Phenytoin, Fosphenytoin, and Other Hydantoins

Chapter 154

John M. Stern

Emilio Perucca

Thomas R. Browne

Introduction

The hydantoins are derivatives of a common five-membered heterocyclic ring that differ according to their unique combinations of alkyl and phenyl substitutions at three positions on the ring (Table 1). Phenytoin (PHT) is the most commonly prescribed hydantoin, and fosphenytoin is a phosphate ester prodrug of PHT used for parenteral administration of PHT. Ethotoin and mephenytoin are prescribed less frequently than PHT but may be useful in specific situations.

Phenytoin

Chemistry

The structural formula of PHT (5,5-diphenylhydantoin) is shown in Table 1. PHT has a molecular weight of 252.26 and is a weak acid with a pK_a of 8.3 to 9.2 under different experimental conditions.⁷⁰ Because of its high pK_a, PHT is relatively insoluble in water at acid or physiologic pH but is quite soluble in water at alkaline pH. These relationships have important clinical consequences, discussed below. The sodium salt of PHT has a molecular weight of 274.25 and contains the equivalent of 91.98% PHT acid.⁷⁰

Multiple reliable methods for determining the concentration of PHT in biologic fluids have been reported. These employ gas–liquid chromatography, high-performance liquid chromatography, and immunoassay techniques.⁸⁷

Pharmacology

PHT has multiple effects on cell function, which presumably explain its therapeutic and toxic effects. Three of these functions seem particularly important. First, PHT causes use-dependent inhibition of sodium channels necessary for the “firing” of action potentials. Sodium channels exist in resting, open, and inactive states. Each time sodium channels open during the passage of an action potential, some sodium channels become inactivated for a period of time before reverting to the resting state. When enough sodium channels become inactivated, the cell can no longer propagate an action potential. By stabilizing the inactivated form of the sodium channel, PHT hastens the process of use-dependent inhibition of action potentials. This phenomenon at least partially accounts for PHT’s ability to control ictal excitability. Second, the ability of PHT to regulate calmodulin and second messenger systems may account for some of its widespread effects on cellular function. Third, PHT has the ability to regulate voltage-dependent neurotransmitter release at the synapse, which may be related in part to its action on calcium or sodium ions. The mechanisms of action of PHT have recently been reviewed in detail elsewhere⁵³ (see Chapter 137).

Clinical Pharmacokinetics

Absorption by Oral Route: General Considerations

As a weak acid with a pK_a of approximately 9.0, PHT is <1% ionized and has a water solubility of 14 μg/mL⁷⁰^,¹⁸⁹ at a pH of 1 to 2. At a pH of 7.5, PHT is 3% ionized and has a water solubility of 100 μg/mL. Thus, only a small amount of PHT is absorbed in the stomach, and most PHT absorption takes place in the small intestine where its solubility is approximately 100 μg/mL.¹⁸⁹

PHT’s low solubility has several important consequences. Not all of an oral dose of PHT is absorbed, and some is lost in the feces. There also are apparently considerable differences in the amount of PHT absorbed by different people, especially when the capsule form is used. Some otherwise normal people require large doses of PHT to reach average drug plasma concentrations, and these people sometimes are accused incorrectly of being noncompliant. Altered PHT absorption is also influenced by certain physiologic states. Pregnancy may be associated with reduced gastrointestinal absorption of PHT.¹⁵⁶ Neonates absorb oral PHT incompletely and erratically.¹⁶^,¹⁴⁰ A final consequence of the marginal intestinal solubility of PHT is that any substance that interferes with the dissolution of PHT or adsorbs PHT in intestinal fluids (e.g., nasogastric feedings, antacids, certain foods, and certain other drugs) will inhibit PHT’s absorption.⁷^,¹⁸⁹

Peak plasma concentration of PHT is usually reached 4 to 8 hours after an oral dose, although the peak may be reached as early as 3 hours or as late as 12 hours.¹⁸⁷^,¹⁸⁹

Differences in Oral Bioavailability among Formulations

There are three types of oral preparations of PHT: Prompt, sustained (extended) release, and liquid suspension. Prompt products are absorbed rapidly in the small intestine, result in an early peak plasma PHT concentration, and must be administered at least twice daily. Sustained-release products such as Dilantin Kapseals and Phenytek are the most commonly prescribed PHT products in the United States, deliver peak plasma concentration values 4 to 8 hours after administration, and may be administered once daily to adults. The liquid suspension is rapidly absorbed, has greater bioavailability than many capsule preparations, and also must be administered at least twice

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daily.¹⁴⁶

Table 1 Hydantoins

Substituents
R₁	R₂	R₃	Name
H	C₆H₅^a	C₆H₅	Phenytoin
CH₂OPO₃Na₂	C₆H₅	C₆H₅	Fosphenytoin
CH₃	C₆H₅	C₂H₅	Mephenytoin
C₂H₅	C₆H₅	C₂H₅	Ethotoin
^aPhenyl ring.

Prompt and sustained-release preparations differ sufficiently in pharmacokinetic properties that they cannot be interchanged. Most generic PHT products marketed in the United States are prompt preparations and cannot be substituted for sustained-release preparations. It should be noted that some preparations (e.g., Dilantin suspension or Dilantin Infatab chewable tablets) contain PHT acid, while others (e.g., Dilantin Kapseals and Phenytek) contain the sodium salt. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments may be necessary when switching from a product formulated with the acid to a product formulated with the sodium salt or vice versa.

Generic substitution of prompt preparations for sustained-release preparations is furthermore problematic because of three risk factors for inequivalence among generic forms of a drug: (a) poor water solubility, (b) nonlinear pharmacokinetics, and (c) narrow therapeutic range of plasma concentration.¹³³^,¹³⁴ PHT possesses all three risk factors, so it is not surprising that comparisons of generic PHT products have yielded conflicting results, with more studies reporting inequivalence than equivalence.³⁹^,⁴⁵^,⁵⁷^,¹²⁷^,¹⁴⁴^,¹⁴⁵^,¹⁴⁶^,¹⁴⁹^,¹⁶⁹^,¹⁹² Two generic sustained-release PHT products were introduced in the United States and later withdrawn because of concerns that they may not be equivalent to brand-name Dilantin.¹⁵^,⁶⁴^,¹⁶⁹ Switching between preparations that are not equivalent may result in decreased drug plasma concentration (increased seizures) or increased drug plasma concentration (increased toxicity).²⁰ Based on this information, an American Academy of Neurology position statement recommends that patients be managed with one form of PHT preparation supplied by one manufacturer.¹³³^,¹³⁴

The oral suspension form of PHT is useful for patients who have difficulty swallowing capsules, especially children. The oral suspension also is useful in patients who do not absorb PHT capsules well.

Absorption by Intramuscular Route

Dissolving PHT in a small volume of liquid for parenteral administration requires a solution pH of 12. When this preparation is injected intramuscularly (i.e., into a medium with a pH of about 7.4), the water solubility of the drug decreases substantially, PHT crystals precipitate in the muscle,²⁰ and the drug is absorbed very slowly.²⁰^,⁸⁸

Peak plasma PHT concentrations occur approximately 24 hours after a single intramuscular injection and are considerably less than the peak concentration produced by the same dose given by intravenous infusion.⁸⁸ PHT should not be given via the intramuscular route in emergency situations (e.g., status epilepticus) because of the slowness of absorption and the relatively low peak plasma concentrations produced by that route.

Use of the intramuscular route for administration of maintenance doses of PHT remains controversial. Eventually, almost all of an intramuscular injection of PHT is absorbed, and regimens for administration of maintenance doses of intramuscular PHT have been reported. However, peak plasma PHT concentrations after an intramuscular injection are variable.⁸⁸ Furthermore, the plasma concentration may fall below therapeutic levels shortly after a switch to the intramuscular route from the oral or intravenous route and may ascend into the toxic range because of accumulation after switching back from the intramuscular to the oral route.⁸⁸ In most situations, maintenance doses of PHT should not be given by the intramuscular route because of the slowness and variability of absorption and because of the danger of over- and undermedication when switching to and from other routes of administration.

Fosphenytoin is a water-soluble phosphate ester prodrug of PHT that eliminates many of the problems of sodium PHT for injection. Fosphenytoin is described below.

Plasma Protein Binding and Distribution

Plasma Protein Binding.

PHT is 69% to 96% protein bound in adults.⁸¹^,¹¹⁰ In the absence of associated disease or displacing agents, the average extent of plasma protein binding is about 90%. Binding is lower in neonates⁵⁹^,¹⁴⁵ and in the elderly.⁸¹

Distribution into Tissues and Other Body Fluids.

The concentration of PHT in brain parenchyma and cerebrospinal fluid (CSF) reaches peak values 15 to 60 minutes after intravenous injection in humans.¹⁸⁹ However, the brain parenchyma concentration of PHT remains greater than the plasma concentration of free PHT once steady-state plasma concentrations are reached.

The concentrations of PHT in CSF, saliva, semen, and bile are essentially identical to the concentrations of free (non–protein-bound) PHT in plasma.¹⁸⁹

PHT freely crosses the placenta.¹⁸⁹ It enters breast milk, with a milk:plasma PHT concentration ratio of about 0.2.¹⁸⁹

Metabolism and Elimination

PHT is excreted in the urine and feces mainly as its metabolites, none of which has significant antiepileptic activity. Less than 5% is excreted in urine in an unmetabolized form.²⁸^,¹⁸⁹ The major route of biotransformation is para-hydroxylation of a phenyl ring by the liver cytochrome P450 system (primarily isoforms CYP2C9 and CYP2C19) to form 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH).⁶^,²⁸ Over 60% of a PHT dose is excreted in urine as p-HPPH, the majority of which is conjugated with glucuronic acid.²⁸^,¹⁸⁹ Minor metabolites include a dihydrodiol derivative; meta-HPPH (mHPPH); diphenylhydantoic acid; 5,5-bis(4-hydroxyphenyl) hydantoin; 5-(3,4-dihydroxyphenyl)-5-phenylhydantoin; and 5-(3-methoxy-4-hydroxyphenyl)-5-phenylhydantoin.²⁸^,¹⁸⁹

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PHT is a prochiral compound. Introduction of a hydroxyl group in one of the phenyl rings leads to the creation of a chiral center and results in the formation of enantiomeric phenolic metabolites. The p-HPPH from human urine consists of a 10:1 mixture of levo- and dextrorotatory isomers.²⁸^,¹⁷³ The amount of m-HPPH in human urine is too low to permit isolation and measurement of optical rotation. The majority of dihydrodiol in human urine is in the S configuration with varying S:R ratios.²^,¹¹¹^,¹¹³^,¹¹⁴^,¹⁵² The S:R ratio is due to an approximately 40 times greater stereoselectivity of CYP2C9 for the S isomer and CYP2C19’s lack of stereoselectivity for either isomer.⁶

Occurrence of Nonlinear (Michaelis-Menten) Pharmacokinetics.

