BUSULFAN- busulfan injection

United States - English - NLM (National Library of Medicine)

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Active ingredient:
Busulfan (UNII: G1LN9045DK) (Busulfan - UNII:G1LN9045DK)
Available from:
Apotex Corp.
Administration route:
INTRAVENOUS
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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 injection is contraindicated in patients with a history of hypersensitivity to any of its components. Risk Summary Busulfan 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 busulfan dose on a mg/m2 basis given during organogenesis caused significant developmental anomalies [see Data ]. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, t
Product summary:
Busulfan injection is packaged as a sterile clean colorless solution in 10 mL single-use clear tubular USP type-I glass vial each containing 60 mg of Busulfan, USP at a concentration of 6 mg per mL for intravenous use, NDC 60505-6177-0. Busulfan injection is distributed as a unit carton of eight vials NDC 60505-6177-8. 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 is a cytotoxic drug. Follow applicable special handling and disposal procedures1 .
Authorization status:
Abbreviated New Drug Application
Authorization number:
60505-6177-0, 60505-6177-8

BUSULFAN- busulfan injection

Apotex Corp.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use BUSULFAN INJECTION safely and

effectively. See full prescribing information for BUSULFAN INJECTION.

BUSULFAN injection, for intravenous use

Initial U.S. Approval: 1999

WARNING: MYELOSUPPRESSION

See full prescribing information for complete boxed warning.

INDICATIONS AND USAGE

Busulfan Injection is an alkylating drug indicated for:

DOSAGE AND ADMINISTRATION

DOSAGE FORMS AND STRENGTHS

60 mg per 10 mL (6 mg per mL) single dose vial (3)

CONTRAINDICATIONS

Busulfan is contraindicated in patients with a history of hypersensitivity to any of its components (4)

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

Most common adverse reactions (incidence greater than 60%) were: myelosuppression, nausea, stomatitis, vomiting,

anorexia, diarrhea, insomnia, fever, hypomagnesemia, abdominal pain, anxiety, headache, hyperglycemia and hypokalemia

(6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-

1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Drugs that Decrease Busulfan Clearance: Metronidazole, itraconazole, iron chelating agents, acetaminophen. (7.1)

Drugs that Increase Busulfan Clearance: Phenytoin. (7.2)

Causes severe and prolonged myelosuppression. (5.1)

Hematopoietic progenitor cell transplantation is required to prevent potentially fatal complications

of the prolonged myelosuppression. (5.1)

Use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor

cell transplantation for chronic myelogenous leukemia (CML) (1)

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)

Seizures: Initiate anticonvulsant prophylactic therapy prior to treatment with busulfan. 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 mcMmin.

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)

USE IN SPECIFIC POPULATIONS

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 10/2018

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: MYELOSUPPRESSION

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Initial Dosing Information

2.2 Preparation and Administration Precautions

2.3 Preparation for Intravenous Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

5.2 Seizures

5.3 Hepatic Veno-Occlusive Disease (HVOD)

5.4 Embryo-fetal Toxicity

5.5 Cardiac Tamponade

5.6 Bronchopulmonary Dysplasia

5.7 Cellular Dysplasia

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

6.3 Oral Busulfan Literature Review

7 DRUG INTERACTIONS

7.1 Drugs that Decrease Busulfan Clearance

7.2 Drugs that Increase Busulfan Clearance

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage and Handling

17 PATIENT COUNSELING INFORMATION

Lactation: Discontinue breastfeeding (8.2)

FULL PRESCRIBING INFORMATION

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

Sections or subsections omitted from the full prescribing information are not listed.

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

dose of busulfan (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 dosing on adjusted ideal body weight

(AIBW):

2.2 Preparation and Administration Precautions

Busulfax injection is incompatible with polycarbonate. Do not use any infusion components (syringes,

filter needles, intravenous tubing, etc.) containing polycarbonate with busulfex 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, 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:

To prepare the final solution for infusion, add 9.3 mL of Busulfan to 93 mL of diluent (normal saline or

D5W) as calculated below:

(9.3 mL Busulfan) x (10) =93 mL of either diluent plus the 9.3 mL of Busulfan 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, 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.

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, USP 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.

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

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

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

The most frequent serious consequence of treatment with busulfan 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

0.5x10 /L at a median of 4 days post-transplant in 100% of patients treated in the busulfan 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/mm or requiring platelet transfusion) occurred at a median of 5-6 days in 98% of patients.

Anemia (hemoglobin less than 8.0 g/dL) occurred in 69% of patients. Use antibiotic therapy and platelet

and red blood cell support when medically indicated.

