Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3527
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Fosphenytoin Sodium (Injection, Solution)
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The dose, concentration
in dosing solutions, and infusion rate of IV Fosphenytoin Sodium Injection,
USP is expressed as phenytoin sodium equivalents (PE) to avoid the
need to perform molecular weight-based adjustments when converting
between fosphenytoin and phenytoin sodium doses. Fosphenytoin Sodium
Injection, USP should always be prescribed and dispensed in phenytoin
sodium equivalent units (PE). Fosphenytoin Sodium Injection, USP has
important differences in administration from those for parenteral
phenytoin sodium (see below). Products
with particulate matter or discoloration should not be used. Prior
to IV infusion, dilute Fosphenytoin Sodium Injection, USP in 5% dextrose
or 0.9% saline solution for injection to a concentration ranging from
1.5 to 25 mg PE/mL. Status Epilepticus If administration of Fosphenytoin Sodium Injection,
USP does not terminate seizures, the use of other anticonvulsants
and other appropriate measures should be considered. IM Fosphenytoin Sodium Injection, USP should not be used in the treatment
of status epilepticus because therapeutic phenytoin concentrations
may not be reached as quickly as with IV administration. If IV access
is impossible, loading doses of Fosphenytoin Sodium Injection, USP
have been given by the IM route for other indications. Nonemergent Loading and Maintenance
Dosing The loading dose of Fosphenytoin
Sodium Injection, USP is 10 - 20 mg PE/kg given IV or IM. The rate
of administration for IV Fosphenytoin Sodium Injection, USP should
be no greater than 150 mg PE/min. Continuous monitoring of the electrocardiogram,
blood pressure, and respiratory function is essential and the patient
should be observed throughout the period where maximal serum phenytoin
concentrations occur, approximately 10 to 20 minutes after the end
of Fosphenytoin Sodium Injection, USP infusions. The initial daily maintenance dose of Fosphenytoin Sodium Injection,
USP is 4 - 6 mg PE/kg/day. IM or IV Substitution For Oral Phenytoin Therapy Fosphenytoin Sodium Injection, USP can be
substituted for oral phenytoin sodium therapy at the same total daily
dose. Dilantin capsules are approximately 90%
bioavailable by the oral route. Phenytoin, supplied as Fosphenytoin
Sodium Injection, USP, is 100% bioavailable by both the IM and IV
routes. For this reason, plasma phenytoin concentrations may increase
modestly when IM or IV Fosphenytoin Sodium Injection, USP is substituted
for oral phenytoin sodium therapy. The rate
of administration for IV Fosphenytoin Sodium Injection, USP should
be no greater than 150 mg PE/min. In controlled
trials, IM Fosphenytoin Sodium Injection, USP was administered as
a single daily dose utilizing either 1 or 2 injection sites. Some
patients may require more frequent dosing. Dosing in Special Populations Patients with Renal or Hepatic
Disease: Due to an increased fraction of unbound phenytoin
in patients with renal or hepatic disease, or in those with hypoalbuminemia,
the interpretation of total phenytoin plasma concentrations should
be made with caution (see CLINICAL PHARMACOLOGY: Special Populations).
Unbound phenytoin concentrations may be more useful in these patient
populations. After IV Fosphenytoin Sodium Injection, USP 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 (see PRECAUTIONS). Elderly Patients: Age does not have a significant impact on the pharmacokinetics of
fosphenytoin following Fosphenytoin Sodium Injection, USP administration.
Phenytoin clearance is decreased slightly in elderly patients and
lower or less frequent dosing may be required. Pediatric: The safety of
Fosphenytoin Sodium Injection, USP in pediatric patients has not been
established.
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| dailymed-instance:descripti... |
Fosphenytoin Sodium Injection is a prodrug intended
for parenteral administration; its active metabolite is phenytoin.