Nonlinear pharmacokinetic properties have major effects on PHT’s clinical usage. The rate of change of plasma concentration (C) of a drug metabolized by an enzyme system can be expressed by the Michaelis-Menten equation:

where t is time, V_max is the maximum velocity of the enzyme system, and K_m is the Michaelis constant of the enzyme system (plasma concentration at which half of the maximum velocity of the enzyme system is attained). The mean steady-state plasma concentration (C_ss) of the drug can be expressed as:

where R is the dosing rate. When C is similar to or greater than K_m, dC/dt will vary in a nonlinear fashion with C; when R is equal to or greater than 0.1 × V_max, C_ss will vary in a nonlinear fashion with R. These observations are the basis of nonlinear pharmacokinetics.

Based on 55 reported determinations, the mean apparent value for PHT’s K_m in adults is 6.3 μg/mL and the range is 1.5 to 30.7 μg/mL. The mean apparent value for PHT’s V_max in adults is 0.45 μg/mL/hr with a range of 0.14 to 1.36 μg/mL/hr based on 54 reported determinations.³^,²⁷^,⁶⁰^,⁶⁶^,⁶⁸^,⁶⁹^,⁷⁹^,¹²¹^,¹⁵⁵ These values appear to be determined principally by arene oxidase enzyme system K_m and V_max values. The other minor pathways of PHT metabolism potentially could have modifying effects on the apparent values of K_m and V_max for PHT.¹⁰⁸ However, attempts to demonstrate an effect of these other pathways on PHT pharmacokinetic parameters in humans have been negative.²⁸^,³⁵

The apparent K_m values computed for humans are based on total (protein-bound and non–protein-bound) PHT plasma concentration. Because only non–protein-bound PHT can be acted on by the metabolizing enzyme system and the non–protein-bound fraction for PHT is approximately 10% in humans,²¹⁰ the K_m of the enzyme responsible for para-hydroxylation of PHT actually should be approximately 0.6 μg/mL. This prediction has been verified in rat liver microsomes.¹⁹³

Eadie et al.⁶⁰ performed the first comprehensive comparison of PHT K_m and V_max values in children and adults. The K_m values from 21 adults (mean 5.8 μg/mL) and 15 children (mean 5.3 μg/mL) were not significantly different. The V_max values from 21 adults (mean 0.48 μg/mL/hr, assuming a PHT volume of distribution of 0.7 L/kg) were significantly (p <0.025) less than the V_max values from 15 children (mean 0.74 μg/mL/hr assuming a PHT volume of distribution of 0.7 L/kg). Suzuki et al.^67a^,¹⁸³ later confirmed these observations regarding K_m and V_max in children. These observations predict that the clearance [V_max/(K_m + C)] of PHT should be greater in children than in adults. This prediction is confirmed by the observations that the elimination half-life of PHT is shorter in children than in adults and that the average dosing rate of PHT (in milligrams per kilogram per day) required to achieve a given plasma concentration is greater in children than in adults.²⁰^,⁵⁶^,⁹⁰

The V_max for PHT increases significantly during pregnan-cy.⁵⁴ This explains part of the observed decrease in PHT steady-state plasma concentration during pregnancy (Equation 2).

PHT will exhibit nonlinear pharmacokinetic properties in the majority of patients because the usual therapeutic plasma concentration values (10 to 20 μg/mL) exceed the usual K_m (6.3 μg/mL), and the usual dosing rate (0.15 to 0.45 μg/mL/hr) is greater than 0.1 times the usual value of V_max (0.45 μg/mL/hr). The consequences of nonlinear pharmacokinetics are discussed in the following sections.

Relationship between Plasma Concentration, Clearance, and Half-life.

According to the Michaelis-Menten equation, drug clearance is equal to V_max/(K_m + C). Drug elimination half-life is equal to 0.693 × volume of distribution/clearance. Thus, PHT clearance will vary inversely with plasma concentration, and PHT elimination half-life will vary directly with plasma concentration (Fig. 1).²⁵^,²⁶^,³⁵ Browne et al.²⁷^,³⁵ described and validated a method for calculating PHT elimination half-life at any given PHT plasma concentration if the patient’s K_m and V_max values for PHT are known. The results (plasma concentration and calculated elimination half-life) for a group of six adult men on PHT monotherapy were 1 μg/mL, 12.8 hours; 10 μg/mL, 25.8 hours; 20 μg/mL, 40.2 hours; and 40 μg/mL, 69.1 hours. Based upon these results, PHT’s commonly believed elimination half-life of 24 hours applies principally to plasma concentration values in the low therapeutic range (10 μg/mL) and the elimination half-life often is longer at higher plasma concentrations (also see Fig. 1). The range of elimination half-life values at a PHT plasma concentration of 40 μg/mL was 37.1 to 96.8 hours. Because of PHT’s long and variable elimination half-life values at toxic plasma concentration values, one cannot predict the time required for PHT plasma concentration to fall from a toxic value to a therapeutic value in a given individual. In such circumstances, one must withhold PHT and obtain daily plasma concentration determination values until the plasma concentration has fallen back into the therapeutic range.

FIGURE 1. Relationship between dosing rate and steady-state plasma concentration for drugs with linear pharmacokinetics and for drugs with nonlinear Michaelis-Menten pharmacokinetics.

Relationship between Steady-State Plasma Phenytoin Concentration and Dosage.

For drugs with Michaelis-Menten pharmacokinetics similar to PHT’s, steady-state plasma concentration increases to a greater extent than dosing rate

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when dosing rate is increased, and plasma concentration decreases to a greater extent than dosing rate when dosing rate is decreased (Equation 2) (see Fig. 2).³²^,⁵⁶^,²⁰⁴ Thus, the steady-state plasma concentration of a drug with these Michaelis-Menten pharmacokinetics at one dosing rate does not directly predict the steady-state plasma concentration of the drug at another dosing rate.

FIGURE 2. Phenytoin clearance and elimination half-life values determined by stable-isotope tracer techniques at 30 different serum concentration values in 18 adult men on PHT monotherapy. (From Browne TR, LeDuc B. Phenytoin: chemistry and biotransformation. In: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic Drugs. 4th ed. New York: Raven Press; 1995:283–300, with permission.)

If the clinician attempts to increase or decrease PHT steady-state plasma concentration by simple linear extrapolation from a known plasma concentration versus dosing rate point, the result is often an unexpectedly high or low plasma concentration when the new steady-state value is attained (Fig. 2). Numerous mathematic and tabular methods have been published that claim to be able to predict the PHT dosing rate necessary to produce a given steady-state plasma concentration from a single steady-state plasma concentration versus dose point, and these methods have been critically reviewed elsewhere.²³^,³²^,¹³¹^,¹³⁸^,¹³⁹ A useful rule of thumb in titrating PHT dosage upward in adults is to increase dosing rate in increments of 100 mg/day at monthly (see below) intervals until a steady-state PHT plasma concentration of 5 to 10 μg/mL (a value approximately equal to K_m) is attained; later increases should not exceed 50 mg/day at monthly intervals.

Nonlinear pharmacokinetics complicates the issue of generic equivalence of PHT products. The weighted mean value for absolute bioavailability of brand-name sustained-release PHT (Dilantin Kapseals, 100 mg, Parke-Davis) was 86% in three studies.²⁰ Less than complete absorption of brand-name PHT is at least in part a consequence of the use of a sustained-release preparation (see above). Different generic preparations of PHT have the potential to differ in bioavailability from the brand-name preparation by 14% or more. Because of PHT’s nonlinear pharmacokinetics, a 14% difference in bioavailability is expected to result in a >14% increase or decrease in steady-state plasma concentration. For example, the bioavailability of a single dose of Mylan extended-release PHT given with a high-fat meal was found to be 13% lower than the bioavailability of Dilantin Kapseals taken under similar conditions.²⁰⁶ Pharmacokinetic simulations based on these data showed that substituting the Mylan product for Dilantin in patients with baseline plasma PHT concentrations within or above the optimal range would be expected to result in a median 37% decrease in PHT concentrations, whereas substituting Dilantin for Mylan would be expected to produce a median 102% increase in PHT concentrations. A national epidemic of PHT intoxication occurred in Australia when a more bioavailable formulation was substituted for an older formulation.¹⁵⁴^,¹⁹⁹ Ludden et al.¹⁰⁸ and Browne et al.³⁶ have reviewed the effect of nonlinear pharmacokinetics on bioavailability studies in more detail.

Effect of Nonlinear Pharmacokinetics on Time to Reach Steady-State Plasma Concentrations.

According to the principles described above, as PHT plasma concentration rises, PHT clearance decreases and elimination half-life decreases (see Table 2 for typical values for these changes in a group of six patients started on PHT monotherapy). This results in a further rise in PHT plasma concentration and a further decrease in PHT clearance. This self-propagating cycle can require a long period of time to go to completion. The time (t) required to attain a given plasma concentration can be computed by the equation:

where V_d is volume of distribution, C_s,t is plasma concentration at time t, and C_s,0 is plasma concentration at time 0.²⁰⁴ Assuming average values for K_m and V_max, it is possible to compute an accumulation half-life (t_1/2A) for PHT as follows:

where _1/2A has units of days and C_ss has units of micrograms per milliliter.⁹⁴ Equations 3 and 4 predict, and empirical data confirm, the following: (a) time to reach steady-state plasma

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concentration will vary nonlinearly with dosing rate; (b) time to reach steady-state plasma concentration will vary linearly with plasma concentration; and (c) the time required to attain new steady-state plasma concentration values after starting PHT therapy or increasing or decreasing PHT dosing rate may be as long as 28 days (Fig. 3).²⁶^,³²^,⁹⁴^,²⁰⁴ Therefore, in some individuals, particularly when the plasma concentration of the drug is in the high range, a PHT plasma concentration value measured <28 days after a change in PHT dosing rate may not be an accurate indication of the ultimate new steady-state

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plasma concentration that will result from the change in dosing rate.

