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
Taxol Warnings, Precautions, Pregnancy, Nursing, Abuse - Paclitaxel
Taxol Warnings, Precautions, Pregnancy, Nursing, Abuse - Paclitaxel
WARNINGS
Anaphylaxis and severe hypersensitivity
reactions characterized by dyspnea and hypotension
requiring treatment,
angioedema, and generalized
urticaria have occurred in 2% of patients receiving TAXOL in clinical
trials. Fatal reactions have occurred in patients despite premedication.
All patients should be pretreated with corticosteroids, diphenhydramine,
and H2 antagonists. (See DOSAGE
AND ADMINISTRATION section.) Patients who experience
severe hypersensitivity
reactions to TAXOL should not be rechallenged with the drug.
Bone marrow suppression
(primarily neutropenia) is dose-dependent and is the dose-limiting
toxicity. Neutrophil nadirs occurred at a median
of 11 days. TAXOL should not be administered to patients with baseline
neutrophil counts of less than 1500 cells/mm3 (<1000
cells/mm3 for patients with KS). Frequent monitoring
of blood counts should
be instituted during TAXOL treatment. Patients should not be re-treated
with subsequent cycles of TAXOL until neutrophils recover
to a level >1500 cells/mm3 ( >1000 cells/ mm3
for patients with KS) and platelets recover to a level >100,000
cells/ mm 3 .
Severe conduction
abnormalities have been documented in < 1% of patients during
TAXOL therapy and in
some cases requiring pacemaker
placement. If patients develop significant
conduction abnormalities
during TAXOL infusion, appropriate therapy
should be administered and continuous cardiac
monitoring should be performed during subsequent therapy
with TAXOL.
Pregnancy: TAXOL can cause
fetal harm when administered
to a pregnant woman. Administration of paclitaxel during the period
of organogenesis to rabbits at doses of 3.0 mg/kg/day (about 0.2
the daily maximum recommended
human dose on a mg/m2
basis) caused embryo-and fetotoxicity, as indicated by intrauterine
mortality, increased
resorptions and increased fetal deaths. Maternal toxicity
was also observed at this dose. No
teratogenic effects were observed at 1.0 mg/kg/day (about 1/15 the
daily maximum recommended
human dose on a mg/m2
basis); teratogenic
potential could not
be assessed at higher doses due to extensive fetal
mortality.
There are no adequate and
well-controlled studies in pregnant
women. If TAXOL is used during pregnancy,
or if the patient becomes
pregnant while receiving
this drug, the patient
should be apprised of the potential
hazard to the fetus. Women of childbearing
potential should be
advised to avoid becoming pregnant.
PRECAUTIONS
Contact of the undiluted concentrate with plasticized polyvinyl
chloride (PVC) equipment or devices used to prepare solutions for
infusion is not recommended.
In order
to minimize patient
exposure to the plasticizer
DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC
infusion bags or sets,
diluted TAXOL solutions should preferably be stored in bottles (glass,
polypropylene) or plastic
bags (polypropylene, polyolefin) and administered through polyethylene-lined
administration
sets.
TAXOL should be administered through an in-line filter
with a microporous membrane not greater than 0.22 microns. Use of
filter devices such
as IVEX2® filters which incorporate
short inlet and outlet
PVC-coated tubing has not resulted in significant
leaching of DEHP.
Hematology: TAXOL therapy
should not be administered to patients with baseline
neutrophil counts
of less than 1,500 cells/mm3 . In
order to monitor
the occurrence of myelotoxicity, it is recommended that frequent
peripheral blood
cell counts be performed
on all patients receiving TAXOL. Patients should not be re-treated
with subsequent cycles of TAXOL until neutrophils recover
to a level >1500 cells/ mm3 and platelets recover
to a level >100,000 cells/mm3 . In the case
of severe neutropenia
(<500 cells/ mm3 for seven days or more) during a
course of TAXOL therapy,
a 20% reduction in
dose for subsequent courses of therapy
is recommended.
For patients with advanced HIV
disease and poor-risk
AIDS-related Kaposi’s sarcoma, TAXOL, at the recommended dose
for this disease, can
be initiated and repeated if the neutrophil
count is at least 1000
cells/mm3 .
