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Phenytoin vs Fosphenytoin

Karen Kirschbaum & Cheryle Gurk-Turner

To cite this article: Karen Kirschbaum & Cheryle Gurk-Turner (1999) Phenytoin vs
Fosphenytoin, Baylor University Medical Center Proceedings, 12:3, 168-172, DOI:
10.1080/08998280.1999.11930167

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Published online: 28 Jan 2018.

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nil PhamulCology notes
~ .
Phenytoin vs fosphenytoin
KAREN KIRSCHBAUM, PHARMD, AND CHERYLE GURK~ TURNER, RPH
Department of Phannacy Services, Baylor University Medical Center, Dallas
I
n 1996, Parke-Davis (Division of Warner-Lambert Com-
pany, Morris Plains, N.J.), the manufacturer of a phenytoin
sodium injection (Dilantin), obtained approval from the
Food and Drug Administration (FDA) to market fosphenytoin
(Cerebyx) 0, 2). Fosphenytoin, the long-awaited phosphate
ester pro-drug of phenytoin, was developed to overcome many
of the complications associated with parenteral phenytoin ad-
ministration and was intended to replace Dilantin (2, 3). To
avoid the need to perform molecular weight-based dosage ad-
justments, the manufacturer has expressed the dose of fos-
phenytoin as phenytoin sodium equivalents (PE) (2,4). Along
with the benefits of fosphenytoin comes an expensive price tag,
forcing clinicians to question whether fosphenytoin is worth the
added cost (5, 6). In this review we discuss the 2 agents and
present the rationale for Baylor University Medical Center's
guidelines for fosphenytoin administration.
Table 1 summarizes the FDA-approved uses for both agents.
Although not approved by the FDA for the indication, pheny-
toin is also effective in the treatment of various atrial and ven-
tricular arrhythmias, including arrhythmias due to digitalis
toxicity. It prolongs the effective refractory period and suppresses
ventricular pacemaker automaticity (7). Furthermore, phenytoin
has been found effective in preventing early onset, posttraumatic
seizures (8). Higher doses are also used in the management of
trigeminal neuralgia (9).
PHARMACOKINETICS
Orally, phenytoin is absorbed primarily in the small intes-
tine, with a small amount absorbed in the stomach. The rate and
extent of absorption depend upon the product formulation and
the physiologic state of the patient. The rapid-release, or prompt,
formulation has a dissolution rate that approximates 85% in 30
minutes, producing peak serum concentrations in 1.5 to 3 hours.
It must be administered at least twice daily to provide therapeu-
tic serum concentrations. The slow-dissolution, or extended,
formulation (Dilantin Kapseal, Parke-Davis, Division of Warner-
Lambert Company, Morris Plains, N.J.) provides peak serum con-
centrations in 4 to 12 hours, allowing for once-daily dosing (7,
9,10).
In patients with normal renal function, phenytoin plasma
protein binding is 87% to 93%. Binding is lower in neonates and
elderly or uremic patients. Concentrations of phenytoin in cere-
168
Table 1. Indications (4, 7)
Agent Brand name Labeled indications for seizure control
fosphenytoin Cerebyx status epilepticus
seizures during/after neurosurgery
short-term substitute for oral phenytoin
phenytoin Dilantin tonic-clonic (grand mal)
complex partial (psychomotor)
status epilepticus
seizures during/after neurosurgery
brospinal fluid are identical to unbound concentrations in
plasma, reaching peak values 15 to 60 minutes after intravenous
administration. Phenytoin also crosses the placenta and can be
found in breast milk (7, 10).
Fosphenvtoin converts to phenytoin, formaldehyde, and
phosphate rapidly and virtually completely, with negligible
amounts of fosphenytoin remaining in plasma 1 hour after admin-
istration. The conversion half-life ranges from 8 to 21 minutes,
with a mean of 15 minutes. Phosphatases in the liver, red blood
