Busulfan (Page 2 of 6)

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:

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)]

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

Non-Hematological Adverse Reactions *

Percent Incidence

BODY AS A WHOLE

Fever

Headache

Asthenia

Chills

Pain

Edema General

Allergic Reaction

Chest Pain

Inflammation at Injection Site

Back Pain

80

69

51

46

44

28

26

26

25

23

CARDIOVASCULAR SYSTEM

Tachycardia

Hypertension

Thrombosis

Vasodilation

44

36

33

25

DIGESTIVE SYSTEM

Nausea

Stomatitis (Mucositis)

Vomiting

Anorexia

Diarrhea

Abdominal Pain

Dyspepsia

Constipation

Dry Mouth

Rectal Disorder

Abdominal Enlargement

98

97

95

85

84

72

44

38

26

25

23

METABOLIC AND NUTRITIONAL SYSTEM

Hypomagnesemia

Hyperglycemia

Hypokalemia

Hypocalcemia

Hyperbilirubinemia

Edema

SGPT Elevation

Creatinine Increased

77

66

64

49

49

36

31

21

NERVOUS SYSTEM

Insomnia

Anxiety

Dizziness

Depression

84

72

30

23

RESPIRATORY SYSTEM

Rhinitis

Lung Disorder

Cough

Epistaxis

Dyspnea

44

34

28

25

25

SKIN AND APPENDAGES

Rash

Pruritus

57

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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