Table 2 Phenytoin pharmacokinetic values for six patients at three times during monotherapy determined with 150-mg tracer doses of stable-isotope-labeled phenytoin^a

	Week 0^b	Week 4^c	Week 12^d	Significance^e (p)
Mean total (labeled and unlabeled)
PHT plasma concentration (μg/ml)	1.2 ± 3.5^f	5.4 ± 2.4	10.0 ± 6.1	<0.01
Clearance (ml/min per kg)^g	0.587 ± 0.149	0.456 ± 0.147	0.387 ± 0.187	<0.05
Elimination half-life (hr)^g	13.2 ± 3.6	18.4 ± 5.0	25.9 ± 9.7	<0.01
^aFrom Brown et al., ref. 20, with permission. ^bWeek 0, value from single-dose (150 mg) study performed before monotherapy. ^cWeek 4, value after 4 weeks on monotherapy (300 mg/day). ^dWeek 12, value after 12 weeks on monotherapy (300–500 mg/day). ^eDifference among values for weeks 0, 4, and 12 by analysis of variance for one group with repeated measures. ^fMean ± standard deviation, here and throughout table. ^gValue for tracer dose of phenytoin.

FIGURE 3. Plot of minimum serum concentration after the nth dose, C_min, versus dose number n. Symbols and dosing rates (g/day) are: ✦, 0.50; •, 0.40; ♢, 0.30; ▪, 0.25; and ▴, 0.20. (From Wagner JG. Time to reach steady state and prediction of steady state concentration for drugs obeying Michaelis Menten elimination kinetics. J Pharmacokinet Biopharmaceut. 1978;6:209–225, with permission.)

Factors Affecting Plasma Phenytoin Concentration Versus Dose Relationship: Age.

Neonates eliminate PHT more slowly than adults or children (see below). Young children metabolize PHT more rapidly than older children and adults, requiring higher milligram-per-kilogram doses of PHT to achieve a given plasma concentration and sometimes not maintaining therapeutic plasma concentrations with once-daily administration.²⁰^,⁵⁶ Plasma-unbound PHT concentrations for a given daily dose tend to be higher in the elderly than in young adults, probably because of a decreased metabolic rate, even though total plasma PHT concentrations may not differ to a major extent between young adults and elderly subjects.⁵^,^6a^,⁶² Elderly individuals may also show a wide (two- to threefold) intraindividual variability in plasma PHT concentrations despite unchanged daily doses, possibly due to day-to-day variability in absorption efficiency.¹¹

Factors Affecting Plasma Phenytoin Concentration Versus Dose Relationship: Pregnancy.

Decreasing total PHT plasma concentrations are usually noted throughout preg-nancy.¹⁰²^,¹⁴⁷^,¹⁸⁶^,¹⁸⁷ However, the plasma concentration of free (unbound), pharmacologically active PHT falls much less than total PHT plasma concentration during pregnancy.¹⁸⁶^,¹⁸⁷ Monitoring of free PHT plasma concentration may be advan-tageous during pregnancy.

Factors Affecting Plasma Phenytoin Concentration Versus Dose Relationship: Hepatic Insufficiency.

The oxidative metabolism of PHT and many other drugs is slowed in patients with hepatic disease.¹⁴⁸ In addition, protein binding may be reduced by any of three occurrences: (a) hypoalbuminemia, (b) displacement by bilirubin or other substances, and (c) changes in the configuration of albumin. The overall result is usually an increase in the total plasma drug concentration, the free (unbound) drug concentration, or both.

Unfortunately, there is no formula for predicting the proper dose of an antiepileptic drug in a patient with hepatic dysfunction based on plasma albumin concentration or liver function tests. One must adjust drug dosage on the basis of clinical response and frequent determinations of the drug plasma concentration.

Factors Affecting Plasma Phenytoin Concentration Versus Dose Relationship: Renal Insufficiency.

Uremic patients receiving PHT have lower total plasma PHT concentrations, higher plasma p-HPPH concentrations, and shorter PHT elimination half-lives than nonuremic patients receiving the same dosage of PHT.⁷²^,⁹⁸^,¹²³ In renal insufficiency, the hepatic biotransformation processes continue and may accelerate, but renal excretion of metabolites is slowed. The high plasma concentration of p-HPPH is presumably a result of impaired renal excretion of the metabolite. The short elimination half-life is presumably caused by increased accessibility of PHT to hepatic biotransformation enzymes as a result of decreased protein binding from low plasma albumin concentration, displacement of PHT from protein-binding sites by p-HPPH and endogenous metabolites, and structural alterations of plasma proteins.¹³⁷ The low total plasma PHT concentration reflects primarily enhanced drug clearance as a result of increased accessibility of PHT to he-patic biotransformation enzymes. Because of the reduced PHT binding to plasma proteins and increased unbound fraction, total plasma PHT concentration in patients with uremia underestimates the concentration of free, pharmacologically active drug. Therefore, therapeutic and toxic effects occur in these patients at lower than usual total plasma PHT concentrations. In individuals with uremia, PHT therapy should be preferably monitored by measuring free (unbound) plasma PHT concentration.

Hemodialysis has little effect on the plasma concentration of PHT.¹⁰⁵

Efficacy

Tonic–Clonic and Partial Seizures

The older literature on the effectiveness of PHT for tonic–clonic and complex partial seizures has been reviewed by Coatsworth.⁴⁶ More recently, a series of trials has compared PHT with other older antiepileptic drugs (carbamazepine, phenobarbital, primidone, and valproic acid) as initial therapy in neonates, in children, and in adults with tonic–clonic and partial seizures.⁴¹^,⁷⁸^,¹¹⁷^,¹¹⁹^,¹⁴¹^,¹⁴⁵^,¹⁵⁷^,¹⁶⁶^,¹⁸⁴^,¹⁹⁴^,¹⁹⁵^,¹⁹⁶^,²⁰⁷ The results of these studies may be summarized as follows: (a) no drug was more effective than PHT in a randomized, prospective double-blind study; (b) PHT and carbamazepine were very similar in efficacy and toxicity; and (c) phenobarbital and primidone generally had more adverse effects than PHT or carbamazepine and, in some studies, were less effective when treating patients with partial seizures. There is also evidence-based data showing that PHT, oxcarbazepine, and lamotrigine have similar efficacy for the initial therapy of partial seizures.¹⁰^,⁷¹^,¹³⁰^,¹⁸¹ Although there have been no direct comparisons of PHT with topiramate and gabapentin, a recent trial suggested that topiramate may have inferior tolerability, and gabapentin inferior efficacy, compared with carbamazepine in patients with newly diagnosed partial seizures.^114b Among newer generations antiepileptic drugs (AEDs), only oxcarbazepine and topiramate are approved by the Food and Drug Administration (FDA) for this indication.

In most of the above studies, tonic–clonic seizures were mostly secondarily generalized seizures in patients with focal epilepsy. However, PHT is also effective for primarily generalized tonic–clonic seizures.¹⁵⁸^,²⁰⁷ Although PHT is effective as prophylaxis against acute symptomatic seizures that may occur soon after traumatic brain injury, it does not decrease the risk of later developing remote symptomatic seizures or epilepsy.⁴⁴

Status Epilepticus

PHT is an important therapy for status epilepticus manifesting with tonic–clonic or partial seizures. A randomized, double-blind trial of four treatments for status epilepticus found lorazepam to be more effective than PHT for seizure control at 1 hour, but it was equally effective to a combination of diazepam and PHT or phenobarbital alone.¹⁸⁸ PHT was inferior to valproic acid for terminating convulsive status epilepticus in a randomized comparison trial of intravenous formulations with each medication given without benzodiazepines and with efficacy measured at the end of the infusion.¹²⁹ However, valproic acid does not have FDA approval for this use.

Other Epileptic Disorders

Older studies, without adequate controls, yielded conflicting results in the value of PHT in treating alcohol withdrawal seizures.¹ However, two modern and well-controlled studies strongly indicate that PHT has no value in treating or preventing alcohol withdrawal seizures.¹^,¹⁶¹

Animal models predict that PHT should not be effective for controlling absence seizures, and clinical experience has shown this prediction to be correct.²⁰⁵^,²⁰⁷

Other Indications

PHT controls trigeminal neuralgia in a smaller percentage of patients than carbamazepine, but the combined use of PHT and carbamazepine for trigeminal neuralgia is sometimes more effective than carbamazepine alone. PHT has been suggested as a therapy for a wide variety of organic and functional diseases of the nervous and cardiovascular systems, as well as for a variety of other conditions.¹³

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Adverse Effects

Dose-related Central Nervous System Adverse Effects

The usual dose-dependent adverse effects of PHT include nystagmus, ataxia, and drowsiness.³⁸^,⁴⁹ Nystagmus is usually horizontal but can include vertical movements at high drug plasma concentrations. The ataxia involves station and gait more than fine motor movements. There is an approximate correlation of signs of PHT intoxication with drug plasma concentration. In the majority of patients, nystagmus appears with drug plasma concentrations of about 20 μg/mL, ataxia with levels of about 30 μg/mL and drowsiness with levels of >40 μg/mL.⁹⁰ However, there is considerable variation among patients in the plasma PHT concentration at which a symptom occurs, and not all patients experience all symptoms. At high plasma concentrations (usually >40 μg/mL), a reversible external ophthalmoplegia may occur.¹⁸⁰ Patients also may experience an excited delirium rather than sedation with therapeutic and toxic PHT plasma concentrations.⁴⁹

Perhaps the most important questions about PHT toxicity are concerned with what, if any, effects the drug has on cognitive function and behavior at typical therapeutic plasma concentrations. The cognitive effects of PHT have been studied extensively. Early studies were flawed by the fact that PHT slows motor speed, causing slowing of timed tests that is not related to slowed cognition. Recent studies indicate that (a) PHT has modest or little effect on cognition, (b) PHT and carbamazepine have similar and modest effects on cognition, and (c) barbiturates may have greater effects on cognition.³⁸^,⁴⁷^,⁵⁵^,¹¹⁷^,¹²⁴^,¹⁷⁶^,²⁰³

A reversible syndrome of “PHT encephalopathy” has been described as a complication of chronic PHT therapy, usually with PHT plasma concentrations in the toxic range.⁴⁹^,¹⁶³ The syndrome is characterized by mental changes, increased slowing and increased paroxysmal activity on electroencephalograms (EEG), increased seizure frequency, and a change in seizure pattern involving development of more tonic components. The mental changes may include drowsiness, progressive decline in higher intellectual function, depression, or euphoria. Focal neurologic signs such as hemiparesis and hemisensory defects may occur. Ataxia and nystagmus may be present or absent, and the CSF protein value may be elevated. This encephalopathy is more common in children, and pre-existing brain damage may be a risk factor for it.¹⁶⁵ All these features generally disappear when PHT is discontinued.