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. Despite

prophylactic therapy with phenytoin, one seizure (1/42 patients) was reported during an autologous

transplantation clinical trial of busulfan. This episode occurred during the cyclophosphamide portion of

the conditioning regimen, 36 hours after the last busulfan dose. Initiate phenytoin therapy or any other

alternative anti-convulsant prophylactic therapy (e.g., benzodiazepines, valproic acid or levetiracetam)

prior to busulfan treatment [see Dosage and Administration (2.1)]. Use caution when administering the

recommended dose of busulfan 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 mcMmin) 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 dose and regimen. Based on clinical examination and laboratory

findings, HVOD was diagnosed in 8% (5/61) of patients treated with busulfan 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 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 [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 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 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 maintained an AUC less than 1,500 mcMmin 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 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 Prior to Allogeneic Hematopoietic Progenitor

Cell Transplantation

Non-Hematological Adverse Reactions

Percent Incidence

BODY AS A WHOLE

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)]

CARDIOVASCULAR SYSTEM

DIGESTIVE SYSTEM

Fever

Headache

Asthenia

Chills

Pain

Edema General

Allergic Reaction

Chest Pain

Inflammation at Injection Site

Back Pain

Tachycardia

Hypertension

Thrombosis

Vasodilation

Nausea

Stomatitis (Mucositis)

Vomiting

METABOLIC AND NUTRITIONAL SYSTEM

NERVOUS SYSTEM

Anorexia

Diarrhea

Abdominal Pain

Dyspepsia

Constipation

Dry Mouth

Rectal Disorder

Abdominal Enlargement

Hypomagnesemia

Hyperglycemia

Hypokalemia

Hypocalcemia

Hyperbilirubinemia

Edema

SGPT Elevation

Creatinine Increased

RESPIRATORY SYSTEM

SKIN AND APPENDAGES

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

Includes all reported adverse reactions regardless of severity (toxicity grades 1-4 )

Insomnia

Anxiety

Dizziness

Depression

Rhinitis

Lung Disorder

Cough

Epistaxis

Dyspnea

Rash

Pruritus

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

6.2 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 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.

6.3 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).

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

GVHD

Pulmonary

Hemorrhagic

Seizure

Cystitis

Death

No Report

Acute≥Grade 2

1 death from

No Report

No Report

≤100d

=35%

Idiopathic

=4.1%

Chronic=41%

Interstitial

(3/73)

(30/73)

Pneumonitis

1 death from

Pulmonary

Fibrosis

Devergie

CML Chronic Phase

GVHD

Pulmonary

Hemorrhagic

Seizure

Cystitis

7.7% (5/65)

Acute≥Grade 2

Interstitial

10.8% (7/65)

No Report

Deaths=4.6%

=41%

Pneumonitis=

(3/65)

(24/59 at risk)

16.9% (11/65)

Ringden

CML, AML, ALL

GVHD

Pulmonary

Hemorrhagic

Seizure

Cystitis

Acute≥Grade 2

Interstitial

GVHD=26%

Pneumonitis

Chronic GVHD

=14%

=45%

Blume

CML, AML, ALL

GVHD

Pulmonary

Hemorrhagic

Seizure

Cystitis

Report

Deaths

Acute≥Grade 2

No Report

No Report

No Report

=4.9%

GVHD=22%

(13/58 at risk)

Chronic GVHD

=31%

(14/45 at risk)

7 DRUG INTERACTIONS

7.1 Drugs that Decrease Busulfan 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 busulfan.

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 may result in reduced busulfan clearance based

upon the known property of acetaminophen to decrease glutathione levels in the blood and tissues.

7.2 Drugs that Increase Busulfan Clearance

Phenytoin increases the clearance of busulfan by 15% or more, possibly due to the induction of

glutathione-S-transferase. Since the pharmacokinetics of busulfan were studied in patients treated with

phenytoin, the clearance of busulfan at the recommended dose may be lower and exposure (AUC)

higher in patients not treated with phenytoin.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

TRM = Transplantation Related Mortality

VOD = Veno-Occlusive Disease of the liver

GVHD = Graft versus Host Disease

Risk Summary

Busulfan 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 busulfan dose on a mg/m 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.

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 busulfan dose on a mg/m

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.

8.2 Lactation

Risk Summary

It is not known whether busulfan is present in human milk. Because many drugs are excreted in human

milk and because of the potential for tumorigenicity shown for busulfan in human and animal studies,

discontinue breastfeeding during treatment with busulfan.

