Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1360
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Fosphenytoin Sodium (Injection, Solution)
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Fosphenytoin Sodium Injection, USP is a
prodrug intended for parenteral
administration; its active metabolite is
phenytoin. Each fosphenytoin sodium
injection vial contains 75 mg/mL
fosphenytoin sodium (hereafter referred to
as fosphenytoin) equivalent to 50 mg/mL phenytoin
sodium after
administration. Fosphenytoin sodium
injection is supplied in vials as a
ready-mixedsolution in Water for Injection,
and Tromethamine (TRIS), buffer adjusted to
pH 8.6 to 9.0 with either Hydrochloric Acid,
or Sodium Hydroxide. Fosphenytoin sodium
injection is a clear, colorless to pale
yellow, sterile solution. The chemical name of fosphenytoin is
5,5-diphenyl-3-[(phosphonooxy)methyl]-2,4
imidazolidinedione disodium salt. The
molecular structure of fosphenytoin is: The molecular weight of fosphenytoin is
406.24. IMPORTANT
NOTE: Throughout all fosphenytoin
sodium injection product labeling,
the amount and concentration of
fosphenytoin is expressed in terms
of phenytoin sodium equivalents
(PE). Fosphenytoin's weight is
expressed as phenytoin sodium
equivalents to avoid the need to
perform molecular weight-based
adjustments when converting between fosphenytoin and phenytoin sodium
doses. Fosphenytoin sodium injection
should always be prescribed and
dispensed in phenytoin sodium
equivalent units (PE) (seeDOSAGE AND
ADMINISTRATION).
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Introduction: Following parenteral
administration of
fosphenytoin sodium
injection, fosphenytoin is
converted to the
anticonvulsant phenytoin.
For every mmol of
fosphenytoin administered,
one mmol of phenytoin is
produced. The
pharmacological and
toxicological effects of fosphenytoin include those
of phenytoin. However, the hydrolysis of
fosphenytoin to phenytoin
yields two metabolites,
phosphate and formaldehyde.
Formaldehyde is subsequently
converted to formate, which
is in turn metabolized via a
folate dependent mechanism.
Although phosphate and
formaldehyde (formate) have
potentially important
biological effects, these
effects typically occur at
concentrations considerably
in excess of those obtained
when fosphenytoin sodium
injection isadministered
under conditions of use
recommended in this
labeling.<br/>Mechanism of Action: Fosphenytoin is a prodrug
of phenytoin and accordingly, its
anticonvulsant effects are
attributable to phenytoin. After IV administration to
mice, fosphenytoin blocked
the tonic phase of maximal
electroshock seizures at
doses equivalent to those
effective for phenytoin. In
addition to its ability to
suppress maximal
electroshock seizures in
mice and rats, phenytoin
exhibits anticonvulsant
activity against kindled
seizures in rats, audiogenic
seizures in mice, and
seizures produced by
electrical stimulation of
the brainstem in rats. The
cellular mechanisms of
phenytoin thought to be
responsible for its
anticonvulsant actions
include modulation of
voltage-dependent sodium
channels of neurons,
inhibition of calcium flux
across neuronal membranes,
modulation of
voltage-dependent calcium
channels of neurons, and
enhancement of the
sodium-potassium ATPase
activity of neurons and
glial cells. The modulation
of sodium channels may be a
primary anticonvulsant
mechanism because this property is shared with
several other
anticonvulsants in addition
to phenytoin.<br/>Pharmacokinetics and Drug
Metabolism:<br/>Fosphenytoin:<br/>Phenytoin (after
fosphenytoin sodium
injection
administration): In general,
IM
administration
of
fosphenytoin
sodium
injection
generates
systemic
phenytoin
concentrations
that are
similar
enough to
oral
phenytoin
sodium to
allow
essentially
interchangeable
use. The
pharmacokinetics
of
fosphenytoin
following IV
administration
of
fosphenytoin
sodium
injection,
however, are
complex, and
when used in
an emergency
setting (eg,
status
epilepticus),
differences
in rate of
availability
of phenytoin
could be
critical.