Movement disorders (usually choreoathetosis and orofacial dyskinesia; rarely asterixis, ballismus, hyperkinesia, external ophthalmoplegia, periodic alternating nystagmus, or downbeat nystagmus) have been reported to be caused by PHT.⁴⁹^,¹⁶⁰^,¹⁸⁰ These disorders usually occur with toxic PHT plasma concentrations but may occur with plasma concentrations in a typically therapeutic range for a smaller minority of patients.⁴⁹

Murphy et al.¹³¹ reported 85 cases of PHT intoxication following unintentional overdose (PHT plasma concentration 30.3 to 95.0 μg/mL, median 46.5 μg/mL). The most frequent symptoms were nystagmus (95%), ataxia (80%), lethargy (22%), and seizures (19%). No patient had cardiac abnormalities attributable to PHT intoxication. Outcome was generally good, but three patients had serious complications (hip fracture, infections).

Dose-related Gastrointestinal Adverse Effects

PHT can cause nausea, vomiting, or constipation. Administration with or immediately after meals can reduce gastrointestinal discomfort.

Dose-related Cardiovascular Adverse Effects

Intravenous administration of PHT may cause hypotension, atrioventricular conduction block, and other dysrhythmias. These effects are related to dose and rate of administration, and conventional practice is to limit the rate of intravenous PHT infusion to 50 mg/min or less. Blood pressure and electrocardiographic (ECG) monitoring are recommended when PHT is administered intravenously, particularly at the higher dosages and infusion rates that are used for loading or for the treatment of status epilepticus. Some patients develop the cardiovascular side effects of the intravenous infusion even at the recommended maximum rate of 50 mg/min.

Chronic Adverse Effects

Effects on the Nervous System.

A loss of cerebellar Purkinje cells has been reported in association with PHT therapy.⁴⁹^,¹⁶³ However, loss of Purkinje cells is a common finding in patients with epilepsy, whether or not they take antiepileptic drugs. Dam⁴⁹ reviewed the human and animal data on the effects of PHT on Purkinje cells and concluded that PHT in therapeutic doses does not lead to changes in the density or substructure of Purkinje cells. Reynolds¹⁶³ concluded that although much of the data on this topic are controversial, there are several convincing clinical reports of chronic cerebellar dysfunction following acute PHT intoxication. Since Reynolds’ review, additional reports of cerebellar atrophy following PHT intoxication have emerged³⁸^,¹¹⁶ as well as reports of PHT-related cerebellar degeneration in patients without seizures.¹³⁵^,¹⁵⁹ Conversely, Murphy et al.¹³¹ found no evidence of permanent cerebellar dysfunction in 85 cases of severe PHT intoxication. Thus, permanent cerebellar dysfunction may be a rare complication of PHT intoxication and may be related to the duration of acute PHT toxicity or to pre-existing pathologic damage in the cerebellum from seizures, other drugs, or other causes.¹⁶³^,¹⁶⁴

Chronic PHT administration may lead in some, but not all, patients to a bilateral peripheral neuropathy characterized by decreased reflexes, decreased nerve conduction velocities (especially motor), and sensory deficits.⁴⁹^,¹⁰⁰^,¹⁶³^,¹⁷⁵^,¹⁷⁸ Most patients are asymptomatic, although a minority of patients complain of weakness or dysesthesia. The occurrence of this complication correlates with the duration of PHT therapy. The neuropathy does not seem to be related to folate level, vitamin B₁₂ level, hemoglobin, blood cell counts, or blood sugar. Administration of folic acid or withdrawal of PHT does not seem to improve the neuropathy.

Cosmetic Adverse Effects.

Gingival hyperplasia occurs in approximately 20% of adult patients on PHT,¹¹⁷ and the incidence may be higher in children.¹⁶³ It usually becomes apparent within 2 to 3 months after commencing PHT therapy and reaches a maximum in 9 to 12 months.¹⁶³ Gingival hyperplasia can be reduced by good oral hygiene. Periodic gingivectomy can remove the excess tissue and improve cosmetic appearance. Discontinuing PHT will result in regression of the gingival changes in 3 to 6 months.¹⁶³ When severe, gingival hyperplasia may negatively impact dental health, so it is not always a purely cosmetic effect.

Enlargement of the lips and nose, coarsening of the facial features, hirsutism, chloasma-like pigmentation, and acne all have been reported to occur in patients on chronic PHT therapy.¹⁶³ Except for hirsutism, which is well documented, the evidence for a cause-and-effect relationship between PHT and these conditions is questionable. The evidence consists of retrospective, nonblinded studies of patients, many of whom took other drugs and had moderate to severe mental retardation, often with institutionalization. Thus, the effects of other drugs, genetics, and environment were not controlled.

Endocrine and Metabolic Adverse Effects.

PHT initially causes an increase in circulating adrenocorticotropic hormone

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(ACTH) and cortisol, but levels of these hormones subsequently decline to below-normal concentrations.¹⁶³ Chronic PHT administration enhances hydroxylation of cortisol and increases urinary excretion of 6-β-hydroxycortisol.¹⁶³

PHT depresses the release of antidiuretic hormone and oxytocin.¹⁶³ PHT also can displace thyroxine (T₄) and triiodothyronine (T₃) from thyroxine-binding globulin,⁴⁹^,¹⁶³^,²¹⁴ which can result in decreased serum T₄ and T₃ to maintain normal free T₄ and free T₃ concentrations and a euthyroid state.¹⁸² Therapeutic plasma concentrations of PHT decrease the insulin secretory response of the pancreas to glucose.¹⁶³ This can result in hyperglycemia.⁴⁹^,¹⁶³

Biochemical abnormalities suggesting metabolic bone disease are common in patients on chronic PHT. These include elevated plasma alkaline phosphatase and reduced plasma calcium and plasma 2-hydroxycholecalciferol.³⁸^,¹⁶³ Bone biopsy studies of patients on chronic PHT therapy reveal decreased bone density in approximately half of patients.⁸^,¹⁵¹ These findings may be secondary to decreased intestinal absorption of calcium, increased hepatic metabolism of vitamin D, or altered parathyroid hormone function.³⁸ Although laboratory abnormalities are common, clinically significant osteomalacia is uncommon in patients taking PHT.³⁸^,¹⁶³ Testosterone and estradiol metabolism are enhanced by PHT.³⁸ Chronic PHT therapy may be associated with elevated plasma concentrations of sex hormone–binding globulin in men and women.⁴⁸ The significance of these findings is uncertain.

PHT may precipitate porphyric attacks in patients with acute intermittent porphyria.

Hematologic Adverse Effects.

Aplastic anemia, leukopenia, thrombocytopenia, erythroid aplasia, and pancytopenia have all been associated with PHT therapy.⁷³^,¹⁵⁰ These side effects are very rare, usually occur during the first few months of therapy, are unrelated to dosage, and are often associated with other evidence of hypersensitivity phenomena.¹⁵⁰ Mild leukopenia (total white blood count 3,000 to 5,000/mm³) is common with chronic administration of many antiepileptic drugs, including PHT.¹¹⁷ This does not usually require discontinuing the drug until the count for segmented forms falls below 1,500/mm³.

Macrocytosis is found in 0% to 36% of patients on chronic PHT therapy.¹⁶³ Subnormal serum folate levels are found in 27% to 91% of patients on chronic PHT therapy, and subnormal CSF folate levels are found in 0% to 45% of such patients.³⁸^,¹⁶³ The mechanism of producing low serum folate levels is not known for certain; possible mechanisms have been reviewed.³⁸ Despite the high incidence of macrocytosis and folate deficiency in patients on PHT, only 0.15% to 0.75% of patients develop megaloblastic anemia.¹⁵⁸ Subnormal serum vitamin B₁₂ levels are found in 0% to 11% of patients on chronic PHT therapy, probably because of malabsorption of vitamin B₁₂ as a secondary effect of low serum folate levels.¹⁵⁸

The clinical importance of these findings is controversial. Megaloblastic anemia that is reversible with folate can occur with PHT, and there is highly controversial evidence that folate deficiency may lead to psychiatric disturbances in patients on PHT that are reversible with folate.¹⁵⁸ These considerations favor routine detection and treatment of folate deficiency in patients on PHT. However, animal research indicates that folate antagonizes the antiepileptic effect of PHT, and there is conflicting clinical evidence that administration of folate may increase seizure frequency in patients taking PHT.¹⁶³ Folate levels are an expensive laboratory test. Indications for folate treatment, the dose and duration of therapy, and the question of whether to give vitamin B₁₂ as well as folate all remain to be clarified. The prophylactic use of folic acid to reduce the risk of birth defects in women of childbearing potential is discussed in Chapters 110 and 114.

Idiosyncratic Reactions (Including Immune-mediated Adverse Effects)

Table 3 signs and symptoms in 38 cases of phenytoin hypersensitivity reaction^a

Sign or symptom	Percentage of patients
Rash
Morbilliform or licheniform	66
Erythema multiforme	18
Stevens-Johnson syndrome	13
Total	74
Fever	13
Abnormal liver function tests	29
Lymphoid hyperplasia	24
Eosinophilia	21
Blood dyscrasias
Leukopenia	16
Thrombocytopenia	5
Anemia	16
Increased atypical lymphocytes	3
Total	31
Serum sickness	5
Albuminuria	5
Renal failure	3
^aFrom Haruda, ref. 67, with permission.

