk of developing HVOD with the recommended Busulfex dose and regimen. Based on clinical examination and laboratory findings, hepatic veno-occlusive disease was diagnosed in 8% (5/61) of patients treated with Busulfex in the setting of allogeneic transplantation, was fatal in 2/5 cases (40%), and yielded an overall mortality from HVOD in the entire study population of 2/61 (3%). Three of the five patients diagnosed with HVOD were retrospectively found to meet the Jones' criteria. The incidence of HVOD reported in the literature from the randomized, controlled trials (see CLINICAL STUDIES) was 7.7%-12%.
Cardiac
Cardiac tamponade has been reported in pediatric patients with thalassemia (8/400 or 2% in one series) who received high doses of oral busulfan and cyclophosphamide as the preparatory regimen for hematopoietic progenitor cell transplantation. Six of the eight children died and two were saved by rapid pericardiocentesis. Abdominal pain and vomiting preceded the tamponade in most patients. No patients treated in the Busulfex (busulfan) Injection clinical trials experienced cardiac tamponade.
Pulmonary
Bronchopulmonary dysplasia with pulmonary fibrosis is a rare but serious complication following chronic busulfan therapy. The average onset of symptoms is 4 years after therapy (range 4 months to 10 years).
Carcinogenicity, Mutagenicity, 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 Busulfex dose on a mg/m2 basis) has been shown to increase the incidence of thymic and ovarian tumors in mice. Four cases of acute leukemia occurred among 19 patients who became pancytopenic in a 243 patient study incorporating busulfan as adjuvant therapy following surgical resection of bronchogenic carcinoma. Clinical appearance of leukemia was observed 5-8 years following oral busulfan treatment. Busulfan is a presumed human carcinogen.
Ovarian suppression and amenorrhea commonly occur in premenopausal women undergoing chronic, low-dose busulfan therapy for chronic myelogenous leukemia. Busulfan depleted oocytes of female rats. Busulfan induced sterility in male rats and hamsters. Sterility, azoospermia and testicular atrophy have been reported in male patients.
The solvent DMA may also impair fertility. A DMA daily dose of 0.45 g/kg/d given to rats for nine days (equivalent to 44% of the daily dose of DMA contained in the recommended dose of Busulfex on a mg/m2 basis) significantly decreased spermatogenesis in rats. A single sc dose of 2.2 g/kg (27% of the total DMA dose contained in Busulfex on a mg/m2 basis) four days after insemination terminated pregnancy in 100% of tested hamsters.
Pregnancy
Busulfan may cause fetal harm when administered to a pregnant woman. Busulfan produced teratogenic changes in the offspring of mice, rats and rabbits when given during gestation. Malformations and anomalies included significant alterations in the musculoskeletal system, body weight gain, and size. In pregnant rats, busulfan produced sterility in both male and female offspring due to the absence of germinal cells in the testes and ovaries. The solvent, DMA, may also cause fetal harm when administered to a pregnant woman. In rats, DMA doses of 400 mg/kg/d (about 40% of the daily dose of DMA in the Busulfex dose on a mg/m2 basis) given during organogenesis caused significant developmental anomalies. The most striking abnormalities included anasarca, cleft palate, vertebral anomalies, rib anomalies, and serious anomalies of the vessels of the heart. There are no adequate and well-controlled studies of either busulfan or DMA in pregnant women. If Busulfex is used during pregnancy, or if the patient becomes pregnant while receiving Busulfex, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Precautions
Hematologic
At the recommended dosage of Busulfex (busulfan) Injection, profound myelosuppression is universal, and can manifest as neutropenia, thrombocytopenia, anemia, or a combination thereof. Patients should be monitored for signs of local or systemic infection or bleeding. Their hematologic status should be evaluated frequently.
Information for Patients
The increased risk of a second malignancy should be explained to the patient.
Laboratory Tests
Patients receiving Busulfex should be monitored daily with a complete blood count, including differential count and quantitative platelet count, until engraftment has been demonstrated.
To detect hepatotoxicity, which may herald the onset of hepatic veno-occlusive disease, serum transaminases, alkaline phosphatase, and bilirubin should be evaluated daily through BMT Day +28.
