In nonemergency situations, AED should be withdrawn slowly; if a patient

receives multiple drugs, each drug should be withdrawn separately. Too-rapid

withdrawal can result in status epilepticus. Clinical studies of AED discontinuation

usually used a 2- to 3-month withdrawal schedule for each drug. The optimal rate of

withdrawal of AED has not been identified. One study compared withdrawal of

individual drugs for a 6-week and a 9-month period and found no difference in

seizure recurrence between the groups.

47 Another study compared seizure frequencies

in patients withdrawn from carbamazepine rapidly (for 4 days) and in patients

withdrawn more slowly (for 10 days).

48 Significantly more generalized tonic–clonic

seizures occurred when carbamazepine was withdrawn rapidly; complex partial

seizures, however, did not occur at a higher rate with rapid withdrawal. Therefore,

withdrawal of each AED for at least 6 weeks would seem to be a safe approach.

Gradual withdrawal is recommended even for medications such as phenobarbital that

have long half-lives and should theoretically be “self-tapering.” In our experience,

gradual reduction of medications such as phenobarbital is associated with a

significantly higher success rate. If AEDs are withdrawn at an appropriate rate and

seizures recur, drug treatment is usually reinstituted. In most patients, good seizure

control is regained by restarting therapy. However, approximately 1% of patients had

recurrent seizures that could not be controlled again with AEDs.

49 This uncommon,

but potentially serious, outcome should be considered when therapy withdrawal is

considered.

CLINICAL ASSESSMENT AND TREATMENT OF

EPILEPSY

Complex Partial Seizures with Secondary

Generalization

DIAGNOSIS

CASE 60-1

QUESTION 1: A.R. is a 14-year-old, 40-kg female high school student. A.R. had three febrile seizures when

she was 3 years old. She received phenobarbital prophylaxis “off and on,” according to her parents, for about 6

months after her second febrile seizure. Since then, she had no reported seizures until 24 hours before

admission. At that time she had a “convulsion” shortly after arriving at school in the morning. A teacher who

witnessed the episode describes her as behaving “oddly” before the seizure. She abruptly got up from her desk

and began to walk clumsily toward the door; she bumped into several desks and did not respond to the teacher’s

attempts to redirect her back to her seat. After approximately 1 minute of this behavior, she fell to the floor and

experienced an apparent generalized tonic–clonic seizure that lasted approximately 90 seconds. During the

episode, she was incontinent of urine and was described as “turning kind of blue.” After this episode, A.R. was

transported to the hospital.

On arrival at the hospital, A.R. appeared drowsy and confused. Laboratory studies—a complete blood count

(CBC), serum glucose, electrolytes, drug and alcohol screen, and lumbar puncture—were normal. Physical

examination and a complete neurologic evaluation were normal. An EEG showed diffuse slowing with focal

epileptiform discharges in the left temporal area; it was interpreted as abnormal. There was no history of recent

illness or injury, although A.R. had stayed up late several nights recently studying for an examination.

A second seizure occurred in the hospital. The nursing staff described an episode similar to the one that

occurred at school. After recovery from each episode, A.R. had no memory of events during the seizures; she

only remembered a “funny feeling” in her stomach and a “buzzing” in her head before she lost consciousness.

She described having these feelings “a couple of times” in the past; she attributed them to “just getting dizzy”

and had not reported them to her parents. After these previous episodes, A.R. described feeling “mixed up” and

groggy for a few minutes. What subjective and objective features of A.R.’s seizures are consistent with a

diagnosis of complex partialseizures with secondary generalization?

A.R.’s clinical pattern of observed seizure activity (an apparent aura preceding

her loss of consciousness), her history of apparent complex partial seizures not

accompanied by generalized seizures, and the findings of focal abnormal activity on

EEG are all concordant with this diagnosis. Postictal confusion and grogginess are

common after both generalized tonic–clonic and complex partial seizures. Her

unusual or inappropriate behavior represents a complex partial seizure that

subsequently generalized. The clinical features, accompanied by her EEG findings,

also help rule out possible atypical absence seizures, which can be confused with

complex partial epilepsy syndromes based on only clinical presentation. In both

syndromes, patients may briefly appear to lose contact with their surroundings and

display automatisms and mild clonic movements during seizure activity. In A.R.’s

case, the EEG and the generalized tonic–clonic seizures during her episodes would

rule out atypical absence as a likely possibility.

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p. 1281

DECISION TO USE ANTIEPILEPTIC DRUG THERAPY

CASE 60-1, QUESTION 2: What factors should be considered in a decision to treat A.R.’s seizures with

AED therapy?

Once a diagnosis of epilepsy is established, the decision to treat the patient with

medication is based on the likelihood of recurrence. The need for AED therapy after

a single seizure is controversial, but according to the 2015 evidenced-based

guideline on this topic, patients should be informed that their seizure recurrence risk

is greatest early within the first 2 years and starting of AED therapy is likely to

reduce recurrence risk within the first 2 years.

4

In A.R.’s case, the potential benefits of immediate introduction of AED therapy

appear to outweigh potential risks. She experienced complex partial seizures and

some were followed by secondarily generalized tonic–clonic seizures. Recurrence of

seizure activity is likely to result in physical injury, social embarrassment, and

interference with her participation in activities typical of a person her age. If her

seizures are not controlled, she faces future limitation of her driving privileges and

may face barriers to employment. Although AED therapy is associated with risks,

they probably are outweighed by the potential benefits.

CHOICE OF ANTIEPILEPTIC DRUG

CASE 60-1, QUESTION 3: Which AEDs are commonly used for A.R.’s seizure type? Based on the

subjective and objective data available, recommend a first-choice AED for A.R. and a plan for initial dosing of

this medication.

Many AEDs would be appropriate choices for A.R.’s complex partial seizures that

can secondarily generalize (Table 60-3).

34

,

50

,

51 Some AEDs are not FDA-approved

as initial monotherapy. Although valproate is effective for treating both generalized

and complex partial seizures,

52

it would not be a good initial choice for this patient

owing to the increased risks in a woman of childbearing age (see Women’s Issues in

Epilepsy section).

Eslicarbazepine, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine,

levetiracetam, oxcarbazepine, perampanel, pregabalin, tiagabine, topiramate, and

zonisamide are effective for control of partial seizures with or without secondary

generalization. Most experience with these drugs was obtained when they were used

as adjunctive agents when previous AED therapies were unsuccessful. Initial clinical

trials with these medications indicate that several of them may be useful as single

agents. Felbamate, lacosamide, lamotrigine, oxcarbazepine, and topiramate have

monotherapy indications. Most of the more recently approved medications appear to

be safe and are usually well tolerated. The usefulness of felbamate is limited,

however, owing to its potential for serious hematologic and hepatic toxicity.

