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Busulfex
Overview
What is Busulfex?
What does Busulfex look like?
What are the available doses of Busulfex?
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What should I talk to my health care provider before I take Busulfex?
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How should I use Busulfex?
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What interacts with Busulfex?
BUSULFEX is contraindicated in patients with a history of hypersensitivity to any of its components.
What are the warnings of Busulfex?
The benefits of immediate-release oral ISDN in patients with acute myocardial infarction or congestive heart failure have not been established. If one elects to use ISDN in these conditions, careful clinical or hemodynamic monitoring must be used to avoid the hazards of hypotension and tachycardia. Because the effects of oral ISDN are so difficult to terminate rapidly, this formulation is not recommended in these settings.
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:
Neurological:
Hepatic:
Cardiac:
Pulmonary:
Carcinogenicity, Mutagenicity, Impairment of Fertility
Busulfan is a mutagen and a clastogen. In in vitro tests it caused mutations in and . 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/m 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/m 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/m 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/m 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.
What are the precautions of Busulfex?
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 venoocclusive 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 .
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:
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 x 10/L) and thrombocytopenia (platelet transfusions or platelet count <20,000/mm). Seventy-nine percent (19/24) of patients experienced lymphopenia (absolute lymphocyte count <0.1 x 10). In 23 patients, the ANC recovered to >0.5 x 10/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 x 10/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:
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 ), 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) x 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 x 1125 µM•min / 800 µM•min = 15.5 mg
Busulfex dose adjustment may be made using this formula and instructions below.
Array
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).
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 AUC Calculation: AUC= AUC+ AUC,
where AUC 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, z. The z 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 AUC (AUC) is to be estimated from the trough, 2 hr, 4 hr and 6 hr concentrations using the linear trapezoidal rule.
Array
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), 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:
Gender, Race:
Renal Insufficiency:
Hepatic Insufficiency:
Other:
| Patient’s Actual | BUSULFEX |
| Body Weight (ABW) | Dosage |
| ≤12 kgs | 1.1 (mg/kg) |
| >12 kgs | 0.8 (mg/kg) |
What are the side effects of Busulfex?
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/m/d for four days. The daily recommended dose of BUSULFEX contains DMA equivalent to 42% of the MTD on a mg/m 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 x 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 x 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.
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.
Gastrointestinal:
Hepatic:
Other:
Oral Busulfan Literature Review.
| *Includes all reported adverse events regardless of severity (toxicity grades 1-4) | 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 Inj Site | 25 | ||||
| Pain Back | 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 | ||||
| *TRM = Transplantation Related Mortality | **VOD = Veno-Occlusive Disease of the liver | ***GVHD = Graft versus Host Disease | Array | ||
| TRM* | VOD** | GVHD*** | Pulmonary | Hemorrhagic | Seizure |
| Cystitis | |||||
| Death | No Report | Acute ≥ Grade 2 | 1 death from | No Report | No Report |
| ≤100d | =35% | Idiopathic | |||
| =4.1% | Chronic =41% | Interstitial | |||
| (3/73) | (30/73) | Pneumonitis | |||
| and | |||||
| 1 death from | |||||
| Pulmonary | |||||
| Fibrosis | |||||
| TRM | VOD | GVHD | Pulmonary | Hemorrhagic | Seizure |
| Cystitis | |||||
| 38% | 7.7% (5/65) | Acute ≥ Grade 2 | Interstitial | 10.8% (7/65) | No report |
| Deaths=4.6% | =41% | Pneumonitis= | |||
| (3/65) | (24/59 at risk) | 16.9% (11/65) | |||
| TRM | VOD | GVHD | Pulmonary | Hemorrhagic | Seizure |
| Cystitis | |||||
| 28% | 12% | Acute ≥ Grade 2 | Interstitial | 24% | 6% |
| GVHD=26% | Pneumonitis | ||||
| Chronic GVHD | =14% | ||||
| =45% | |||||
| TRM | VOD | GVHD | Pulmonary | Hemorrhagic | Seizure |
| Cystitis | |||||
| No Report | Deaths | Acute ≥ Grade 2 | No Report | No Report | No Report |
| =4.9% | GVHD=22% | ||||
| (13/58 at risk) | |||||
| Chronic GVHD | |||||
| =31% | |||||
| (14/45 at risk) |
What should I look out for while using Busulfex?
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What might happen if I take too much Busulfex?
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How should I store and handle Busulfex?
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Clinical Information
Chemical Structure
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Non-Clinical Toxicology
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
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