Introduction References
Annotated Bibliography
Questions
Managing
Phenytoin Serum Levels in the ED
Case
Presentation
A 35-year old otherwise
healthy male with a history of a seizure disorder since childhood
presents to the emergency department with EMS personnel after having
had a seizure. He was postictal upon EMS arrival but in the emergency
department he is at his normal baseline mental status. He states that
his last seizure was approximately 2 years ago. He ran out of his
phenytoin approximately 2 weeks ago and has not picked up the prescription
that is waiting for him at a local pharmacy. He has normal vital signs
and a normal physical exam. His serum phenytoin level is undetectable.
This presentation will
address the following questions:
1. What is the most effective
phenytoin or fosphenytoin dosing strategy for preventing short-term
seizure recurrence in a patient with a pre-existing seizure disorder
who presents to the ED with a “subtherapeutic” serum phenytoin level?
2. What are the pharmacokinetic
concerns as they relate to achieving a serum phenytoin level >
10 mg/L?
3. What adverse effects
are associated with oral, intravenous and intramuscular dosing of
phenytoin and fosphenytoin?
4. What is the risk of
seizure recurrence in a patient who is discharged from the emergency
department?
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Managing
Phenytoin Serum Levels in the ED
Introduction
There is much debate among emergency
physicians as to the safest, most efficient and cost effective way
to treat a patient who has had a recent seizure and has a subtherapeutic
serum phenytoin level. Common
contemporary dosing strategies include:
1.
Administering
an intravenous loading dose of phenytoin or fosphenytoin and then
starting/restarting daily oral maintenance dosing
2.
Administering
an oral loading dose of phenytoin and then starting/restarting daily
oral maintenance dosing
3.
Starting/restarting
daily oral maintenance dosing without administering a loading dose
Emergency
physicians should understand that the most important measure of a
particular antiepileptic drug dosing strategy should be efficacy in
preventing seizure recurrence when viewed in conjunction with adverse
events and cost.
What
is the relationship between a “therapeutic” serum phenytoin level
and the prevention of seizures?
Most
laboratories report a “therapeutic” serum phenytoin level between
10-20 mg/L. The term
“therapeutic” serum phenytoin level is a misleading since many patients
remain seizure free at serum levels less than 10 mg/L and some patients
may require a serum level greater than 20 mg/L to control their seizures.
(Carter, Leppik 1983) Patients are more likely to have adverse effects
when their serum phenytoin level rises above 20 mg/dL but many patients
will experience adverse effects at “therapeutic” levels. (Ambrosetto,
Product information) Most pharmacokinetic studies use achievement
of a serum phenytoin level > 10 mg/L as the primary outcome
variable. Although achieving a serum phenytoin level > 10
mg/L may be a measure of pharmacokinetic efficacy, a more relevant
measure of clinical efficacy should be prevention of seizure recurrence
with an acceptable adverse effects profile.
What
are the pharmacokinetic concerns as they relate to achieving a serum
phenytoin level > 10 mg/L?
A
serum phenytoin level > 10 mg/L can be achieved by any of
the common contemporary dosing strategies.
Oral phenytoin dosing at the “appropriate” daily maintenance
dose, without a loading dose, can achieve a serum phenytoin level
> 10 mg/L in 3-7 days. (Buchanan, Gugler, Svensmark).
Although many common references recommend that adult dosing
be initiated at 300 mg per day, many patients will not achieve a serum
phenytoin level >
10 mg/L at this daily dose. (Physician’s Desk Reference) Two volunteer
studies showed that less than 20% of adult patients taking 300 mg
per day achieved a serum level > 10 mg/L. (Buchanan, Gugler)
The reasons for this are multifactorial and include failure to dose
the medication based upon a patient’s weight and individual differences
in metabolism. Regardless of the initial dosing strategy employed
patients require a daily maintenance dosing to maintain their serum
level > 10 mg/L. Patients who are discharged on daily maintenance
dosing, even those that receive a loading dose, need follow-up to
make sure that they are receiving the appropriate daily maintenance
dose of phenytoin.
