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Fosphenytoin Sodium Injection, USP
Brief Summary of Prescribing Information
WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH
RAPID INFUSION RATES
The rate of intravenous fosphenytoin administration should not
exceed 150 mg phenytoin sodium equivalents (PE) per minute
because of the risk of severe hypotension and cardiac arrhythmias.
Careful cardiac monitoring is needed during and after
administering intravenous fosphenytoin. Although the risk of
cardiovascular toxicity increases with infusion rates above the
recommended infusion rate, these events have also been reported at
or below the recommended infusion rate. Reduction in rate of
administration or discontinuation of dosing may be needed (see
WARNINGS and DOSAGE AND ADMINISTRATION).
Fosphenytoin sodium injection, USP is a prodrug intended for
parenteral administration; its active metabolite is phenytoin. 1.5 mg
fosphenytoin sodium, USP (hereafter referred to as fosphenytoin)
equivalent to 1 mg phenytoin sodium and is referred to as 1 mg
phenytoin equivalents (PE). The amount and concentration of
fosphenytoin is always expressed in terms of mg PE.
Fosphenytoin injection is marketed in 2 mL vials containing a total of
100 mg PE and 10 mL vials containing a total of 500 mg PE. The
concentration of each vial is 50 mg PE/mL. Fosphenytoin 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
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 weight of fosphenytoin is 406.24.
IMPORTANT NOTE: Throughout all fosphenytoin injection
product labeling, the amount and concentration of fosphenytoin are
always 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 substituting fosphenytoin for phenytoin or vice
Care should be taken to ensure that fosphenytoin is always
prescribed and dispensed in phenytoin sodium equivalent (PE) (see
DOSAGE AND ADMINISTRATION).
Following parenteral administration of fosphenytoin 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 is administered under conditions of use recommended in
Mechanism of Action
Fosphenytoin is a prodrug of phenytoin and accordingly, its
anticonvulsant effects are attributable to phenytoin.
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 phen ytoin on ventricular
automaticity, fosphenytoin injection is contraindicated in patients with
sinus bradycardia, sino-atrial block, second and third degree A-V block,
and Adams-Stokes syndrome.
Coadministration of fosphenytoin is contraindicated with delavirdine
due to potential for loss of virologic response and possible resistance to
delavirdine or to the class of non-nucleoside reverse transcriptase
DOSES OF FOSPHENYTOIN ARE ALWAYS EXPRESSED IN
TERMS OF MILLIGRAMS OF PHENYTOIN SODIUM
EQUIVALENTS (mg PE). 1 mg PE IS EQUIVALENT TO 1 mg
DO NOT, THEREFORE, MAKE ANY ADJUSTMENT IN THE
RECOMMENDED DOSES WHEN SUBSTITUTING
FOSPHENYTOIN FOR PHENYTOIN SODIUM OR VICE
VERSA. FOR EXAMPLE, IF A PATIENT IS RECEIVING 1000
mg PE OF FOSPHENYTOIN, THAT IS EQUIVALENT TO 1000
mg OF PHENYTOIN SODIUM.
Status Epilepticus Dosing Regimen
Because of the increased risk of adverse cardiovascular reactions
associated with rapid administration, do not administer
fosphenytoin at a rate greater than 150 mg PE/min.
The dose of IV fosphenytoin (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 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
phenytoin sodium 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.
Cardiovascular Risk Associated with Rapid Infusion
As non-emergency therapy, intravenous fosphenytoin should be
administered more slowly. Because of the risks of cardiac and local
toxicity associated with IV fosphenytoin, oral phenytoin should be
used whenever possible.
Because adverse cardiovascular reactions have occurred during
and after infusions, careful cardiac monitoring is needed during
and after the administration of intravenous fosphenytoin.
Reduction in rate of administration or discontinuation of dosing
may be needed.
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 judgment 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.
