Fosphenytoin, a phosphate ester prodrug of phenytoin, is highly water-soluble. Its
solubility allows this preparation to be administered parenterally without the need
for solubilization using propylene glycol or the adjustment of pH to nonphysiologic
levels. Therefore, fosphenytoin may be administered either IM or IV with less risk of
tissue damage and venous irritation than with parenteral administration of
(See also subsequent discussion of IV administration of phenytoin and
fosphenytoin.) After administration, fosphenytoin is rapidly absorbed and converted
to phenytoin by phosphatase enzymes. Ultimately, the bioavailability of phenytoin
from IM fosphenytoin administration is 100%.
Fosphenytoin is available as a solution containing 50 mg PE/mL. By labeling
fosphenytoin this way, no dosing adjustments are necessary when converting from
phenytoin sodium to fosphenytoin or vice versa. Although the prescriber ordered 275
mg PE, S.D. may be underdosed. His oral dosage of phenytoin suspension is
providing the equivalent of 300 mg/day of sodium phenytoin. Phenytoin suspension
and chewable tablets contain free acid, whereas capsules contain sodium phenytoin.
Therefore, phenytoin capsule products contain only 92% of the labeled content as
phenytoin acid (i.e., a 100-mg sodium phenytoin capsule contains only 92 mg of
phenytoin acid). He should receive a 300-mg dose of fosphenytoin daily to fully
replace his current dosage of phenytoin suspension.
Assuming that S.D. will be given 300 mg PE of fosphenytoin daily, he will require
a total of 6 mL of this injection given IM. This medication is well tolerated when
given IM, and S.D.’s full daily dose can be given in a single injection without
causing excessive discomfort. Some clinicians report administering IM injections of
fosphenytoin as large as 20 mL in a single site without adverse consequences or
It is also possible to divide his daily dosage into two
injections given in two different sites, although many patients prefer to receive fewer
problem maintaining him on his current dose of phenytoin?
Gum hyperplasia related to phenytoin is common and troublesome. Prevalence is
estimated at 40% to 50% of treated patients.
103 Prevalence and incidence rates,
however, are misleading because the occurrence and severity of hyperplasia are
related to the dose and serum concentration of phenytoin.
is of obvious cosmetic importance. Also, as in G.R., formation of pockets of tissue
leads to difficulties with oral hygiene, and halitosis may result.
The mechanism of phenytoin-induced gingival hyperplasia is not well understood.
The drug is excreted in saliva and saliva phenytoin concentrations and hyperplasia
are correlated; however, this correlation may simply reflect higher serum
concentrations producing a greater pharmacologic effect. Phenytoin may stimulate
gingival mast cells to release heparin and other mediators that may encourage
synthesis of excessive amounts of new connective tissue by f ibroblasts. Local
irritation caused by dental plaque and food particles may further stimulate this
Three approaches to the treatment of existing hyperplasia
reduction or replacement of phenytoin with an alternative AED, if possible, which
will permit partial or complete reversal of hyperplasia; (b) surgical gingivectomy,
which will correct the problem temporarily, but hyperplasia eventually recurs; and
(c) periodontal treatment, which will eliminate local irritants and maintains oral
hygiene. Treatment for existing hyperplasia and prevention of further tissue
enlargement is important. Assuming that phenytoin is producing adequate seizure
control, a combination of gingivectomy and follow-up periodontal treatment may be
Oral hygiene programs appear to reduce the degree and severity of gingival
hyperplasia when they are initiated before phenytoin therapy is started.
who are beginning phenytoin therapy should be educated about the role of oral
hygiene in diminishing this side effect. The use of dental floss, gum stimulators, and
water-flossing appliances may be beneficial adjuncts to other oral hygiene
Patients chronically maintained on intoxicating doses of phenytoin appear to be at
risk for developing irreversible cerebellar damage and/or peripheral neuropathy.
Cerebellar degeneration, resulting in symptoms such as dysarthria, ataxic gait,
intention tremor, and muscular hypotonia, is of particular concern; this complication
has been observed after episodes of acute phenytoin intoxication.
seizures also can cause cerebellar degeneration secondary to hypoxia. For this
reason, the relative importance of phenytoin in the development of this condition is
controversial. Nevertheless, cerebellar degeneration has been reported in several
patients without hypoxic seizures.
Symptomatic phenytoin-related peripheral neuropathy is rare, although
electrophysiologic evidence of impaired neuronal conduction is found in many
108 Symptomatic patients may complain of paresthesias, muscle weakness,
and occasional muscle wasting. Knee and ankle tendon reflexes are absent in 18% of
patients on long-term phenytoin therapy; the upper limbs are rarely affected.
Although areflexia may be irreversible,
109 electrophysiologic abnormalities may be
closely related to excessive serum phenytoin concentrations and are reversible after
dosage reduction or discontinuation.
In G.R., the general discomfort of mild phenytoin intoxication and the potential for
producing cerebellar degeneration necessitate a therapy alteration. The phenytoin
dose should be reduced to 330 mg/day because it may produce adequate seizure
control without toxic symptoms. Should seizures recur at this lower dosage, it may be
advisable to consider an alternative AED.