Drug Interactions
Itraconazole decreases busulfan clearance by up to 25%, and may produce an AUC >1500 µM∙min in some patients. Fluconazole, and the 5-HT3 antiemetics odansetron (Zofran®) and granisetron (Kytril®) have all been used with Busulfex.
Phenytoin increases the clearance of busulfan by 15% or more, possibly due to the induction of glutathione-S-transferase. Since the pharmacokinetics of Busulfex were studied in patients treated with phenytoin, the clearance of Busulfex at the recommended dose may be lower and exposure (AUC) higher in patients not treated with phenytoin.
Because busulfan is eliminated from the body via conjugation with glutathione, use of acetaminophen prior to (<72 hours) or concurrent with Busulfex may result in reduced busulfan clearance based upon the known property of acetaminophen to decrease glutathione levels in the blood and tissues.
Pregnancy
Pregnancy Category D
See WARNINGS.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorgenicity shown for busulfan in human and animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Special Populations
Pediatric
The effectiveness of Busulfex in the treatment of CML has not been specifically studied in pediatric patients. An open-label, uncontrolled study evaluated the pharmacokinetics of Busulfex in 24 pediatric patients receiving Busulfex as part of a conditioning regimen administered prior to hematopoietic progenitor cell transplantation for a variety of malignant hematologic (N=15) or non-malignant diseases (N=9). Patients ranged in age from 5 months to 16 years (median 3 years). Busulfex dosing was targeted to achieve an area under the plasma concentration curve (AUC) of 900-1350 µM∙min with an initial dose of 0.8 mg/kg or 1.0 mg/kg (based on ABW) if the patient was >4 or ≤4 years, respectively. The dose was adjusted based on plasma concentration after completion of dose 1.
Patients received Busulfex doses every six hours as a two‑hour infusion over four days for a total of 16 doses, followed by cyclophosphamide 50 mg/kg once daily for four days. After one rest day, hematopoietic progenitor cells were infused. All patients received phenytoin as seizure prophylaxis. The target AUC (900-1350±5% µM∙min) for Busulfex was achieved at dose 1 in 71% (17/24) of patients. Steady state pharmacokinetic testing was performed at dose 9 and 13. Busulfex levels were within the target range for 21 of 23 evaluable patients.
All 24 patients experienced neutropenia (absolute neutrophil count <0.5×109/L) and thrombocytopenia (platelet transfusions or platelet count <20,000/mm3). Seventy-nine percent (19/24) of patients experienced lymphopenia (absolute lymphocyte count <0.1×109). In 23 patients, the ANC recovered to >0.5×109/L (median time to recovery = BMT day +13; range = BMT day +9 to +22). One patient who died on day +20 had not recovered to an ANC >0.5×109/L.
Four (17%) patients died during the study. Two patients died within 28 days of transplant; one with pneumonia and capillary leak syndrome, and the other with pneumonia and veno-occlusive disease. Two patients died prior to day 100; one due to progressive disease and one due to multi-organ failure.
Adverse events were reported in all 24 patients during the study period (BMT day -10 through BMT day +28) or post-study surveillance period (day +29 through +100). These included vomiting (100%), nausea (83%), stomatitis (79%), hepatic veno-occlusive disease (HVOD) (21%), graft-versus host disease (GVHD) (25%), and pneumonia (21%).
Based on the results of this 24-patient clinical trial, a suggested dosing regimen of Busulfex in pediatric patients is shown in the following dosing nomogram:
| Patient's Actual Body Weight (ABW) | Busulfex Dosage |
|---|---|
| ≤12 kgs | 1.1 (mg/kg) |
| >12 kgs | 0.8 (mg/kg) |
Simulations based on a pediatric population pharmacokinetic model indicate that approximately 60% of pediatric patients will achieve a target Busulfex exposure (AUC) between 900 to 1350 µM∙min with the first dose of Busulfex using this dosing nomogram. Therapeutic drug monitoring and dose adjustment following the first dose of Busulfex is recommended.
Dose Adjustment Based on Therapeutic Drug Monitoring
Instructions for measuring the AUC of busulfan at dose 1 (see Blood Sample Collection for AUC Determination), and the formula for adjustment of subsequent doses to achieve the desired target AUC (1125 µM∙min), are provided below.