Studies have
therefore
empirically
determined
an infusion
rate for
fosphenytoin
sodium
injection
that gives a
rate and
extent of
phenytoin
systemic
availability
similar to
that of a 50
mg/min
phenytoin
sodium
infusion. A dose of
15 to 20 mg
PE/kg of
fosphenytoin
sodium
injection
infused at
100 to 150
mg PE/min
yields
plasma free
phenytoin
concentrations
over time
that
approximate
those
achieved
when an
equivalent
dose of
phenytoin
sodium (eg,
parenteral Dilantin)
is
administered
at 50 mg/min
(seeDOSAGE
AND
ADMINISTRATION,WARNINGS). FIGURE 1.
Mean plasma
unbound
phenytoin
concentrations
following IV
administration
of 1200 mg
PE
fosphenytoin sodium
injection
infused at
100 mg
PE/min
(triangles)
or 150 mg
PE/min
(squares)
and 1200 mg
Dilantin
infused at
50 mg/min
(diamonds)
to healthy
subjects (N
=
12).
Inset shows
time course
for the
entire
96-hour
sampling
period. Following
administration
of single IV
fosphenytoin
sodium
injection doses of 400
to 1200 mg
PE, mean
maximum
total
phenytoin
concentrations
increase in
proportion
to dose, but
do not
change
appreciably
with changes
in infusion
rate. In
contrast,
mean maximum
unbound
phenytoin
concentrations
increase
with both
dose and
rate.<br/>Special Populations:<br/>Clinical Studies: Infusion
tolerance
was
evaluated in
clinical
studies. One
double-blind
study
assessed
infusion
site
tolerance of
equivalent
loading
doses (15-20
mg PE/kg) of
fosphenytoin
sodium
injection
infused at
150 mg
PE/min or
phenytoin
infused at
50 mg/min.
The study
demonstrated better local
tolerance
(pain and
burning at
the infusion
site), fewer
disruptions
of the
infusion,
and a
shorter
infusion
period for
fosphenytoin
sodium
injection-treated
patients (Table
1). Fosphenytoin
sodium
injection-treated
patients,
however,
experienced
more
systemic
sensory
disturbances
(seePRECAUTIONS,
Sensory Disturbances). Infusion
disruptions
in
fosphenytoin
sodium
injection-treated
patients
were
primarily
due to
systemic
burning,
pruritus,
and/or
paresthesia
while those
in
phenytoin-treated
patients
were
primarily
due to pain
and burning
at the
infusion
site (seeTable
1). In a
double-blind
study
investigating
temporary
substitution
of
fosphenytoin
sodium
injection
for oral
phenytoin,
IM
fosphenytoin
sodium
injection
was as
well-tolerated
as IM
placebo. IM
fosphenytoin
sodium
injection
resulted in
a slight
increase in
transient,
mild to moderate
local
itching (23%
of patients
vs 11% of IM
placebo-treated
patients at
any time
during the
study). This
study also
demonstrated
that
equimolar
doses of IM
fosphenytoin
sodium
injection
may be
substituted
for oral
phenytoin
sodium with
no dosage
adjustments
needed when
initiating
IM or
returning to
oral
therapy. In
contrast,
switching between IM
and oral
phenytoin
requires
dosage
adjustments
because of
slow and
erratic
phenytoin
absorption
from
muscle.
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Fosphenytoin sodium injection is
contraindicated in patients who have
demonstrated hypersensitivity to
fosphenytoin sodium injection or its
ingredients, or to phenytoin or other
hydantoins. Because of the effect of parenteral
phenytoin on ventricular automaticity,
fosphenytoin sodium injection is
contraindicated in patients with sinus
bradycardia, sino-atrial block, second and
third degree A-V block, and Adams-Stokes
syndrome.
