Busulfan Injection

• It is used before bone marrow or stem cell transplant.
• It may be given to you for other reasons. Talk with the doctor.

• If you have an allergy to busulfan or any other part of busulfan injection.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are breast-feeding or plan to breast-feed.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

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:

      -   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 16th 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+0.91x (height in cm -152)

               Women: IBW (kg)=45+0.91x (height in cm -152)

        - For obese or severely obese patients, base Busulfan Injection dosing on adjusted ideal body weight (AIBW):

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

Preparation and Administration Precautions

DO NOT USE POLYCARBONATE SYRINGES OR POLYCARBONATE FILTER NEEDLES WITH Busulfan Injection.

Use an administration set with minimal residual hold-up volume (2-5 cc) 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.

Preparation for Intravenous Administration

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) × (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) × (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 ×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 5mL 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.

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

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)]
• 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)]

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 x2 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 BMT Day +28 at a rate greater than or equal to 20% in patients treated with Busulfan Injection prior to allogeneic hematopoietic cell transplantation.

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

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 (reported as MedRA terms) 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.

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 [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).

1TRM = Transplantation Related Mortality
2VOD = Veno-Occlusive Disease of the liver
3GVHD = Graft versus Host Disease

Itraconazole decreases busulfan clearance by up to 25%, and may produce an AUC greater than 1500 μM•min in some patients. Fluconazole (200 mg) has been used with Busulfan Injection.

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.

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.

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.

How Supplied

Busulfan Injection is packaged as a sterile solution in 10 mL single-use clear glass vials each containing 60 mg of busulfan at a concentration of 6 mg per mL for intravenous use. NDC 51817-170-01

Busulfan Injection is distributed as a unit carton of eight vials.  NDC 51817-170-01

Storage and Handling

Unopened vials of Busulfan Injection must be stored under refrigerated conditions between 2°C to 8°C (36°F to 46°F).

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 procedures1.

   Inform patients of the possibility of developing low blood cell counts and the need for hematopoietic progenitor cell infusion. Instruct patients to immediately report to their healthcare provider if fever develops [seeWarnings and Precautions (5.1)].

   Inform patients of the risks associated with the use of Busulfan Injection as well as the plan for regular blood monitoring during therapy. Specifically inform patients of the following: The risk of veno-occlusive liver disease [see Warnings and Precautions (5.3)].

   Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions (5.4)and Use in Specific Populations (8.1)].

   Advise females and males of reproductive potential to use effective contraception during and after treatment with Busulfan Injection [see Use in Specific Populations (8.3)]

   Advise females to discontinue breastfeeding during treatment with Busulfan Injection [see Use in Specific Populations (8.2)].

   Advise females and males of reproductive potential that Busulfan Injection may cause temporary or permanent infertility [see Use in Specific Populations (8.3)].

Manufactured by:

Pharmascience Inc.
Candiac, Quebec
Canada J5R 1J1

Pharmascience Inc. Material code 30324-02