Antiepileptic Drug Impact on Bone
Some AEDs have a negative impact on bone density. People with epilepsy treated
with these drugs are at increased risk for bone disorders and fractures.
duration of AED therapy and exposure to multiple AEDs are thought to predict bone
loss. Enzyme-inducing AEDs (carbamazepine, phenytoin, and phenobarbital) have
been associated with bone loss and an increased risk for fracture. Valproate,
although not an enzyme inducer, is associated with decreased bone mineral density in
111 Less is known about the impact of newer AEDs on bone mineral
112 Because of the length of phenytoin use, G.R. is at risk. His bone health
should be further evaluated by a DEXA scan to examine his bone mineral density.
G.R. should be evaluated for other risk factors of reduced bone health (e.g.,
immobility, poor diet, family history). Oral calcium and vitamin D supplementation
should be implemented. Depending on the outcome of evaluation, a change from
phenytoin to an AED with less or no effect on bone should be considered.
New-onset Seizures in the Elderly
for the treatment of J.R.’s epilepsy?
There are relatively few head-to-head comparative studies of AEDs in patients
with epilepsy. Even fewer studies address the comparative efficacy of AEDs in
elderly patients. Three studies, in particular, are important when discussing AED
treatment in elderly persons with epilepsy.
113 compared lamotrigine (n = 102) with carbamazepine (n = 48) in
elderly patients with newly diagnosed epilepsy via a double-blind, randomized,
parallel study. Discontinuation rates because of adverse effects (the primary outcome
parameter) were higher for carbamazepine (42%) than for lamotrigine (18%). Using
time to first seizure as a measure of efficacy, no differences were found between the
suggested that lamotrigine is “acceptable” as initial treatment in elderly patients
with newly diagnosed epilepsy.
Carbamazepine (600 mg/day), gabapentin (1,500 mg/day), and lamotrigine (150
mg/day) were compared for efficacy and tolerability in 593 patients older than 55
years of age (mean age, 72 years) with newly diagnosed epilepsy.
efficacy was similar in all three groups, study termination for adverse events varied
between treatment groups. Carbamazepine had the highest termination rate (31%),
followed by gabapentin (21.6%), and then lamotrigine (12.1%) (P = 0.001). The
authors concluded that lamotrigine and gabapentin should be considered as initial
therapy for new-onset seizures in older patients with epilepsy.
115 evaluated carbamazepine (controlled-release), lamotrigine, and
levetiracetam in 359 patients 60 years of age and older (mean age, 71.4 years) with
newly diagnosed partial epilepsy via a double-blind, randomized, multicenter trial.
As with the other two studies, efficacy (as measured by seizure freedom rates), did
not differ between the three drugs. But retention rate at week 58 (primary outcome)
was significantly higher for levetiracetam (61.5%) than for carbamazepine (45.8%)
(P = 0.02). The retention rate for lamotrigine (55.6%) was close to that of
These studies in elderly patients with new-onset epilepsy suggest that gabapentin,
lamotrigine or levetiracetam would be good choices for initial treatment of J.R.’s
epilepsy. It is noteworthy that none of these AEDs are FDA-approved for newly
It is also important to consider drug-interaction profile, dosing frequency, and drug
costs when selecting AED therapy. Generally, elderly persons take more medicines
than younger individuals. For example, the average number of concomitant
medications in the study by Rowan et al.
114 was seven. J.R. is likely to be taking other
medicines for diabetes and hypertension. Gabapentin, lamotrigine, nor levetiracetam
causes drug–drug interactions, although lamotrigine is influenced more so than
gabapentin or levetiracetam by other medicines. Doses of gabapentin and
levetiracetam have to be adjusted for renal function.
Comparative studies identified minimal differences in efficacy. Newer AEDs,
however, showed better tolerability than the older AEDs. In general, elderly patients
not only respond to AEDs at lower doses and concentrations but they also exhibit
toxicity symptoms at lower doses than do younger patients. Age-related declines in
renal and hepatic function may account for those observations. The pharmacokinetics
of many AEDs have been studied in the elderly and a decrease in clearance is noted
116 Decreased clearance of AEDs in the elderly has often
been cited as a reason for their increased responsiveness to these drugs.
The impact of AEDs on cognition is an important issue for all patients with
epilepsy and perhaps it is an even greater issue in elderly patients.
evidenced from the study by Rowan et al.,
114 CNS toxicities such as dizziness,
unsteady gait, and ataxia are common adverse effects of AEDs in elderly patients.
These symptoms may increase the risk of falls, which are of particular concern in
light of the potential negative effects of AEDs on bone mineral density.
J.R. and his family should be informed about the benefits and risks associated with
each AED and they should also be incorporated into the decision-making process.
AED therapy in the elderly should follow the “start low and go slow” adage, and
elderly patients should be monitored for both efficacy (via a seizure calendar) and
toxicity (reporting any intolerable side effects).
CHOICE OF MEDICATION AND INITIATION OF ETHOSUXIMIDE
T.D., and how should therapy with this drug be initiated?