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General: (fosphenytoin sodium
injection specific):<br/>Sensory
Disturbances: Severe
burning,
itching,
and/or
paresthesia
were
reported by
7 of 16
normal
volunteers
administered
IV
fosphenytoin
sodium
injection at
a dose of
1200 mg PE
at the
maximum rate
of
administration
(150 mg
PE/min). The
severe
sensory
disturbance
lasted from
3 to 50
minutes in 6
of these subjects and
for 14 hours
in the
seventh
subject. In
some cases,
milder
sensory
disturbances
persisted
for as long
as 24 hours.
The location
of the
discomfort
varied among
subjects
with the
groin
mentioned
most
frequently
as an area
of
discomfort.
In a
separate
cohort of 16
normal
volunteers
(taken from
2 other
studies) whowere
administered
IV
fosphenytoin
sodium
injection at
a dose of
1200 mg PE
at the
maximum rate
of
administration
(150 mg
PE/min),
none
experienced
severe
disturbances,
but most
experienced
mild to
moderate
itching or
tingling. Patients
administered
fosphenytoin
sodium
injection at
doses of 20
mg PE/kg at 150 mg
PE/min are
expected to
experience
discomfort
of some
degree. The
occurrence
and
intensity of
the
discomfort
can be
lessened by
slowing or
temporarily
stopping the
infusion. The effect
of
continuing
infusion
unaltered in
the presence
of these
sensations
is unknown.
No permanent
sequelae
have been
reported thus far.
The
pharmacologic
basis for
these
positive
sensory
phenomena is
unknown, but
other
phosphate
ester drugs,
which
deliver
smaller
phosphate
loads, have
been
associated
with
burning,
itching,
and/or
tingling
predominantly
in the groin
area.<br/>Phosphate Load: The
phosphate
load
provided by
fosphenytoin
sodium
injection
(0.0037 mmol
phosphate/mg
PE
fosphenytoin
sodium
injection)
should be
considered
when
treating
patients who
require
phosphate
restriction,
such as those with
severe renal
impairment.<br/>IV Loading in Renal
and/or Hepatic
Disease or in Those
With Hypoalbuminemia: After IV
administration
to patients
with renal
and/or
hepatic
disease, or
in those
with hypoalbuminemia,
fosphenytoin
clearance to
phenytoin
may be
increased
without a
similar
increase in
phenytoin
clearance.
This has the
potential to
increase the
frequency
and severity
of adverse
events (seeCLINICAL
PHARMACOLOGY,
Special
Populations,
andDOSAGE
AND ADMINISTRATION,
Dosing
in
Special
Populations).<br/>General: (phenytoin associated): Fosphenytoin sodium
injection is notindicated for the
treatment of absence
seizures. A small percentage of
individuals who have been
treated with phenytoin have
been shown to metabolize the
drug slowly. Slow metabolismmay be due to
limited enzyme availability
and lack of induction; it
appears to be genetically
determined. Phenytoin and other
hydantoins are
contraindicated in patients
who have experienced
phenytoin hypersensitivity.
Additionally, caution should
be exercised if using
structurally similar (eg,
barbiturates, succinimides,
oxazolidinediones, and other
related compounds) in these
same patients. Phenytoin has been
infrequently associated with
the exacerbation of porphyria.
Caution should be exercised
when fosphenytoin sodium
injection is used in
patients with this disease. Hyperglycemia,
resulting from phenytoin's
inhibitory effect on insulin
release, has been reported.
Phenytoin may also raise the serum glucose concentrations
in diabetic patients. Plasma
concentrations of phenytoin
sustained above the optimal
range may produce
confusional states referred
to as���delirium,������psychosis,���or���encephalopathy,���or rarely,
irreversible cerebellar
dysfunction. Accordingly, at
the first sign of acute
toxicity,
determination of plasma
phenytoin concentrations is
recommended (see PRECAUTIONS,
Laboratory
Tests).