A variety of signs and symptoms in various combinations may occur as a result of PHT hypersensitivity reactions (see Table 3). The majority of such reactions occur during the first 3 months of PHT therapy.⁷⁵^,¹¹⁸ One exception to this is the “purple glove syndrome,” which is a triad of edema, pain, and discoloration in the limb distal to the infusion site of intravenous PHT that typically occurs within a day of receiving PHT. The reaction occurs in about 2% to 6% of patients and usually resolves with conservative treatment; however, surgical treatment sometimes is necessary.⁴⁰^,¹³⁶

Rashes, which are most common in children (especially when large starting doses are used) and young adults, usually occur within the first 10 days of PHT therapy and may be accompanied by fever, leukopenia, or lymphadenopathy.⁴⁹ The incidence of rash in adults starting PHT is approximately 10%.¹¹⁷^,¹¹⁸ These symptoms disappear when the drug is discontinued and reappear with readministration of PHT.⁴⁹

More serious dermatologic disorders that can be rare side effects of PHT include erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis.⁴⁹ The relative risk of PHT causing Stevens-Johnson syndrome or toxic epidermal necrolysis has been estimated to be about 290 (95% confidence interval, 9 to 9,239).¹⁰⁴

A “serum sickness”-like illness with rash, fever, arthralgias, and atypical lymphocytes may occur with PHT administration.⁴⁹ In addition to discontinuing PHT, cortico-steroids may be helpful in treating this disorder.⁴⁹

Hepatitis (hepatic necrosis, inflammation, cholangitis) is a rare but serious complication that usually occurs during the first 6 weeks of PHT therapy.⁴⁹^,¹⁴³ It usually occurs in association with other symptoms of hypersensitivity such as rash (100%), fever (90%), lymphadenopathy (75%), or blood dyscrasias.⁴⁹^,¹⁴³

Systemic lupus erythematosus (SLE) has been reported in association with PHT therapy.⁴⁹ In some cases, SLE appears to result from PHT administration, but in other cases, pre-existing

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SLE probably caused a seizure disorder that caused PHT to be prescribed.⁴⁹

Although lymphadenopathy is not uncommon with PHT therapy, the question of whether PHT can cause malignant lymphomas remains controversial.¹⁵⁰^,¹⁷³ Cases with features such as lymphadenopathy, fever, eosinophilia, hepatomegaly, splenomegaly, and certain malignant-appearing features on lymph node biopsy that remitted when PHT was stopped have been reported.⁴⁹^,¹⁵⁰ A smaller number of cases of persistent malignant lymphoma after PHT was discontinued has been reported.⁴⁹^,¹⁵⁰ It is difficult to know whether such symptoms are caused by PHT, other drugs, or the spontaneous appearance of malignant lymphoma. Nevertheless, it is prudent to discontinue PHT in a patient with lymphadenopathy.

PHT may suppress both humoral and cellular immune mechanisms.¹⁷⁹ Production of immunoglobulin A (IgA) is reduced.³⁸ Antinuclear antibodies and lymphocytotoxins of the IgM class have been found in patients taking PHT.¹³⁸

Idiosyncratic reactions involving primarily the bone marrow may also occur, and have been listed in the section on hematologic adverse effects.

One case of fatal allergic interstitial nephritis in association with PHT therapy has been reported.¹²³ PHT has been reported to precipitate autoimmune myasthenia gravis in patients not known to have the disease and to exacerbate the disease in patients known to have it.⁶⁶^,¹⁷⁸

Teratogenicity

The absolute and relative (compared to other therapeutic options) teratogenicity of PHT is an extremely complex topic. The following general observations apply.³⁸^,⁵¹^,⁵²^,¹¹⁵ First, there may be an increased risk of malformations (cleft lip and palate, cardiac defects, cranial anomalies, limb anomalies, hypospadias, intestinal atresia, and possibly mental retardation) in infants born to mothers with epilepsy taking no medication. This, however, has not been established conclusively, and was not found to occur in a large population-based case-control study.⁸⁰ Second, these malformations, which were formerly termed “fetal hydantoin syndrome,” are more common in mothers taking most antiepileptic drugs. Third, the risk is especially high in mothers taking two or more drugs in combination. Fourth, there is significant additional risk, especially for neural tube defects, in infants born to mothers taking valproic acid.²¹¹ Genetics, severity of epilepsy, nutritional status (including folic acid intake), and drugs all may play a role in determining risk of malformation.³⁸^,⁵¹^,⁵² Available evidence does not support the notion that prenatal exposure to PHT involves a greater teratogenicity risk compared with exposure to other established antiepileptic drugs.^146a For more information on existing data and the management of epilepsy in women of childbearing potential and during pregnancy, the reader is referred to recent reviews⁵¹^,⁵²^,^146a and to Chapters 110 and 114 in this book.

Drug Interactions

Effects of Other Drugs on the Pharmacokinetics of Phenytoin

A comprehensive description of drug–drug interactions affecting PHT pharmacokinetics can be found in recent reviews,^{114a,144a,144b,146b} and only the most relevant examples will be discussed in this section.

Administration of PHT with some antacids^144b or with certain nasogastric or enteral feedings⁷^,^210a can result in impaired PHT absorption and a marked fall in plasma PHT concentration, with the attendant risk of loss of seizure control.^147b

Highly protein-bound drugs can displace PHT from plasma protein-binding sites. Unless additional mechanisms are involved, these interactions are not clinically significant because the displaced drug redistributes rapidly into a large volume of distribution and is eliminated through a compensatory increase in drug clearance: The overall result is a fall in total PHT concentration, but the concentration of free, pharmacologically active PHT is unchanged.^144a Clinicians need to be aware of the interaction when interpreting plasma PHT concentration in these patients, especially because the presence of a displacing drug may produce both therapeutic and toxic effects of PHT at low total plasma PHT concentrations. Therefore, a decrease in total plasma PHT concentration caused by these interactions should not lead to an automatic increase in PHT dosage. Valproic acid is the drug most commonly responsible for displacing PHT from plasma protein-binding sites, and it may also inhibit PHT metabolism. When valproic acid is added on to the therapeutic regimen of patients stabilized on PHT, total plasma PHT concentrations usually decrease, whereas free PHT concentrations remain unchanged or even may increase.¹²⁰^,^210a

Most drug interactions causing a change in PHT pharmacokinetics involve interference with PHT metabolism.^91,144b,148 The metabolism of PHT can be accelerated or slowed by drugs that induce or inhibit CYP2C9 and CYP2C19.³³^,⁹¹^,⁹⁵^,⁹⁹^,¹⁴⁸ As described by Kutt,⁹¹ marked changes in plasma PHT concentration occur commonly with only a few drugs and less commonly with other drugs in unusually susceptible individuals. Most interacting combinations can be used if clinically indicated with careful clinical and laboratory monitoring to guide dosage adjustments as necessary. Interactions that involve an acceleration in PHT metabolism and a decrease in plasma PHT concentration include rifampicin and folic acid.^144b Vigabatrin,²⁹ cisplatin, and other antineoplastic drugs^201a also may lower plasma PHT concentrations, but the mechanism underlying these interactions is unclear. Drugs that have been reported to inhibit PHT metabolism and to increase plasma PHT levels, at least in some patients, include felbamate, oxcarbazepine, valproic acid, carbamazepine, clobazam, topiramate, methsuximide, sulthiame, stiripentol, fluoxetine, fluvoxamine, imipramine, sertraline, trazodone, viloxazine, chloramphenicol, fluconazole, isoniazid, miconazole, sulfaphenazole, some antineoplastic drugs (doxifluridine, fluorouracil, tamoxifen, tegafur), allopurinol, amiodarone, azapropazone, cimetidine, chlorpheniramine, dextropropoxyphene, diltiazem, disulfiram, omeprazole, phenylbutazone, sulfinpyrazone, tacrolimus, ticlopidine, and tolbutamide. In the case of highly protein-bound drugs that displace PHT from plasma protein-binding sites (e.g., valproic acid, tolbutamide, phenylbutazone), the increase in plasma PHT concentration may be limited to the free, unbound fraction, and may not be apparent when only total PHT concentrations are monitored.^{21,91,114a,114b,146b,208}

Effects of Phenytoin on the Pharmacokinetics of Other Drugs

PHT is a potent inducer of microsomal drug-metabolizing enzymes and by this mechanism it accelerates the metabolism of a large number of concurrently administered drugs, thereby decreasing their plasma concentrations.^{114a,114b,146b} Antiepileptic drugs whose plasma concentration is decreased by PHT include carbamazepine, lamotrigine, topiramate, tiagabine, zonisamide, felbamate, and many benzodiazepine drugs.^101,146b,215 PHT also lowers the plasma concentration of valproic acid¹²² and increases the production of the “4-en” valproic acid metabolite, thought to be responsible for hepatic toxicity.¹⁰⁰ Other drugs whose plasma concentration may be lowered by PHT include oral contraceptive steroids, dexamethasone and other glucocorticoids, nisoldipine, felodipine and most

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other dihydropyridine calcium antagonists, cyclosporin A, certain antineoplastic agents, meperidine, methadone, acetaminophen, theophylline, chloramphenicol, itraconazole, indinavir, doxycycline, praziquantel, folic acid, digitoxin, bishydroxycoumarin, warfarin (for which an initial decline in the plasma concentration may be followed by an increase in plasma warfarin concentration and increased anticoagulant response), metyrapone, 25-hydroxycholecalciferol, and thyroxine.⁹¹ Many of the above interactions are clinically important and may result in loss of pharmacologic effect of the affected drug. Coadministration of PHT has been reported to raise the plasma concentration of phenobarbital derived from primidone and N-desmethylmethsuximide derived from methsuximide.²¹^,⁹¹^,⁹⁵

Indications

Oral Treatment

PHT is indicated for the treatment of partial seizures, with or without secondary generalization, and for the treatment of primarily generalized tonic–clonic seizures. Because PHT may potentially aggravate other generalized seizure types such as absence and myoclonic seizures,^147a it is not the best choice to treat primarily generalized tonic–clonic seizures in syndromes associated with other generalized seizure types. As discussed in more detail in Chapter 118, the choice of an AED is dictated not only by its efficacy spectrum, but also by other considerations such as adverse effects, drug interaction potential, cost, and individual characteristics of the patients. The use of PHT varies considerably across countries and across different clinical settings. While many physicians consider PHT as a valuable treatment option for initial treatment, others prefer to utilize PHT as a second-line agent due to concerns with its dose-dependent pharmacokinetics, cosmetic side effects (particularly in young women), and potential for drug interactions (particularly in the elderly).