cells, and tissue convert the parent agent to phenytoin, indepen-
dent of the serum concentrations of either the parent or active
drug. In patients with hepatic or renal disease, fosphenytoin may
have a conversion half-life that is 50% that of healthy patients.
This faster conversion rate may be due, in part, to decreased pro-
tein binding secondary to hypoalbuminemia 0, 3).
After intramuscular administration, fosphenytoin is 98% to
99% absorbed and is therefore considered bioequivalent to in-
travenous administration of the same agent. However, the pro-
cess of absorption appears to be the rate-limiting step in the
attainment of therapeutic serum levels. Therapeutic phenytoin
concentrations are achieved 30 minutes after intramuscular ad-
ministration, and peak concentrations occur at 3 hours 0, 2).
When injectable phenytoin (pH of 12) is administered intramus-
cularly, the water solubility of the drug decreases substantially,
causing the drug to precipitate at the injection site. This results
in slow and erratic absorption (7, 10).
Like phenytoin, fosphenytoin binds extensively to albumin.
It displaces any lingering phenytoin from plasma protein bind-
BUMC PROCEEDINGS 1999;12:168-172
JULY 1999 PHENYTOIN VS FOSPHENYTOIN
ing sites, increasing up to 30% the unbound phenytoin fraction
available for antiepileptic activity. This occurs mainly during the
conversion of the pro-drug to the active phenytoin compound
(30 to 60 minutes after administration). Phenytoin displacement
ishighest after intravenous administration of a large loading dose
of fosphenytoin (-15 mg/kg) infused at a rapid rate (50 to 150
mg PE/min). This displacement phenomenon transiently offsets
the delay required for fosphenytoin to convert to active com-
pound after intravenous administration. Phenytoin binding re-
turns to normal as plasma fosphenytoin levels decline. In
contrast, little displacement is noted after intramuscular admin-
istration of fosphenytoin due to the greater time required for drug
absorption from the injection site (1, 3, 4).
COMPARATIVE SAFETY
Intravenous fosphenytoin vs intravenous phenytoin
Jamerson et al reviewed the frequency, severity, and time
course of venous irritation after administration of a single intra-
venous dose of phenytoin compared with an equimolar dose of
fosphenytoin. Twelve volunteers were randomly given a 30-
minute peripheral infusion of either undiluted phenytoin (250
mg) or fosphenytoin (375 mg). They returned 14 to 21 days later
and received an infusion of the crossover agent in the other fore-
arm. The subjects were then asked to assess any venous irrita-
tion (pain, burning, or itching) on a lO-point ordinal scale, while
the investigators evaluated the injection site for phlebitis, indu-
ration, exudation, and cording in a blind manner. Follow-up
continued for 120 hours after the infusion. All 12 patients re-
ported pain at the infusion site during the phenytoin infusion,
while only 2 reported pain in this area during the fosphenytoin
administration. Eight subjects experienced phlebitis with pheny-
toin, but the investigators found only 1 case of phlebitis with
fosphenytoin (P < 0.05). Six patients had cording with pheny-
toin; no cording was found with fosphenytoin (11).
In a study partially funded by Parke-Davis, Boucher et al
randomly assigned 116 neurosurgical patients who required anti-
convulsant prophylaxis or treatment to receive either intrave-
nous fosphenytoin (n = 88) or intravenous phenytoin (n = 28)
in a double-blind trial. Those patients assigned to the intrave-
nous fosphenytoin group received a mean loading dose of 1082
mg PE, followed by a mean maintenance dose of 411 mg PE. The
28 patients assigned to the phenytoin group received a mean
loading dose of 1082 mg, followed by a mean maintenance dose
of 422 mg. Treatment was continued for 3 to 14 days. Seizures
were reported in 3% of the intravenous fosphenytoin and 7% of