Fosphenytoin sodium
injection dose reduction is
indicated if phenytoin
concentrations are excessive; if symptoms
persist, administration of
fosphenytoin sodium
injection should be
discontinued. The liver is the primary site of biotransformation of
phenytoin; patients with
impaired liver function,
elderly patients, or those
who are gravely ill may show
early signs of toxicity. Phenytoin and other
hydantoins are not indicated
for seizures due to
hypoglycemic or other
metabolic causes.
Appropriate diagnostic
procedures should be
performed as indicated. Phenytoin has the potential
to lower serum folate
levels.<br/>Laboratory Tests: Phenytoin doses are usually
selected to attain
therapeutic plasma total
phenytoin concentrations of
10 to 20��g/mL, (unbound
phenytoin concentrations of 1 to 2��g/mL). Following
fosphenytoin sodium
injection administration, it
is recommended that
phenytoin concentrationsnot be
monitored until conversion
to phenytoin is essentially
complete. This occurs within
approximately 2 hours after
the end of IV infusion and 4
hours after IM injection. Prior to complete
conversion, commonly used
immunoanalytical techniques,
such as
TDx/TDxFLx���(fluorescence polarization)
and Emit 2000
(enzyme multiplied), may
significantly overestimate
plasma phenytoin
concentrations because of cross-reactivity with
fosphenytoin. The error is
dependent on plasma
phenytoin and fosphenytoin
concentration (influenced by
fosphenytoin sodium
injection dose, route and
rate of administration, and
time of sampling relative to
dosing), and analytical
method. Chromatographic
assay methods accurately
quantitate phenytoin
concentrations in biological
fluids in the presence of
fosphenytoin. Prior to
complete conversion, blood
samples for phenytoin
monitoring should be
collected in tubes
containing EDTA as an
anticoagulant to minimizeex vivoconversion of
fosphenytoin to phenytoin.
However, even with specific assay methods, phenytoin
concentrations measured
before conversion of
fosphenytoin is complete
will not reflect phenytoin
concentrations ultimately
achieved.<br/>Drug Interactions: No drugs are known to interfere with the
conversion of fosphenytoin
to phenytoin. Conversion
could be affected by
alterations in the level of
phosphatase activity, but
given the abundance and wide
distribution of phosphatases
in the body it is unlikely
that drugs would affect this
activity enough to affect
conversion of fosphenytoin
to phenytoin. Drugs highly
bound to albumin could
increase the unbound
fraction of fosphenytoin.
Although, it is unknown
whether this could result in
clinically significant
effects, caution is advised
when administering
fosphenytoin sodium
injection with other drugs
that significantly bind to
serum albumin. The pharmacokinetics and
protein binding of
fosphenytoin, phenytoin, and
diazepam were not altered
when diazepam and
fosphenytoin sodium
injection were concurrently
administered in single
submaximal doses. The most significant drug
interactions following
administration of
fosphenytoin sodium
injection are expected to
occur with drugs that
interact with phenytoin.
Phenytoin is extensively
bound to serum plasma
proteins and is prone to
competitive displacement.
Phenytoin is metabolized by
hepatic cytochrome P450
enzymes and is particularly
susceptible to inhibitory
drug interactions because it is subject to saturable
metabolism. Inhibition of
metabolism may produce
significant increases in
circulating phenytoin
concentrations and enhance
the risk of drug toxicity.
