BUSULFAN (Page 3 of 6)

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.
*
TRM = Transplantation Related Mortality
VOD = Veno-Occlusive Disease of the liver
GVHD = Graft versus Host Disease
Clift CML Chronic Phase
TRM * VOD GVHD 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

7 DRUG INTERACTIONS

7.1 Drugs that Decrease Busulfan Injection 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 Injection.

Decreased clearance of busulfan was observed with concomitant use with deferasirox. The mechanism of this interaction is not fully elucidated. Discontinue iron chelating agents well in advance of administration of Busulfan Injection to avoid increased exposure to busulfan.

Because busulfan is eliminated from the body via conjugation with glutathione, use of acetaminophen prior to (less than 72 hours) or concurrent with Busulfan Injection may result in reduced busulfan clearance based upon the known property of acetaminophen to decrease glutathione levels in the blood and tissues.

7.2 Drugs that Increase Busulfan Injection 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 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Busulfan Injection 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 Injection 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, 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 Injection dose on a mg/m2 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.

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