Ethosuximide, valproate, and lamotrigine are commonly used to treat absence
epilepsy in the United States. Ethosuximide is a succinimide agent that blocks T-type
calcium currents in the thalamus. The drug is effective against absence seizures, but
is ineffective against other seizure types. Patients who receive ethosuximide,
predominantly children, generally tolerate the drug well and, given its lack of
idiosyncratic hepatic toxicity, it has historically been preferred over valproate by
many prescribers for the treatment of childhood absence epilepsy. Valproate, a
carboxylic acid derivative with broad-spectrum activity against many focal-onset and
generalized-onset seizure types, is highly effective but is associated with adverse
effects (dose-related, non-dose-related, and severe idiosyncratic) that limits the
drug’s use among some patient groups. In addition to ethosuximide and valproate,
lamotrigine also has been recommended as an initial monotherapy agent for treatment
of absence epilepsy, although it is not FDA-approved for this indication
Valproate, ethosuximide, and lamotrigine were directly compared for efficacy in
the treatment of newly diagnosed childhood absence epilepsy.
valproate and ethosuximide (based on freedom from treatment failure) were not
significantly different, but were significantly higher than for lamotrigine. Attentional
dysfunction was significantly more common with valproate than with ethosuximide.
Valproate was also more efficacious than lamotrigine for treatment of idiopathic
generalized seizures (including absence) in the Standard and New Antiepileptic
124 Most authorities now consider ethosuximide the drug of first
choice for treatment of absence seizures. Valproate is more likely to cause significant
nausea and initial drowsiness and it is more likely to interact with other drugs,
including AEDs. Valproate usually is reserved for patients whose absence seizures
do not respond to ethosuximide.
125 Clonazepam, a benzodiazepine, often is effective
for control of absence seizures. Therapy with this drug is limited by prominent CNS
side effects (sedation, ataxia, and mood changes) and development of tolerance to its
antiepileptic effect after long-term use.
126 Most authorities consider clonazepam a
fourth-choice drug for treatment of absence seizures.
T.D. should be started on ethosuximide at a dosage of 15 to 20 mg/kg/day or 250
mg twice daily. The daily dose can be increased by 250 mg every 10 to 14 days as
necessary to control seizures. Because the average half-life of ethosuximide in
children is ~30 hours, a delay of 10 to 14 days between dosage increments allows ~7
days for achievement of steady state and 7 days for assessment of response.
Patient or Caregiver Education
Educating T.D. and her parents regarding the importance of regular drug
administration is extremely helpful in ensuring successful therapy. Nonadherence is
common in patients taking AEDs, and rapid discontinuation of these drugs (often
secondary to nonadherence) may precipitate status epilepticus. The concept that
medication controls rather than cures the seizure disorder should be strongly
reinforced. It is also critical to inform both the parents and T.D. that a therapeutic
response may not occur immediately and that dosage adjustments may be necessary.
Common Drugs for the Treatment of Absence Seizures
AED Regimen Adverse Effects Comments
Initial 5–10 mg/kg/day (sprinkle
caps or syrup); then ↑ by 5–10
mg/kg/day weekly to therapeutic
(especially for patients receiving
achieve optimal clinical results.
Initial 20 mg/kg/day or 250 mg
AED, antiepileptic drug; BID, 2 times daily; ER, extended release; GI, gastrointestinal.
CASE 60-7, QUESTION 2: What subjective or objective clinical data should be monitored in T.D. for
evidence of ethosuximide’s therapeutic and adverse effects?
T.D.’s seizure frequency and any side effects she experiences are the primary
monitoring parameters. If ethosuximide serum concentrations are used to assist in
dosing, 40 to 100 mcg/mL is the usual target range; however, a clearly defined
toxicity syndrome does not reliably develop when ethosuximide serum concentrations
exceed 100 mcg/mL. Gradual and cautious increases in ethosuximide dosage when
serum concentrations are beyond the upper limits of the “usual therapeutic range”
may improve response in resistant patients. Although ethosuximide traditionally is
administered in divided doses, its long half-life allows successful use of single daily
doses for many patients. Clinicians should be alert to acute side effects of nausea and
vomiting that are associated with large single doses of ethosuximide; should these
occur, divided daily doses may be necessary.
Laboratory monitoring for idiosyncratic hematologic toxicity from ethosuximide
often is recommended. Ethosuximide causes neutropenia in approximately 7% of
patients. Although this reaction often is transient, even if the drug is continued, rare
patients may exhibit fatal pancytopenia. Presumably, early detection of neutropenia
by means of periodic CBC will allow discontinuation of the drug and potential
reversal of this adverse effect.
127 These hematologic reactions, however, can occur
unpredictably at any time during therapy and often are missed by routine laboratory
monitoring. Patient or caregiver education regarding signs and symptoms associated
with leukopenia and pancytopenia (e.g., sudden onset of severe sore throat with oral
lesions, easy bruisability, increased bleeding tendency) and instructions to consult
the physician if these symptoms occur may be more important than laboratory
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