the intravenous phenytoin patients, which was not statistically
significant (NS). Sixty-six percent of the fosphenytoin patients
and 61% of the phenytoin patients experienced a decrease in
their systolic blood pressure >20 mm Hg (NS). Adverse events
necessitated reduced infusion rates in 14% of the intravenous
fosphenytoin and 36% of the intravenous phenytoin recipients
(NS). Six percent of those patients receiving fosphenytoin and
25% of those receiving intravenous phenytoin reported mild
injection site irritation (P < 0.05). The authors concluded that
intravenous fosphenytoin was better tolerated than intravenous
phenytoin in this patient population (12).
169
Intravenous fosphenytoin vs intramuscular fosphenytoin
Leppik and colleagues administered maintenance doses of
fosphenytoin (range, 150 to 450 mg PE) to 43 patients at 4 cen-
ters during an open-label, crossover study of patients with well-
controlled seizures. A total of 32 patients received fosphenytoin
intramuscularly, and 37 patients were given the agent intrave-
nously. There were no statistically significant changes in heart
rate, respiration, or diastolic blood pressure in either group. How-
ever, patients did experience a significant decrease in systolic
blood pressure 15 minutes to 2 hours after intravenous adminis-
tration and 30 minutes to 4 hours after intramuscular adminis-
tration (P < 0.05). Forty-four percent of the patients receiving
intravenous fosphenytoin and 25% of the patients receiving in-
tramuscular fosphenytoin had> 1 episode of nystagmus. In addi-
tion, 21% of patients receiving intravenous fosphenytoin had
paresthesias, and 17% of those patients receiving intramuscular
fosphenytoin reported pain at the injection site. The significance
of these events was not addressed (13).
COMPARATIVE EFFICACY
Phenytoin has been used in the treatment of seizures since
its anticonvulsant activity wasfirst discovered about 50 yearsago.
Although no placebo-controlled trial has been performed to prove
phenytoin anticonvulsant efficacy, extensive clinical experience
has provided the basisfor its acceptance as an antiepileptic agent.
In fact, many efficacystudies, including fosphenytoin trials, have
used phenytoin as the comparison drug (14).
Phenytoin: status epilepticus
Treiman and colleagues performed a multicenter, random-
ized, double-blind trial comparing the efficacy oflorazepam, 0.1
rug/kg: phenytoin, 18 mg/kg; diazepam, 0.15 mg/kg, plus pheny-
toin, 18 mg/kg; and phenobarbital, 15 mg/kg, in 518 patients with
generalized status epilepticus. Treatment success was defined as
no motor or electroencephalographic seizure 20 to 60 minutes
from the start of treatment. The authors reported that each treat-
ment was equally effective; however, lorazepam alone was supe-
rior to phenytoin alone when seizures were assessed 20 minutes
after initial drug administration. Unfortunately, this study did not
examine the current preferred treatment of status epilepticus,
lorazepam followed by phenytoin (15).
Fosphenytoin: status epilepticus
The use of intravenous fosphenytoin for the treatment of
status epilepticus was studied in an open-label, single-dose trial
of patients having ~2 generalized seizureswithout regaining con-
sciousness between seizures (16). Fifty patients (93%) who re-
ceived fosphenytoin at a mean dose of 1450 mg (range, 324 to
3000 mg) delivered at a mean infusion rate of 182 mg/min (range,
55 to 327 mg/min) had seizures terminate within 30 minutes of
receiving the drug. In 27 of 28 patients, total phenytoin concen-
trations ~ 10 ~mL and free phenytoin concentrations ~ 1 ~mL
were achieved within 10 to 20 minutes of fosphenytoin initiation.
Some patients experienced a decline in their blood pressure, but
this was not considered clinically significant (16, 17).
170 BAYLOR UNIVERSITY MEDICAL CENTER PRlX:EEDINGS VOLUME 12, NUMBER 3

