These Highlights Do Not Include All The Information Needed To Use Busulfan Injection Safely And Effectively. See Full Prescribing Information For Busulfan Injection.

Additional Adverse Reactions by Body System

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

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label

NDC 25021-241-10

Rx only

Busulfan Injection

60 mg per 10 mL

(6 mg per mL)

Discard Unused Portion

For Intravenous Infusion Only

10 mL Single-Dose Vial

Caution: Must be Diluted Before Use

Caution: Cytotoxic Agent

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 Busulfan Injection. Despite prophylactic therapy with phenytoin, one seizure (1/42 patients) was reported during an autologous transplantation clinical trial of Busulfan Injection. This episode occurred during the cyclophosphamide portion of the conditioning regimen, 36 hours after the last Busulfan Injection dose. Initiate phenytoin therapy or any other alternative anti-convulsant prophylactic therapy (e.g., benzodiazepines, valproic acid or levetiracetam) prior to Busulfan Injection treatment [see Dosage and Administration (2.1)]. Use caution when administering the recommended dose of Busulfan Injection to patients with a history of a seizure disorder or head trauma or who are receiving other potentially epileptogenic drugs.

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 Injection 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 Myleran^® 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.

• OSHA Hazardous Drugs. OSHA. [Accessed on June 18, 2014 from http://www.osha.gov/SLTC/hazardousdrugs/index.html]

Busulfan is a bifunctional alkylating agent known chemically as 1,4-butanediol, dimethanesulfonate. The molecular formula of busulfan is CH₃SO₂O(CH₂)₄OSO₂CH₃ with a molecular weight of 246 g/mole. Busulfan has the following chemical structure:

Busulfan Injection (busulfan) 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 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 3.4 to 3.9.

Busulfan Injection is supplied as follows:

For Intravenous Infusion Only

The effectiveness of Busulfan Injection in the treatment of CML has not been specifically studied in pediatric patients. An open-label, uncontrolled study evaluated the pharmacokinetics of Busulfan Injection in 24 pediatric patients receiving Busulfan Injection 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). Busulfan Injection dosing was targeted to achieve an area under the plasma concentration curve (AUC) of 900 to 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 Busulfan Injection 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 to 1350 ± 5% μM•min) for Busulfan Injection was achieved at dose 1 in 71% (17/24) of patients. Steady state pharmacokinetic testing was performed at dose 9 and 13. Busulfan Injection 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 x 10⁹/L) and thrombocytopenia (platelet transfusions or platelet count less than 20,000/mm³). Seventy-nine percent (19/24) of patients experienced lymphopenia (absolute lymphocyte count less than 0.1 x 10⁹). In 23 patients, the ANC recovered to greater than 0.5 x 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 x 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 Busulfan Injection 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 Busulfan Injection exposure (AUC) between 900 to 1350 μM•min with the first dose of Busulfan Injection using this dosing nomogram. Therapeutic drug monitoring and dose adjustment following the first dose of Busulfan Injection is recommended.

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

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 Injection 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.

Busulfan Injection is contraindicated in patients with a history of hypersensitivity to any of its components.

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Myelosuppression [see Warnings and Precautions (5.1)]
• Seizures [see Warnings and Precautions (5.2)]
• Hepatic Veno-Occlusive Disease (HVOD) [see Warnings and Precautions (5.3)]
• Embryo-fetal Toxicity [see Warnings and Precautions (5.4)]
• Cardiac Tamponade [see Warnings and Precautions (5.5)]
• Bronchopulmonary Dysplasia [see Warnings and Precautions (5.6)]
• Cellular Dysplasia [see Warnings and Precautions (5.7)]

• Drugs that Decrease Busulfan Injection Clearance: Metronidazole, itraconazole, iron chelating agents, acetaminophen. (7.1)
• Drugs that Increase Busulfan Injection Clearance: Phenytoin. (7.2)

The most frequent serious consequence of treatment with Busulfan Injection 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 x 10⁹/L at a median of 4 days post-transplant in 100% of patients treated in the Busulfan Injection 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 to 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.

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

Busulfan Injection 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.

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.

Busulfan Injection 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.

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.

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.

Busulfan Injection diluted in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP is stable at room temperature (25°C) for up to 8 hours but the infusion must be completed within that time.

Busulfan Injection diluted in 0.9% Sodium Chloride Injection, USP is stable at refrigerated conditions (2°C to 8°C) for up to 12 hours but the infusion must be completed within that time.

Busulfan Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.¹

Busulfan Injection 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 Busulfan Injection [see Use in Specific Populations (8.1, 8.3)].