Each vial contains 75 mg/mL fosphenytoin sodium (hereafter referred
to as fosphenytoin) equivalent to 50 mg/mL
phenytoin sodium after administration. Fosphenytoin Sodium
Injection, USP is supplied in vials as a ready-mixed solution in Water
for Injection, USP, and Tromethamine, USP (TRIS), buffer adjusted
to pH 8.6 to 9.0 with either Hydrochloric Acid, NF, or Sodium Hydroxide,
NF. Fosphenytoin Sodium Injection, USP 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 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, USP should always be prescribed and dispensed in
phenytoin sodium equivalent units (PE) (see DOSAGE AND ADMINISTRATION).
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Introduction Following parenteral administration, 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, USP
is administered under conditions of use recommended in this labeling. 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, andseizures 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. Pharmacokinetics and Drug Metabolism Fosphenytoin Absorption/Bioavailability:
Intravenous: When
administered by IV infusion, maximum plasma fosphenytoin concentrations
are achieved at the end of the infusion. Fosphenytoin has a half-life
of approximately 15 minutes. Intramuscular: Fosphenytoin is completely
bioavailable following IM administration of Fosphenytoin Sodium Injection,
USP. Peak concentrations occur at approximately 30 minutes postdose.
Plasma fosphenytoin concentrations following IM administration are
lower but more sustained than those following IV administration due
to the time required for absorption of fosphenytoin from the injection
site. Distribution: Fosphenytoin is extensively bound (95% to 99%) to human plasma proteins,
primarily albumin. Binding to plasma proteins is saturable with the
result that the percent bound decreases as total fosphenytoin concentrations
increase. Fosphenytoin displaces phenytoin from protein binding sites.
The volume of distribution of fosphenytoin increases with Fosphenytoin
Sodium Injection, USP dose and rate, and ranges from 4.3 to 10.8 liters. Metabolism and Elimination: The conversion half-life of fosphenytoin to phenytoin is approximately
15 minutes. The mechanism of fosphenytoin conversion has not been
determined, but phosphatases probably play a major role. Fosphenytoin
is not excreted in urine. Each mmol of fosphenytoin is metabolized
to 1 mmol of phenytoin, phosphate, and formate (see CLINICAL PHARMACOLOGY,
Introduction and PRECAUTIONS, Phosphate Load for Renally Impaired
Patients). Phenytoin
(after Fosphenytoin Sodium Injection, USP administration) In general, IM administration of Fosphenytoin
Sodium Injection, USP generates systemic phenytoin concentrations
that are similar enough to oral phenytoin sodium to allow essentially
interchangeable use. The pharmacokinetics of
fosphenytoin following IV administration, 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, USP that gives a rate and extent of phenytoin systemic
availability similar to that of a 50 mg/min phenytoin sodiuminfusion. A dose of 15 to 20 mg PE/kg of Fosphenytoin Sodium Injection,
USP 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 (see DOSAGE AND ADMINISTRATION, WARNINGS). Following administration of single IV Fosphenytoin
Sodium Injection, USP 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. Absorption/Bioavailability:
Fosphenytoin is completely converted to phenytoin following
IV administration, with a half-life of approximately 15 minutes. Fosphenytoin
is also completely converted to phenytoin following IM administration
and plasma total phenytoin concentrations peak in approximately 3
hours. Distribution: Phenytoin is highly bound to plasma proteins, primarily albumin,
although to a lesser extent than fosphenytoin. In the absence of fosphenytoin,
approximately 12% of total plasma phenytoin is unbound over the clinically
relevant concentration range. However, fosphenytoin displaces phenytoin