Carbamazepine has several advantages that make it a preferred first-choice agent

in the opinion of many clinicians. In comparison with phenytoin, carbamazepine is

less sedating and is not associated with dysmorphic effects, such as hirsutism, acne,

gingival hyperplasia, and coarsening of facial features. Carbamazepine’s

pharmacokinetic profile also makes dosage adjustment easier. In A.R.’s case, the

lack of cosmetic side effects may be especially significant because she may be taking

medication for many years. In addition, reduced sedation may be important with

respect to her school performance.

CARBAMAZEPINE THERAPY

Initiation and Dosage

Initiation of treatment with full therapeutic maintenance doses of carbamazepine often

causes excessive side effects such as nausea, vomiting, diplopia, and significant

sedation. Therefore, carbamazepine therapy should be initiated gradually and patients

should be allowed time to acclimate to the effects of the drug. Final dosing

requirements are difficult to anticipate in individual patients. A reasonable starting

dosage of carbamazepine for A.R. would be 100 mg twice a day; her dosage could

be increased by 100 to 200 mg/day every 7 to 14 days. The rapidity of increases will

depend on A.R.’s tolerance for the drug and the frequency of her seizures.

Hematologic Toxicity

CASE 60-1, QUESTION 4: Carbamazepine has been associated with hematologic and hepatic toxicities.

What is the incidence and significance of these toxicities? How should A.R. be monitored for them?

Aplastic anemia and agranulocytosis have occurred in association with carbamazepine therapy.

53 Several

cases have been fatal; however, most cases occurred in older patients treated for trigeminal neuralgia. Many

patients were receiving other medications, and occasionally the reports were incomplete; thus, assessment of a

causal role for carbamazepine is difficult.

54 Severe blood dyscrasias from carbamazepine seem rare (estimated

prevalence <1/50,000) and have predominantly occurred in nonepileptic patients. The lack of severe

hematologic toxicity in various published series and clinical trials in patients with epilepsy has been notable.

55

,

56

Leukopenia is relatively common in patients taking carbamazepine. It is usually mild and often reverses

despite continued administration of the drug.

55 Total leukocyte counts may fall to less than 4,000 cells/μL in

some patients, but differentials and platelet and erythrocyte counts remain normal. Symptoms (e.g., fever, sore

throat) that might suggest early stages of agranulocytosis do not occur. Carbamazepine-associated hematologic

disorders are unrelated to drug dosage; thus, these reactions appear to be idiosyncratic.

Routine Hematologic Testing

Laboratory monitoring of A.R.’s hematologic status is recommended during

carbamazepine therapy. The likelihood of early detection of aplastic anemia or

agranulocytosis through frequent blood counts is low, however, and such monitoring

is costly.

55

,

57 Because hematologic toxicity from carbamazepine primarily occurs

early in therapy, a CBC should be obtained before therapy and at monthly intervals

during the first 2 to 3 months of therapy; thereafter, a yearly or every-other-year

CBC, white blood cell count with differential, and platelet count should be sufficient.

Hepatotoxicity

Carbamazepine-related liver damage is extremely rare despite its being frequently

mentioned as a potential problem and strong warnings in the package insert.

58

,

59

Hepatic adverse reactions are believed to be idiosyncratic or immunologically

based. Aggressive laboratory monitoring of liver function tests (LFTs) probably is

unnecessary.

57 Alkaline phosphatase and γ-glutamyl-transferase concentrations often

are elevated in patients taking carbamazepine (and other AEDs). This is believed to

result from hepatic enzyme induction and is not necessarily evidence for hepatic

disease.

60

In summary, hepatic and hematologic toxicities of carbamazepine are rare.

Although potentially serious, they are best monitored on clinical grounds rather than

by ongoing, intensive laboratory testing. Patients, families, or caregivers should be

aware that the appearance of unusual symptoms (e.g., jaundice, abdominal pain,

excessive bruising and bleeding, or sudden onset of severe sore throat with fever)

should be reported to a health care professional. Baseline (pretreatment)

determination of A.R.’s hepatic and hematologic status, possibly with monthly

follow-up testing for 2 to 3 months, probably will be sufficient.

56

,

57 Thereafter, a

CBC and a liver function battery should probably be evaluated

p. 1281

p. 1282

only every 1 to 2 years, unless signs or symptoms of hepatic or hematologic

disorders are observed.

Pharmacokinetics and Autoinduction of Metabolism

CASE 60-1, QUESTION 5: For the subsequent 6 weeks, A.R.’s carbamazepine dosage was gradually

increased to 400 mg twice daily (BID) (20 mg/kg/day). Until the last dose increase, she had been experiencing

one or two complex partial seizures weekly; she had experienced only one generalized tonic–clonic seizure

since her hospitalization. One week after the increase to 20 mg/kg/day, her serum carbamazepine concentration

was 9 mcg/mL just before her first dose of the day. No seizures occurred for 4 weeks, and she tolerated the

medication well. Subsequent to the 4-week seizure-free period, she again began experiencing one seizure

weekly. What factor(s) might be responsible for this reversal of seizure control?

Several factors may account for this change. It is important always to consider the

possibility of poor medication adherence when clinical response changes

unexpectedly. This should be investigated, and A.R. and her family should be

educated regarding the importance of regular medication intake.

The observed changes in A.R.’s seizure control may also be due to unique features

of carbamazepine pharmacokinetics. Carbamazepine is a potent inducer of hepatic

cytochrome P-450 (CYP3A4). The drug is also a substrate for this enzyme. As a

result, carbamazepine not only stimulates the metabolism of other CYP3A4 substrates

but also induces its own metabolism by autoinduction. Carbamazepine’s half-life

after single acute doses is approximately 35 hours; with chronic dosing, its half-life

decreases to 15 to 25 hours. This increase in clearance necessitates increased

carbamazepine doses, increased frequency of administration, or both. Autoinduction

of carbamazepine metabolism appears to be related to dose and serum concentration.

Approximately 1 month may be required for the autoinduction process to reach

completion after each increase in carbamazepine dose.

61

Assuming that adherence was not the main problem, A.R.’s carbamazepine dose

should be increased. The drug’s pharmacokinetics are generally linear with respect

to acute dosage changes.