8.3 Females and Males of Reproductive Potential

Contraception

Females

Busulfan can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations

(8.1)]. Advise females of reproductive potential to use effective contraception during treatment with

busulfan and for 6 months following cessation of therapy.

Males

Busulfan may damage spermatozoa and testicular tissue, resulting in possible genetic fetal

abnormalities. Males with female sexual partners of reproductive potential should use effective

contraception during treatment with busulfan and for 3 months after cessation of therapy [see Nonclinical

Toxicology (13.1)].

Infertility

Females

Ovarian suppression and amenorrhea commonly occur in premenopausal women undergoing chronic,

low-dose busulfan therapy for chronic myelogenous leukemia. Busulfan may cause temporary or

permanent infertility in prepubertal girls or in females of child-bearing potential treated with high-dose

busulfan in the conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation.

Males

Sterility, azoospermia, and testicular atrophy have been reported in male patients.

8.4 Pediatric Use

The effectiveness of busulfan in the treatment of CML has not been specifically studied in pediatric

patients. An open-label, uncontrolled study evaluated the pharmacokinetics of busulfan in 24 pediatric

patients receiving busulfan 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 dosing was targeted

to achieve an area under the plasma concentration curve (AUC) of 900 to 1350 mcMmin 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 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% mcMmin) for busulfan was achieved at dose 1 in 71% (17/24) of

patients. Steady state pharmacokinetic testing was performed at dose 9 and 13. Busulfan levels were

within the target range for 21 of 23 evaluable patients.

All 24 patients experienced neutropenia (absolute neutrophil count (ANC) less than 0.5x10 /L) and

thrombocytopenia (platelet transfusions or platelet count less than 20,000/mm ). Seventy-nine percent

(19/24) of patients experienced lymphopenia (absolute lymphocyte count less than 0.1x10 ). In 23

patients, the ANC recovered to greater than 0.5x10 /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 >0.5x10 /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 in pediatric

patients is shown in the following dosing nomogram:

Busulfan Dosing Nomogram

Patient’s Actual

Body Weight (ABW)

Busulfan 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 busulfan exposure (AUC) between 900 to 1350 mcMmin with

the first dose of busulfan using this dosing nomogram. Therapeutic drug monitoring and dose adjustment

following the first dose of busulfan 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 mcMmin), are provided below.

Adjusted dose (mg) = Actual Dose (mg) x Target AUC (mcMmin)/Actual AUC (mcMmin)

For example, if a patient received a dose of 11 mg busulfan and if the corresponding AUC measured

was 800 mcMmin, for a target AUC of 1125 mcMmin, the target mg dose would be:

9

Mg dose =11 mg x 1125 mcMmin /800 mcMmin =15.5 mg

Busulfan injection dose adjustment may be made using this formula and instructions below.

Blood Sample Collection for AUC Determination

Calculate the AUC (mcMmin) based on blood samples collected at the following time points:

For dose 1:2 hr (end of infusion), 4 hr and 6 hr (immediately prior to the next scheduled busulfan

administration). Actual sampling times should be recorded.

For doses other than dose 1: Pre-infusion (baseline), 2 hr (end of infusion), 4 hr and 6 hr (immediately

prior to the next scheduled busulfan 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

Busulfan AUC calculations may be made using the following instructions and appropriate standard

pharmacokinetic formula:

If the AUC is assessed subsequent to Dose 1, steady-state AUC (AUC

) is to be estimated from

the trough, 2 hr, 4 hr and 6 hr 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 busulfan injection infusion. Collect the blood sample from a peripheral IV line to avoid contamination

with infusing drug. If the blood sample is taken directly from the existing central venous catheter

(CVC), DO NOT COLLECT THE BLOOD SAMPLE WHILE THE DRUG IS INFUSING to

ensure that the end of infusion sample is not contaminated with any residual drug. At the end of infusion

(2 hr), disconnect the administration tubing and flush the CVC line with 5 mL of normal saline prior to

the collection of the end of infusion sample from the CVC port. Collect the blood samples from a

different port than that used for the busulfan injection infusion. When recording the busulfan injection

infusion stop time, do not include the time required to flush the indwelling catheter line. Discard the

administration tubing at the end of the two-hour infusion [see Dosage and Administration (2.3)].

8.5 Geriatric Use

Clinical studies of busulfan did not include sufficient numbers of subjects aged 65 and over to

determine whether they respond differently from younger subjects.

