A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Myleran Side Effects, and Drug Interactions - Busulfan
Myleran Side Effects, and Drug Interactions - Busulfan
SIDE EFFECTS
Dimethylacetamide (DMA), the solvent
used in the BUSULFEX formulation, was studied in 1962 as a potential
cancer chemotherapy
drug. In a Phase 1, trial the maximum
tolerated dose (MTD) was 14.8
g/m 2 /d for four days. The daily recommended dose
of BUSULFEX contains DMA equivalent to 42% of the MTD on a mg/m 2
basis. The dose-limiting toxicities in the Phase 1 study were hepatotoxicity
as evidenced by increased liver transaminase (SGOT) levels and neurological
symptoms as evidenced by hallucinations. The hallucinations had a pattern
of onset at one day post completion
of DMA administration
and were associated with EEG changes.
The lowest dose at which hallucinations were recognized was equivalent
to 1.9 times that delivered in a conditioning
regimen utilizing BUSULFEX
0.8 mg/kg every 6 hours x 16 doses. Other neurological toxicities included
somnolence, lethargy, and confusion. The relative contribution of DMA
and/or other concomitant medications to neurologic and hepatic
toxicities observed with BUSULFEX is difficult to ascertain.
Treatment with BUSULFEX at the recommended dose
and schedule will
result in profound myelosuppression
in 100% of patients, including granulocytopenia, thrombocytopenia, anemia,
or a combined loss of formed
elements of the blood.
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.
BUSULFEX Clinical Trials.
In the BUSULFEX allogeneic
stem cell
transplantation clinical
trial, all patients were treated with BUSULFEX 0.8 mg/kg as a two-hour
infusion every six hours for 16 doses over four days, combined with cyclophosphamide
60 mg/kg x 2 days. Ninety three percent
(93%) of evaluable patients receiving this dose
of BUSULFEX maintained A.C. less
than 1,500 mMCmin for dose 9,
which has generally been considered the level that minimizes the risk
of VOD.
Table 3:
Summary of the Incidence (>20%) of Non-Hematologic Adverse Events
through BMT Day +28 in Patients
who Received BUSULFEX Prior to Allogeneic Hematopoietic Progenitor Cell
Transplantation
|
NON-HEMATOLOGICAL
ADVERSE EVENTS*
|
PERCENT
INCIDENCE
|
| BODY
AS A WHOLE |
|
| Fever |
80
|
| Headache |
69
|
| Asthenia |
51
|
| Chills |
46
|
| Pain |
44
|
| Edema
General |
28
|
| Allergic
Reaction |
26
|
| Chest
Pain |
26
|
| Inflammation
at Inj Site |
25
|
| Pain
Back |
23
|
| CARDIOVASCULAR
SYSTEM |
|
| Tachycardia
|
44
|
| Thrombosis
|
33
|
| Hypertension
|
36
|
| Vasodilation
|
25
|
| DIGESTIVE
SYSTEM |
|
| Nausea
|
98
|
| Stomatitis
(Mucositis) |
97
|
| Vomiting
|
95
|
| Anorexia
|
85
|
| Diarrhea
|
84
|
| Abdominal
Pain |
72
|
| Dyspepsia
|
44
|
| Constipation
|
38
|
| Dry
Mouth |
26
|
| Rectal
Disorder |
25
|
| Abdominal
Enlargement |
23
|
| METABOLIC
AND NUTRITIONAL SYSTEM |
|
| Hypomagnesemia
|
77
|
| Hypokalemia
|
64
|
| Hyperglycemia
|
66
|
| Hypocalcemia
|
49
|
| Hyperbilirubinemia
|
49
|
| Edema
|
36
|
| SGPT
Elevation |
31
|
| Creatinine
Increased |
21
|
| NERVOUS
SYSTEM |
|
| Insomnia
|
84
|
| Anxiety
|
72
|
| Dizziness
|
30
|
| Depression
|
23
|
| RESPIRATORY
SYSTEM |
|
| Rhinitis
|
44
|
| Lung
Disorder |
34
|
| Cough
|
28
|
| Epistaxis
|
25
|
| Dyspnea
|
25
|
| SKIN
AND APPENDAGES |
|
| Rash
|
57
|
| Pruritus
|
28
|
* All reported adverse events regardless of severity
(toxicity grades 1-4)
The following sections describe clinically significant
events occurring in the BUSULFEX clinical
trials, regardless of drug attribution.
