N/A: Package Insert and Label Information

N/A- busulfan injection
American Regent, Inc.

WARNING: MYELOSUPPRESSION

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 )].

1 INDICATIONS AND USAGE

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.

2 DOSAGE AND ADMINISTRATION

2.1 Initial Dosing Information

  • 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:

o 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).

o Cyclophosphamide 60 mg per kg intravenously as a one-hour infusion on each of two days beginning no sooner than six hours following the 16th dose of busulfan injection(Days -3 and -2).

o 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.

o 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)

o For obese or severely obese patients, base busulfan injection dosing on adjusted ideal body weight (AIBW):

AIBW = IBW + 0.25 x (actual weight -- IBW).

2.2 Preparation and Administration Precautions

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.

2.3 Preparation for Intravenous Administration

Busulfan injection must be diluted prior to intravenous infusion with either 0.9% Sodium Chloride Injection (normal saline) or 5% Dextrose Injection (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 mLbusulfan 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.

DO NOT put the busulfan injection into an intravenous bag or large-volume syringe that does not contain normal saline or D5W. Always add the busulfan injection to the diluent, not the diluent to the busulfan injection. Mix thoroughly by inverting several times.

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 or 5% Dextrose Injection. 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.

3 DOSAGE FORMS AND STRENGTHS

Busulfan Injection is supplied as a clear, colorless, sterile, solution in 10 mL single-dose vial containing 60 mg of busulfan at a concentration of 6 mg per mL for intravenous use only.

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

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.

5.2 Seizures

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.

5.3 Hepatic Veno-Occlusive Disease (HVOD)

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.

5.4 Embryo-fetal Toxicity

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 withbusulfan injection [see Use in Specific Populations (8.1, 8.3)].

5.5 Cardiac Tamponade

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.

5.6 Bronchopulmonary Dysplasia

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).

5.7 Cellular Dysplasia

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.

6 ADVERSE REACTIONS

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

6.1 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 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.

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 Busulfan Injection Prior to Allogeneic Hematopoietic Progenitor Cell Transplantation
*
Includes all reported adverse reactions regardless of severity (toxicity grades 1-4)

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

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

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