from plasma protein binding sites. This increases the fraction of
phenytoin unbound (up to 30% unbound) during the period required for
conversion of fosphenytoin to phenytoin (approximately 0.5 to 1 hour
postinfusion). Metabolism
and Elimination: Phenytoin derived from administration of
Fosphenytoin Sodium Injection, USP is extensively metabolized in the
liver and excreted in urine primarily as 5-(p-hydroxyphenyl)- 5-phenylhydantoin
and its glucuronide; little unchanged phenytoin (1%-5% of the Fosphenytoin
Sodium Injection, USP dose) is recovered in urine. Phenytoin hepatic
metabolism is saturable, and following administration of single IV
Fosphenytoin Sodium Injection, USP doses of 400 to 1200 mg PE, total
and unbound phenytoin AUC values increase disproportionately with
dose. Mean total phenytoin half-life values (12.0 to 28.9 hr) following
Fosphenytoin Sodium Injection, USP administration at these doses are
similar to those after equal doses of parenteral Dilantin and tend
to be greater at higher plasma phenytoin concentrations. Special Populations Patients with
Renal or Hepatic Disease: Due to an increased fraction of
unbound phenytoin in patients with renal or hepatic disease, or in
those with hypoalbuminemia, the interpretation of total phenytoin
plasma concentrations should be made with caution (see DOSAGE AND
ADMINISTRATION). Unbound phenytoin concentrations may be more useful
inthese patient populations. After IV administration of Fosphenytoin
Sodium Injection, USP 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 (see PRECAUTIONS). Age: The effect of age was evaluated
in patients 5 to 98 years of age. Patient age had no significant impact
on fosphenytoin pharmacokinetics. Phenytoin clearance tends to decrease
with increasing age (20% less in patients over 70 years of age relative
to that in patients 20-30 years of age). Phenytoin dosing requirements
are highly variable and must be individualized (see DOSAGE AND ADMINISTRATION). Gender and Race: Gender and race have no significant impact on fosphenytoin or phenytoin
pharmacokinetics. Pediatrics: Only limited pharmacokinetic data are available
in children (N=8; age 5 to 10 years). In these patients with status
epilepticus who received loading doses of Fosphenytoin Sodium Injection,
USP, the plasma fosphenytoin, total phenytoin, and unbound phenytoin
concentration-time profiles did not signal any major differences from
those in adult patients with status epilepticus receiving comparable
doses. 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,
USP 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 patients treated with Fosphenytoin Sodium Injection, USP
(Table 1). Patients treated with Fosphenytoin Sodium Injection,
USP, however, experienced more systemic sensory disturbances (see
PRECAUTIONS, Sensory Disturbances). Infusion disruptions in patients
treated with Fosphenytoin Sodium Injection, USP 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
(see Table 1). In a double-blind study investigating
temporary substitution of Fosphenytoin Sodium Injection, USP for oral
phenytoin, IM Fosphenytoin Sodium Injection, USP was as well-tolerated
as IM placebo. IM Fosphenytoin Sodium Injection, USP 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, USP maybe 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, USP is contraindicated
in patients who have demonstrated hypersensitivity to Fosphenytoin
Sodium Injection, USP or its ingredients, or to phenytoin or other
hydantoins. Because of the effect of parenteral
phenytoin on ventricular automaticity, Fosphenytoin Sodium Injection,
USP 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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Fosphenytoin Sodium Injection, USP is supplied as
follows: 10 mL per vial - Each vial contains
fosphenytoin sodium 750 mg equivalent to 500 mg of phenytoin sodium: List Number 4857-10. Packages of 10. 2 mL per vial - Each vial contains fosphenytoin sodium 150 mg equivalent
to 100 mg of phenytoin sodium: List Number 4857-02.