Intravenous
loading of either phenytoin or fosphenytoin usually achieves a peak
serum phenytoin level > 10 mg/L within minutes following
completion of the infusion.
(Carducci, Kugler, Leppik, Salem).
Oral
loading of phenytoin as a single dose and in divided doses can produce
a serum phenytoin level > 10 mg/L in some cases within 3-10
hours and in most cases within 24 hours following the initial ingestion.
(Osborn, Ratanakorn, Record, Wildner 1973)
Intramuscular
loading of fosphenytoin as a single dose and in divided dose can reliably
produce serum phenytoin level > 10 mg/L in most cases within
1-2 hours and in almost all cases within 24 hours following injection.
(Boucher, Browne 1989, Kugler, Uthman, Wilder 1996)
What adverse effects are associated with oral, intravenous and intramuscular
dosing of phenytoin and fosphenytoin?
Irrespective
of the dosing strategy, the most common adverse effects associated
with phenytoin and fosphenytoin include ataxia, nystagmus, tremor
and somnolence. (Wilder 1996)
Fosphenytoin,
the disodium phosphate ester of phenytoin, is a parenteral phenytoin
pro-drug that is rapidly converted to phenytoin by blood and tissue
phosphatases following intravenous and intramuscular injection. (Browne,
Leppich) Many of the
adverse local effects including phlebitis, purple glove syndrome and
tissue necrosis associated with intravenous and intramuscular phenytoin,
occur much less frequently when fosphenhytoin is administered by these
routes. (Comer, Marchetti, O’Brien, Kilarski) Many of the adverse
systemic effects including impairment of myocardial contractility,
dysrhythmias, hypotension and cardiac arrest associated with intravenous
phenytoin administration, have also been reported much less frequently
with intravenous fosphenytoin administration. (Earnest, Russell, York).
This difference in adverse effects between parenteral phenytoin
and fosphenytoin is believed to be in part related to the fact that
parenteral phenytoin preparations contain propylene glycol (40%) and
ethanol (10%) and are adjusted to a pH of 12.
Fosphenytoin, which is more water-soluble, does not contain
these same diluents and has a more physiologic pH of 8.6 to 9. (Browne
1996)
Although it is difficult to make comparisons between studies with
respect to adverse events since most studies do not report adverse
effects in a standardized form and often do not evaluate for their
severity, fosphenytoin appears to have a better safety profile than
intravenously and intramuscularly administered phenytoin. (Boucher,
Jamerson, Henken)
The
acquisition costs of fosphenytoin are considerably more than those
for either parenteral or oral phenytoin products. In 10/2001 it costs
approximately $95.00 for 1000 mg of fosphenytoin, $5.50 for 1000 mg
of parenteral phenytoin and $5.00 for 1000 mg of oral phenytoin. (Kuffner). These prices are consistent with those previously published.
(Browne 1998)
What is the risk of seizure recurrence in a patient who is discharged
from the ED after received phenytoin?
Data
on the risk of seizure recurrence is commonly reported in years not
days. (Hauser) The baseline
rate of seizure recurrence within a few days to a few weeks of ED
discharge for the patient population of interest is unknown. Without
knowing the background prevalence of short-term seizure recurrence,
individual studies that address the rate of seizure short-term recurrence
are difficult to interpret and compare.
It
is difficult to make comparisons between the few studies that did
report the rate of seizure recurrence since most of these studies
included patients with many different etiologies for their seizures.
The underlying cause of seizures is likely an important variable in
determining the rate of seizure recurrence. (Cranford)
The
rate of seizure recurrence could be estimated in two studies, one
involving intravenous phenytoin loading (Cranford, Leppik) and one
involving oral phenytoin loading (Osborn).
Cranford
et al. administered various doses of intravenous phenytoin, mostly15-18
mg/kg, to 139 patients on 159 occasions for “repetitive seizures”.
Cranford reported that 17/159 (28%) patients had a recurrence
of seizures despite a therapeutic phenytoin level and that seizures
were controlled in 80% of patients.