Fosphenytoin: substitutionfor oral phenytoin cardiac monitoring is recommended during administration of in-
Two hundred forty patients who were receiving oral pheny- travenous loading doses. In addition, intravenous phenytoin may
toin for either a seizure disorder or postoperative seizure prophy- cause hypotension if it is administered at rates exceeding 50 mg!
laxis were enrolled in a multicenter, randomized, double-blind, min (2, 11).
placebo-controlled study. Patients were randomized to receive Adverse effects specific to fosphenytoin include burning,
either 5 days of treatment with their regular oral phenytoin dose itching, and paresthesias that may last up to 14 hours in some
plus an intramuscular placebo (n = 61) or an equimolar dose of patients. Although the area of discomfort varies, several reports
intramuscular fosphenytoin plus an oral placebo (n = 179). The localize these areas of discomfort to the groin, back, lower abdo-
incidence of adverse events in the 2 groups was similar (fos- men, head, and neck. These paresthesias usually occur during
phenytoin, 68%; phenytoin, 62%; NS), but there were differences intravenous administration of larger doses at rapid infusion rates.
in the types of adverse events reported: nystagmus (15% vs 8%), Hypotension may also occur after intravenous infusions of high
tremor (10% vs 13%), headache (9% vs 5%), incoordination (8% doses at rapid rates. Cardiac monitoring is recommended during
vs 5%), ecchymosis (7% vs 5%), somnolence (7% vs 10%), and administration and for 10 to 20 minutes after completion of in-
dizziness (5% vs 3%), in fosphenytoin and phenytoin, respec- travenous loading doses. Also, fosphenytoin contains 0.0037
tively. In 13 patients who underwent a more in-depth pharrna- mMol phosphate/mg PE and has the potential to contribute to
cokinetic evaluation, intramuscular fosphenytoin was found to phosphate accumulation in patients with renal dysfunction
produce plasma phenytoin concentrations equal to or greater than (3,4, 10).
those produced with an equimolar dose of oral phenytoin.
Fosphenytoin-treated patients experienced 0.13 seizures per day DOSING AND ADMINISTRATION
compared with the phenytoin-treated patients who had a mean Since phenytoin and fosphenytoin are both highly protein
of 0.18 seizuresper day (NS). Overthe 5 days of therapy, the mean bound, dosage adjustments may be required in patients with re-
trough phenytoin concentrations in the fosphenytoin group rose nal/hepatic disease or in those who have hypoalbuminemia. As
slightly, which the authors felt wasconsistent with the differences the unbound drug concentration correlates better with pheny-
in bioavailability between intramuscular fosphenytoin (99%) and toin's efficacy and toxicity, it may be prudent to make these dos-
oral therapy (90%). As a result, the investigators suggested that age adjustments based on free phenytoin or adjusted phenytoin
it might be prudent to measure serum phenytoin concentrations serum concentrations (4, 20).
after 3 to 4 days of the intramuscular substitution (18). Loading doses of both phenytoin and fosphenytoin require
dilution prior to intravenous administration (4, 7). Injectable
ADVERSE REACTIONS phenytoin is compatible only with 0.9% saline and should be
Adverse effects of phenytoin include gingival hyperplasia, infused through an in-line filter because of its potential to pre-
hirsutism, and, in some patients, behavioral changes and cogni- cipitate at physiologic pH. Also, as a result of the hypotension
tive dysfunction. In addition, nausea, emesis, nystagmus, ataxia, and bradycardia associated with intravenous phenytoin admin-
lethargy, and seizures can occur at toxic concentrations. Pheny- istration, a maximum rate of 50 mg/min is recommended (25 mg/
toin can also cause a mild increase in liver enzymes that does not min in the elderly and patients with cardiac disease) (7).
require discontinuation of therapy. More
serious adverse effects include thrombo-
cytopenia, anemia, leukemia, and lymph- Table 2. Comparison of dosing recommendations (4, 7)
adenopathy. Phenytoin may also cause
Stevens-Johnson syndrome or toxic epi- Dosing parameter Fosphenytoin Phenytoin
dermal necrolysis. If a rash appears during Oral
phenytoin therapy, it is recommended that Initial adult dose not available 100 mg. 3 times a day
the drug be discontinued immediately. An Initial pediatric dose not available 5 mg/kg/day
exfoliative, bullous, or purpuric rash is sug- Intravenous
gestive of Stevens-Johnson syndrome. Loading dose 15-20 mgPE/kg 15-20mg/kg
However, if the rash is morbilliform or Maintenance dose 4-6 mgPE/kg/day 100mg every 6-8 hours
scarlatiniform, therapy may be resumed Maintenance (oral substitute) same as oral phenytoin dose same as oral dose
after the rash has resolved (7,10, 19). Maximum infusion rate 150mgPE/min 50mg/min
Injectable phenytoin can cause local Minimum timefor 1-gram load 6.7 minutes 20minutes
or injection site reactions such as pain, Compatible with saline yes yes
burning, or itching; however, the fre- Compatible with 5%dextrose yes no
quency of such complaints is poorly de-
Intramuscular
scribed. Depressed atrial and ventricular
Nonemergent loading dose 10-20mgPE/kg not recommended
conduction and ventricular fibrillation
Maintenance dose 4-6 mg PE/kg not recommended*
have also been associated with the intra-
Maintenance (oral substitute) same as oral phenytoin dose dose may need to beincreased 50%
venous use of phenytoin. These complica-
tions are more commonly encountered in ·can begiven 100mgevery 6-8 hours for upto 1 week
elderly or debilitated patients. As a result,
JULY 1999 PHENYTOIN VS FOSPHENYTOIN