Phenytoin is a potent
inducer of hepatic
drug-metabolizing enzymes. The most commonly occurring
drug interactions are listed
below: Monitoring of plasma
phenytoin concentrations may
be helpful when possible
drug interactions are
suspected (see PRECAUTIONS,
Laboratory
Tests).<br/>Drug/Laboratory Test Interactions: Phenytoin may decrease
serum concentrations of
T. It
may also produce
artifactually low results in
dexamethasone or metyrapone
tests. Phenytoin may also
cause increased serum
concentrations of glucose,
alkaline phosphatase, and
gamma glutamyl
transpeptidase (GGT). Care should be taken when
using immunoanalytical
methods to measure plasma
phenytoin concentrations
following fosphenytoin
sodium injection
administration (seePRECAUTIONS,
Laboratory
Tests).<br/>Carcinogenesis, Mutagenesis,
Impairment of Fertility: The carcinogenic potential
of fosphenytoin has not been studied. Assessment of the
carcinogenic potential of
phenytoin in mice and rats
is ongoing. Structural chromosome
aberration frequency in
cultured V79 Chinese hamster
lung cells was increased by
exposure to fosphenytoin in
the presence of metabolic
activation. No evidence of
mutagenicity was observed in
bacteria (Ames test) or
Chinese hamster lung cellsin vitro,
and no evidence for
clastogenic activity was
observed in an in vivomouse bone marrow
micronucleus test. No effects on fertility
were noted in rats of either
sex given fosphenytoin.
Maternal toxicity and
altered estrous cycles,
delayed mating, prolonged
gestation length, and
developmental toxicity were
observed following
administration of
fosphenytoin during mating, gestation, and lactation at
doses of 50 mg PE/kg or
higher (approximately 40% of
the maximum human loading
dose or higher on a
mg/mbasis).<br/>Pregnancy:<br/>Pregnancy Category
D:<br/>Pediatric Use: The safety of fosphenytoin
sodium injection in
pediatric patients has not
been
established.<br/>Geriatric Use: No systematic studies in
geriatric patients have been
conducted. Phenytoin
clearance tends to decrease
with increasing age (seeCLINICAL
PHARMACOLOGY,
Special
Populations).
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| dailymed-instance:overdosag... |
Nausea, vomiting, lethargy, tachycardia,
bradycardia, asystole, cardiac arrest,
hypotension, syncope, hypocalcemia,
metabolic acidosis, and death have been
reported in cases of overdosage with
fosphenytoin. The median lethal dose of fosphenytoin
given intravenously in mice and rats was 156
mg PE/kg and approximately 250 mg PE/kg, or
about 0.6 and 2 times, respectively, the
maximum human loading dose on a
mg/mbasis. Signs of acute
toxicity in animals included ataxia, labored breathing, ptosis, and hypoactivity. Because fosphenytoin sodium injection is a
prodrug of phenytoin, the following
information may be helpful. Initial symptoms
of acute phenytoin toxicity are nystagmus,
ataxia, and dysarthria. Other signs include
tremor, hyperreflexia, lethargy, slurred
speech, nausea, vomiting, coma, and
hypotension. Depression of respiratory and
circulatory systems leads to death. There
are marked variations among individuals with
respect to plasma phenytoin concentrations
where toxicity occurs. Lateral gaze
nystagmus usually appears at 20��g/mL,
ataxia at 30��g/mL, and dysarthria and
lethargy appear when the plasma
concentration is over 40��g/mL. However,
phenytoin concentrations as high as 50��g/mL
have been reported without evidence of
toxicity. As much as 25 times the
therapeutic phenytoin dose has been taken,
resulting in plasma phenytoin concentrations
over 100��g/mL, with complete recovery. Treatment is nonspecific since there is no
known antidote to fosphenytoin sodium
injection or phenytoin overdosage. The
adequacy of the respiratory and circulatory
systems should be carefully observed, and
appropriate supportive measures employed.
Hemodialysis can be considered since
phenytoin is not completely bound to plasma
proteins. Total exchange transfusion has
been used in the treatment of severe
intoxication in children. In acute
overdosage the possibility of other CNS
depressants, including alcohol, should be
borne in mind. Formate and phosphate are metabolites of
fosphenytoin and therefore may contribute tosigns of toxicity following overdosage.
Signs of formate toxicity are similar to
those of methanol toxicity and are
associated with severe anion-gap metabolic
acidosis. Large amounts of phosphate,
delivered rapidly, could potentially cause
hypocalcemia with paresthesia, muscle
spasms, and seizures. Ionized free calcium
levels can be measured and, if low, used to
guide treatment.