Adjusted dose (mg) = Actual Dose (mg) × Target AUC (µM∙min)/Actual AUC (µM∙min)
For example, if a patient received a dose of 11 mg busulfan and if the corresponding AUC measured was 800 µM∙min, for a target AUC of 1125 µM∙min, the target mg dose would be:
Mg dose =11 mg ×1125 µM∙min /800 µM∙min =15.5 mg
Busulfex dose adjustment may be made using this formula and instructions below.
Blood Sample Collection for AUC Determination
Calculate the AUC (µM∙min) based on blood samples collected at the following time points:
For dose 1:2 hr (end of infusion), 4 hr and 6 hr (immediately prior to the next scheduled Busulfex administration). Actual sampling times should be recorded.
For doses other than dose 1: Pre-infusion (baseline), 2 hr (end of infusion), 4 hr and 6 hr (immediately prior to the next scheduled Busulfex administration).
AUC calculations based on fewer than the three specified samples may result in inaccurate AUC determinations.
For each scheduled blood sample, collect one to three mL of blood into heparinized (Na or Li heparin) Vacutainer® tubes. The blood samples should be placed on wet ice immediately after collection and should be centrifuged (at 4°C) within one hour. The plasma, harvested into appropriate cryovial storage tubes, is to be frozen immediately at -20°C. All plasma samples are to be sent in a frozen state (i.e., on dry ice) to the assay laboratory for the determination of plasma busulfan concentrations.
Calculation of AUC
Busulfex AUC calculations may be made using the following instructions and appropriate standard pharmacokinetic formula:
- Dose 1 AUCinfinity Calculation: AUCinfinity = AUC0-6hr + AUCextrapolated, where AUC0-6hr is to be estimated using the linear trapezoidal rule and AUC extrapolated can be computed by taking the ratio of the busulfan concentration at Hour 6 and the terminal elimination rate constant, λz. The λz must be calculated from the terminal elimination phase of the busulfan concentration vs. time curve. A "0" pre-dose busulfan concentration should be assumed, and used in the calculation of AUC.
If the AUC is assessed subsequent to Dose 1, steady-state AUCss (AUC0-6hr) is to be estimated from the trough, 2 hr, 4 hr and 6 hr concentrations using the linear trapezoidal rule.
Instructions for Drug Administration and Blood Sample Collection for Therapeutic Drug Monitoring
An administration set with minimal residual hold up (priming) volume (1-3 mL) should be used for drug infusion to ensure accurate delivery of the entire prescribed dose and to ensure accurate collection of blood samples for therapeutic drug monitoring and dose adjustment.
Prime the administration set tubing with drug solution to allow accurate documentation of the start time of Busulfex infusion. Collect the blood sample from a peripheral IV line to avoid contamination with infusing drug. If the blood sample is taken directly from the existing central venous catheter (CVC), DO NOT COLLECT THE BLOOD SAMPLE WHILE THE DRUG IS INFUSING to ensure that the end of infusion sample is not contaminated with any residual drug. At the end of infusion (2 hr), disconnect the administration tubing and flush the CVC line with 5 cc of normal saline prior to the collection of the end of infusion sample from the CVC port. Collect the blood samples from a different port than that used for the Busulfex infusion. When recording the Busulfex infusion stop time, do not include the time required to flush the indwelling catheter line. Discard the administration tubing at the end of the two‑hour infusion.
See Preparation for Intravenous Administration section for detailed instructions on drug preparation.
Geriatric
Five of sixty-one patients treated in the Busulfex clinical trial were over the age of 55 (range 57-64). All achieved myeloablation and engraftment.
Gender, Race
Adjusting Busulfex dosage based on gender or race has not been adequately studied.
Renal Insufficiency
Busulfex has not been studied in patients with renal impairment.
Hepatic Insufficiency
Busulfex has not been administered to patients with hepatic insufficiency.
Other
Busulfan may cause cellular dysplasia in many organs. Cytologic abnormalities characterized by giant, hyperchromatic nuclei have been reported in lymph nodes, pancreas, thyroid, adrenal glands, liver, lungs and bone marrow. This cytologic dysplasia may be severe enough to cause difficulty in the interpretation of exfoliative cytologic examinations of the lungs, bladder, breast and the uterine cervix.
