Source: FDA, National Drug Code (US) Revision Year: 2020
BUSULFEX is contraindicated in patients with a history of hypersensitivity to any of its components.
The most frequent serious consequence of treatment with BUSULFEX at the recommended dose and schedule is prolonged myelosuppression, occurring in all patients (100%). Severe granulocytopenia, thrombocytopenia, anemia, or any combination thereof may develop. Hematopoietic progenitor cell transplantation is required to prevent potentially fatal complications of the prolonged myelosuppression. Monitor complete blood counts, including white blood cell differentials, and quantitative platelet counts daily during treatment and until engraftment is demonstrated. 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 filgrastim was used in the majority of patients. Thrombocytopenia (less than 25,000/mm³ or requiring platelet transfusion) occurred at a median of 5-6 days in 98% of patients. Anemia (hemoglobin less than 8.0 g/dL) occurred in 69% of patients. Use antibiotic therapy and platelet and red blood cell support when medically indicated.
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. Initiate phenytoin therapy or any other alternative anti-convulsant prophylactic therapy (e.g., benzodiazepines, valproic acid or levetiracetam) prior to BUSULFEX treatment [see Dosage and Administration (2.1)]. Use caution 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.
Current literature suggests that high busulfan area under the plasma concentration verses time curve (AUC) values (greater than 1,500 µM∙min) may be associated with an increased risk of developing 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, HVOD 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 was 7.7%-12% [see Clinical Studies (14)]. Monitor serum transaminases, alkaline phosphatase, and bilirubin daily through BMT Day +28 to detect hepatotoxicity, which may herald the onset of HVOD.
BUSULFEX can cause fetal harm when administered to a pregnant woman based on animal data. Busulfan was teratogenic in mice, rats, and rabbits. The solvent, DMA, may also cause fetal harm when administered to a pregnant woman based on findings in animals. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during and after treatment with BUSULFEX [see Use in Specific Populations (8.1, 8.3)].
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. Monitor for signs and symptoms, promptly evaluate and treat if cardiac tamponade is suspected.
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).
BUSULFEX 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.
The following adverse reactions are discussed in more detail in other sections of the labeling:
A literature review identified four randomized, controlled trials that evaluated a high-dose oral busulfan-containing conditioning regimen for allogeneic bone marrow transplantation in the setting of CML [see Clinical Studies (14)]. The safety outcomes reported in those trials are summarized in Table 2 below for a mixed population of hematological malignancies (AML, CML, and ALL).
Table 2. Summary of safety analyses from the randomized, controlled trials utilizing a high dose oral busulfan-containing conditioning regimen that were identified in a literature review:
| Clift CML Chronic Phase | |||||
|---|---|---|---|---|---|
| TRM* | VOD† | GVHD‡ | Pulmonary | Hemorrhagic Cystitis | Seizure |
| Death ≤100d =4.1% (3/73) | No Report | Acute≥Grade 2=35% Chronic=41% (30/73) | 1 death from Idiopathic Interstitial Pneumonitis And 1 death from Pulmonary Fibrosis | No Report | No Report |
| Devergie CML Chronic Phase | |||||
| TRM | VOD | GVHD | Pulmonary | Hemorrhagic Cystitis | Seizure |
| 38% | 7.7% (5/65) Deaths=4.6% (3/65) | Acute≥Grade 2=41% (24/59 at risk) | Interstitial Pneumonitis=16.9% (11/65) | 10.8% (7/65) | No Report |
| Ringden CML, AML, ALL | |||||
| TRM | VOD | GVHD | Pulmonary | Hemorrhagic Cystitis | Seizure |
| 28% | 12% | Acute≥Grade 2 GVHD=26% Chronic GVHD =45% | Interstitial Pneumonitis =14% | 24% | 6% |
| Blume CML, AML, ALL | |||||
| TRM | VOD | GVHD | Pulmonary | Hemorrhagic Cystitis | Seizure |
| No Report | Deaths =4.9% | Acute≥Grade 2 GVHD=22% (13/58 at risk) Chronic GVHD =31% (14/45 at risk) | No Report | No Report | No Report |
* TRM = Transplantation Related Mortality
† VOD = Veno-Occlusive Disease of the liver
‡ GVHD = Graft versus Host Disease
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
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.
In the BUSULFEX (busulfan) Injection allogeneic stem cell transplantation clinical trial, all patients were treated with BUSULFEX 0.8 mg per kg as a two‑hour infusion every six hours for 16 doses over four days, combined with cyclophosphamide 60 mg per 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.
Table 1 lists the non-hematologic adverse reactions events through Bone Marrow Transplantation (BMT) Day +28 at a rate greater than or equal to 20% in patients treated with BUSULFEX prior to allogeneic hematopoietic cell transplantation.