Dose 1 AUC

Calculation: AUC

= AUC

+AUC

, where AUC

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 . The λ

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.

infinity

infinity

0-6hr

e xtrapolate d

0-6hr

0-6hr

10 OVERDOSAGE

There is no known antidote to busulfan other than hematopoietic progenitor cell transplantation. In the

absence of hematopoietic progenitor cell transplantation, the recommended dosage for busulfan 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.

11 DESCRIPTION

Busulfan is a bifunctional alkylating agent known chemically as Butane-1, 4-diyl dimethanesulfonate.

Busulfan Injection is intended for intravenous administration. It is supplied as a clear, colorless, sterile,

solution in 10 mL single dose vials. Each vial of Busulfan Injection contains 60 mg (6 mg/mL) of

busulfan, USP the active ingredient, a white crystalline powder with a molecular formula of C H O S

and a molecular weight of 246.30 g/mole. Busulfan has the following chemical structure:

Busulfan is dissolved 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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.3 Pharmacokinetics

The pharmacokinetics of busulfan were studied in 59 patients participating in a prospective trial of a

busulfan-cyclophosphamide preparatory regimen prior to allogeneic hematopoietic progenitor stem

cell transplantation. Patients received 0.8 mg/kg busulfan every six hours, for a total of 16 doses over

four days. Fifty-five of fifty-nine patients (93%) administered busulfan maintained AUC values below

the target value (less than1500 mcMmin).

Table 3: Steady State Pharmacokinetic Parameters Following Busulfan Infusion (0.8 mg per kg;

N=59)

Mean

CV (%)

Range

(ng per mL)

1222

496-1684

AUC (mcMmin)

1167

556-1673

CL (mL per min per kg)

2.52

1.49-4.31

Busulfan pharmacokinetics showed consistency between dose 9 and dose 13 as demonstrated by

reproducibility of steady state C

and a low coefficient of variation for this parameter.

Distribution: Busulfan achieves concentrations in the cerebrospinal fluid approximately equal to those in

plasma. Busulfan primarily binds to albumin (Mean ± standard deviation=32.4 ± 2.2%).

Metabolism: Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously

and by glutathione S-transferase (GST) catalysis. This conjugate undergoes extensive oxidative

metabolism in the liver.

Excretion: Following administration of

C-labeled busulfan to humans, approximately 30% of the

radioactivity was excreted into the urine over 48 hours; negligible amounts were recovered in feces.

Specific Populations

Pediatric Patients: In a pharmacokinetic study of busulfan in 24 pediatric patients, the population

pharmacokinetic (PPK) estimates of busulfan for clearance (CL) and volume of distribution (V) were

determined. For actual body weight, PPK estimates of CL and V were 4.04 L/hr per 20 kg (3.37 mL per

min per kg; interpatient variability 23%); and 12.8 L per 20 kg (0.64 L per kg; interpatient variability

11%).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 dose on a mg/m

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 on a

mg/m basis) significantly decreased spermatogenesis in rats. A single subcutaneous dose of 2.2 g/kg

(27% of the total DMA dose contained in busulfan on a mg/m basis) four days after insemination

terminated pregnancy in 100% of tested hamsters [see Use in Specific Populations (8.3)].

14 CLINICAL STUDIES

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 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

Clearance normalized to actual body weight for all patients.

component of a conditioning regimen for transplantation, which were identified in a literature review of

five established commercial databases.

Prospective Clinical Trial of Busulfan: The prospective trial was a single-arm, open-label study in 61

patients who received busulfan as part of a conditioning regimen for allogeneic hematopoietic stem cell

transplantation. The study included patients with acute leukemia past first remission (first or subsequent

relapse), with high-risk first remission, or with induction failure; chronic myelogenous leukemia (CML)

in chronic phase, accelerated phase, or blast crisis; primary refractory or resistant relapsed Hodgkin’s

disease or non-Hodgkin’s lymphoma; and myelodysplastic syndrome. Forty-eight percent of patients

(29/61) were heavily pretreated, defined as having at least one of the following: prior radiation, greater

than or equal to 3 prior chemotherapeutic regimens, or prior hematopoietic stem cell transplant.

Seventy-five percent of patients (46/61) were transplanted with active disease.