Adverse Reactions
Dimethylacetamide (DMA), the solvent used in the Busulfex formulation, was studied in 1962 as a potential cancer chemotherapy drug. In a Phase 1 trial, the maximum tolerated dose (MTD) was 14.8 g/m2/d for four days. The daily recommended dose of Busulfex contains DMA equivalent to 42% of the MTD on a mg/m2 basis. The dose-limiting toxicities in the Phase 1 study were hepatotoxicity as evidenced by increased liver transaminase (SGOT) levels and neurological symptoms as evidenced by hallucinations. The hallucinations had a pattern of onset at one day post completion of DMA administration and were associated with EEG changes. The lowest dose at which hallucinations were recognized was equivalent to 1.9 times that delivered in a conditioning regimen utilizing Busulfex 0.8 mg/kg every 6 hours ×16 doses. Other neurological toxicities included somnolence, lethargy, and confusion. The relative contribution of DMA and/or other concomitant medications to neurologic and hepatic toxicities observed with Busulfex is difficult to ascertain.
Treatment with Busulfex at the recommended dose and schedule will result in profound myelosuppression in 100% of patients, including granulocytopenia, thrombocytopenia, anemia, or a combined loss of formed elements of the blood.
Adverse reaction information is primarily derived from the clinical study (N=61) of Busulfex and the data obtained for high-dose oral busulfan conditioning in the setting of randomized, controlled trials identified through a literature review.
Busulfex Clinical Trials
In the Busulfex (busulfan) Injection allogeneic stem cell transplantation clinical trial, all patients were treated with Busulfex 0.8 mg/kg as a two‑hour infusion every six hours for 16 doses over four days, combined with cyclophosphamide 60 mg/kg ×2 days. Ninety-three percent (93%) of evaluable patients receiving this dose of Busulfex maintained an AUC less than 1,500 µM∙min for dose 9, which has generally been considered the level that minimizes the risk of HVOD.
| Non-Hematological Adverse Events* | Percent Incidence |
|---|---|
| |
| BODY AS A WHOLE | |
| Fever | 80 |
| Headache | 69 |
| Asthenia | 51 |
| Chills | 46 |
| Pain | 44 |
| Edema General | 28 |
| Allergic Reaction | 26 |
| Chest Pain | 26 |
| Inflammation at Injection Site | 25 |
| Back Pain | 23 |
| CARDIOVASCULAR SYSTEM | |
| Tachycardia | 44 |
| Hypertension | 36 |
| Thrombosis | 33 |
| Vasodilation | 25 |
| DIGESTIVE SYSTEM | |
| Nausea | 98 |
| Stomatitis (Mucositis) | 97 |
| Vomiting | 95 |
| Anorexia | 85 |
| Diarrhea | 84 |
| Abdominal Pain | 72 |
| Dyspepsia | 44 |
| Constipation | 38 |
| Dry Mouth | 26 |
| Rectal Disorder | 25 |
| Abdominal Enlargement | 23 |
| METABOLIC AND NUTRITIONAL SYSTEM | |
| Hypomagnesemia | 77 |
| Hyperglycemia | 66 |
| Hypokalemia | 64 |
| Hypocalcemia | 49 |
| Hyperbilirubinemia | 49 |
| Edema | 36 |
| SGPT Elevation | 31 |
| Creatinine Increased | 21 |
| NERVOUS SYSTEM | |
| Insomnia | 84 |
| Anxiety | 72 |
| Dizziness | 30 |
| Depression | 23 |
| RESPIRATORY SYSTEM | |
| Rhinitis | 44 |
| Lung Disorder | 34 |
| Cough | 28 |
| Epistaxis | 25 |
| Dyspnea | 25 |
| SKIN AND APPENDAGES | |
| Rash | 57 |
| Pruritus | 28 |
The following sections describe clinically significant events occurring in the Busulfex clinical trials, regardless of drug attribution. For pediatric information, see Special Populations – Pediatric section.
Hematologic
At the indicated dose and schedule, Busulfex produced profound myelosuppression in 100% of patients. Following hematopoietic progenitor cell infusion, recovery of neutrophil counts to ≥500 cells/mm3 occurred at median day 13 when prophylactic G-CSF was administered to the majority of participants on the study. The median number of platelet transfusions per patient on study was 6, and the median number of red blood cell transfusions on study was 4. Prolonged prothrombin time was reported in one patient (2%).