Hematologic: At the indicated dose
and schedule, BUSULFEX produced profound myelosuppression
in 100% of patients. Following hematopoietic progenitor cell
infusion, recovery
of neutrophil counts to
³500 cells/mm 3 occurred at
median day 13 when prophylactic
G-CSF was adminstered to the majority of participants on the study. The
median number of platelet
transfusions per patient
on study was 6, and the median number of red
blood cell
transfusions on study was 4. Prolonged prothrombin time was reported in
one patient (2%).
Gastrointestinal: Gastrointestinal toxicities were frequent and
generally considered to be related to the drug. Few were categorized as
serious. Mild or moderate nausea
occurred in 92% of patients in the allogeneic clinical trial, and mild
or moderate vomiting in occurred
in 95% through BMT day 28; nausea
was severe in 7%. The incidence
of vomiting during BUSULFEX
administration (BMT Day –7 to –4) was 43% in the allogeneic
clinical trial. Grade 3-4
stomatitis developed in
26% of the participants, and grade
3 esophagitis developed in 2%. Grade 3- 4 diarrhea
was reported in 5% of the allogeneic
study participants, while mild or moderate diarrhea
occurred in 75%. Mild or moderate constipation
occurred in 38% of patients; ileus developed in 8% and was severe in 2%.
Forty-four percent (44%) of
patients reported mild or moderate dyspepsia. Two percent
(2%) of patients experienced mild hematemesis. Pancreatitis developed
in 2% of patients. Mild or moderate rectal discomfort occurred in 24%
of patients. Severe anorexia
occurred in 21% of patients and was mild/moderate in 64%.
Hepatic: Hyperbilirubinemia occurred in 49% of patients in the
allogeneic BMT trial. Grade 3/4
hyperbilirubinemia
occurred in 30% of patients within 28 days of transplantation
and was considered life-threatening in 5% of these patients. Hyperbilirubinemia
was associated with graft-versus-host disease in six patients and with
veno-occlusive disease
in 5 patients. Grade 3/4 SGPT
elevations occurred in 7% of patients. Alkaline phosphatase increases
were mild or moderate in 15% of patients. Mild or moderate jaundice developed
in 12% of patients, and mild or moderate hepatomegaly
developed in 6%.
Hepatic veno-occlusive disease: Hepatic veno-occlusive disease (HVOD)
is a recognized potential complication of conditioning therapy prior to transplant.
Based on clinical examination and laboratory findings, hepatic veno-occlusive
disease was diagnosed in 8% (5/61) of patients treated with BUSULFEX 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.
Graft-versus-host disease: Graft-versus-host disease
developed in 18% of patients (11/61) receiving allogeneic
transplants; it was severe in 3%, and mild or moderate in 15%. There were
3 deaths (5%) attributed to GVHD.
Edema: Patients receiving allogeneic transplant exhibited some form
of edema (79%), hypervolemia, or documented weight increase (8%); all events
were reported as mild or moderate.
Infection/Fever: Fifty-one percent
of patients experienced one or more episodes of infection. Pneumonia was
fatal in one patient
(2%) and life-threatening in 3% of patients. Fever was reported in 80%
of patients; it was mild or moderate in 78% and severe in 3%. Forty-six
percent (46%) of patients
experienced chills.
Cardiovascular: Mild or moderate tachycardia
was reported in 44% of patients. In
7 patients (11%) it was first reported during BUSULFEX administration.
Other rhythm abnormalities,
which were all mild or moderate, included arrhythmia
(5%), atrial fibrillation
(2%), ventricular extrasystoles
(2%), and third degree heart
block (2%). Mild or moderate
thrombosis occurred in
33% of patients, and all episodes were associated with the central
venous catheter. Hypertension was reported in 36% of patients and was
Grade 3/4 in 7%. Hypotension occurred in 11% of patients and was Grade
3/4 in 3%. Mild vasodilation
(flushing and hot flashes) was
reported in 25% of patients. Other cardiovascular
events included cardiomegaly
(5%), mild ECG abnormality (2%),
grade 3/4 left-sided heart
failure in one patient
(2%), and moderate pericardial effusion
(2%). These events were reported primarily in the post-cyclophosphamide
phase.