62 A 50% increase in dosage to 1,200 mg/day should reestablish seizure control. Depending on A.R.’s clinical status, further increases in

dosage may be necessary.

Bioequivalence of Generic Dosage

CASE 60-1, QUESTION 6: A.R.’s dosage was increased to 600 mg BID. Four weeks later, she was still

experiencing approximately one complex partial seizure weekly. A repeat trough serum carbamazepine

concentration was 6.5 mcg/mL. On questioning, A.R. denied missing doses of medication, and a tablet count

confirmed apparently accurate drug intake. A.R. relates that she experiences some mild nausea after her doses,

but she has not vomited. It is noted that her pharmacist has begun substituting a generic carbamazepine tablets

for the Tegretol that was previously dispensed. What role, if any, might this change in carbamazepine

formulation have played in the failure of A.R.’s serum concentrations to increase as expected? What other

factors might be considered in explaining this situation?

Several manufacturers market generic carbamazepine tablets. Bioavailability data

supplied by the manufacturers are based on single-dose or short multiple-dose

studies in healthy subjects. Therefore, it is impossible to completely predict the

results of a change from Tegretol to generic carbamazepine for maintenance therapy

in an individual patient.

63 Because of variations in amount of drug available from

different products, some patients with epilepsy (aka “generic-brittle”) cannot tolerate

changes in formulations between brand and generic, generic and generic, or generic

and brand.

64 Changes in seizure control from too little drug or toxicity from too much

drug have been reported with changes between formulations for several AEDs. On

the other hand, two recent in-depth bioequivalence studies have found no evidence to

support any pharmacokinetic differences between brand and generic products of

lamotrigine in patients with epilepsy.

65

,

66

Bioavailability data suggest that the generic carbamazepine preparations currently

on the market may be substituted for Tegretol with little need for dosage adjustment.

Nonetheless, in A.R.’s case, substitution of generic carbamazepine may be a possible

cause for the loss of seizure control. Readjustment of her dose to gain seizure control

and consistent use of one manufacturer’s product (either brand or generic) might

alleviate this problem. Three extended-release forms of carbamazepine (Tegretol

XR, Carbatrol, and Equetro) are available and may provide an alternative for A.R.

These formulations allow more reliable absorption of drug when administered on a

twice-daily dosing schedule. Many patients can better tolerate carbamazepine when

these forms are used because large fluctuations in plasma concentrations are avoided.

Use of Tegretol XR to avoid 3-times-daily or 4-times-daily dosing schedules has

been shown to increase adherence for many patients.

67

It is important to counsel

patients on the fact that the empty Oros tablet shell from the Tegretol XR dose does

not dissolve as it passes through the gastrointestinal (GI) tract, and it may be visible

in the stool. Patients need to understand that the carbamazepine has been absorbed,

and that this is an empty shell. Tegretol XR tablets lose their extended-release

properties when broken or crushed; Carbatrol beads may be emptied onto food or

administered via feeding tube.

68 Equetro is not FDA-approved for epilepsy, it is

indicated for the treatment of acute manic and mixed episodes associated with

bipolar I disorder.

In conclusion, it may be impossible to identify a single cause for the unexpected

change in A.R.’s seizure control. Common reasons for loss of seizure control include

sleep deprivation, increased stress, acute illness, and/or medication nonadherence.

TREATMENT FAILURE AND ALTERNATIVE ANTIEPILEPTIC DRUGS

CASE 60-2

QUESTION 1: R.H., a 19-year-old, 64-kg young woman, has experienced simple partial seizures, complex

partial seizures, and secondarily generalized tonic–clonic seizures for the past 2 years. She could not tolerate

treatment with phenytoin (severe gingival hyperplasia and mental “dullness”) or valproate (hair loss, tremor, and

a weight gain of 8 kg). In addition, neither phenytoin nor valproate was dramatically effective in reducing her

seizures. She currently receives carbamazepine 600 mg 3 times daily (TID). For the past 3 months, while being

treated with carbamazepine, she has had approximately five simple partial seizures, three complex partial

seizures, and one generalized tonic–clonic seizure. This represents an approximate 30% reduction in her

frequency of seizures. She tolerates her present dose of carbamazepine but has experienced significant

drowsiness, incoordination, and mental confusion at higher doses. What are possible therapeutic options for

R.H.? Evaluate the newer AEDs and their possible usefulness for R.H.

R.H. is exhibiting a partial response to maximally tolerated doses of

carbamazepine. An alteration in her current AED regimen is indicated. She has not

tolerated other AEDs because of side effects. Although valproate is effective for

control of partial seizures, it is not considered an alternative in a woman of

childbearing age.

p. 1282

p. 1283

R.H.’s CNS side effects (e.g., persistent drowsiness) with other AEDs would

make many clinicians reluctant to consider medications such as phenobarbital or

primidone as either alternatives or adjunctive agents to her current carbamazepine

regimen. Use of one of the newer AEDs as adjunctive medication may be of value for

R.H.

New AEDs marketed in the United States since 1993 for maintenance treatment of

epilepsy include the following: eslicarbazepine, ezogabine, felbamate, gabapentin,

lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin,

tiagabine, topiramate, and zonisamide (Table 60-6). Clinical trials for new AEDs are

most often carried out in patients with partial seizures refractory to standard AEDs.

Most of these newer or “second-generation” AEDs were initially FDA-approved as

“add-on” or adjunctive treatment in patients with partial seizures with or without

secondary generalization. Also, consensus is that some of these AEDs may be

effective as broad-spectrum agents; for example, lamotrigine appears to be a useful

treatment in absence seizures.

Side Effects

Common side effects for the newer AEDs are described in Table 60-6. Most of them

are less sedating than older medications such as phenobarbital or phenytoin. The

most common side effects seen in the clinical trials with eslicarbazepine were ataxia,

blurred and double vision, dizziness, fatigue, headache, nausea, somnolence, tremor,

vertigo, and vomiting.

69

Gabapentin and tiagabine have not been associated with serious side effects;

gabapentin can cause weight gain

70 and tiagabine can cause nonspecific dizziness

relatively frequently.

71

Common adverse effects associated with lacosamide include dizziness, headache,

diplopia, and nausea. Gradual escalation to the desired dose reduces the adverse

event risk.

The most serious adverse effect associated with lamotrigine is skin rash. Rashes

occur in approximately 10% of treated patients, usually in the first 8 weeks.

72 Rashes

leading to hospitalization occurred in 1 of 300 adults and 1 of 100 children.