Table 1. Summary of the Incidence (greater than or equal to 20%) of Non-Hematologic Adverse Reactions through BMT Day +28 in Patients who Received BUSULFEX Prior to Allogeneic Hematopoietic Progenitor Cell Transplantation:
| Non-Hematological Adverse Reactions* | 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 |
* Includes all reported adverse reactions regardless of severity (toxicity grades 1-4)
Hematologic: Prolonged prothrombin time
Gastrointestinal: Esophagitis, ileus, hematemesis, pancreatitis, rectal discomfort
Hepatic: Alkaline phosphatase increases, jaundice, hepatomegaly
Graft-versus-host disease: Graft-versus-host disease. There were 3 deaths (5%) attributed to GVHD.
Edema: Hypervolemia, or documented weight increase
Infection: Infection, pneumonia (fatal in one patient and life-threatening in 3% of patients)
Cardiovascular: Arrhythmia, atrial fibrillation, ventricular extrasystoles, third degree heart block, thrombosis (all episodes were associated with the central venous catheter), hypotension, flushing and hot flashes, cardiomegaly, ECG abnormality, left-sided heart failure, and pericardial effusion
Pulmonary: Hyperventilation, alveolar hemorrhage (fatal in 3%), pharyngitis, hiccup, asthma, atelectasis, pleural effusion, hypoxia, hemoptysis, sinusitis, and interstitial fibrosis (fatal in a single case)
Neurologic: Cerebral hemorrhage, coma, delirium, agitation, encephalopathy, confusion, hallucinations, lethargy, somnolence
Renal: BUN increased, dysuria, oliguria, hematuria, hemorrhagic cystitis
Skin: Alopecia, vesicular rash, maculopapular rash, vesiculo-bullous rash, exfoliative dermatitis, erythema nodosum, acne, skin discoloration
Metabolic: Hypophosphatemia, hyponatremia
Other Events: Injection site pain, myalgia, arthralgia, ear disorder
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post-approval use of BUSULFEX (busulfan) Injection:
Blood and Lymphatic System Disorders: febrile neutropenia
Gastrointestinal Disorders: tooth hypoplasia
Metabolism and Nutrition Disorders: tumor lysis syndrome
Vascular Disorders: thrombotic microangiopathy (TMA)
Infections and Infestations: severe bacterial, viral (e.g., cytomegalovirus viremia) and fungal infections; and sepsis.
Itraconazole decreases busulfan clearance by up to 25%. Metronidazole decreases the clearance of busulfan to a greater extent than does itraconazole; metronidazole coadministration has been associated with increased busulfan toxicity. Fluconazole (200 mg) has been used with BUSULFEX.
Decreased clearance of busulfan was observed with concomitant use with deferasirox. The mechanism of this interaction is not fully elucidated. Discontinue iron chelating agents well in advance of administration of BUSULFEX to avoid increased exposure to busulfan.
Because busulfan is eliminated from the body via conjugation with glutathione, use of acetaminophen prior to (less than 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.
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.
BUSULFEX can cause fetal harm when administered to a pregnant woman based on animal data. Busulfan was teratogenic in mice, rats, and rabbits following administration during organogenesis. The solvent, DMA, may also cause fetal harm when administered to a pregnant woman. In rats, DMA doses of approximately 40% of the daily dose of DMA in the BUSULFEX dose on a mg/m² basis given during organogenesis caused significant developmental anomalies (see Data). There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.
Following administration during organogenesis in animals, busulfan caused malformations and anomalies, including 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, N,N-dimethylacetamide (DMA), administered to rats at doses of 400 mg/kg/day (about 40% of the daily dose of DMA in the BUSULFEX dose on a mg/m² basis) 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.
It is not known whether BUSULFEX is present in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for busulfan in human and animal studies, discontinue breastfeeding during treatment with BUSULFEX.
BUSULFEX can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with BUSULFEX and for 6 months following cessation of therapy.
BUSULFEX may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during treatment with BUSULFEX and for 3 months after cessation of therapy [see Nonclinical Toxicology (13.1)].
Ovarian suppression and amenorrhea commonly occur in premenopausal women undergoing chronic, low-dose busulfan therapy for chronic myelogenous leukemia. BUSULFEX may cause temporary or permanent infertility in prepubertal girls or in females of child-bearing potential treated with high-dose BUSULFEX in the conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation.
Sterility, azoospermia, and testicular atrophy have been reported in male patients.
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 per kg or 1.0 mg per kg (based on Actual Body Weight (ABW)) if the patient was greater than 4 or less than or equal to 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 per 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 (ANC) less than 0.5×109/L) and thrombocytopenia (platelet transfusions or platelet count less than 20,000/mm 3). Seventy-nine percent (19/24) of patients experienced lymphopenia (absolute lymphocyte count less than 0.1×10 9). In 23 patients, the ANC recovered to greater than 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 reactions 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%), 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:
BUSULFEX Dosing Nomogram:
| Patient’s Actual Body Weight (ABW) | BUSULFEX Dosage |
|---|---|
| less than or equal to12 kgs | 1.1 (mg per kg) |
| greater than 12 kgs | 0.8 (mg per 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.
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.
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.
BUSULFEX AUC calculations may be made using the following instructions and appropriate standard pharmacokinetic formula:
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.
Use an administration set with minimal residual hold up (priming) volume (1 to 3 mL) 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 mL 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 Dosage and Administration (2.3)].
Clinical studies of BUSULFEX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
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