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Fosphenytoin
Sodium
|
| dailymed-instance:fullName |
Fosphenytoin Sodium (Injection, Solution)
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| dailymed-instance:warning |
DOSES OF
FOSPHENYTOIN SODIUM INJECTION ARE
EXPRESSED AS THEIR PHENYTOIN SODIUM
EQUIVALENTS IN THIS LABELING
(PE=phenytoin sodium
equivalent). DO NOT, THEREFORE,
MAKE ANY ADJUSTMENT IN THE
RECOMMENDED DOSES WHEN SUBSTITUTING
FOSPHENYTOIN SODIUM INJECTION FOR
PHENYTOIN SODIUM OR VICE
VERSA. The following warnings are based on
experience with fosphenytoin sodium
injection or phenytoin.<br/>Status Epilepticus Dosing Regimen: The dose of IV
fosphenytoin sodium
injection (15 to 20
mg PE/kg) that is
used to treat status
epilepticus is
administered at a
maximum rate of 150
mg PE/min. The
typical fosphenytoin
sodium injection
infusion
administered to a 50
kg patient would
take between 5 and 7 minutes. Note that
the delivery of an
identical molar dose
of phenytoin using
parenteral Dilantin
or generic phenytoin
sodium injection
cannot be
accomplished in less
than 15 to 20
minutes because of
the untoward
cardiovascular
effects that
accompany the direct
intravenous
administration of
phenytoin at rates
greater than 50
mg/min. If rapid phenytoin loading
is a primary goal, IV
administration of
fosphenytoin sodium
injection is preferred
because the time to achieve
therapeutic plasma phenytoin
concentrations is greater
following IM than that
following IV administration
(see DOSAGE AND
ADMINISTRATION).<br/>Withdrawal Precipitated Seizure,
Status Epilepticus: Antiepileptic drugs should
not be abruptly discontinued because of the possibility
of increased seizure
frequency, including status
epilepticus. When, in the
judgement of the clinician,
the need for dosage
reduction, discontinuation,
or substitution of
alternative antiepileptic
medication arises, this
should bedone gradually.
However, in the event of an
allergic or hypersensitivity
reaction, rapid substitution
of alternative therapy may
be necessary. In this case,
alternative therapy should
be an antiepileptic drug not
belonging to the hydantoin
chemical class.<br/>Cardiovascular Depression: Hypotension may occur,
especially after IV
administration at high doses
and high rates of
administration. Following
administration of phenytoin,
severe cardiovascular
reactions and fatalities
have been reported with
atrial and ventricular
conduction depression and
ventricular fibrillation.
Severe complications are
most commonly encounteredin
elderly or gravely ill
patients. Therefore, careful
cardiac monitoring is needed
when administering IV
loading doses of
fosphenytoin sodium injection. Reduction in rate
of administration or
discontinuation of dosing
may be needed. Fosphenytoin sodium
injection should be used
with caution in patients
with hypotension and severe
myocardial
insufficiency.<br/>Rash: Fosphenytoin sodium injection should be
discontinued if a skin rash
appears. If the rash is
exfoliative, purpuric, or
bullous, or if lupus
erythematosus,
Stevens-Johnson syndrome, or
toxic epidermal necrolysis
is suspected, use of this
drug should not be resumed
and alternative therapy
should be considered. If the
rash is of a milder type
(measles-like or
scarlatiniform), therapy may
be resumed after the rash
has completely disappeared.
If the rash recurs upon
reinstitution of therapy,
further fosphenytoin sodium
injection or phenytoin
administration is
contraindicated.<br/>Hepatic Injury: Cases of acute
hepatotoxicity, including
infrequent cases of acute
hepatic failure, have been
reported with phenytoin.