Intravenous Treatment

PHT is an important therapy for tonic–clonic and partial status epilepticus. Its best use for status epilepticus is in combination with a benzodiazepine, which should be given first because of the benzodiazepine’s faster onset of antiseizure effect.¹²⁵ A more detailed discussion of the role of PHT in the treatment of status epilepticus is provided in Chapter 127.

Dosing Recommendations

Initiation of Treatment and Dose Adjustment

The usual initial dosage in adults is 300 mg/day, and the usual initial dosage in children is 5 mg/kg/day. Because of the very slow metabolism of PHT in premature and term infants, the usual doses of PHT can produce toxic plasma concentrations in these infants.¹⁰⁶ It is often impossible to predict the proper dosage of PHT in such patients, and the dosage must be adjusted by frequent monitoring of PHT plasma concentration.

Clinical response should be monitored carefully after initiating treatment. In patients with unusually slow rates of PHT metabolism, the usual starting dosage may result in excessively high plasma PHT concentrations and occurrence of adverse effects. More commonly, the usual daily dose of 300 mg/day may not produce good seizure control, and the dosage must then be raised until seizure control is obtained or toxicity precludes further increases. In raising the dosage of PHT, one is faced with two conflicting considerations. In some patients, a small increase in PHT dosage will result in an unexpectedly great increase in plasma concentration and drug toxicity owing to the phenomenon of concentration-dependent metabolism. This result argues for increasing the dosage in small increments. Other patients absorb PHT poorly and require large increases in dosage to achieve therapeutic drug plasma concentrations. This would argue for increasing dosage in large increments. One workable compromise is to increase PHT dosage in 100 mg/day increments until a plasma concentration of 10 μg/mL is reached. After that, further increments of 50 mg/day or 30 mg/day can be added. Only one increment should be added every 4 weeks or longer because it may take that much time to reach a steady-state plasma concentration and to discern the full therapeutic and toxic effects of the dosage regimen. Monitoring plasma PHT concentration is invaluable during the process of dose individualization, or whenever there is an unexpected change in clinical response (Chapter 104).

As noted above, some patients who do not absorb PHT capsules well will absorb the oral suspension form much better. If a patient is taking a dose of 500 mg/day and does not have a therapeutic plasma concentration and noncompliance has been excluded, it may be helpful to switch from the capsule form to the oral suspension form. This often results in therapeutic (and sometimes toxic) plasma concentrations. PHT oral suspension must be shaken well before each dose to prevent the drug from settling in the bottom of the bottle, resulting in undermedication when the suspension is taken from the top of the bottle and overmedication when it is taken from the bottom of the bottle.

Divided Dose Versus Single Daily Dose

Several groups have shown that once-daily administration of extended-release PHT will maintain therapeutic plasma concentrations in the majority of adults, although there can be a twofold difference between maximum and minimum PHT plasma concentrations because for some patients, particularly when the plasma PHT concentration is in the low range, the elimination half-life can be <24 hours.²⁰^,²⁸^,⁹⁰^,¹⁸⁷ Because once-daily administration is the most convenient dosage schedule for many patients, it probably encourages increased compliance. However, there are four groups of patients who should receive PHT in two divided doses. The first group is patients of any age taking immediate-release PHT. The second group is adults who have side effects associated with peak plasma concentrations after once-daily administration. The third group includes patients of any age with poorly controlled seizures. Dividing the dose of PHT will result in a smaller fall in PHT plasma concentration at times of minimum drug serum concentration. The fourth group is children, because children metabolize PHT more rapidly than adults and cannot always maintain a therapeutic plasma concentration with once-daily administration.²⁰^,⁵⁶^,¹⁰⁶ Even with their more rapid rate of elimination of PHT, children can maintain therapeutic plasma concentrations with twice-daily administration.⁵⁶

FIGURE 4. Plot of plasma phenytoin concentration versus composite score for overall response (efficacy and toxicity) to drug (0, no seizures and no side effects; 1–20, good response; 21–49, acceptable but less than optimal response; 50+, unacceptable seizure frequency or toxicity). (From Schumacher GE, Barr JT, Browne TR, et al., and the Veterans Administration Epilepsy Cooperative Study Group. Test performance characteristics of the serum phenytoin concentration [SPC]: the relationship between SPC and patient response. Ther Drug Monit. 1991;13:318–324, with permission.)

Administration of PHT in three or four divided doses is almost never necessary and should be avoided. Patients often omit doses of drugs that must be taken at school or work, and three- or four-dose daily regimens often lead to increased noncompliance.²⁰

The largest dose of PHT is usually given at bedtime. This reduces drowsiness, ataxia, and other side effects that can be associated with peak PHT plasma concentrations.

Loading Dose

It can take several weeks to reach a steady-state plasma PHT concentration when therapy is initiated with the usual

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maintenance doses. If it is necessary to achieve a plasma concentration in the therapeutic range rapidly, a loading dose can be given. Therapeutic plasma concentrations can be achieved very quickly with an intravenous loading dose in emergency situations. The intravenous loading dose of PHT is 15 to 20 mg/kg (see Chapter 127). Specific information on intravenous dosing recommendations for the treatment of status epilepticus is provided in Chapter 127.

Administration of an oral loading dose of PHT is less rapid but less dangerous than intravenous loading. In adults, administration of 400 mg followed after 4 hours with 300 mg followed after 4 hours with a final 300-mg dose will result in therapeutic PHT plasma concentrations 14 to 20 hours after the first dose and steady-state plasma concentrations 36 to 40 hours after the first dose.¹⁹⁸ More rapid administration of oral PHT in alert patients may result in gastrointestinal upset, drowsiness, and “spacey” feelings.

In children, oral loading with PHT can be accomplished by administering four doses of 5 to 6 mg/kg at 8-hour intervals. With this regimen, plasma concentrations of 10 μg/mL or more are reached 16 to 38 hours after the first dose.

Administration of a loading dose of PHT via the intramuscular route is not possible using injectable sodium phenytoin (see above). However, a loading dose of PHT can be administered via the intramuscular route using fosphenytoin (see below).

Plasma Phenytoin Concentration as an Aid to Dose Adjustment

The average dosage (in milligrams per kilogram) required to achieve a given plasma PHT concentration is greater in children than in adults.²⁰^,⁹⁰ However, the plasma concentration produced by a given dose of PHT varies so much that it is impossible to predict a given patient’s drug plasma concentration from the dosage.⁹⁰ Laboratory tests are the only assured method of determining a patient’s drug plasma concentration.

The commonly provided target range provided by clinical laboratories for PHT plasma concentration is usually 10 to 20 μg/mL. The lower limit of 10 μg/mL is determined by the observation that the majority of patients with PHT plasma concentrations <10 μg/mL do not achieve good seizure control.²⁰^,⁹⁰ The upper limit of 20 μg/mL is determined by the observation that the majority of patients will show signs or symptoms of PHT intoxication with plasma concentrations above this value.²⁰^,⁹⁰ However, the range of 10 to 20 μg/mL is only a guideline or set of reference points. In a study of optimally managed patients, Schumacher et al.¹⁷¹ found that approximately 25% of patients on PHT monotherapy had plasma concentrations in each of four groups: 5 to 10 μg/mL, 10 to 15 μg/mL, 15 to 20 μg/mL, and 20 to 25 μg/mL (Fig. 4). Other reports also confirm that some patients do best with PHT plasma concentrations above or below the provided range.⁷⁷^,¹⁰⁹ The use of plasma concentration monitoring as

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a guide to dosage adjustment is discussed in more detail in Chapter 104.

Precautions

PHT should be used cautiously in patients with generalized epilepsies, due to the potential of precipitating or aggravating seizure types against which the drug is ineffective, particularly absence and myoclonic seizures. The use of PHT in patients with liver impairment also requires caution because of the increased likelihood of dose-related adverse effects. Observation for rash, especially after initiation of treatment, is warranted because of the possibility of a serious dermatologic reaction such as Stevens-Johnson syndrome or toxic epidermal necrolysis.

Contraindications

PHT is contraindicated in patients with known hypersensitivity to hydantoin drugs. Other contraindications include progressive myoclonic epilepsy of the Unverricht-Lundborg type^146a and acute intermittent porphyria.

Because of its effect on ventricular automaticity, the intravenous use of phenytoin is contraindicated in sinus bradycardia, sinoatrial block, second- and third-degree atrioventricular block, and patients with Adams-Stokes syndrome.

Fosphenytoin

Chemistry

Fosphenytoin (disodium phosphate ester of phenytoin; ACC-9653; CI 982; Cerebyx) (Table 1) is a phosphate-ester prodrug of PHT developed as a replacement for standard injectable sodium PHT.²⁸ After absorption, PHT is cleaved from the prodrug by phosphatase enzymes. Fosphenytoin has a molecular weight of 406.3. Thus, 1.5 mg of fosphenytoin releases 1.0 mg of phenytoin. To simplify discussion, all fosphenytoin doses in this paper have been converted to “PHT equivalent doses” (fosphenytoin dose divided by 1.5). Unlike PHT, fosphenytoin is freely soluble in aqueous solutions (including standard intravenous solutions). The water solubility of fosphenytoin at 37°C is 7.5 × 10⁴ μg/mL (vs. 20.5 μg/mL for PHT).³⁴ Because it is much more water soluble than PHT, fosphenytoin is formulated as a simple aqueous solution in trimethamine (Tris) buffer at pH 8.8.¹⁴² In contrast, injectable sodium PHT is formulated with 40% propylene glycol and 10% ethanol in water adjusted to pH 12 with sodium hydroxide. The propylene glycol and high pH can cause local toxicity at injection sites (see below).

Pharmacology

The pharmacologic activity of fosphenytoin on the nervous system is via PHT released from fosphenytoin. The mechanism of action of PHT is discussed above.