If there was anoxic or metabolic disturbances seizures were
controlled in less than 40% of patients. Leppik et al. reported results
from this same group of patients. Interestingly, the rate of seizure
recurrence over 24 hours could not be correlated to the serum phenytoin
level. Seizure recurrence occurred in 6% of patients with “antiepileptic
drug withdrawal”, 11% of patients with “epilepsy cause undetermined”
and 18% of patients with “miscellaneous condition”
Osborn
et al administered a single 18 mg/kg oral dose of phenytoin capsules
or suspension to 44 patients who presented to the emergency department
following “one or more recent seizures” who had an with undetectable
serum phenytoin level, were awake and had the ability to take oral
phenytoin. Patients were
observed for at least 8 hours.
No patient had a seizure recurrence.
Based
upon these studies it appears that the rate of seizure recurrence
varies from 6-28%, but may be independent of whether or not the patient
received an AED.
What
is the most effective phenytoin or fosphenytoin dosing strategy for
preventing short term seizure recurrence in a patient with a pre-existing
seizure disorder who presents to the emergency department within 24
hours of having had a seizure without status epilepticus and who is
determined to have a “subtherapeutic” serum phenytoin level?
There
are three potential strategies for managing subtherapeutic phenytoin
levels in a patient on phenytoin who presents to the ED having had
a seizure:
1.
Administering
an intravenous loading dose of phenytoin or fosphenytoin and then
starting/restarting daily oral maintenance dosing
2.
Administering
an oral loading dose of phenytoin and then starting/restarting daily
oral maintenance dosing
3.
Starting/restarting
daily oral maintenance dosing without administering a loading dose
The
medical literature does not contain enough information to determine
which of the three strategies is best. There are no well-designed
studies that address the short-term rate of seizure recurrence and
the short-term rate and severity of adverse events by directly comparing
any of the common contemporary dosing strategies. A serum phenytoin
level > 10 mg/L can be achieved by all of the common contemporary
dosing strategies and by intramuscular administration of fosphenytoin.
Fewer adverse events are associated with fosphenytoin administration
when compared to parenteral phenytoin administration but fosphenytoin
is significantly more expensive.
Emergency
physicians need to understand the pharmacokinetic, pharmacoeconomic
and adverse event profiles of phenytoin and fosphenytoin as well as
the limitations of the available medical literature.
Emergency physicians who understand these issues are best suited
to help their patients make informed decisions regarding the different
dosing strategies.
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Managing
Phenytoin Serum Levels in the ED
References
Ambrosetto G, Tassinari CA, Baruzzi A et al:
Phenytoin encephalopathy as probable idiosyncratic reaction:
case report. Epilepsia
1977; 18:405.
Boucher
BA, Feler CA, Dean C, et al. The safety, tolerability and pharmacokinetics
of fosphenytoin after intramuscular and intravenous administration
in neurosurgery patients. Pharmacotherapy
1996;16:638-645.
Browne
TR, Davoudi H, Donn KH, et al.
Bioavailability of ACC-9653 (Phenytoin prodrug). Epilepsia
1989;30:S27-S32.
Browne
TR. Intravenous phenytoin.
Cheap but not necessarily a bargain. Neurology 1998;51:942-943.
Buchanan
RA, Kinkel AW, Goulet JR. The metabolism of diphenylhydantoin (Dilantin)
following once-daily administration. Neurology 1972;22:126-130.
Carducci B, Hedges JR, Beal JC, et al. Emergency phenytoin
loading by constant intravenous infusion. Ann Emerg Med 1984;13:1027-1032.
Carter
CH. Use of parenteral diphenylhydantoin (Dilantin) sodium in control
of status epilepticus. Arch
Neurol Psychiatry 1958;79:136-137.
Comer
JB: Extravasation from intravenous phenytoin. Am J Intrav Ther Clin
Nutr 1984;11:23-29.
Cranford RE, Leppik IE, Patrick B, et al. Intravenous phenytoin:
clinical and pharmacokinetic aspects. Neurology 1978;28:874-880.
Earnest EP, Marx JA, Drury LR: Complications of IV phenytoin
for acute treatment of seizures: recommendations for usage. JAMA 1983;6:762-765.