These incidents have been
associated with a
hypersensitivity syndrome
characterized by fever, skin
eruptions, and
lymphadenopathy, and usually
occur within the first 2
months of treatment. Other
common manifestations
include jaundice,
hepatomegaly, elevated serum
transaminase levels, leukocytosis, and
eosinophilia. The clinical
course of acute phenytoin
hepatotoxicity ranges from
prompt recovery to fatal
outcomes. In these patients
with acute hepatotoxicity,
fosphenytoin sodium
injection should be
immediately discontinued and
not
readministered.<br/>Hemopoietic System: Hemopoietic complications, some fatal, have
occasionally been reported
in association with
administration of phenytoin.
These have included
thrombocytopenia,
leukopenia,
granulocytopenia,
agranulocytosis, and
pancytopenia with or without
bone marrow suppression. There have been a number of
reports that have suggested
a relationship between
phenytoin and the
development of
lymphadenopathy (local or
generalized), including
benign lymph node
hyperplasia, pseudolymphoma,
lymphoma, and Hodgkin's
disease. Although a cause
and effect relationship has
not been established, the
occurrence of lymphadenopathy indicates
the need to differentiate
such a condition from other
types of lymph node
pathology. Lymph node
involvement may occur with
or without symptoms and
signs resembling serum
sickness, eg, fever, rash,
and liver involvement. In
all cases of
lymphadenopathy, follow-up
observation for an extended
period is indicatedand
every effort should be made
to achieve seizure control
using alternative
antiepileptic
drugs.<br/>Alcohol Use: Acute alcohol intake may
increase plasma phenytoin
concentrations while chronic
alcohol use may decrease
plasma
concentrations.<br/>Usage in Pregnancy:<br/>Clinical:<br/>Preclinical: Increased
frequencies
of
malformations
(brain,
cardiovascular,
digit, and
skeletal
anomalies),
death,
growth
retardation,
and
functional
impairment
(chromodacryorrhea,
hyperactivity,
circling)
were
observed
among the
offspring of
rats
receiving
fosphenytoin
during
pregnancy.
Most of the
adverse
effects on
embryo-fetal
development occurred at
doses of 33
mg PE/kg or
higher
(approximately
30% of the
maximum
human
loading dose
or higher on
a
mg/mbasis),
which
produced
peak
maternal
plasma
phenytoin
concentrations
of
approximately
20��g/mL or
greater.
Maternal
toxicity was
often
associated
with these
doses and
plasma
concentrations,
however,
there is no evidence to
suggest that
the
developmental
effects were
secondary to
the maternal
effects. The
single
occurrence
of a rare
brain
malformation
at a
nonmaternotoxic
dose of 17
mg PE/kg
(approximately
10% of the
maximum
human
loading dose
on a
mg/mbasis) was
also
considered
drug-induced.
The
developmental
effects of
fosphenytoin
in rats were
similar to
those which
have been
reported
following
administration
of phenytoin
to pregnant
rats. No effects
on
embryo-fetal
development
were
observed
when rabbits
were given
up to 33 mg
PE/kg of
fosphenytoin
(approximately
50% of the
maximum
human
loading dose
on a
mg/mbasis)
during
pregnancy.
Increased resorption
and
malformation
rates have
been
reported
following
administration
of phenytoin
doses of 75
mg/kg or
higher
(approximately
120% of the
maximum
human
loading dose
or higher on
a
mg/mbasis) to
pregnant
rabbits.
|
| dailymed-instance:indicatio... |
Fosphenytoin sodium injection is indicated
for short-term parenteral administration
when other means of phenytoin administration
are unavailable, inappropriate or deemed
less advantageous. The safety and
effectiveness of fosphenytoin sodium
injection in this use has not been
systematically evaluated for more than 5
days. Fosphenytoin sodium injection can be used
for the control of generalized convulsive
status epilepticus and prevention and
treatment of seizures occurring during
neurosurgery. It can also be substituted,
short-term, for oral phenytoin.
|
| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
Fosphenytoin Sodium
|