"The U.S. Food and Drug Administration today approved Gazyva (obinutuzumab) for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).
CLL is a blood and bone ma"...
The following adverse reactions are discussed in more detail in other sections of the labeling:
- Myelosuppression [see WARNINGS AND PRECAUTIONS]
- Seizures [see WARNINGS AND PRECAUTIONS]
- HVOD [see WARNINGS AND PRECAUTIONS]
- Embryo-fetal Toxicity [see WARNINGS AND PRECAUTIONS]
- Cardiac Tamponade [see WARNINGS AND PRECAUTIONS]
- Bronchopulmonary Dysplasia [see WARNINGS AND PRECAUTIONS]
- Cellular Dysplasia [see WARNINGS AND PRECAUTIONS]
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 BUSULFEX and the data obtained for high-dose oral busulfan conditioning in the setting of randomized, controlled trials identified through a literature review.
In the BUSULFEX (busulfan) Injection allogeneic stem cell transplantation clinical trial, all patients were treated with BUSULFEX 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 BUSULFEX 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 BUSULFEX 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 BUSULFEX Prior to Allogeneic Hematopoietic Progenitor
|Non-Hematological Adverse Reactions1||Percent Incidence|
|BODY AS A WHOLE|
|Inflammation at Injection Site||25|
|METABOLIC AND NUTRITIONAL SYSTEM|
|SKIN AND APPENDAGES|
|1 Includes all reported adverse reactions regardless of severity (toxicity grades 1-4)]|
Additional Adverse Reactions by Body System
Hematologic: Prolonged prothrombin time
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)
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure. The following adverse reactions (reported as MedRA terms) have been identified during post-approval use of BUSULFEX (busulfan) Injection:
Metabolism and Nutrition Disorders: tumor lysis syndrome
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]. 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 busulfancontaining
conditioning regimen that were identified in a literature review.
|Clift CML Chronic Phase|
|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|
|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|
|28%||12%||Acute≥Grade 2 GVHD=26% Chronic GVHD =45%||Interstitial Pneumonitis =14%||24%||6%|
|Blume CML, AML, ALL|
|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|
|1 TRM = Transplantation Related Mortality
2 VOD = Veno-Occlusive Disease of the liver
3GVHD = Graft versus Host Disease
Read the Busulfex (busulfan) Side Effects Center for a complete guide to possible side effects
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 BUSULFEX.
Phenytoin increases the clearance of busulfan by 15% or more, possibly due to the induction of glutathione-S-transferase. Since the pharmacokinetics of BUSULFEX were studied in patients treated with phenytoin, the clearance of BUSULFEX 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 BUSULFEX may result in reduced busulfan clearance based upon the known property of acetaminophen to decrease glutathione levels in the blood and tissues.
Read the Busulfex Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 1/28/2015
This monograph has been modified to include the generic and brand name in many instances.
Additional Busulfex Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.