Because fosphenytoin exhibits a relative decrease in protein
binding with higher doses administered at higher rates of infu-
sion, it is recommended that loading doses of fosphenytoin be
administered at 150 mg PE/min when rapid achievement of
therapeutic plasma concentrations is critical. In nonemergent
situations, administration at lower infusion rates (50 to 100 mg
PE/min) will produce a slightly lower and delayed maximum free
phenytoin concentration. Fosphenytoin is compatible with both
dextrose and saline solutions at concentrations ranging from 1.5
to 25 mg PE/mL. Intramuscular fosphenvtoin injection volumes
of up to 30 mL at a single site have been used and were well tol-
erated, but, as a rule, many patients will not tolerate this injection
volume; a maximum of 5 mL per site is recommended (3, 4, 21).
A comparison of additional dosing recommendations is pro-
vided in Table 2.
RECOMMENDED MONITORING
Serum phenytoin determinations should be obtained at least
I hour after completion of a loading dose infusion. Follow-up
phenytoin concentrations are recommended at least 5 to 7 half-
lives after treatment initiation, dose change, or drug change (I.e.,
when any drug known to interact with phenytoin is added or
deleted from the patient's regimen). Samples are typically col-
lected in a serum (red-top) tube that does not contain an antico-
agulant (1, 7).
Cardiac and respiratory monitoring recommendations for
fosphenytoin are the same as those for phenytoin. In order to al-
low time for fosphenytoin to convert to phenytoin, serum pheny-
toin concentrations should be obtained at least 2 hours after
completion of an intravenous loading dose of fosphenvtoin or 4
hours after an intramuscular dose ( 1, 3). However, unlike patients
receiving phenytoin, patients receiving fosphenytoin should have
their blood samples collected in tubes containing EDTA as an
anticoagulant (lavender top) to minimize ex vivo conversion of
fosphenytoin to phenytoin (1).
DISCUSSION
Due to the disparity in acquisition costs between injectable
phenytoin and injectable fosphenvtoin, some institutions have
reservations about adding fosphenytoin to their formularies. A
single study addressing the potential pharmacoeconomic impact
of fosphenytoin was conducted by Marchetti and colleagues. The
study, conducted in 1994, employed an activity-based, cost-
accounting model and was funded by Parke-Davis. The conclu-
sions of the study were in favor of fosphenytoin; however, many
published criticisms question the study's design, cost-accounting
methods, and bias potential (22).
Fosphenytoin's better tolerability and more rapid intravenous
administration rate make it attractive for loading doses. However,
given the time course required for its conversion by tissue phos-
phatases, it does not deliver therapeutic levels of phenytoin at a
more rapid rate than injectable phenytoin. To date, fosphenytoin
has not shown a statistically (or clinically) significant reduction
in cardiovascular side effects over injectable phenytoin. In addi-
tion, the product's storage requirement of refrigeration and the
potential for medication errors with multiple forms of intravenous
phenytoin make it a less desirable product.
171
Baylor University Medical Center has made both phenytoin
and fosphenytoin available as formulary choices. However, guide-
lines for the use of fosphenytoin injection have been developed
for its use at the institution. These guidelines are presented in
the Appendix.
References
1. Boucher BA. Fosphenytoin: a novel phenytoin prodrug. Pharmacotherapy
1996;16:777-791.
2. Fierro LS. Savulich DH. Benezra DA. Safety of fosphenytoin sodium. Am
] Health Syst Pharm 1996;53:2707-2712. .
3. Browne TR. Kugler AR. Eldon MA. Pharmacology and pharmacokinetics
of fosphenvtoin. Neurology I996;46( 6 Suppl 1):S3-S7.
4. Cerebvx package insert. Morris Plains. N.J.: Parke-Davis. 1996.
5. Miller MH. Fosphenytoin: worth the cost? Ann Emerg Med 1997;29:823.
6. Marble EL. Cost of phenytoin. Ann Emerg Med 1998;31:138-139.
7. Phenytoin. In McEvoy GK. ed. AHFS Drug Information. Bethesda. Md.:
American Society of Health-System Pharmacists. 1999:1861-1864.
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randomized. double-blind study of phenytoin for the prevention of post-
traumatic seizures. N Engl] Med 1990;323:497-502.
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1081.
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Epilepsy: A Comprehensive Textbook. Philadelphia: Lippincott-Raven Pub-
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JR. Venous irritation related to intravenous administration of phenytoin
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Kramer RE. Young B. Parks BRJr. Kugler AR. The safety. tolerability. and
pharmacokinetics of fosphenytoin after intramuscular and intravenous
administration in neurosurgery patients. Pharmacotherapy 1996;16:638-645.
13. Leppik IE. Boucher BA. Wilder BJ. Murthy VS. Watridge C. Graves NM.
Rangel RJ. Rask CA. Turlapatv P. Pharmacokinetics and safety of a pheny-
toin prodrug given i.v. or l.m. in patients. Neurology 1990;40:456-460.
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Handforth A. Faught E. Calabrese VP. Uthman BM. Ramsay RE. Mamdani
MB. A comparison of four treatments for generalized convulsive status
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S19.
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Kugler AR. Safety and tolerance of multiple doses of intramuscular fos-
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NeuroI1996;53:764-768.
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172 BAYLOR UN IV ERSITY MEDICAL C ENTER PROCEEDINGS VOLUME 12. N UMBER 3