Busulfan Injection causes severe and prolonged myelosuppression at the recommended dosage.

Hematopoietic progenitor cell transplantation is required to prevent potentially fatal complications of the prolonged myelosuppression [see Warnings and Precautions (5.1)].

• Seizures: Initiate anticonvulsant prophylactic therapy prior to treatment with Busulfan Injection. Monitor patients with history of seizure disorder, head trauma or receiving epileptogenic drugs (5.2)
• Hepatic Veno-Occlusive Disease (HVOD): Increased risk of developing HVOD at AUC greater than 1,500 μM•min. Monitor serum transaminases, alkaline phosphatase and bilirubin daily (5.3)
• Embryo-fetal Toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception (5.4, 8.1, 8.3)
• Cardiac tamponade has been reported in pediatric patients with thalassemia who received high doses of oral busulfan and cyclophosphamide. Abdominal pain and vomiting preceded the tamponade in most patients (5.5)

• Pre-medicate with anticonvulsants (e.g. benzodiazepines, phenytoin, valproic acid or levetiracetam) and antiemetic (2.1, 5.2)
• Dilute and administer as intravenous infusion. Do not administer as intravenous push or bolus (2.1, 2.3)
• Recommended adult dose: 0.8 mg per kg of ideal body weight or actual body weight, whichever is lower, administered intravenously via a central venous catheter as a two-hour infusion every six hours for four consecutive days for a total of 16 doses (2.1)

Injection: 60 mg per 10 mL (6 mg per mL) as a clear, colorless, sterile, solution in a single-dose vial for intravenous infusion only.

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 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.

• Lactation: Advise women not to breastfeed (8.2)

• Administer Busulfan Injection in combination with cyclophosphamide as a conditioning regimen prior to bone marrow or peripheral blood progenitor cell replacement. For patients weighing more than 12 kg, the recommended doses are:
  • Busulfan Injection 0.8 mg per kg (ideal body weight or actual body weight, whichever is lower) intravenously via a central venous catheter as a two-hour infusion every six hours for four consecutive days for a total of 16 doses (Days -7, -6, -5 and -4).
  • Cyclophosphamide 60 mg per kg intravenously as a one-hour infusion on each of two days beginning no sooner than six hours following the 16^th dose of Busulfan Injection (Days -3 and -2).
  • Administer hematopoietic progenitor cells on Day 0.
• Premedicate patients with anticonvulsants (e.g., benzodiazepines, phenytoin, valproic acid or levetiracetam) to prevent seizures reported with the use of high dose Busulfan Injection. Administer anticonvulsants 12 hours prior to Busulfan Injection to 24 hours after the last dose of Busulfan Injection [see Warnings and Precautions (5.2)].
• Administer antiemetics prior to the first dose of Busulfan Injection and continue on a fixed schedule through Busulfan Injection administration.
• Busulfan Injection clearance is best predicted when the Busulfan Injection dose is administered based on adjusted ideal body weight. Dosing Busulfan Injection based on actual body weight, ideal body weight or other factors can produce significant differences in Busulfan Injection clearance among lean, normal and obese patients.
  • Calculate ideal body weight (IBW) as follows (height in cm, and weight in kg):
    •  
      Men: IBW (kg) = 50 + 0.91 x (height in cm - 152)
    •  
      Women: IBW (kg) = 45 + 0.91 x (height in cm - 152)
  • For obese or severely obese patients, base Busulfan Injection dosing on adjusted ideal body weight (AIBW):
    •  
      AIBW = IBW + 0.25 x (actual weight - IBW).

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).

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 Busulfan Injection and the data obtained for high-dose oral busulfan conditioning in the setting of randomized, controlled trials identified through a literature review.

In the Busulfan Injection allogeneic stem cell transplantation clinical trial, all patients were treated with Busulfan Injection 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 x 2 days. Ninety-three percent (93%) of evaluable patients receiving this dose of Busulfan Injection 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 Busulfan Injection prior to allogeneic hematopoietic cell transplantation.

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).

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 Busulfan Injection dose and regimen. Based on clinical examination and laboratory findings, HVOD was diagnosed in 8% (5/61) of patients treated with Busulfan Injection 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% to 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.

Busulfan Injection is incompatible with polycarbonate. Do not use any infusion components (syringes, filter needles, intravenous tubing, etc.) containing polycarbonate with Busulfan Injection.

Use an administration set with minimal residual hold-up volume (2 mL to 5 mL) for product administration.