Gastrointestinal
Gastrointestinal toxicities were frequent and generally considered to be related to the drug. Few were categorized as serious. Mild or moderate nausea occurred in 92% of patients in the allogeneic clinical trial, and mild or moderate vomiting occurred in 95% through BMT Day +28; nausea was severe in 7%. The incidence of vomiting during Busulfex administration (BMT Day –7 to –4) was 43% in the allogeneic clinical trial. Grade 3-4 stomatitis developed in 26% of the participants, and Grade 3 esophagitis developed in 2%. Grade 3-4 diarrhea was reported in 5% of the allogeneic study participants, while mild or moderate diarrhea occurred in 75%. Mild or moderate constipation occurred in 38% of patients; ileus developed in 8% and was severe in 2%. Forty-four percent (44%) of patients reported mild or moderate dyspepsia. Two percent (2%) of patients experienced mild hematemesis. Pancreatitis developed in 2% of patients. Mild or moderate rectal discomfort occurred in 24% of patients. Severe anorexia occurred in 21% of patients and was mild/moderate in 64%.
Hepatic
Hyperbilirubinemia occurred in 49% of patients in the allogeneic BMT trial. Grade 3/4 hyperbilirubinemia occurred in 30% of patients within 28 days of transplantation and was considered life-threatening in 5% of these patients. Hyperbilirubinemia was associated with graft-versus-host disease in six patients and with hepatic veno-occlusive disease in 5 patients. Grade 3/4 SGPT elevations occurred in 7% of patients. Alkaline phosphatase increases were mild or moderate in 15% of patients. Mild or moderate jaundice developed in 12% of patients, and mild or moderate hepatomegaly developed in 6%.
Hepatic veno-occlusive disease
Hepatic veno-occlusive disease (HVOD) is a recognized potential complication of conditioning therapy prior to transplant. Based on clinical examination and laboratory findings, hepatic veno-occlusive disease was diagnosed in 8% (5/61) of patients treated with Busulfex in the setting of allogeneic transplantation, was fatal in 2/5 cases (40%), and yielded an overall mortality from HVOD in the entire study population of 2/61 (3%). Three of the five patients diagnosed with HVOD were retrospectively found to meet the Jones' criteria.
Graft-versus-host disease
Graft-versus-host disease developed in 18% of patients (11/61) receiving allogeneic transplants; it was severe in 3%, and mild or moderate in 15%. There were 3 deaths (5%) attributed to GVHD.
Edema
Patients receiving allogeneic transplant exhibited some form of edema (79%), hypervolemia, or documented weight increase (8%); all events were reported as mild or moderate.
Infection/Fever
Fifty-one percent (51%) of patients experienced one or more episodes of infection. Pneumonia was fatal in one patient (2%) and life-threatening in 3% of patients. Fever was reported in 80% of patients; it was mild or moderate in 78% and severe in 3%. Forty-six percent (46%) of patients experienced chills.
Cardiovascular
Mild or moderate tachycardia was reported in 44% of patients. In 7 patients (11%) it was first reported during Busulfex administration. Other rhythm abnormalities, which were all mild or moderate, included arrhythmia (5%), atrial fibrillation (2%), ventricular extrasystoles (2%), and third degree heart block (2%). Mild or moderate thrombosis occurred in 33% of patients, and all episodes were associated with the central venous catheter. Hypertension was reported in 36% of patients and was Grade 3/4 in 7%. Hypotension occurred in 11% of patients and was Grade 3/4 in 3%. Mild vasodilation (flushing and hot flashes) was reported in 25% of patients. Other cardiovascular events included cardiomegaly (5%), mild ECG abnormality (2%), Grade 3/4 left-sided heart failure in one patient (2%), and moderate pericardial effusion (2%). These events were reported primarily in the post-cyclophosphamide phase.
Pulmonary
Mild or moderate dyspnea occurred in 25% of patients and was severe in 2%. One patient (2%) experienced severe hyperventilation; and in 2 (3%) additional patients it was mild or moderate. Mild rhin
No comments:
Post a Comment