Appendix. Guidelines for the use of fosphenytoin (Cerebyx) injection

Guii:telines
Fosphenytoin isawater-soluble pro-drug of phenytoin that can be administered intravenously at a more rapid rate and is
less likely to cause injection site reactions than parenteral phenytoin. Fosphenytoin can also be administered intramuscu-
larly. Though the agent has some definite pharmaceutical advantages, it carries an extremely high cost compared with
intravenous phenytoin (-32 to 38 times the cost of phenytoin).Thus, it is necessary to limit fosphenytoin use to clinical
situations where its pharmaceutical characteristics provide a clear clinical advantage compared with injectable pheny-
toin.

Background
Fosphenytoin is preferred over phenytoin injection for thefollowing groups of patients:
1) Patients who are in status epilepticus or otherwise in need of rapid intravenous loading with phenytoin but who DO
NOT have central intravenous access. Use of concomitant agents such as an intravenous benzodiazepine will typically
be needed as well. Once the emergent dose of fosphenytoin has been given, phenytoin injection should be used for
any subsequent doses if thepatient has adequate intravenous access.
2) Patients who have previously experienced significant phlebitis, continuing pain at the injection site, or hypotension
secondary to receiving injectable phenytoin at theappropriate rate of <50 mg/min. Fosphenytoin iscontraindicated in
patients who are hypersensitive to phenytoin.
3) Patients in whom the intramuscular route of administration is required, e.g., patients temporarily unable to take oral
phenytoin who donot have an intravenous access.

Fos l1en}'.!oin dosing ani:! ai:!ministration

Although 75 mg of fosphenytoin isequivalent to 50 mg phenytoin, alldoses of fosphenytoin should be explicitly prescribed
in terms of phenytoin equivalent (PE) doses to reduce thepotential for error and simplify dose conversion.
1) For status epilepticus, a loading dose of 15-20 mg PE/kg isadministered at 100-150 mg PE/min.
2) Oral phenytoin should be used for maintenance if feasible. If the clinical situation fulfills one of the above criteria,
fosphenytoin may be given. The usual maintenance dose for fosphenytoin is4-6 mg PE/kg/day, eitherintramuscularly
or intravenously.
3) Administration rates of 50 mg PE/min may be better tolerated in patients who are elderly or hypoalbuminemic or who
have cardiovascular, renal, or hepatic disease.
4) Patients receiving intramuscular fosphenytoin as a temporary substitutefor oral phenytoin should receive their same
total daily PE dose.
5) When giving the drug intramuscularly, the appropriate volume required per injection site should be determined. For
many patients, thedose will need to be divided among two or more injections of 5 ml.

Fosp.l1eny'!oin monitoring recommendations

1) For patients receiving intravenous fosphenytoin loading doses, themanufacturer recommends continuous electrocar-
diography, blood pressure, and respiratory function monitoring during theinfusion and for at least 10-20 minutes af-
ter completion.
2) Because fosphenytoin must be metabolically converted to phenytoin in vivo, serum phenytoin concentrations should
not be measured until at least 2 hours after intravenous loading or at least 4 hours after an intramuscular dose.