Widespread, maculopapular rashes usually appear and may progress to erythema

multiforme or toxic epidermal necrolysis. Lamotrigine-related rashes may resolve

rapidly when lamotrigine is discontinued. Coadministration of valproate with

lamotrigine may increase the likelihood of dermatologic reactions; it is partly for this

reason that more conservative dosage titration and lower maintenance doses of

lamotrigine are recommended for patients receiving concomitant valproate. Higher

starting doses and more rapid dose escalation than those recommended by the

manufacturer also increase the risk of skin rash.

Levetiracetam is generally well tolerated, with the most common adverse events in

clinical trials being asthenia, vertigo, flu syndrome, headache, rhinitis, and

somnolence. The most serious adverse effects are behavioral and are more common

in patients with a history of behavioral problems.

73 Levetiracetam should be used

with caution in patients with a history of suicidal ideations.

Oxcarbazepine, a keto derivative of carbamazepine, is essentially a prodrug for

the monohydroxy active metabolite.

74 Oxcarbazepine probably causes less frequent,

less severe adverse effects compared with carbamazepine, with the exception of

hyponatremia. Hyponatremia is more common with oxcarbazepine than with

carbamazepine. Baseline and periodic serum sodium monitoring is indicated during

oxcarbazepine therapy. The most commonly reported side effects of oxcarbazepine in

clinical trials include ataxia, dizziness, fatigue, nausea, somnolence, and diplopia.

Adverse effects of pregabalin are dose dependent and usually occur within the first

2 weeks of treatment.

75 Somnolence, dizziness, and ataxia are most common.

Pregabalin also appears to be associated with a dose-related weight gain.

Topiramate can cause cognitive disturbances, lethargy, and impaired mental

concentration when given in large daily doses (especially in combination with other

AEDs) or when the dosage is titrated too aggressively.

76 Topiramate has caused

nephrolithiasis in approximately 1.5% of treated patients. This adverse effect is

believed to be related to inhibition of carbonic anhydrase by topiramate, with

resulting increased urinary pH and decreased citrate excretion. Topiramate can also

cause acute, secondary angle-closure glaucoma, which presents within the first month

of therapy. Topiramate is associated with weight loss.

Zonisamide is a sulfonamide derivative and thus is contraindicated in patients

allergic to sulfonamides.

77 The most commonly reported adverse events include

ataxia, somnolence, agitation, and anorexia. Kidney stones have developed in 3% to

4% of patients, some of whom had a family history of nephrolithiasis.

Pharmacokinetics

The newer AEDs have somewhat different pharmacokinetic profiles from those of

older agents. They also differ in their tendency to interact with other AEDs.

Gabapentin is excreted entirely by the kidneys as unchanged drug and is not

significantly bound to plasma protein. Gabapentin has a relatively short half-life and

should be administered 3 times daily.

78

Lacosamide is excreted mostly by the kidneys. Dosage reductions are warranted

for patients with renal impairment (creatinine clearance <30 mL/minute). It is less

than 15% bound to plasma protein, has a 12- to 13-hour half-life, and is administered

twice daily.

79

Lamotrigine is primarily eliminated by hepatic glucuronidation and excretion of

metabolites in the urine. Other AEDs, such as carbamazepine and phenytoin, induce

the hepatic metabolism of lamotrigine. When lamotrigine is coadministered with

enzyme-inducing drugs, its half-life decreases from approximately 24 to 15 hours.

Valproate inhibits lamotrigine metabolism, causing increases in half-life and serum

concentrations.

80

,

81 Patients treated with both lamotrigine and carbamazepine may

experience more nausea, drowsiness, and ataxia. It appears likely that this interaction

represents a pharmacodynamic interaction between lamotrigine and carbamazepine.

82

Levetiracetam has a short half-life and is eliminated primarily by renal

mechanisms. Dosage reductions are warranted for patients with renal impairment

(creatinine clearance <80 mL/minute). The drug has a low potential for interactions

with other drugs.

83

Both eslicarbazepine acetate and oxcarbazepine are prodrugs. They cause less

hepatic enzyme induction than carbamazepine and may therefore be less likely to

interact with other medications. Both, however, increase the metabolism of oral

contraceptive hormones.

84

,

85 Because eslicarbazepine and oxcarbazepine have

similar mechanisms of action to that of carbamazepine, it is unlikely that either would

offer significant benefits to R.H. because she has not responded to maximal tolerated

doses of carbamazepine.

69

,

74

Pregabalin is excreted entirely by the kidneys as unchanged drug and is not

significantly bound to serum proteins. Unlike gabapentin, which requires more

frequent dosing, pregabalin can be administered 2 or 3 times daily.

75

Tiagabine has a relatively short half-life (4–7 hours). It should be administered at

least twice daily.

71 Concurrently administered enzyme-inducing AEDs may reduce

the half-life of tiagabine to 2 to 3 hours and necessitate use of larger daily doses and,

possibly, shorter dosing intervals. Tiagabine is highly protein-bound (96%), and it is

displaced from protein-binding sites by valproate, salicylate, and naproxen. The

clinical significance of these protein-binding interactions is unknown.

Topiramate has a half-life of approximately 20 hours, which allows twice-daily

administration. It is only partially excreted by hepatic metabolism; approximately

70% of the drug is excreted unchanged by the kidneys. Topiramate is minimally

protein-bound (~10%–15%). When topiramate is coadministered with enzymeinducing agents, topiramate clearance is increased. This interaction may necessitate

titration to somewhat higher doses when topiramate is used with enzyme-inducing

drugs.

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p. 1284

Table 60-6

Drugs Used for the Treatment of Partial and Generalized Tonic–Clonic Seizures

AED Regimen Adverse Effects Comments

Carbamazepine

(Tegretol, Tegretol

XR, Carbatrol,

Equetro)

Initial 200 mg BID (adults) or

100 mg BID (children) and

weekly until therapeutic

response or target serum

concentrations. Usual

maintenance doses 7–15

mg/kg/day in adults; 10–40

mg/kg/day in children

Sedation, visual

disturbance may limit

dosage. Severe blood

dyscrasias extremely rare.

Mild leukopenia more

common. Laboratory

monitoring of little value.