Serious Dermatologic Reactions
Serious and sometimes fatal dermatologic reactions, including toxic
epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have
been reported with phenytoin treatment. The onset of symptoms is
usually within 28 days, but can occur later. Fosphenytoin should be
discontinued at the first sign of a rash, unless the rash is clearly not
drug-related. If signs or symptoms suggest SJS/TEN, use of this drug
should not be resumed and alternative therapy should be considered. If
a rash occurs, the patient should be evaluated for signs and symptoms
of Drug Reaction with Eosinophilia and Systemic Symptoms (see
DRESS/Multiorgan Hypersensitivity below).
Drug Reaction with Eosinophilia and Systemic Symptoms
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS),
also known as Multiorgan hypersensitivity, has been reported in
patients taking antiepileptic drugs, including phenytoin and
fosphenytoin. Some of these events have been fatal or life-threatening.
DRESS typically, although not exclusively, presents with fever, rash,
and/or lymphadenopathy, in association with other organ system
involvement, such as hepatitis, nephritis, hematological abnormalities,
myocarditis, or myositis sometimes resembling an acute viral infection.
Eosinophilia is often present. Because this disorder is variable in its
expression, other organ systems not noted here may be involved. It is
important to note that early manifestations of hypersensitivity, such as
fever or lymphadenopathy, may be present even though rash is not
evident. If such signs or symptoms are present, the patient should be
evaluated immediately. Fosphenytoin should be discontinued if an
alternative etiology for the signs or symptoms cannot be established.
Cases of acute hepatotoxicity, including infrequent cases of acute
hepatic failure, have been reported with phenytoin. These events may
be part of the spectrum of DRESS or may occur in isolation. 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 should be immediately discontinued and not
Hematopoietic 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
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 DRESS. 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.
Acute alcohol intake may increase plasma phenytoin concentrations
while chronic alcohol use may decrease plasma concentrations.
Usage in Pregnancy
Risks to Mother
An increase in seizure frequency may occur during pregnancy because
of altered phenytoin pharmacokinetics. Periodic measurement of plasma
phenytoin concentrations may be valuable in the management of
pregnant women as a guide to appropriate adjustment of dosage (see
PRECAUTIONS, Laboratory Tests). However, postpartum
restoration of the original dosage will probably be indicated.
Risks to the Fetus
If this drug is used during pregnancy, or if the patient becomes pregnant
while taking the drug, the patient should be apprised of the potential
harm to the fetus.
General: (Fosphenytoin specific)
Severe burning, itching, and/or paresthesia were reported by 7 of 16
normal volunteers administered IV fosphenytoin 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 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 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.
Local Toxicity (Purple Glove Syndrome)
Edema, discoloration, and pain distal to the site of injection (described
as “purple glove syndrome”) have also been reported following
peripheral intravenous fosphenytoin injection. This may or may not be
associated with extravasation. The syndrome may not develop for
several days after injection.
The phosphate load provided by fosphenytoin (0.0037 mmol
phosphate/mg PE fosphenytoin) should be considered when treating
patients who require phosphate restriction, such as those with severe
IV Loading in Renal and/or Hepatic Disease or in Those with
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
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
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.
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 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 were
concurrently administered in single submaximal doses.
The most significant drug interactions following administration of
fosphenytoin 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 CYP2C9 and CYP2C19 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:
Note: The list is not intended to be inclusive or comprehensive.
Individual drug package inserts should be consulted.
Drugs that affect phenytoin concentrations:
• Drugs that may increase plasma phenytoin concentrations include:
acute alcohol intake, amiodarone, anti-epileptic agents
(ethosuximide, felbamate, oxcarbazepine, methsuximide,
topiramate), azoles (fluconazole, ketoconazole, itraconazole,
miconazole, voriconazole), capecitabine, chloramphenicol,
chlordiazepoxide, disulfiram, estrogens, fluorouracil, fluoxetine,
fluvastatin, fluvoxamine, H2-antagonists (e.g ., cimetidine),
halothane, isoniazid, methylphenidate, omeprazole, phenothiazines,
salicylates, sertraline, succinimides, sulfonamides (e.g.,
sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-
trimethoprim), ticlopidine, tolbutamide, trazodone and warfarin.
• Drugs that may decrease plasma phenytoin concentrations include:
anticancer drugs usually in combination (e.g., bleomycin,
carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine,
chronic alcohol abuse, diazepam, diazoxide, folic acid,
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