Busulfan Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures. Skin reactions may occur with accidental exposure. Use gloves when preparing Busulfan Injection. If Busulfan Injection or diluted Busulfan Injection solution contacts the skin or mucosa, wash the skin or mucosa thoroughly with water.

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration whenever the solution and container permit. Do not use if particulate matter is seen in the Busulfan Injection vial.

Busulfan Injection must be diluted prior to intravenous infusion with either 0.9% Sodium Chloride Injection, USP (normal saline) or 5% Dextrose Injection, USP (D5W). The diluent quantity should be 10 times the volume of Busulfan Injection, so that the final concentration of busulfan is approximately 0.5 mg per mL. Calculation of the dose for a 70 kg patient would be performed as follows:

•  
  (70 kg patient) x (0.8 mg per kg) ÷ (6 mg per mL) = 9.3 mL Busulfan Injection (56 mg total dose).

To prepare the final solution for infusion, add 9.3 mL of Busulfan Injection to 93 mL of diluent (normal saline or D5W) as calculated below:

•  
  (9.3 mL Busulfan Injection) x (10) = 93 mL of either diluent plus the 9.3 mL of Busulfan Injection to yield a final concentration of busulfan of 0.54 mg per mL (9.3 mL x 6 mg per mL ÷ 102.3 mL = 0.54 mg per mL).

All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical laminar flow safety hood while wearing gloves and protective clothing.

Always add the Busulfan Injection to the diluent, not the diluent to the Busulfan Injection. Mix thoroughly by inverting several times. Discard unused portion.

Infusion pumps should be used to administer the diluted Busulfan Injection solution. Set the flow rate of the pump to deliver the entire prescribed Busulfan Injection dose over two hours. Prior to and following each infusion, flush the indwelling catheter line with approximately 5 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. DO NOT infuse concomitantly with another intravenous solution of unknown compatibility. WARNING: RAPID INFUSION OF BUSULFAN INJECTION HAS NOT BEEN TESTED AND IS NOT RECOMMENDED.

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 Busulfan Injection.

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 Busulfan Injection 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 Busulfan Injection 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 Busulfan Injection were studied in patients treated with phenytoin, the clearance of Busulfan Injection at the recommended dose may be lower and exposure (AUC) higher in patients not treated with phenytoin.

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 Injection 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 Injection 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 Injection on a mg/m² basis) four days after insemination terminated pregnancy in 100% of tested hamsters [see Use in Specific Populations (8.3)].

Additional Adverse Reactions by Body System

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

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label

NDC 25021-241-10

Rx only

Busulfan Injection

60 mg per 10 mL

(6 mg per mL)

Discard Unused Portion

For Intravenous Infusion Only

10 mL Single-Dose Vial

Caution: Must be Diluted Before Use

Caution: Cytotoxic Agent

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 Busulfan Injection. Despite prophylactic therapy with phenytoin, one seizure (1/42 patients) was reported during an autologous transplantation clinical trial of Busulfan Injection. This episode occurred during the cyclophosphamide portion of the conditioning regimen, 36 hours after the last Busulfan Injection dose. Initiate phenytoin therapy or any other alternative anti-convulsant prophylactic therapy (e.g., benzodiazepines, valproic acid or levetiracetam) prior to Busulfan Injection treatment [see Dosage and Administration (2.1)]. Use caution when administering the recommended dose of Busulfan Injection to patients with a history of a seizure disorder or head trauma or who are receiving other potentially epileptogenic drugs.

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 Injection 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 Myleran^® 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.

• OSHA Hazardous Drugs. OSHA. [Accessed on June 18, 2014 from http://www.osha.gov/SLTC/hazardousdrugs/index.html]

Busulfan is a bifunctional alkylating agent known chemically as 1,4-butanediol, dimethanesulfonate. The molecular formula of busulfan is CH₃SO₂O(CH₂)₄OSO₂CH₃ with a molecular weight of 246 g/mole. Busulfan has the following chemical structure:

Busulfan Injection (busulfan) 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 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 3.4 to 3.9.

Busulfan Injection is supplied as follows:

For Intravenous Infusion Only

The effectiveness of Busulfan Injection in the treatment of CML has not been specifically studied in pediatric patients. An open-label, uncontrolled study evaluated the pharmacokinetics of Busulfan Injection in 24 pediatric patients receiving Busulfan Injection 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). Busulfan Injection dosing was targeted to achieve an area under the plasma concentration curve (AUC) of 900 to 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 Busulfan Injection 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 to 1350 ± 5% μM•min) for Busulfan Injection was achieved at dose 1 in 71% (17/24) of patients. Steady state pharmacokinetic testing was performed at dose 9 and 13. Busulfan Injection 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 x 10⁹/L) and thrombocytopenia (platelet transfusions or platelet count less than 20,000/mm³). Seventy-nine percent (19/24) of patients experienced lymphopenia (absolute lymphocyte count less than 0.1 x 10⁹). In 23 patients, the ANC recovered to greater than 0.5 x 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 x 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 Busulfan Injection 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 Busulfan Injection exposure (AUC) between 900 to 1350 μM•min with the first dose of Busulfan Injection using this dosing nomogram. Therapeutic drug monitoring and dose adjustment following the first dose of Busulfan Injection is recommended.