Clinical Pharmacokinetics

Absorption

The extent of absorption (absolute bioavailability) of fosphe-nytoin has been determined by measurements of the ratios of the area under the plasma concentration versus time curve (AUC) for PHT derived from fosphenytoin versus the AUC values for standard injectable sodium PHT administered by the intravenous route. A ratio of 1.0 indicates complete bioavailability. In single-dose studies in drug-free volunteers by the intravenous²⁴^,⁸⁵ and intramuscular²⁴ routes and in single-dose intravenous studies in patients with therapeutic PHT plasma concentrations,³⁴ the AUC ratios obtained were close to 1.0. Bioavailability studies of drugs with nonlinear pharmacokinetics (such as PHT) present special difficulties, which have recently been reviewed.²⁸^,³⁴^,³⁶ Unlike intravenous administration, which has peak serum fosphenytoin concentration at the end of the infusion, the peak serum concentration of intramuscularly administered fosphenytoin occurs approximately 30 minutes after the injection. For both intravenous and intramuscular administration, the time of peak fosphenytoin serum concentration is not as clinically meaningful as the time of peak PHT serum concentration, which results from enzymatic conversion. When fosphenytoin is given intravenously, peak total (free + bound) PHT concentrations occur 30 to 60 minutes after starting the infusion, whereas peak free PHT concentrations occur at 15 to 30 minutes.^65a The difference in time to peak between total and free PHT is due to the fact that fosphe-nytoin displaces PHT from its plasma protein-binding sites in a concentration-dependent manner.^65a The peak in plasma PHT concentration after intramuscular injection of fosphenytoin occurs at about 1.5 to 4 hours, and it is significantly lower compared with the peak concentration produced by intravenous fosphenytoin or PHT.

Plasma Protein Binding and Distribution

Fosphenytoin is a very polar, water-soluble molecule with a volume of distribution of 0.04 to 0.13 L/kg, and it remains largely in the plasma compartment, distributing more widely after its cleavage into PHT and the phosphate moiety.¹³^,³⁴^,^65a^,⁹⁹^,¹⁰³

Fosphenytoin binds competitively to the same plasma protein-binding sites as PHT.⁶²^,⁶³^,⁸⁴ Thus, in the presence of fosphenytoin, the free PHT plasma concentration (for PHT derived from fosphenytoin or from previous administration) is higher than expected. The free PHT fraction increases with increasing fosphenytoin plasma concentration and with increasing fosphenytoin infusion rate (especially rates >50 mg/min). Prior administration of diazepam has no effect on the protein binding of fosphenytoin.⁸⁴

Metabolism and Elimination

PHT is cleaved from fosphenytoin by phosphatase enzymes present in liver, red blood cells, and other tissues.¹⁴² The half-life for conversion of fosphenytoin to PHT is approximately 8 to 15 minutes with modest interindividual variability.³^,¹⁴^,¹⁹^,²⁴^,²⁸^,³⁴^,⁶³^,⁶⁸^,¹⁰³^,¹⁴² The conversion half-life of fosphenytoin appears to be independent of plasma concentration of fosphenytoin or PHT.¹⁹^,²⁴^,³⁴^,⁶³^,¹⁰³ The clearance of fosphenytoin is approximately 200 mL/min at lower dosing and infusion rates and increases to approximately 400 mL/min at higher dosing and infusion rates, presumably because of changes in distribution (see above).¹⁹^,²⁴^,³⁴^,⁶³^,¹⁰³ The conversion half-life of fosphenytoin to PHT is shorter in patients with he-patic or renal disease, possibly because of differences in protein binding.⁴

FIGURE 5. Mean free plasma phenytoin (PHT) concentration following administration of 1,200-mg doses of PHT and fosphenytoin (in PHT equivalents) to 12 healthy subjects. (From Browne TR, Kugler AR, Eldon MA. Pharmacology and pharmacokinetics of fosphe-nytoin. Neurology. 1996;46(Suppl 1):S3–S7. with permission.)

Direct renal excretion of fosphenytoin is small (0% to 4% of dose) and clinically insignificant.³⁴^,¹⁴² PHT derived from fosphenytoin is eliminated in the same way as PHT administered as such.¹⁹^,²⁴^,³⁴^,¹⁰³

Efficacy

Being a prodrug of PHT, fosphenytoin has an efficacy profile equivalent to that of PHT.

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Adverse Effects

Animal⁹³^,¹⁷⁷^,¹⁹⁷^,¹⁹⁹^,²⁰⁰^,²⁰⁵ and human⁵⁰^,⁶⁰^,⁶²^,⁶³^,⁸⁶^,⁸⁷^,¹⁰³^,²⁰⁹ studies show convincingly that fosphenytoin causes fewer local adverse effects (burning and pain) when given by the intramuscular route (20% incidence, usually mild) or the intravenous route (<5% incidence, usually mild) compared with standard injectable sodium PHT. This is presumably a result of differences in the physicochemical characteristics of the formulations (see above).

Animal and human work indicates that most of the toxicity associated with fosphenytoin is attributable to enzymatically derived PHT.¹⁹^,⁴³^,⁵⁰^,⁶²^,⁶³^,⁷⁴^,⁹⁷^,¹⁰³^,¹⁶⁸^,¹⁷⁷ The most common side effects reported for fosphenytoin in large clinical trials are nystagmus, headache, ataxia, and somnolence.⁵⁰^,⁹⁷ Pruritus or paresthesias of the groin, back, lower abdomen, head, or neck rarely occur during PHT infusions, but have been reported in 0% to 30% of volunteers or patients in various studies of parenteral fosphenytoin.¹⁹^,¹⁰³^,¹⁴² Pruritus and paresthesias usually occur during intravenous administration of higher doses and at higher dosing rates and rapidly resolve without sequelae.¹⁹^,¹⁰³^,¹⁴²

The maximum rate of infusion of standard sodium PHT for injection is determined by cardiac depression (hypotension, atrioventricular block). This rate is usually stated to be 50 mg/min, although there are no definitive published data to establish it. Similarly, the maximum rate of infusion of fosphenytoin is determined by cardiac depression, presumably from PHT derived from fosphenytoin. It has been found that infusion of fosphenytoin at a rate of 150 mg PHT equivalents/min produces free PHT plasma concentrations similar to those produced by standard injectable sodium PHT infused at 50 mg/min (Fig. 5). The incidence of cardiac depression with fosphenytoin infused at 150 PHT equivalents/min is similar to or less than the incidence with sodium phenytoin infused at 50 mg/min, possibly because of elimination of propylene glycol from the fosphenytoin preparation.²²

Role in Epilepsy Treatment

Indications

Fosphenytoin is a valuable alternative to parenteral PHT. Its main indications are the treatment of status epilepticus and as parenteral replacement therapy for oral PHT in patients temporarily unable to take PHT orally.

Dosing Recommendations

Intravenous Treatment of Status Epilepticus.

The half-life for conversion of fosphenytoin to PHT is 8 to 15 minutes, potentially slowing its effectiveness in treating status epilepticus. However, this observation is offset by two other observations. First, fosphenytoin can be infused safely at a rate of 150 mg/min of PHT equivalents, whereas the maximum safe infusion rate for PHT is 50 mg/min. Second, the free fraction of plasma PHT is increased in the presence of fosphenytoin, especially at high fosphenytoin infusion rates. Volunteers and patients receiving fosphenytoin infusions at 150 mg/min have free PHT plasma concentrations equivalent (in time and extent) to those produced by standard injectable sodium PHT infused at 50 mg/min (Fig. 5).²⁸^,⁶²^,⁶³ As expected, the dosing rates of these two drugs produce similar systemic toxicity, but there is less local toxicity with the fosphenytoin preparation.²⁸^,⁶²^,⁶³

The administration of fosphenytoin for status epilepticus is recommended in the FDA-approved prescribing information to be 15 to 20 mg PHT equivalents/kg intravenously at a rate of 100 to 150 mg PHT equivalents/min. A reduction of the infusion rate by 25% to 50% has been suggested when infusing fosphenytoin in patients with renal or hepatic disease, hypoalbuminemia, and the elderly.^65a In all patients, continuous monitoring of electrocardiogram, blood pressure, and respiratory function is recommended during the infusion and for 20 minutes after the infusion has completed, although the risk of autonomic complications is less than that from intravenous PHT. Because of the delay related to the conversion of fosphenytoin to PHT, a benzodiazepine or other more immediate-acting antiseizure medication is recommended to be given concomitantly with fosphenytoin.

Intramuscular Loading Dose.

An intramuscular loading dose of fosphenytoin equivalent to 9 to 12 mg/kg of PHT will produce a maximum PHT plasma concentration of approximately 12 μg/mL 4 hours after injection.⁵⁰ These parameters are acceptable for management or prophylaxis of chronic epilepsy but not for status epilepticus. Intramuscular loading doses of fosphenytoin often need to be divided into two injection sites because of the associated large fluid volume.

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Intramuscular Maintenance Dose.

After administering a loading dose of PHT (or in patients on chronic PHT therapy with therapeutic PHT plasma concentration values), therapeutic PHT plasma concentrations can be maintained with equimolar (equal to usual oral PHT dosing rate) doses of intramuscular fosphenytoin for at least 14 days.⁵⁰^,⁵⁸^,²⁰⁹ When switching patients from oral PHT to equimolar doses of intramuscular fosphenytoin, however, plasma PHT levels may increase significantly, due to greater bioavailability of intramuscular fosphenytoin compared with oral PHT.^65a Therefore, regular monitoring of PHT levels is recommended in these patients. Numerous studies report less local toxicity at injection sites with fosphenytoin than with PHT.⁵⁰^,⁵⁸^,²⁰⁹

Role of Plasma Level Monitoring.

Determinations of fosphenytoin plasma concentration are of little clinical value because fosphenytoin largely remains in the plasma compartment and is rapidly converted to PHT. However, methods for determination of fosphenytoin plasma concentration have been developed for research purposes.⁶⁸^,¹⁰³^,¹⁶⁸ For clinical purposes, fosphenytoin therapy can be monitored by measuring plasma PHT concentrations.

Ethotoin

Chemistry

Ethotoin (3-ethyl-5-phenylhydantoin; Table 1) is a white crystalline compound with a molecular weight of 204.22.⁸⁹ Ethotoin contains a chiral center at the 5 position of the hydantoin ring. The specific rotation of the R (-) enantiomer is 88 degrees. Ethotoin is insoluble in water but is soluble is most organic solvents. Published methods of detection include gas chromatography, mass spectrometry, and high-performance liquid chromatography (HPLC).⁸⁹

Pharmacology

The addition of an ethyl group in position 3 and the deletion of one phenyl group from position 5 in the hydantoin ring (Table 1) result in a compound that is both less potent against maximal electroshock seizures in animals and less toxic than PHT.⁸⁹^,¹²⁸ Ethotoin has some activity against pentylenetetrazol seizures in animals but has proved to have little effect on absence seizures in patients.⁴⁶^,⁸⁹^,¹²⁸ The mechanisms of action of ethotoin have not been studied but may be similar to those of PHT.