Pulmonary: Mild or moderate dyspnea
occurred in 25% of patients and was severe in 2%. One patient
(2%) experienced severe hyperventilation; and in 2 (3%) additional patients
it was mild or moderate. Mild rhinitis and mild or moderate cough
were reported in 44% and 28% of patients, respectively. Mild epistaxis
events were reported in 25%. Three patients (5%) on the allogeneic study
developed documented alveolar
hemorrhage. All required mechanical ventilatory support
and all died. Non-specific interstitial fibrosis was found on wedge
biopsies performed with video assisted thoracoscopy in one patient
on the allogeneic study
who subsequently died from respiratory failure on BMT
Day +98. Other pulmonary
events, reported as mild or moderate, included pharyngitis
(18%), hiccup (18%), asthma
(8%), atelectasis (2%),
pleural effusion (3%), hypoxia
(2%), hemoptysis (3%),
and sinusitis (3%).
Neurologic: The most commonly reported adverse events of the central
nervous system
were insomnia (84%), anxiety
(75%), dizziness (30%),
and depression (23%). Severity
was mild or moderate except for one patient (1%) who experienced severe
insomnia. One patient (1%)
developed a life-threatening cerebral hemorrhage
and a coma as a terminal
event following multi-organ failure after VOD. Other events considered
severe included delirium
(2%), agitation (2%), and encephalopathy
(2%). The overall incidence
of confusion was 11% and 5% of patients were reported to have experienced
hallucinations. The patient
who developed delirium and
hallucination on the
allogeneic study had onset of confusion
at the completion of BUSULFEX. The overall incidence of lethargy
in the allogeneic BUSULFEX
clinical trial was 7%, and
somnolence was reported
in 2%. One patient (2%) treated
in an autologous transplantation study experienced a seizure
while receiving cyclophosphamide, despite prophylactic
treatment with phenytoin.
Renal: Creatinine was mildly or moderately elevated in 21% of
patients. BUN was increased in
3% of patients and to a grade
3/4 level in 2%. Seven percent
of patients experienced dysuria,
15% oliguria, and 8% hematuria.
There were 4 (7%) Grade 3/4 cases of hemorrhagic
cystitis in the allogeneic
clinical trial.
Skin: Rash (57%) and pruritus
(28%) were reported; both conditions were predominantly mild. Alopecia
was mild in 15% of patients and moderate in 2%. Mild vesicular
rash was reported in 10% of patients
and mild or moderate maculopapular
rash in 8%. Vesiculo-bullous
rash was reported in 10%, and
exfoliative dermatitis
in 5%. Erythema nodosum was reported in 2%, acne
in 7%, and skin discoloration
in 8%.
Metabolic: Hyperglycemia was observed in 67% of patients and Grade
3/4 hyperglycemia was
reported in 15%. Hypomagnesemia was mild or moderate in 77% of patients;
hypokalemia was mild or
moderate in 62% and severe in 2%; hypocalcemia
was mild or moderate in 46% and severe in 3%; hypophosphatemia was mild
or moderate in 17%; and hyponatremia
was reported in 2%.
Other: Other reported events included headache
(mild or moderate 64%, severe 5%), abdominal
pain (mild or moderate 69%, severe
3%), asthenia (mild or moderate 49%, severe 2%), unspecified pain
(mild or moderate 43%, severe 2%), allergic
reaction (mild or moderate
24%, severe 2%), injection site inflammation
(mild or moderate 25%), injection
site pain
(mild or moderate 15%), chest
pain (mild or moderate 26%),
back pain
(mild or moderate 23%), myalgia
(mild or moderate 16%), arthralgia
(mild or moderate 13%), and ear
disorder in 3%.
Deaths: There were two deaths through BMT
day +28 in the allogeneic transplant setting. There were an additional
six deaths BMT day +29 through
BMT day +100 in the allogeneic
transplant setting.
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 4
below for a mixed population
of hematological malignancies (AML, CML, and ALL).
Table 4:
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
|
|
TRM*
|
VOD**
|
GVHD ***
|
Pulmonary
|
Hemorrhagic Cystitis
|
Seizure
|
|
Death ³100d
=4.1%
(3/ 73)
|
No Report
|
Acute³
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)
|
Acute³
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%
|
Acute³
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%
|
Acute³
Grade 2
GVHD = 22%
(13/58 at risk)
Chronic GVHD
=
31%
(14/ 45 at risk)
|
No Report
|
No Report
|
No Report
|
- *TRM = Transplantation Related Mortality
- **VOD = Veno-Occlusive Disease of the liver
- ***GVHD = Graft versus Host Disease
DRUG INTERACTIONS
Itraconazole decreases busulfan
clearance by up to 25%,
and may produce AUCs > 1500 µM·min in some patients. Fluconazole,
and the 5-HT3 antiemetics odansetron (Zofran) and granisetron (Kytril)
have all 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 (<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.
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