Asian patients positive for

HLA-B*1502 are at 10-

fold higher risk for

Stevens–Johnson

syndrome/toxic epidermal

necrolysis. Hepatotoxicity

rare. May cause

hyponatremia. Long-term

use may cause

osteomalacia

Usually little sedation and

minimal interference with

cognitive function or

behavior. Preferred by

most for partial or

secondarily generalized

seizures. Extended-release

products may allow less

frequent dosing with

fewer peak serum

concentration-related side

effects. These products

may also facilitate

adherence

Phenytoin (Dilantin,

Phenytek)

Initiate at maintenance dose of

4–5 mg/kg/day (300–400

mg/day). Titrate on basis of

Nystagmus, ataxia,

sedation may limit dosage.

Gum hyperplasia, hirsutism

Clearance and half-life

change with dose. Small ↑

in dose (30-mg capsule)

Fosphenytoin

(Cerebyx)

clinical response and target

serum concentration. 3–4 weeks

between dose ↑ recommended

because of potentially slow

accumulation

common. Long-term use

may cause osteomalacia.

Peripheral neuropathy,

hypersensitivity with liver

damage rare. Possible

increased risk of Stevens–

Johnson syndrome/toxic

epidermal necrolysis in

Asian patients positive for

HLA-B*1502

recommended as plasma

concentrations exceed 7–

10 mcg/mL. Cautious use

of suspension; dose

measurement and potential

mixing difficulties. IM

administration not

recommended. Potential

precipitation in IV

solutions. Fosphenytoin

(Cerebyx) recommended

for IM and IV use due to

faster administration rate,

admixture compatibility,

and lower rate of injection

site complications

Valproate

(Depakene,

Depakote,

Depakote-ER,

Depacon)

See Table 60-7 – –

Phenobarbital Initial 1 mg/kg/day; titrate to

therapeutic response. 2–3

weeks between dose ↑

Sedation (chronic),

behavior disturbances

common, especially in

children. Possibly impairs

learning and intellectual

performance. Long-term

use may cause

osteomalacia

Considered outmoded for

AED therapy in most

patients; adverse effects

outweigh benefits. IV use

for refractory status

epilepticus

Pregabalin (Lyrica) Initial 50 mg BID then titrate to

therapeutic response with

maximal daily dose at 600

mg/day in divided doses (BID or

TID)

Potentialside effects

include dizziness, blurred

vision and weight gain

No significant interactions

with other AEDs. Can be

useful for patients with

concomitant pain disorders

Gabapentin

(Neurontin)

Initial 300 mg/day with titration

to 900–1,800 mg/day for 1–2

weeks. Doses of 2,400 mg/day

and higher have been well

tolerated. Owing to short halflife, TID or QID dosing

recommended

Sedation, dizziness, and

ataxia relatively common

with initiation of therapy.

Gabapentin therapy

usually not associated with

prominent side effects.

Commonly associated with

weight gain

Excreted unchanged by

kidneys. No significant

drug–drug interactions.

Absorption dose

dependent; fraction

absorbed

↓ as size of

individual dose ↑

Lamotrigine

(Lamictal)

When added to enzyme inducers

alone: Initiate at 50 mg daily HS

or 50 mg BID. Daily dose can

be ↑ by 50–100 mg every 7–14

days. Usual maintenance doses

of 400–500 mg/day. BID dosing

may be necessary with enzyme

inducer cotherapy.

When added to valproate alone:

Initiate at 25 mg QOD HS.

Daily dose can be ↑ by 25 mg

Dizziness, diplopia,

sedation, ataxia, and

blurred vision can be

common with initiation of

therapy; limit speed of

titration. Incidence of

serious rash ranges from

0.8–8.0 per 1,000

Significant ↑ in clearance

of lamotrigine when

coadministered with

enzyme inducers.

Significant

↓

in clearance

when coadministered with

valproate. Slow, gradual

titration of dose may

reduce risk of skin rash.

Estrogen increases

clearance

every 14 days. Usual

maintenance doses of 100–200

mg/day.

For patients not taking valproate

or an enzyme inducer: Initiate at

25 mg QD HS. Daily dose can

be ↑ by 25 mg every 14 days.

Usual daily doses of 225–375

mg/day

p. 1284

p. 1285

Tiagabine (Gabitril) Initial 4 mg/day. ↑ by 4 mg/day

at 7 days. Then ↑ daily dose by

4–8 mg every week. Maximal

recommended dose of 32

mg/day in adolescents or 56

mg/day in adults. BID to QID

dosing recommended

Drowsiness, nervousness,

difficulty with

concentration or attention,

tremor. Nonspecific

dizziness described by

some patients

Increased clearance when

given with enzyme

inducers. TID or QID

doses probably needed.

Potential for proteinbinding displacement

interactions with other

highly protein-bound drugs

(e.g., valproate).

Significance of proteinbinding displacement not

known. Substrate for

CYP3A4

Topiramate

(Topamax, Trokendi,

Qudexy)

Initial 50 mg HS. ↑ daily dose by

50 mg every 7 days. 200–400

mg/day recommended as target

dosage range. Larger daily

doses associated with increased

CNS side effects. BID dosing

recommended

Sedation, dizziness,

difficulty concentrating,

confusion. May be dose

related. Possible weight

loss. Weak CA inhibitor;

may cause or predispose

to kidney stones; CA

inhibition also possibly

related to paresthesias in

up to 15%. Risk of

hypohidrosis and

hyperthermia especially in

children. Rarely

associated with angleclosure glaucoma

Approximately 70% renal

elimination. Phenytoin and

carbamazepine may

reduce topiramate plasma

concentrations and

potentially increase dosage

requirements. Topiramate

may cause small ↑ in

phenytoin plasma

concentration. Advise

patients to drink plenty of

fluids. May affect oral

contraceptives above 200

mg/day

Levetiracetam

(Keppra, KeppraXR, Spritam)

Initial 250–500 mg BID. ↑ by

500–1,000 mg/day every 2

weeks. Usual maximal dose is

3,000 mg/day. Doses up to 4,000

mg/day have been used. BID

dosing recommended

Somnolence, dizziness,

asthenia are commonly

reported. Behavioral

symptoms (agitation,

emotional lability, hostility,

depression, and

depersonalization)

reported

No hepatic (CYP450 or

UGT) metabolism. 66%

excreted unchanged in

urine. Less than 10%

protein bound. No

significant drug

interactions reported

Lacosamide

(Vimpat)

Initiate at 50 mg BID. Increase

weekly by 100 mg/day. Target

doses of 200–400 mg/day.

Dizziness, ataxia, diplopia,

headache, nausea. May

slow cardiac conduction.