Clinical Pharmacokinetics

Peak plasma concentrations of ethotoin occur 2 to 4 hours after oral doses.⁸⁹^,¹⁹⁰ Ethotoin is 46% protein bound.¹⁹⁰ The elimination half-life of small, single doses of the drug is 3 to 12 hours, and the drug has no active metabolites.⁸²^,⁸⁹^,¹⁹⁰ The absorption and elimination of the two isomers of ethotoin are similar.⁸² Therefore, the package insert states that ethotoin must be given in four or more divided doses to minimize fluctuations between peak and trough plasma concentrations.

The major metabolic pathway of ethotoin is ring hydroxylation, similar to PHT.⁸⁹ Also similar to PHT, ethotoin appears to have nonlinear pharmacokinetic properties.⁸²^,¹²⁶^,²¹³ Because drugs with nonlinear pharmacokinetic properties have longer elimination half-lives at steady-state plasma concentrations than at the low plasma concentrations of single-dose studies, it may be possible to administer ethotoin three times daily.³⁰ The details of ethotoin metabolism have been reviewed recently elsewhere.⁸⁹

Efficacy

There are no controlled trials of ethotoin. Uncontrolled studies indicate that ethotoin has some efficacy against tonic–clonic and complex partial seizures but probably does not control such seizures as efficiently as PHT.⁴⁶^,¹²⁸^,¹⁷² The lack of efficacy of ethotoin may be related in part to the large doses necessary to obtain seizure control and to the necessity to administer the drug in four to six divided doses daily. The drug has little or no efficacy against simple partial and absence seizures.⁴⁶^,¹²⁸

Adverse Effects

Side effects occur less frequently than with PHT and include rash (2%), anorexia and vomiting (3%), drowsiness, nystagmus, and occasionally lymphadenopathy.¹²⁸ Ataxia occurred only with large doses.¹²⁸ Gingival hyperplasia has not been reported.¹²⁸ Congenital malformations similar to those associated with PHT have been reported in association with ethotoin.⁶⁵

Role in Epilepsy Treatment

Indications

Ethotoin is approved by the FDA for the treatment of tonic–clonic and complex partial seizures. However, due to the lack of sound evidence for efficacy from controlled trials, ethotoin is very rarely used in the current treatment of epilepsy. Uncontrolled reports have suggested that ethotoin may be used for the treatment of patients with (a) tonic–clonic seizure disorders and hypersensitivity to more potent agents¹²⁸; (b) refractory partial or generalized seizures¹²^,¹²⁶; and (c) good therapeutic effect but cosmetic side effects with PHT. However, due to the availability of many alternative agents with better documented efficacy and safety, switch to ethotoin therapy rarely is justified.

Dosing Recommendations

In adults, the initial dose should be 1,000 mg/day or less. Dosage is then gradually increased for several days until the optimal dosage is reached. Most adults require 2,000 to 3,000 mg daily. Doses of <2,000 mg/day seldom are effective.

In children, the initial dose should be 750 mg/day or less. The usual maintenance dose is 500 to 1,000 mg/day, although daily doses of up to 3,000 mg are sometimes necessary.

Ethotoin usually is administered in four to six divided doses daily because of its short elimination half-life in single-dose studies. The drug should be taken after meals, and the doses should be divided as evenly as possible. The optimal range of ethotoin plasma concentration is estimated at 15 to 50 μg/mL.⁴²^,⁹⁶^,¹⁹¹ Because of the concentration-dependent pharmacokinetics, it may be possible to administer ethotoin three times per day once steady-state plasma concentration has been reached.³⁰

Mephenytoin

Chemistry

Mephenytoin is a white crystalline substance with a molecular weight of 218.25 (Table 1). Because of the asymmetric carbon atom at position 5 of the hydantoin ring, mephenytoin is produced as a racemic mixture. The chemical details of the isomers

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of mephenytoin have been reviewed elsewhere.⁸⁹ Mephenytoin, Nirvanol (active metabolite), and other mephenytoin metabolites can be quantified by HPLC,⁸⁹ and other methods exist to quantify the enantiomers of these molecules.⁸⁹

Pharmacology

N-methylation at position 3 in the hydantoin ring and substitution of an ethyl for one phenyl group at position 5 provide a broader spectrum of action in animal screening tests for antiepileptic activity than PHT. Mephenytoin has some protective effect against pentylenetetrazol seizures, whereas PHT does not.⁸⁹^,¹²⁸ However, these structural changes in mephenyt-oin also result in greater neurotoxicity and smaller potency and protective index against maximal electroshock seizures than seen with PHT.⁸⁹^,¹²⁸ The basic mechanisms of action of mephenytoin have not been studied but may be similar to those of PHT.

Clinical Pharmacokinetics

Peak plasma concentrations of mephenytoin occur 45 to 120 minutes after an oral dose.⁸⁹^,¹⁹⁰ Mephenytoin is partly hydroxylated, and partly demethylated to the active metabolite Nirvanol (5-ethyl-5-phenylhydantoin).⁸⁹^,¹⁸⁵^,¹⁹⁰ Nirvanol is partly eliminated by renal excretion and partly by p-hydroxylation and glucuronide formation.⁸⁹^,^209a A number of other minor metabolic pathways of mephenytoin have been reported.⁸⁹ The protein binding of mephenytoin is 39%, and that of Nirvanol is 29%.¹⁹⁰

There is a marked enantioselectivity in the metabolism of mephenytoin. While the S-enantiomer is rapidly hydroxylated by CYP2C19 and eliminated with a half-life of about 1 hour, the R-enantiomer has a half-life of about 70 hours and is slowly demethylated to R-Nirvanol, which, in turn, is eliminated very slowly (half-life of 150 to 200 hours), mostly by renal excretion, and accumulates in plasma at concentrations much higher than those of the parent drug.⁸⁹^,¹⁹⁰^,¹⁹¹ Subjects with genetically determined CYP2C19 deficiency (about 4% of Caucasians and 20% of Japanese) do not hydroxylate S-mephenytoin efficiently and, as a result, both enantiomers are converted to Nirvanol. S-Nirvanol derived from S-mephenytoin in these subjects is also cleared more slowly, and also accumulates at high concentrations.⁸⁹^,^204a^,^209a Because of the high levels of S-mephenytoin and Nirvanol in poor CYP2C19 metabolizers, these subjects are at increased risk for concentration-dependent toxicity. Because of the long elimination half-life of Nirvanol, mephenytoin needs to be given only once or twice a day, and many weeks may be required to reach steady-state plasma concentrations.¹⁹¹^,^209a

Efficacy

There have been no controlled clinical trials of mephenyt-oin. Uncontrolled trials reported that a majority of patients with tonic–clonic or simple partial seizures will experience a considerable reduction in seizure frequency with mephenyt-oin, whereas only a minority of patients with complex partial seizures respond favorably.⁴⁶^,⁸⁹^,¹²⁸ Absence seizures do not seem to be affected.⁴⁶^,¹²⁸

Adverse Effects

Compared with PHT, mephenytoin causes less ataxia, less gingival hyperplasia, and less nausea and vomiting.¹²⁸ These advantages are offset by a greater incidence of drowsiness, serious dermatitis, agranulocytosis, aplastic anemia, and hepatitis.¹²⁸ The incidence of fatalities and serious side effects appears to be greater with mephenytoin than with PHT.¹²⁸^,¹⁹¹ The package insert should be consulted for instructions on monitoring for adverse affects.

Drug Interactions

The drug interactions of mephenytoin are numerous and complex.¹⁹⁰^,¹⁹¹ Autoinduction of metabolism of mephenyt-oin and Nirvanol occurs, leading to a downward drift of plasma concentration of both drugs with chronic administration. Also, mutual induction of metabolism occurs when mephenytoin is coadministered with carbamazepine or barbiturates. At low plasma concentrations of mephenyt-oin, Nirvanol, and PHT, there is mutual induction of biotransformation (with a fall in drug plasma concentrations), whereas at high plasma concentration, there is mutual inhibition of biotransformation (with an increase in drug plasma concentrations).

Role in Epilepsy Treatment

Indications

Mephenytoin is approved by the FDA for treatment of tonic–clonic, simple partial, and complex partial seizures. Because of the availability of safer, newer drugs, mephenytoin is used very rarely in the current treatment of epilepsy.

Dosing Recommendations

The initial dosage is 50 to 100 mg/day during the first week. The daily dosage is then increased by 50 or 100 mg at weekly intervals until seizure control is obtained or toxicity precludes further increases. Increases in dosage should not be made more often than once a week. Because of the toxicity of mephenytoin, one should attempt to control seizures with the smallest possible dose. The average daily dose required is 200 to 600 mg in adults and 100 to 400 mg in children.

Total combined mephenytoin plus Nirvanol plasma concentration must be determined for therapeutic drug monitoring. Total concentrations of 1.5 to 40 μg/mL have been reported for patients having a good response.¹⁷²^,¹⁹⁰^,¹⁹¹

Summary and Conclusions

PHT is a well-established option for the initial treatment of partial and generalized tonic–clonic seizures. It possesses proven efficacy and, in its extended-release formulation, may be administered once daily for many adults. Prescribers of PHT should be familiar with its nonlinear pharmacokinetic properties, its potential drug interactions, and its several formulations. PHT is an important therapy for status epilepticus, and fosphenytoin is a parenterally administered PHT prodrug that offers some advantages in terms of local tolerability and safety over injectable formulations of PHT. Ethotoin has been reported to be of benefit in treating complex partial and tonic–clonic seizures, but there are no controlled trials supporting this claim and its usage is limited by labeling indicating administration four to six times per day. Mephenytoin has also been reported to be effective for the treatment of partial and tonic–clonic seizures, based on results of uncontrolled trials. However, its use is limited by a number of side effects including

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drowsiness, dermatitis agranulocytosis, aplastic anemia, and hepatitis.

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	Epilepsy: A Comprehensive Textbook 2nd Edition
	© 2008 Lippincott Williams & Wilkins

Epilepsy: A Comprehensive Textbook2nd Edition

Epilepsy: A Comprehensive Textbook
2nd Edition