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

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 Injection 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.

Busulfan Injection is contraindicated in patients with a history of hypersensitivity to any of its components.

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Myelosuppression [see Warnings and Precautions (5.1)]
• Seizures [see Warnings and Precautions (5.2)]
• Hepatic Veno-Occlusive Disease (HVOD) [see Warnings and Precautions (5.3)]
• Embryo-fetal Toxicity [see Warnings and Precautions (5.4)]
• Cardiac Tamponade [see Warnings and Precautions (5.5)]
• Bronchopulmonary Dysplasia [see Warnings and Precautions (5.6)]
• Cellular Dysplasia [see Warnings and Precautions (5.7)]

• Drugs that Decrease Busulfan Injection Clearance: Metronidazole, itraconazole, iron chelating agents, acetaminophen. (7.1)
• Drugs that Increase Busulfan Injection Clearance: Phenytoin. (7.2)

The most frequent serious consequence of treatment with Busulfan Injection 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 x 10⁹/L at a median of 4 days post-transplant in 100% of patients treated in the Busulfan Injection 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 to 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.

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

Busulfan Injection 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.

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.

Busulfan Injection 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.

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.

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.

Busulfan Injection diluted in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP is stable at room temperature (25°C) for up to 8 hours but the infusion must be completed within that time.

Busulfan Injection diluted in 0.9% Sodium Chloride Injection, USP is stable at refrigerated conditions (2°C to 8°C) for up to 12 hours but the infusion must be completed within that time.

Busulfan Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.¹

Busulfan Injection 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 Busulfan Injection [see Use in Specific Populations (8.1, 8.3)].

Busulfan Injection causes severe and prolonged myelosuppression at the recommended dosage.

Hematopoietic progenitor cell transplantation is required to prevent potentially fatal complications of the prolonged myelosuppression [see Warnings and Precautions (5.1)].

• Seizures: Initiate anticonvulsant prophylactic therapy prior to treatment with Busulfan Injection. Monitor patients with history of seizure disorder, head trauma or receiving epileptogenic drugs (5.2)
• Hepatic Veno-Occlusive Disease (HVOD): Increased risk of developing HVOD at AUC greater than 1,500 μM•min. Monitor serum transaminases, alkaline phosphatase and bilirubin daily (5.3)
• Embryo-fetal Toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception (5.4, 8.1, 8.3)
• Cardiac tamponade has been reported in pediatric patients with thalassemia who received high doses of oral busulfan and cyclophosphamide. Abdominal pain and vomiting preceded the tamponade in most patients (5.5)

• Pre-medicate with anticonvulsants (e.g. benzodiazepines, phenytoin, valproic acid or levetiracetam) and antiemetic (2.1, 5.2)
• Dilute and administer as intravenous infusion. Do not administer as intravenous push or bolus (2.1, 2.3)
• Recommended adult dose: 0.8 mg per kg of ideal body weight or actual body weight, whichever is lower, administered intravenously via a central venous catheter as a two-hour infusion every six hours for four consecutive days for a total of 16 doses (2.1)

Injection: 60 mg per 10 mL (6 mg per mL) as a clear, colorless, sterile, solution in a single-dose vial for intravenous infusion only.

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 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.

• Lactation: Advise women not to breastfeed (8.2)