Currently only indicated

for treatment of partial

seizures in adults. IV form

Maximum recommended dose is

400 mg/day

Caution is advised in

patients with seconddegree AV block.

Syncope has been

reported

available; currently only

approved for short-term

replacement of oral

therapy. Little evidence of

significant risk of drug–

drug interactions. Some

hepatic metabolism by

CYP2C19; significant

renal elimination Oxcarbazepine

(Trileptal, Oxtellar)

Monotherapy: Initial 300 mg

BID. ↑ weekly up to 1,200

mg/day. Can increase to 2,400

mg/day.Adjunctive therapy:

Initial 300 mg BID. ↑ weekly up

to 1,200 mg/day

Dizziness, somnolence,

diplopia, nausea, and

ataxia are commonly

reported. May cause

hyponatremia; most cases

asymptomatic, more

common in elderly. A 25%

cross-sensitivity for skin

rash reported between

oxcarbazepine and

carbamazepine

Parent is a prodrug; the

MHD is the active

component. Readily

converted to MHD via

omnipresent cytosolic

enzymes. Lacks

autoinduction properties.

In doses >1,200 mg/day,

may affect oral

contraceptives

Zonisamide

(Zonegran)

Initial 100 mg daily. ↑ by 100

mg/day every 2 weeks. Usual

maintenance doses of 200–400

mg/day; maximum 600 mg/day

Somnolence, nausea,

ataxia, dizziness,

headache, and anorexia

are common. Weight loss

and nephrolithiasis

reported. Serious skin

eruptions, oligohidrosis,

and hyperthermia have

also occurred

Broad spectrum, long halflife. 35% of dose is

excreted unchanged in the

urine. Also a substrate of

CYP3A4; enzyme

induction may increase

clearance. Advise patients

to drink plenty of fluids

Ezogabine (Potiga) Initial 100 mg TID. ↑ by 150

mg/day every week. 600–1,200

mg/day recommended as target

dosage range. TID dosing

recommended

Dizziness, fatigue and

somnolence are commonly

reported. Urinary

retention, confusion, and

hallucinations. Reddishorange urine discoloration

is benign. Prolongs QT

interval. Retinal

abnormalities and potential

vision loss

Phenytoin and

carbamazepine reduce

ezogabine exposure by

30%–35%. Higher doses

may be needed. Monitor

vision and eye examination

p. 1285

p. 1286

Perampanel

(Fycompa)

Initial 2 mg once daily HS (not

on enzyme-inducing AEDs) or 4

mg once daily HS (on enzymeinducing AEDs). ↑ by 2 mg/day

every week. 4–12 mg/day

recommended as target dosage

range. Once-daily dosing HS

recommended

Dizziness, gait disturbance,

somnolence and fatigue

are commonly reported.

Risk of falls in elderly

patients. Aggression,

hostility, irritability, anger

and homicidal ideation.

May be worsened by

alcohol

Avoidance of alcohol is

recommended. Enzymeinducing AEDs reduce

perampanel exposure by

50%–67%. Higher doses

may be needed.

Perampanel 12 mg/day

may reduce effectiveness

of hormonal

contraceptives containing

levonorgestrel

Eslicarbazepine

(Aptiom)

Initial 400 mg once daily. ↑ by

400 mg/day after one week.

Maximum recommended dose is

1,200 mg/day. Once-daily dosing

recommended

Dizziness, somnolence,

nausea, and headache

Enzyme-inducing AEDs

reduce eslicarbazepine

exposure. Higher doses

may be needed. May

reduce effectiveness of

hormonal contraceptives

AED, antiepileptic drugs; AV, atrioventricular; BID, twice daily; CA, carbonic anhydrase; CNS, central nervous

system; CYP, cytochrome P-450; GI, gastrointestinal; HS, at bedtime; IM, intramuscular; IV, intravenous; MHD,

monohydroxy derivative; PE, phenytoin sodium equivalent; QID, four times daily; QOD, every other day; SIADH,

syndrome of inappropriate antidiuretic hormone secretion; TID, three times daily; UGT, uridine diphosphate

glucuronosyltransferase; VPA, valproic acid.

Zonisamide has a long half-life and low protein binding. It is eliminated by both

hepatic metabolism and renal excretion. The average half-life of zonisamide is 63

hours, but there is wide interpatient variation. Serum levels of zonisamide are

reduced by enzyme-inducing AEDs but clinical consequences of pharmacokinetic

interactions with zonisamide are rare.

77

On the basis of efficacy and side effect characteristics, gabapentin, lacosamide,

lamotrigine, levetiracetam, pregabalin, tiagabine, topiramate, or zonisamide could be

considered for use as adjunctive therapy for R.H. In young, active patients such as

R.H., sedation might prove to be a problem; however, it is not clear that any of these

drugs predictably causes more initial or long-term sedation. The short half-lives of

gabapentin and tiagabine and the associated need for R.H. to take several doses

during the day might decrease her adherence. Therefore, lacosamide, lamotrigine,

levetiracetam, pregabalin, topiramate, or zonisamide would be reasonable choices

on the basis of convenience. Because the patient is not tolerating carbamazepine, it

does not make sense to switch to either eslicarbazepine or oxcarbazepine.

The reason that ezogabine, felbamate, and perampanel were not discussed in the

side effects and pharmacokinetics sections above is that these authors do not believe

they are good options for R.H. at this point. Ezogabine and perampanel are very new

to the market at the time of this writing and both have FDA boxed warnings (vision

problems and behavioral reactions, respectively). Felbamate’s usefulness is

seriously limited by its association with aplastic anemia and hepatic failure.

Potential Therapies

Other AEDs that may become available in the near future include brivaracetam,

ganaxolone, and huperzine A.

86 These drugs may become useful as alternatives or

adjuncts to established and newer medications in the future.

With advancing technology and knowledge about genes and brain networks, future

treatment strategies should move from controlling symptoms of epilepsy with AEDs

to prevention and cure. For AED-resistant epilepsy, much research is examining the

role of multidrug transporters (e.g., P-glycoprotein) at the blood–brain barrier. These

proteins may act as a defense mechanism by limiting the accumulation of AED in the

brain.

87 Although it has not yet had much of an impact on the clinical care of patients

with epilepsy, pharmacogenetics of AED therapy is continually advancing.

88

LAMOTRIGINE THERAPY

Initiation and Dosage Titration

CASE 60-2, QUESTION 2: R.H. is to be started on lamotrigine as adjunctive therapy to her carbamazepine.