Patients received 16 busulfan doses of 0.8 mg per kg every 6 hours as a two-hour infusion for 4 days,

followed by cyclophosphamide 60 mg per kg once per day for two days (BuCy2 regimen). All patients

received 100% of their scheduled busulfan regimen. No dose adjustments were made. After one rest

day, allogeneic hematopoietic progenitor cells were infused. The efficacy parameters in this study

were myeloablation (defined as one or more of the following: absolute neutrophil count [ANC] less

than 0.5x10 /L, absolute lymphocyte count [ALC] less than 0.1x10 /L, thrombocytopenia defined as a

platelet count less than 20,000/mm or a platelet transfusion requirement) and engraftment (ANC greater

than or equal to 0.5x10 /L).

All patients (61/61) experienced myeloablation. The median time to neutropenia was 4 days. All

evaluable patients (60/60) engrafted at a median of 13 days post-transplant (range 9 to 29 days); one

patient was considered non-evaluable because he died of a fungal pneumonia 20 days after BMT and

before engraftment occurred. All but 13 of the patients were treated with prophylactic G-CSF. Evidence

of donor cell engraftment and chimerism was documented in all patients who had a chromosomal sex

marker or leukemic marker (43/43), and no patient with chimeric evidence of allogeneic engraftment

suffered a later loss of the allogeneic graft. There were no reports of graft failure in the overall study

population. The median number of platelet transfusions per patient was 6, and the median number of red

blood cell transfusions per patient was 4.

Twenty-three patients (38%) relapsed at a median of 183 days post-transplant (range 36 to 406 days).

Sixty-two percent of patients (38/61) were free from disease with a median follow-up of 269 days post-

transplant (range 20 to 583 days). Forty-three patients (70%) were alive with a median follow up of 288

days post-transplant (range 51 to 583 days). There were two deaths before BMT Day +28 and six

additional patients died by BMT Day +100. Ten patients (16%) died after BMT Day +100, at a median

of 199 days post-transplant (range 113 to 275 days).

Oral Busulfan Literature Review: Four publications of randomized, controlled trials that evaluated a

high-dose oral busulfan-containing conditioning regimen (busulfan 4 mg/kg/d x4 days +

cyclophosphamide 60 mg/kg/d x2 days) for allogeneic transplantation in the setting of CML were

identified. Two of the studies (Clift and Devergie) had populations confined to CML in chronic phase

that were randomized between conditioning with busulfan/cyclophosphamide (BU/CY) and

cyclophosphamide/total body irradiation (CY/TBI). A total of 138 patients were treated with BU/CY in

these studies. The populations of the two remaining studies (Ringden and Blume) included patients with

CML, acute lymphoblastic leukemia (ALL), and acute myelogenous leukemia (AML). In the Nordic

BMT Group study published by Ringden, et al., 57 patients had CML, and of those, 30 were treated with

BU/CY. Patients with CML in chronic phase, accelerated phase, and blast crisis were eligible for this

study. The participants with CML (34/122 patients) in a SWOG study published by Blume, et al., had

disease beyond first chronic phase. Twenty of those CML patients were treated with BU/CY, and the

TBI comparator arm utilized etoposide instead of cyclophosphamide.

Table 4 summarizes the efficacy analyses reported from these 4 studies.

Table 4: Summary of efficacy analyses from the randomized, controlled trials utilizing a high

dose oral busulfan-containing conditioning regimen identified in a literature review.

Clift, 1994

CML Chronic Phase;

3 year Overall

3 year DFS

Relapse

Time to Engraftment

Survival

(p=0.43)

(ANC greater than or

equal to 500)

BU/CY

CY/TBI

BU/CY

CY/TBI

BU/CY

CY/TBI

BU/CY

CY/TBI

22.6 days

22.3 days

Devergie, 1995

CML Chronic Phase;

5 year Overall Survival

5 year DFS (p=0.75)

Relapse (Relative Risk

analysis

Time to Engraftment

(ANC greater than or

equal to 500)

(p=0.5)

BU/CY:CY/TBI)

(p=0.04)

BU/CY

CY/TBI

BU/CY

CY/TBI

BU/CY

CY/TBI

BU/CY

CY/TBI

60.6%

65.8%

59.1%

51.0%

4.10

None

None

±11.7%

±12.5%

±11.8%

±14%

(95%CI =1.00 - 20.28)

Given

Given

Ringden, 1994

CML, AML, ALL;

3 year Overall

3 year Relapse Free

Relapse

Time to Engraftment

Survival

Survival

(p=0.9)

(ANC greater than 500)

(p<0.03)

(p=0.065)

BU/CY

CY/TBI

BU/CY

CY/TBI

BU/CY

CY/TBI

BU/CY

CY/TBI

20 days

20 days

Blume, 1993

CML, AML, ALL; Relative Risk Analysis BU/CY: Etoposide/TBI

RR of Mortality

RR of Relapse

Time to Engraftment

(Relative Risk analysis

BU/CY:Eto/TBI)