• Administer Busulfan Injection in combination with cyclophosphamide as a conditioning regimen prior to bone marrow or peripheral blood progenitor cell replacement. For patients weighing more than 12 kg, the recommended doses are:
  • Busulfan Injection 0.8 mg per kg (ideal body weight or actual body weight, whichever is lower) intravenously via a central venous catheter as a two-hour infusion every six hours for four consecutive days for a total of 16 doses (Days -7, -6, -5 and -4).
  • Cyclophosphamide 60 mg per kg intravenously as a one-hour infusion on each of two days beginning no sooner than six hours following the 16^th dose of Busulfan Injection (Days -3 and -2).
  • Administer hematopoietic progenitor cells on Day 0.
• Premedicate patients with anticonvulsants (e.g., benzodiazepines, phenytoin, valproic acid or levetiracetam) to prevent seizures reported with the use of high dose Busulfan Injection. Administer anticonvulsants 12 hours prior to Busulfan Injection to 24 hours after the last dose of Busulfan Injection [see Warnings and Precautions (5.2)].
• Administer antiemetics prior to the first dose of Busulfan Injection and continue on a fixed schedule through Busulfan Injection administration.
• Busulfan Injection clearance is best predicted when the Busulfan Injection dose is administered based on adjusted ideal body weight. Dosing Busulfan Injection based on actual body weight, ideal body weight or other factors can produce significant differences in Busulfan Injection clearance among lean, normal and obese patients.
  • Calculate ideal body weight (IBW) as follows (height in cm, and weight in kg):
    •  
      Men: IBW (kg) = 50 + 0.91 x (height in cm - 152)
    •  
      Women: IBW (kg) = 45 + 0.91 x (height in cm - 152)
  • For obese or severely obese patients, base Busulfan Injection dosing on adjusted ideal body weight (AIBW):
    •  
      AIBW = IBW + 0.25 x (actual weight - IBW).

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).

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 Busulfan Injection and the data obtained for high-dose oral busulfan conditioning in the setting of randomized, controlled trials identified through a literature review.

In the Busulfan Injection allogeneic stem cell transplantation clinical trial, all patients were treated with Busulfan Injection 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 x 2 days. Ninety-three percent (93%) of evaluable patients receiving this dose of Busulfan Injection 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 Busulfan Injection prior to allogeneic hematopoietic cell transplantation.

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).

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 Busulfan Injection dose and regimen. Based on clinical examination and laboratory findings, HVOD was diagnosed in 8% (5/61) of patients treated with Busulfan Injection 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% to 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.

Busulfan Injection is incompatible with polycarbonate. Do not use any infusion components (syringes, filter needles, intravenous tubing, etc.) containing polycarbonate with Busulfan Injection.

Use an administration set with minimal residual hold-up volume (2 mL to 5 mL) for product administration.

Busulfan Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures. Skin reactions may occur with accidental exposure. Use gloves when preparing Busulfan Injection. If Busulfan Injection or diluted Busulfan Injection solution contacts the skin or mucosa, wash the skin or mucosa thoroughly with water.

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration whenever the solution and container permit. Do not use if particulate matter is seen in the Busulfan Injection vial.

Busulfan Injection must be diluted prior to intravenous infusion with either 0.9% Sodium Chloride Injection, USP (normal saline) or 5% Dextrose Injection, USP (D5W). The diluent quantity should be 10 times the volume of Busulfan Injection, so that the final concentration of busulfan is approximately 0.5 mg per mL. Calculation of the dose for a 70 kg patient would be performed as follows:

•  
  (70 kg patient) x (0.8 mg per kg) ÷ (6 mg per mL) = 9.3 mL Busulfan Injection (56 mg total dose).

To prepare the final solution for infusion, add 9.3 mL of Busulfan Injection to 93 mL of diluent (normal saline or D5W) as calculated below:

•  
  (9.3 mL Busulfan Injection) x (10) = 93 mL of either diluent plus the 9.3 mL of Busulfan Injection to yield a final concentration of busulfan of 0.54 mg per mL (9.3 mL x 6 mg per mL ÷ 102.3 mL = 0.54 mg per mL).

All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical laminar flow safety hood while wearing gloves and protective clothing.

Always add the Busulfan Injection to the diluent, not the diluent to the Busulfan Injection. Mix thoroughly by inverting several times. Discard unused portion.

Infusion pumps should be used to administer the diluted Busulfan Injection solution. Set the flow rate of the pump to deliver the entire prescribed Busulfan Injection dose over two hours. Prior to and following each infusion, flush the indwelling catheter line with approximately 5 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. DO NOT infuse concomitantly with another intravenous solution of unknown compatibility. WARNING: RAPID INFUSION OF BUSULFAN INJECTION HAS NOT BEEN TESTED AND IS NOT RECOMMENDED.

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 Busulfan Injection.

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 Busulfan Injection 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 Busulfan Injection 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 Busulfan Injection were studied in patients treated with phenytoin, the clearance of Busulfan Injection at the recommended dose may be lower and exposure (AUC) higher in patients not treated with phenytoin.

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 Injection 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 Injection 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 Injection on a mg/m² basis) four days after insemination terminated pregnancy in 100% of tested hamsters [see Use in Specific Populations (8.3)].