Outline a treatment plan for initiating and monitoring therapy for R.H. What should R.H. and her family be told

about this medication and how to use it?

Lamotrigine therapy should be initiated in R.H. with a slow upward dosage

titration to minimize early sedative effects and reduce the likelihood of skin rash. An

initial dosage of 50 mg/day given at bedtime is recommended; the daily dose can be

increased by 50 mg every 1 to 2 weeks. Because R.H. is currently receiving

carbamazepine, induction of liver enzymes is likely to increase her dosage

requirements for lamotrigine and allow a less conservative dosage titration. A twicedaily schedule is recommended for maintenance therapy. Usual maintenance dosages

of lamotrigine are approximately 300 to 500 mg/day. A patient’s ability to tolerate

this medication ultimately determines dosage limitations. Onset of side effects (e.g.,

nausea, diplopia, ataxia, and dizziness) may prevent further dosage increases.

R.H. should be told that she may feel drowsy and possibly experience headache

and upset stomach, but that these side effects usually disappear with ongoing therapy.

She should contact her physician or other health care professional if severe side

effects occur that make it difficult to take the medication; this is especially important

if she exhibits a rash.

Side Effects and Possible Interaction with Carbamazepine

CASE 60-2, QUESTION 3: Two days after her dosage of lamotrigine was increased to 300 mg/day (12

weeks after beginning therapy), R.H. noticed that her vision was blurring; she also complained of feeling dizzy

and having difficulty maintaining her balance. Previously, she had experienced only mild, occasional nausea. She

had continued to experience seizures at approximately the same frequency she had before the initiation of

lamotrigine. Her

p. 1286

p. 1287

physician had encouraged her to continue taking the medication and explained that it would take time to

increase the dose to possibly effective levels. Her current carbamazepine serum concentration is essentially

unchanged when compared with when she was taking it in monotherapy. Do these new side effects represent

treatment failure with lamotrigine? If not, how might these new side effects be managed?

R.H.’s side effects may limit further dosage increases. Her current side effects

might represent carbamazepine intoxication, lamotrigine side effects, or an

interaction between these two medications. Because R.H. tolerated the same

carbamazepine dose previously, carbamazepine “intoxication” seems a less likely

cause. Assessing the role of lamotrigine as the only cause is difficult. Obtaining a

lamotrigine serum concentration to aid in assessing her adverse effects is not likely to

be helpful. A usual “therapeutic range” for lamotrigine serum concentrations has not

been established. Clinical studies have failed to demonstrate a significant correlation

between lamotrigine serum concentrations and either therapeutic or adverse

responses.

89

,

90 Her symptoms may also be related to an apparent pharmacodynamic

interaction between lamotrigine and carbamazepine.

82 The effects experienced by

some patients taking both drugs may be relieved by reducing the carbamazepine

dosage.

LEVETIRACETAM THERAPY

Initiation and Dosage Titration

CASE 60-2, QUESTION 4: R.H.’s carbamazepine dosage was reduced from 1,800 mg/day to 1,400 mg/day.

After 5 days, her side effects persisted and her seizure frequency appeared to be increasing. The clinician

decides to abandon lamotrigine therapy and institute treatment with levetiracetam. Recommend a plan for

initiating R.H.’s levetiracetam treatment.

R.H. previously tolerated and had a better therapeutic response to a higher

carbamazepine dose. Therefore, the dosage of carbamazepine should be returned to

1,800 mg/day before levetiracetam therapy is initiated. Little specific information is

available to help determine how lamotrigine can be safely discontinued. As a general

rule, rapid discontinuation of AEDs is not recommended in other than emergency

situations. Therefore, immediate reduction of R.H.’s lamotrigine dosage to 200

mg/day would seem reasonable. This dosage could then be reduced by 50 to 100 mg

every week until lamotrigine is discontinued.

Levetiracetam treatment should be instituted immediately for R.H. because of her

continuing seizures. Levetiracetam does not interact with other AEDs. Therefore,

discontinuing lamotrigine during initiation of levetiracetam should not create

difficulties in assessing R.H.’s response. Levetiracetam should be initiated at a

dosage of 250 to 500 mg 2 times daily.

83 Although the manufacturer recommends

initiating treatment at 500 mg twice daily, patients may better tolerate lower initial

doses and more gradual titration. R.H.’s daily levetiracetam dose can be increased

by 500 to 1,000 mg every 2 or 3 weeks, according to her tolerance of side effects and

her change in seizure frequency. Although the drug reaches steady state quickly,

allowing at least 2 weeks for observation before dosage increases may improve

patient tolerability and allow for a more thorough evaluation of therapeutic response.

At present, the relationship between serum concentrations of levetiracetam and

therapeutic response or symptoms of intoxication is not well defined. Therefore,

R.H.’s dose should be titrated to the maximal tolerated amount required to control

her seizures. In controlled trials, no clear benefits were apparent at doses greater

than 3,000 mg/day.

Patient Education

R.H. should be informed that with levetiracetam she may experience side effects

similar to those she had with lamotrigine. R.H.’s mood should be assessed at each

visit. Much reassurance and encouragement may need to be given along with this

information to help ensure that R.H. adheres to her treatment regimen. Many patients

become discouraged when multiple trials of medication are necessary and side

effects are prominent. They may express feelings of being “guinea pigs” and may

become uncooperative with the therapeutic plan. Given that RH’s seizures are still

not well controlled, driving restrictions that were likely put into place earlier should

be continued. RH should be counseled not to drive until she is seizure-free and her

driving privileges have been reinstated according to applicable state law. This

restriction can be very hard for some patients to accept because it can significantly

decrease their independence.

PHENYTOIN THERAPY

Initiation and Dosage

CASE 60-3

QUESTION 1: J.N., an 18-year-old, 88-kg male college student, was diagnosed with epilepsy. He experiences

generalized tonic–clonic seizures that last 2 minutes approximately 3 times monthly. J.N. describes a “churning”

feeling in his abdomen before his seizures; this is followed by involuntary right-sided jerking of his upper

extremities. An EEG showed diffuse slowing with focal epileptiform discharges in the left temporal area; it was

interpreted as abnormal. No correctable cause for his seizure disorder was identified despite a thorough

workup. He has no other medical conditions and takes no routine medications. He was treated initially with

carbamazepine up to 600 mg/day. He could not tolerate the medication because of nausea and diplopia despite

relatively low doses. J.N.’s physician has elected to implement a therapeutic trial of phenytoin. Recommend an

initial dosage. What information should be provided to J.N. about his new medication?