Packages of 25. Both sizes of vials contain
Tromethamine, USP (TRIS), Hydrochloric Acid, NF, or Sodium Hydroxide,
NF, and Water for Injection, USP. Fosphenytoin Sodium Injection, USP should always
be prescribed in phenytoin sodium equivalent units (PE) (see DOSAGE
AND ADMINISTRATION). Storage Store under refrigeration at 2��C to 8��C
(36��F to 46��F). Do not store at room temperature for more
than 48 hours. Vials that develop particulate matter should not be
used. Revised: August, 2006
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General: (Fosphenytoin Sodium Injection, USP specific): Sensory Disturbances Severe burning, itching, and/or paresthesia
were reported by 7 of 16 normal volunteers administered IV Fosphenytoin
Sodium Injection, USP 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) who were administered IV Fosphenytoin
Sodium Injection, USP 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, USP
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. Phosphate Load The
phosphate load provided by Fosphenytoin Sodium Injection, USP (0.0037
mmol phosphate/mg PE Fosphenytoin Sodium Injection, USP) should be
considered when treating patients who require phosphate restriction,
such as those with severe renal impairment. 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 (see CLINICAL PHARMACOLOGY: Special Populations, and DOSAGE
AND ADMINISTRATION: Dosing in Special Populations).<br/>General: (phenytoin associated): Fosphenytoin Sodium Injection, USP is not indicated 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 metabolism may 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
(e.g., 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, USP 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,
USP dose reduction is indicated if phenytoin concentrations are excessive;
if symptoms persist, administration of Fosphenytoin Sodium Injection,
USP 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 mcg/mL, (unbound
phenytoin concentrations of 1 to 2 mcg/mL). Following Fosphenytoin
Sodium Injection, USP administration, it is recommended that phenytoin
concentrations not 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, USP 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
minimize ex vivo conversion
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, USP 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,
USP were concurrently administered in single submaximal doses. The most significant drug interactions following administration
of Fosphenytoin Sodium Injection, USP 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 andis 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 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, USP administration (see 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 cells in
vitro, and no evidence for clastogenic activity was observed
in an in vivo mouse 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 - Category D: (see WARNINGS):<br/>Use in Nursing Mothers: It is not known whether fosphenytoin is excreted
in human milk. Following administration of Dilantin,
phenytoin appears to be excreted in low concentrations in human milk.
Therefore, breast-feeding is not recommended for women receiving Fosphenytoin
Sodium Injection, USP.<br/>Pediatric Use: The safety of Fosphenytoin Sodium Injection, USP
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 (see CLINICAL PHARMACOLOGY: Special Populations).
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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, USP 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 leadsto death. There are marked variations
among individuals with respect to plasma phenytoin concentrations
where toxicity occurs. Lateral gaze nystagmus usually appears at 20
mcg/mL, ataxia at 30 mcg/mL, and dysarthria and lethargy appear when
the plasma concentration is over 40 mcg/mL. However, phenytoin concentrations
as high as 50 mcg/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 mcg/mL, with
complete recovery. Treatment is nonspecific
since there is no known antidote to Fosphenytoin Sodium Injection,
USP 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 to signs
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 calciumlevels can be measured and, if
low, used to guide treatment.
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Fosphenytoin Sodium
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Fosphenytoin Sodium (Injection, Solution)
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The more important adverse clinical events caused
by the IV use of Fosphenytoin Sodium Injection, USP or phenytoin are
cardiovascular collapse and/or central nervous system depression.
Hypotension can occur when either drug is administered rapidly by
the IV route. The rate of administration is very important; for Fosphenytoin
Sodium Injection, USP, it should not exceed 150 mg PE/min. The adverse clinical events most commonly observed with
the use of Fosphenytoin Sodium Injection, USP in clinical trials were
nystagmus, dizziness, pruritus, paresthesia, headache, somnolence,
and ataxia. With two exceptions, these events are commonly associated
with the administration of IV phenytoin. Paresthesia and pruritus,
however, were seen much more often following Fosphenytoin Sodium Injection,
USP administration and occurred more often with IV Fosphenytoin Sodium
Injection, USP administration than with IM Fosphenytoin Sodium Injection,
USP administration. These events were dose and rate related; most
alert patients (41 of 64; 64%) administered doses of���15 mg
PE/kg at 150 mg PE/min experienced discomfort of some degree. These
sensations, generally described as itching, burning, or tingling,
were usually not at the infusion site. The location of the discomfort
varied with the groin mentioned most frequently as a site of involvement.
