Busulfex Drug Information

is indicated for use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia. BUSULFEX is an alkylating drug indicated for: Use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia (CML)

Clinical Trials Experience

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 for 2 days.

Ninety-three percent (93%) of evaluable patients receiving this dose of BUSULFEX maintained an AUC less than 1,500 micromole per 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 Includes all reported adverse reactions regardless of severity (toxicity grades 1 to4) 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 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

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of BUSULFEX (busulfan) Injection. 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. 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.

Oral Busulfan Literature Review

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 . 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 TRM = Transplantation Related Mortality VOD VOD = Veno-Occlusive Disease of the liver GVHD GVHD = Graft versus Host Disease 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

Drugs that Decrease

BUSULFEX Clearance 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.

Drugs that Increase

BUSULFEX Clearance 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.

Pregnancy Risk Summary 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/m 2 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 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Data Animal Data 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/m 2 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.

Pediatric Use 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 micromole per 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% micromole per 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 × 10 9 /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 × 10 9 /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 × 10 9 /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 micromole per min with the first dose of BUSULFEX using this dosing nomogram. Therapeutic drug monitoring and dose adjustment following the first dose of BUSULFEX is recommended.

Dose Adjustment Based on Therapeutic Drug Monitoring Instructions for measuring the AUC of busulfan at Dose 1 (see Blood Sample Collection for AUC Determination ) and the formula for adjustment of subsequent doses to achieve the desired target AUC (1125 micromole per min), are provided below. Adjusted dose (mg) = Actual dose (mg) × Target AUC (micromole per min)/Actual AUC (micromole per min) For example, if a patient received a dose of 11 mg busulfan and if the corresponding AUC measured was 800 micromole per min, for a target AUC of 1125 micromole per min, the target mg dose would be: Mg dose =11 mg × 1125 micromole per min /800 micromole per min =15.5 mg BUSULFEX dose adjustment may be made using this formula and instructions below. Blood Sample Collection for AUC Determination Calculate the AUC (micromole per min) based on blood samples collected at the following time points: For dose 1:2 hour (end of infusion), 4 hour and 6 hour (immediately prior to the next scheduled BUSULFEX administration). Actual sampling times should be recorded.

For doses other than Dose 1: Pre-infusion (baseline), 2 hour (end of infusion), 4 hour and 6 hour (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 infinity Calculation: AUC infinity = AUC 0-6hr +AUC extrapolated, where AUC 0-6hr is to be estimated using the linear trapezoidal rule and AUC extrapolated can be computed by taking the ratio of the busulfan concentration at Hour 6 and the terminal elimination rate constant, λ z. The λ 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 ss (AUC 0-6hr ) is to be estimated from the trough, 2 hour, 4 hour and 6 hour concentrations using the linear trapezoidal rule. Instructions for Drug Administration and Blood Sample Collection for Therapeutic Drug Monitoring 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 hour), 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.

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

There is no known antidote to BUSULFEX other than hematopoietic progenitor cell transplantation. In the absence of hematopoietic progenitor cell transplantation, the recommended dosage for BUSULFEX 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.