BU/CY

Eto/TBI

BU/CY

Eto/TBI

BU/CY

Eto/TBI

BU/CY

Eto/TBI

0.97

Not Given

1.02

Not Given

(95% CI=0.64-1.48)

(95% CI=0.56-1.86)

BU = Busulfan

CY = Cyclophosphamide

TBI = Total Body Irradiation

DFS = Disease Free Survival

ANC = Absolute Neutrophil Count

15 REFERENCES

1. OSHA Hazardous Drugs. OSHA. [Accessed on June 18, 2014 from

http://www.osha.gov/SLTC/hazardousdrugs/index.html]

Eto = etoposide. TBI was combined with etoposide in the comparator arm of this study.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Busulfan injection is packaged as a sterile clean colorless solution in 10 mL single-use clear tubular

USP type-I glass vial each containing 60 mg of Busulfan, USP at a concentration of 6 mg per mL for

intravenous use, NDC 60505-6177-0.

Busulfan injection is distributed as a unit carton of eight vials NDC 60505-6177-8.

16.2 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 is a cytotoxic drug. Follow applicable special handling and disposal procedures .

17 PATIENT COUNSELING INFORMATION

Myelos uppres s ion

Advise 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 [see Warnings and Precautions (5.1)].

Seizures

Advise patients of the possibility of seizures and that they will be given medication to prevent them.

Patients should be asked to report a history of seizure or head trauma [see Warnings and Precautions

(5.2)].

Hepatic Veno-Occlusive Disease (HVOD)

Advise 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)].

Embryo-fetal Toxicity

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)].

Females of Reproductive Potential

Advise females of reproductive potential to use effective contraception during treatment with

busulfan injection and for 6 months following cessation of therapy [see Use in Specific Populations

(8.3)].

Males of Reproductive Potential

Advise males with female sexual partners of reproductive potential to use effective contraception

during treatment with busulfan injection and for 3 months following cessation of therapy [see Use in

Specific Populations (8.3)].

Lactation

Advise females to discontinue breastfeeding during treatment with busulfan injection [see Use in Specific

Populations (8.2)].

Infertility

Advise females and males of reproductive potential that busulfan may cause temporary or permanent

infertility [see Use in Specific Populations (8.3)].

Cardiac Tamponade

Advise patients of the risk of cardiac tamponade. Instruct patients to report to their healthcare provider

symptoms of abdominal pain and vomiting [see Warnings and Precautions (5.5)].

Bronchopulmonary Dysplasia

Advise patients of the possibility of bronchopulmonary dysplasia with pulmonary fibrosis with chronic

busulfan therapy. Instruct patients to report symptoms of shortness of breath and cough to their

healthcare provider. These symptoms could occur several months or years after therapy with busulfan

[see Warnings and Precautions (5.6)].

Manufactured by:

Manufactured for:

MSN Laboratories Private Limited, Nandigama, Telangana 509216, IndiaApotex Corp.

M.L.No.: 5/MN/TS/2014/F/G

Weston, Florida 33326

Revised: October 2018

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

R only

NDC 60505-6177-0

Busulfan Injection

60 mg/10 mL (6 mg/mL)

For Intravenous Infusion Only

Caution: Must be diluted before use.

CYTOTOXIC AGENT

1 X 10 mL Single-Dose Vial

APOTEX CORP.

x

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

Rx only

NDC 60505-6177-0

Busulfan Injection

60 mg/10 mL (6 mg/mL)

For Intravenous Infusion Only

Caution: Must be diluted before use.

CYTOTOXIC AGENT

1 X 10 mL Single-Dose Vial

Apotex Corp.

1 X 10 mL Single-Dose Vial

APOTEX CORP.

BUSULFAN

busulfan injection

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 0 50 5-6 177

Route of Administration

INTRAVENOUS

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

Busulfa n (UNII: G1LN9 0 45DK) (Busulfan - UNII:G1LN9 0 45DK)

Busulfa n

6 mg in 1 mL

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:6 0 50 5-6 177-

8 in 1 CARTON

0 8 /19 /20 19

1

NDC:6 0 50 5-6 177-

10 mL in 1 VIAL, SINGLE-DOSE; Type 0 : No t a Co mbinatio n

Pro duc t

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA210 448

0 8 /19 /20 19

Labeler -

Apotex Corp. (845263701)

Revised: 8/2019

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