The paresthesia and pruritus were transient events that occurred within
several minutes of the start of infusion and generally resolved within
10 minutes aftercompletion of Fosphenytoin Sodium Injection, USP
infusion. Some patients experienced symptoms for hours. These events
did not increase in severity with repeated administration. Concurrent
adverse events or clinical laboratory change suggesting an allergic
process were not seen (see PRECAUTIONS, Sensory Disturbances). Approximately 2% of the 859 individuals who received Fosphenytoin
Sodium Injection, USP in premarketing clinical trials discontinued
treatment because of an adverse event. The adverse events most commonly
associated with withdrawal were pruritus (0.5%), hypotension (0.3%),
and bradycardia (0.2%). Dose and Rate Dependency of Adverse Events Following
IV Fosphenytoin Sodium Injection, USP: The incidence of
adverse events tended to increase as both dose and infusion rate increased.
In particular, at doses of���15 mg PE/kg and rates���150
mg PE/min, transient pruritus, tinnitus, nystagmus, somnolence, and
ataxia occurred 2 to 3 times more often than at lower doses or rates. Incidence in Controlled Clinical
Trials All adverse events were recorded
during the trials by the clinical investigators using terminology
of their own choosing. Similar types of events were grouped into standardized
categories using modified COSTART dictionary terminology. These categories
are used in the tables and listings below with the frequencies representing
the proportion of individuals exposed to Fosphenytoin Sodium Injection,USP or comparative therapy. The prescriber should
be aware that these figures cannot be used to predict the frequency
of adverse events in the course of usual medical practice where patient
characteristics and other factors may differ from those prevailing
during clinical studies. Similarly, the cited frequencies cannot be
directly compared with figures obtained from other clinical investigations
involving different treatments, uses or investigators. An inspection
of these frequencies,however, does provide the prescribing physician
with one basis to estimate the relative contribution of drug and nondrug
factors to the adverse event incidences in the population studied. Incidence in Controlled Clinical
Trials - IV Administration To Patients With Epilepsy or Neurosurgical
Patients: Table 2 lists treatment-emergent adverse events
that occurred in at least 2% of patients treated with IV Fosphenytoin
Sodium Injection, USP at the maximum dose and rate in a randomized,
double-blind, controlled clinical trial where the rates for phenytoin
and Fosphenytoin Sodium Injection, USP administration would have resulted
in equivalent systemic exposure to phenytoin. Incidence in Controlled
Trials - IM Administration to Patients With Epilepsy: Table
3 lists treatment-emergent adverse events that occurred in at least
2% of patients treated with Fosphenytoin Sodium Injection, USP in
a double-blind, randomized, controlled clinical trial of adult epilepsy
patients receiving either IM Fosphenytoin Sodium Injection, USP substituted
for oral Dilantin or continuing oral Dilantin. Both treatments were
administered for 5 days. Adverse Events During
All Clinical Trials Fosphenytoin Sodium
Injection, USP has been administered to 859 individuals during all
clinical trials. All adverse events seen at least twice are listed
in the following, except those already included in previous tables
and listings. Events are further classified within body system categories
and enumerated in order of decreasing frequency using the following
definitions: frequent adverse events are defined as those occurring
in greater than 1/100 individuals; infrequent adverse events are those
occurring in 1/100 to 1/1000 individuals. Body As a Whole: Frequent: fever, injection-site reaction, infection, chills,
face edema, injection-site pain; Infrequent: sepsis, injection-site inflammation, injection-site edema, injection-site
hemorrhage, flu syndrome, malaise, generalized edema, shock, photosensitivity
reaction, cachexia, cryptococcosis. Cardiovascular: Frequent: hypertension; Infrequent: cardiac arrest, migraine, syncope, cerebral hemorrhage, palpitation,
sinus bradycardia, atrial flutter, bundle branch block, cardiomegaly,
cerebral infarct, postural hypotension, pulmonary embolus, QT interval
prolongation, thrombophlebitis, ventricular extrasystoles, congestive
heart failure. Digestive: Frequent: constipation; Infrequent: dyspepsia, diarrhea, anorexia,