Gugler
R, Manion CV, Azarnoff DL. Phenytoin: pharmacokinetics and bioavailability.
Clin Pharmacol Ther 1976;19:135-142.
Hauser
WA, Rich SS, Lee JRJ, et al. Risk of recurrent seizures after two
unprovoked seizures. N Engl J Med 1998;338:429-434.
Heneken
SA, Knapp LE, Smith MF, et al. Tolerance of intravenous fosphenytoin
(Cerebrex) compared with Dilantin: an overview of 3 studies. Epilepsia 1996;37(suppl 5):157 (abstract).
Jamerson
BD, Dukes GE, Brouwer KR, et al. Venous irritation related to intravenous
administration of phenytoin versus fosphenytoin. Pharmacotherapy 1994;14:47-52.
Kilarski
DJ, Buchanan C, Von Behren L. Soft-tissue damage associated with intravenous
phenytoin. N Engl J Med 1984;311:1186-1187.
Kuffner
EK: personal communication with hospital pharmacy 10/2001.
Kugler
AR, Knappp LE, Eldon MA. Rapid attainment of therapeutic phenytoin
concentrations following administration of loading doses of fosphenytoin:
a meta-analysis. Neurology
1996;46:A176.
Leppik
IE, Patrick BK, Cranford RE. Treatment of acute seizures and status
epilepticus with intravenous phenytoin. Adv Neurol
1983;34:447-451.
Marchetti
A, Magar R, Fisher J, et al. A pharmacoeconomic evaluation of intravenous
fosphenytoin (Cerebyx) versus phenytoin (Dilantin) in hospital emergency
departments. Clin Ther 1996;18:953-966.
O’Brien
TJ, Cascino GD, So EL, et al. Incidence and clinical consequence of
the purple glove syndrome in patients receiving intravenous phenytoin.
Neurology 1998;51:1034-1039.
Osborn
HH, Zisfein J, Sparano R. Single-dose oral phenytoin loading. Ann
Emerg Med 1987;16:407-412.
Product
Information: DilantinÒ phenytoin. Parke-Davis.
Rantanakorn
D, Kaojarern S, Phuapradit P, et al. Single oral loading dose of phenytoin:
a pharmacokinetics study. J Neurolo Sci 1997;147:89-92.
Record KE, Rapp RP, Young B, et al. Oral
phenytoin loading in adults: rapid achievement of therapeutic plasma
levels. Ann Neurol 1979;5:268-270.
Russell
MA, Bousvaros G: Fatal results from diphenylhydantoin administered
intravenously. JAMA 1968;206:2118-2119.
Salem RB, Wilder BJ, Yost RI, et al. Rapid infusion of phenytoin
sodium loading dose. Am J Hosp Pharm 1981;38:354-357.
Svensmark O, Schiller PJ, Buchthal F. 5-5-Diphenylhydantoin
(Dilantin) blood levels after oral or intravenous dosage in man. Acta
Pharmacol Toxicol 1960;16:331-346.
Uthman
BM, Wilder BJ, Ramsay RE. Intramuscular use of fosphenytoin: an overview.
Neurology 1996;46:S24-S28.
Wilder BJ, Serrano EE, Ramsey RE. Plasma diphenylhydantoin
levels after loading and maintenance doses. Clin Pharcol Ther 1973;14:797-801.
Wilder
BJ, Campbell K, Ramsay RE, et al. Safety and tolerance of multiple
dose of intramuscular fosphenytoin substituted for oral phenytoin
in epilepsy or neurosurgery. Arch Neurol 1996;53:764-768.
York
RC, Coleridge ST. Cardiopulmonary arrest following intravenous phenytoin
loading. Am J Emerg Med
1988;6:255-259.
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Managing
Phenytoin Serum Levels in the ED
Annotated
Bibliography
Osborn
HH, Zisfein J, Sparano R. Single-dose oral phenytoin loading. Ann
Emerg Med 1987;16:407-412.
A
prospective study administering 18 mg/kg of oral phenytoin at one
time to 44 patients with a recent seizure an no detectable serum phenytoin.