Hypersensitivity Reactions: Patients with a history
of severe hypersensitivity reactions to products containing Cremophor®
EL (e.g., cyclosporin for injection
concentrate and teniposide for injection concentrate) should not
be treated with TAXOL. In
order to avoid the occurrence
of severe hypersensitivity
reactions, all patients treated with TAXOL should be premedicated
with corticosteroids (such as dexamethasone), diphenhydramine and
H2 antagonists (such as cimetidine
or ranitidine). Minor symptoms such
as flushing, skin reactions,
dyspnea, hypotension
or tachycardia do not require interruption of therapy. However,
severe reactions, such as hypotension
requiring treatment,
dyspnea requiring bronchodilators,
angioedema or generalized urticaria
require immediate
discontinuation of TAXOL (paclitaxel) Injection and aggressive symptomatic
therapy. Patients who have developed severe hypersensitivity
reactions should not be rechallenged with TAXOL.
Cardiovascular: Hypotension, bradycardia,
and hypertension
have been observed during administration
of TAXOL, but generally do not require treatment. Occasionally TAXOL
infusions must be interrupted or discontinued because of initial
or recurrent hypertension. Frequent vital
sign monitoring, particularly
during the first hour of TAXOL infusion,
is recommended. Continuous cardiac monitoring is not required except
for patients with serious conduction abnormalities. (See WARNINGS
section.)
Nervous System: Although, the occurrence of peripheral
neuropathy is frequent, the development
of severe symptomatology
is unusual and requires a dose
reduction of 20% for
all subsequent courses of TAXOL.
TAXOL contains dehydrated alcohol
USP, 396 mg/mL; consideration should be given to possible CNS
and other effects of alcohol. (See PRECAUTIONS
: Pediatric
Use section.)
Hepatic: There is evidence
that the toxicity of
TAXOL is enhanced in patients with elevated liver
enzymes. Caution should be exercised when administering TAXOL to
patients with moderate to severe hepatic
impairment and dose adjustments
should be considered.
Injection Site Reaction: Injection site
reactions, including reactions secondary
to extravasation, were usually mild and consisted of erythema, tenderness,
skin discoloration, or
swelling at the injection
site. These reactions have been observed more frequently with the
24-hour infusion than with the 3-hour infusion. Recurrence of skin
reactions at a site of
previous extravasation
following administration
of TAXOL at a different site, i.e., "recall", has been
reported rarely.
Rare reports of more severe events such
as phlebitis, cellulitis,
induration, skin exfoliation, necrosis
and fibrosis have been
received as proof of the
continuing surveillance
of TAXOL safety. In some
cases the onset of the injection site
reaction either occurred
during a prolonged infusion
or was delayed by a week to ten days.
A specific treatment
for extravasation
reactions is unknown at this time. Given the possibility of extravasation,
it is advisable to closely monitor the infusion
site for possible infiltration
during drug administration.
Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenIc potential of TAXOL has not been studied.
Paclitaxel has been shown to be clastogenic
in vitro ( chromosome aberrations in human
lymphocytes) and in vivo ( micronucleus
test in mice). Paclitaxel was not mutagenic in the Ames test
or the CHO/ HGPRT gene mutation
assay.
Administration of paclitaxel prior to and during mating
produced impairment of fertility
in male and female
rats at doses equal to or greater than 1 mg/kg/day (about 0.04 the
daily maximum recommended
human dose
on a mg/m2 basis). At
this dose, paclitaxel caused reduced fertility
and reproductive indices, and increased embryo-and fetotoxicty.
(See WARNINGS
section.)
Pregnancy
Pregnancy "Category D". (See WARNINGS
section.)
Nursing Mothers
It is not known whether the drug
is excreted in human milk.
Following intravenous
administration
of carbon-14 labeled
TAXOL to rats on days 9 to 10 postpartum,
milk concentrations of
radioactivity exceeded and declined in parallel with the plasma
concentrations. Because many drugs are excreted in human
milk and because of the
potential for serious
adverse reactions in nursing
infants, it is recommended that nursing be discontinued when receiving
TAXOL therapy.
Pediatric Use
The safety and effectiveness
of TAXOL in pediatric patients have not been established.
There have been reports of central
nervous system
(CNS) toxicity in an
ongoing investigational clinical
trial in pediatric
patients in which TAXOL was infused intravenously over 3 hours at
doses ranging from 350 mg/m2 to 420 mg/m2
. The toxicity is most
likely attributable to the high dose
of the ethanol component
of the TAXOL vehicle given over a short infusion
time. The use of concomitant
antihistamines may intensify this effect. Although a direct effect
of the paclitaxel itself cannot be discounted, the high doses used
in this study (over twice the recommended adult
dosage) must be considered in assessing the safety of TAXOL for
use in this population.
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