gastrointestinal hemorrhage, increased salivation, liver function
tests abnormal, tenesmus, tongue edema, dysphagia, flatulence, gastritis,
ileus. Endocrine: Infrequent: diabetes insipidus. Hematologic and Lymphatic: Infrequent: thrombocytopenia,
anemia, leukocytosis, cyanosis, hypochromic anemia, leukopenia, lymphadenopathy,
petechia. Metabolic
and Nutritional: Frequent: hypokalemia; Infrequent: hyperglycemia,
hypophosphatemia, alkalosis, acidosis, dehydration, hyperkalemia,
ketosis. Musculoskeletal: Frequent: myasthenia; Infrequent: myopathy, leg cramps, arthralgia,
myalgia. Nervous:
Frequent: reflexes
increased, speech disorder, dysarthria, intracranial hypertension,
thinking abnormal, nervousness, hypesthesia; Infrequent: confusion, twitching, Babinski sign positive,
circumoral paresthesia, hemiplegia, hypotonia, convulsion, extrapyramidal
syndrome, insomnia, meningitis, depersonalization, CNS depression,
depression, hypokinesia, hyperkinesia, brain edema, paralysis, psychosis,
aphasia, emotional lability, coma, hyperesthesia, myoclonus, personality
disorder, acute brain syndrome, encephalitis, subdural hematoma, encephalopathy,
hostility, akathisia, amnesia, neurosis. Respiratory: Frequent: pneumonia; Infrequent: pharyngitis, sinusitis, hyperventilation, rhinitis, apnea, aspiration
pneumonia, asthma, dyspnea, atelectasis, cough increased, sputum increased,
epistaxis, hypoxia, pneumothorax, hemoptysis, bronchitis. Skin and Appendages: Frequent: rash; Infrequent: maculopapular rash, urticaria,
sweating, skin discoloration, contact dermatitis, pustular rash, skin
nodule. Special Senses: Frequent: taste perversion; Infrequent: deafness, visual field defect,
eye pain, conjunctivitis, photophobia, hyperacusis, mydriasis, parosmia,
ear pain, taste loss. Urogenital: Infrequent: urinary retention, oliguria, dysuria, vaginitis, albuminuria, genital
edema, kidney failure, polyuria, urethral pain, urinary incontinence,
vaginal moniliasis.
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DOSES OF FOSPHENYTOIN SODIUM
INJECTION, USP 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, USP FOR PHENYTOIN SODIUM OR VICE VERSA. The following warnings are based on experience
with Fosphenytoin Sodium Injection, USP or phenytoin. Status Epilepticus Dosing Regimen Do not administer
Fosphenytoin Sodium Injection, USP at a rate greater than 150 mg PE/min. The dose of IV Fosphenytoin
Sodium Injection, USP (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, USP 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, USP is preferred because the time to achieve therapeutic
plasma phenytoin concentrations is greater following IM than that
following IV administration (see DOSAGE AND ADMINISTRATION). 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 be done 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. 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 encountered
in elderly or gravely ill patients. Therefore, careful cardiac monitoring
is needed when administering IV loading doses of Fosphenytoin Sodium
Injection, USP. Reduction in rate of administration or discontinuation
of dosing may be needed. Fosphenytoin Sodium
Injection, USP should be used with caution in patients with hypotension
and severe myocardial insufficiency. Rash Fosphenytoin
Sodium Injection, USP 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, USP or phenytoin administration is contraindicated. 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, USP should be
immediately discontinued and not readministered. 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, e.g., fever, rash, and liver
involvement. In all cases of lymphadenopathy, follow-up observation
for an extended period is indicated and every effort should be made
to achieve seizure control using alternative antiepileptic drugs. Alcohol Use Acute alcohol intake may increase plasma phenytoin concentrations
while chronic alcohol use may decrease plasma concentrations. Usage in Pregnancy Clinical: 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 mcg/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 non-maternotoxic 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.
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Fosphenytoin Sodium Injection, USP 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, USP
in this use has not been systematically evaluated for more than 5
days. Fosphenytoin Sodium Injection, USP 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.
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| dailymed-instance:name |
Fosphenytoin Sodium
|