Only approximately 50% of patients had therapeutic serum levels
at 10 hours post administration.
No patient had a recurrent seizure during the 8-hour observation
period regardless of serum level
Rantanakorn
D, Kaojarern S, Phuapradit P, et al. Single oral loading dose of phenytoin:
a pharmacokinetics study. J Neurolo Sci 1997;147:89-92
Two
part study of the pharmacokinetics of oral phenytoin loading.
In part I 19 healthy volunteers received 15 mg/kg; serum levels
were in the therapeutic range within 2-3 hours.
Authors concluded that the appropriate dosing for males was
19 mg/kg, and for females, 25 mg/kg.
In part II, phenytoin loading was performed on seizure patients
with therapeutic levels within 2-3 hours.
Concluded that single oral loading was safe and effective.
Earnest
M, Marx J, Drury L. Complications of intravenous phenytoin for acute
treatment of seizures. MAMA 1983: 249:762-765.
Prospective
study of the complications from intravenous phenytoin loading in an
ED. 200 patients had
a total of 72 complications: 29 with burning at infusion site, 36
with drug intoxication, 7 with hypotension or arrhythmias.
Authors recommend infusions at 40 mg/min or less and provide
excellent guidelines for safe administration.
Donovan
P, Cline D. Phenytoin administration by constant intravenous infusion:
Selective rates of administration. Ann Emerg Med 1991; 20:139-142.
Prospective
study of 42 adults receiving intravenous phenytoin, 15 mg/kg.
Concluded that infusions can be safely given at 50 mg/min to
patients with no cardiovascular disease and 25 mg/min to those with
cardiovascular disease.
Leppik
I, Boucher R, Wilder B, et al. Phenytoin prodrug: Preclinical and
clinical studies. Epilepsia 1989 (suppl 2); 30:S22-S26.
This
was one of the first publications on the pharmacokinetics of fosphenytoin
demonstrating its safety of administration and its low side effect
profile. In an open label
component of the study 25 volunteers received intravenous fosphenytoin,
one experienced significant hypotension that was easily corrected.
Wilder
B, Rangel R. Phenytoin: Clinical Use. In: Levy R, Mattson R, Meldrum
B, et al (eds). Antiepileptic
Drugs. Raven Press, New York 1989; 233-239.
This
is an excellent overview of phenytoin; it indications, its pharmacokinetics,
and its administration.
O’Brian
T, Cascino G, So E, Hanna D. Incidence and clinical consequences of
the purple glove syndrome in patients receiving intravenous phenytoin.
Neurology 1998; 51:1034-1039.
Retrospective
review of 179 consecutive patients who received intravenous phenytoin;
6% developed the purple glove syndrome.
One patient required surgical therapy while the others resolved
with conservative therapy.
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Managing
Phenytoin Serum Levels in the ED
Questions
1)
Which of the following is a reported side effect of intravenous loading
of phenytoin?
a)
Vein
sclerosis
b)
Hypotension
c)
Ataxia
d)
Purple
glove syndrome
e)
All
2)
The oral loading dose for phenytoin is:
a)
5
mg / kg
b)
10
mg / kg
c)
20
mg / kg
d)
30
mg / kg
e)
40
mg / kg
3)
Which of the following is a correct statement:
a)
Fosphenytoin
is will precipitate in dextrose solutions and must only be administered
in normal saline.
b)
Fosphenytoin
can be administered intramuscular but absorption is erratic and therapeutic
levels are not reached for at least 4 hours
c)
Fosphenytoin
does not cause hypotension and does not require cardiac monitoring
when administered intravenously
d)
Fosphenytoin
requires a propylene glycol vehicle which limits its infusion rate
e)
Fosphenytoin
is over 98% bioavailable when given intravenously
4)
In patients who are loaded orally with single dose phenytoin, when is
it estimated that their serum level will be in the therapeutic range?
a)
1
hour
b)
3
hour
c)
5
hour
d)
7
hour
e)
9
hour
Answers
1.
e.
2.
c.
3.
e.
4.
c.
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