Selecting a nontoxic, therapeutic dose of any AED is difficult without having

information about the drug’s disposition in the individual patient (i.e., prior dosages

and clinical response). Although “average” dosages and resulting serum

concentrations for phenytoin often are quoted, interpatient variability is significant.

An initial phenytoin dosage of 400 mg/day (approximately 4.5 mg/kg/day) would be

appropriate for J.N. In most patients, phenytoin therapy is initiated at or near the

anticipated maintenance dose (e.g., 300 or 400 mg daily in J.N.). If tolerability

problems arise, J.N.’s phenytoin dose could be reduced to 200 mg daily (or 100 mg

every 12 hours) and increased by 100 mg/day at weekly intervals until 400 mg/day is

reached. Recently, there has been significant interest in using patient-specific genetic

information to more accurately dose certain drugs, including phenytoin, with the

goals of achieving a therapeutic effect quickly and avoiding dose-related toxicity.

Although certain CYP2C9 homozygous allele variants have been shown to confer

“slow-metabolizer” status on patients treated with phenytoin,

91 CYP2C9 genotyping

of patients is not presently a part of routine clinical practice.

Patient Education

In addition to the name and strength of the medication and instructions for when and

how it should be taken, J.N. should be informed that he may experience initial mild

sedation from phenytoin. He should be cautioned that symptoms such as blurred or

double vision, dysarthria, dizziness, or staggering may indicate that his dosage is too

high; he should be instructed to notify his physician, pharmacist, or other health care

professional

p. 1287

p. 1288

of these symptoms. It is also a good idea to inform patients, at the beginning of

therapy, that adjustments of medication dosage may be necessary before the regimen

is stabilized. While RH is at relatively low risk for osteomalacia given his age and

gender, he should be informed that long-term use of phenytoin (as well as other

AEDs; see Table 60-6) is associated with an increased risk of bone mineral loss and

that this adverse effect warrants monitoring periodically.

Accumulation Pharmacokinetics

CASE 60-3, QUESTION 2: What are the characteristics of phenytoin accumulation pharmacokinetics?

Phenytoin exhibits dose-dependent (Michaelis–Menten or capacity-limited)

pharmacokinetics; therefore, the usual pharmacokinetic concepts of “clearance” and

“half-life” are meaningless. The apparent half-life of phenytoin changes with the dose

and serum concentration. Thus, the time required to reach a new steady state after

dose alteration is difficult to predict because it depends on the dose itself and the

patient’s pharmacokinetic parameters, Vmax and Km.

92 Vmax

is a kinetic constant

representing the maximal rate of phenytoin elimination from the body. Km is the

Michaelis constant, the serum concentration at which the rate of elimination is 50%

of Vmax

. Values for these parameters vary widely among patients; as a result, patterns

of phenytoin accumulation and the time required to achieve steady state also vary.

Many clinicians assume that phenytoin’s apparent half-life is approximately 24

hours, and they wait 5 to 7 days before assessing the patient’s clinical response and

measuring serum phenytoin concentrations. Both clinical studies

93 and model

simulations

94 using observed values for Km and Vmax have been used to estimate time

required for serum concentrations of phenytoin to reach steady state. Up to 30 days

may be needed for this to occur either with doses sufficient to produce steady state

serum concentrations of 10 to 15 mcg/mL or with doses of 4 mg/kg/day.

92

,

95

Occasionally, such a dose may exceed a patient’s Vmax

; the result is extremely high

serum phenytoin concentrations, with probable intoxication. It is important not to

assume that steady state has been reached unless widely spaced, serial serum

concentrations indicate that accumulation has ceased. Alterations in phenytoin dosage

before steady state has been reached can result in significant fluctuations in serum

concentrations and the patient’s clinical status. Such situations occur frequently and

result in unnecessary confusion and expense. As always, serum concentrations in J.N.

must be interpreted in the context of his clinical response.

Phenytoin Intoxication

CASE 60-3, QUESTION 3: J.N. was started on phenytoin and is now taking 200 mg every 12 hours. One

week after achieving this dose, mild lateral gaze nystagmus was noted, but J.N. had no subjective complaints

and was seizure-free. After 3 weeks, J.N. complained of double vision and feeling “drunk” and “unsteady.”

Significant nystagmus was present. How should J.N.’s phenytoin dosage be altered?

J.N.’s signs and symptoms indicate phenytoin intoxication. Dosage reduction is

indicated. Reducing J.N.’s dosage to 360 mg/day (accomplished using both 100-mg

and 30-mg phenytoin capsules) would be reasonable. A larger reduction may result

in a loss of seizure control. Many clinicians also would have J.N. omit one day’s

dose of phenytoin before beginning the new maintenance dosage. This would

accelerate the decline in phenytoin serum levels. After this dosage change, clinical

response should be monitored closely. The new maintenance dose may still be

excessive, if J.N.’s Vmax

for phenytoin is low. If this were the case, continued

accumulation of drug would occur despite the dosage reduction.

92

Intramuscular (IM) Phenytoin and Fosphenytoin (Phenytoin Prodrug)

CASE 60-4

QUESTION 1: S.D. is a 24-year-old male institutionalized patient with a history of complex partial and

secondarily generalized tonic–clonic seizures. Within the past year, his phenytoin formulation was switched

from phenytoin sodium capsules to phenytoin suspension because S.D. was suspected of “cheeking” his

medicines and not swallowing the capsules. He has had no seizures in the past 3 months on 275 mg/day of

phenytoin suspension. S.D. has now been transferred to the acute medical unit after a 2-day history of anorexia,

nausea, occasional vomiting, and abdominal pain accompanied by diarrhea. His chart now states “nothing by

mouth.” IM fosphenytoin, 275 mg (phenytoin sodium equivalents [PEs]) per day, has been ordered. Discuss the

use of IM fosphenytoin, and devise a dosage regimen for S.D.

S.D. is a candidate for parenteral administration of his AED. If placement of an IV

line for fluid administration is not planned, then IM administration is an acceptable

approach to treatment; however, the type of phenytoin product administered will need

to be changed. Phenytoin, itself, should not be administered by IM injection.

Injectable phenytoin is highly alkaline (pH 12) and extremely irritating to tissue.

After IM injection, the drug may precipitate at the injection site because of the change

in pH. As a result, phenytoin crystals form a repository or depot from which the drug

is slowly absorbed.

96–98 Often injection site discomfort is noted, although severe

muscle damage does not seem to occur.

98