Introduction ReferencesOral Versus Intravenous Loading of AnticonvmulsantsCase PresentationA 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. Questions: 1. Which phenytoin or fosphenytoin dosing strategy would you use 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? 2. What is the optimal method for achieving a serum phenytoin level between 10-20 mg/L within 24 hours? 3. What are the difference between phenytoin and fosphenytoin?
Key Learning Points: 1. No well designed study has addressed 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 used to treat a patient with who presents to the emergency department after having had a seizure with a “subtherapeutic” phenytoin level. 2. A serum phenytoin level > 10 mg/L can be achieved by all of the common contemporary dosing strategies including intravenous loading, oral loading and starting/restarting oral maintenance dosing. 3. Fewer adverse local effects (phlebitis, purple glove syndrome and tissue necrosis) and fewer adverse systemic effects (impairment of myocardial contractility, dysrhythmias, hypotension and cardiac arrest) are associated with intravenous fosphenytoin administration when compared to intravenous phenytoin administration. 4. 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. 5. Fosphenytoin is significantly more expensive than intravenous phenytoin. Oral Versus Intravenous Loading of AnticonvulsantsIntroduction 1. Which phenytoin or fosphenytoin dosing strategy would you use 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? a.
Administer an intravenous loading dose of phenytoin and then start/restart
daily oral maintenance dosing b.
Administer an intravenous loading dose of fosphenytoin and then start/restart
daily oral maintenance dosing c.
Administer an oral loading dose of phenytoin and then start/restart
daily oral maintenance dosing d.
Start/restart daily oral maintenance dosing without administering
a loading dose
2.
Which of the following adult dosing strategies is unlikely to achieve
a serum phenytoin level between 10-20 mg/L within 24 hours? a.
Intravenous loading dose of phenytoin or fosphenytoin b.
Intramuscular loading dose of fosphenytoin c.
Oral loading dose of phenytoin d.
Start/restart oral maintenance dosing without administering a loading
dose
3.
Which of the following statements regarding fosphenytoin is FALSE?
a.
Fosphenytoin causes less ataxia, nystagmus, tremor and somnolence
than phenytoin. b.
Fosphenytoin causes fewer local effects (phlebitis, purple glove syndrome
and tissue necrosis) and fewer systemic effects (impairment of myocardial
contractility, dysrhythmias, hypotension and cardiac arrest) than
phenytoin. c.
Fosphenytoin can be safely administered by the intramuscular route.
d.
Fosphenytoin can be administered intravenously at a faster rate than
phenytoin.
What
does the medical literature say are the options for treatment?
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
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
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.
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).
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%) 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 intramucularly administered phenytoin. (Boucher, Henken, Jameson)
What
are the pharmacoeconomic concerns as they relate to phenytoin and
fosphenytoin?
The
acquisition costs of fosphenytoin are considerably more than those
for either parenteral or oral phenytoin products. In 4/2002 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 emergency department?
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 emergency department 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) Based upon
the available literature it appears that the rate of seizure recurrence
following emergency department discharge varies from 6-20%. (Cranford,
Huff, Leppick, Osborn).
No
well-designed study has compared the rate of seizure recurrence for
patients with different etiologies of seizures using any of the common
contemporary dosing strategies.
What
guidelines currently exist?
There
are no commonly distributed guidelines that specifically address the
issue of 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. This is likely due to the fact that the medical
literature does not contain enough information to answer this question.
If
no guidelines exist, what would you recommend?
Emergency
physicians who understand the pharmacokinetic, pharmacoeconomic and
adverse event profiles of phenytoin and fosphenytoin as well as the
limitations of the available medical literature are best suited to
help their patients make informed decisions regarding the different
dosing strategies. When
I want to achieve a “therapeutic” serum phenytoin level as soon as
possible or prior to emergency department discharge I administer either
fosphenytoin or phenytoin intravenously. Examples:
1.
Patient had a prolonged seizure. 2.
Patient has a recent history of multiple seizures or status epilepticus.
3.
Upon emergency department discharge the patient is likely to be in
a environment/situation where another seizure carries an increased
risk of morbidity/mortality. Such environments/situations include
operating a motor vehicle or dangerous machinery, a hazardous occupational
setting, homelessness and suboptimal social situations. 4.
Medicolegal concerns
I
always want to minimize the risk of adverse local and systemic effects
associated with intravenous loading, so, when available, I administer
fosphenytoin. Examples:
1.
Patients who have poor intravenous access or small intravenous catheters
(children) 2.
Patients are agitated. 3.
There may be suboptimal supervision during dosing. 4.
Medicolegal concerns.
When
I want to minimize the amount of time a patient is in the emergency
department, when cost is an especially important issue and when the
indication for phenytoin therapy is questionable, I administer oral
phenytoin. Examples:
1.
Emergency department resources are at a critical level. 2.
Alcoholic patients whose seizures are likely secondary to alcohol
withdrawal.
Class
A None
specified
Class
B None
specified
Class
C None
of the following common contemporary dosing strategies has been proven
to be superior to any of the others with respect to the rate of seizure
recurrence including: 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
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