Joe B. Wilder MD*
Joseph Bruni MD, FRCP(C)**
* Associate Professor, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
** Associate Professor, Department of Medicine, University of Toronto; and Consultant Neurologist, Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada
Discovery of the anticonvulsant properties of phenytoin (PHT) by Merritt and Putnam (1) in 1938 created a revolution in the treatment of epilepsy and anticonvulsant drug research. Their questioning of the traditional idea that sedation was requisite for anticonvulsant activity opened a new era of drug development and patient management. PHT was the first drug to control seizures without producing sedation, and its efficacy against seizures induced in animals by the maximal electroshock test (2) indicated its efficacy in tonic-clonic and partial seizures. For the first time, an antiepileptic drug (AED) that was effective clinically had been tested experimentally in pioneering work in animal models.
Since the introduction of PHT, many drugs have been licensed in the United States for the treatment of epilepsy. Almost all of these are recommended for the treatment of partial and tonic-clonic seizures. Since the mid-1980s, controlled, randomized clinical trials and double-blind studies comparing other AEDs with PHT (3, 4, 5, 6, 7, 8, 9, 10, 11, 12) have shown that PHT remains one of the most effective drugs for the treatment of partial and generalized tonic-clonic seizures. When compared with newer AEDs, PHT is equally effective as lamotrigine and oxcarbazepine as monotherapy in the treatment of localization-related epilepsy (13).
Oral preparations of PHT are either the sodium salt of PHT or PHT acid. The sodium salt is a crystalline preparation that is absorbed slowly from the gastrointestinal tract and has relatively slow clearance, which in adolescents and adults usually permits single or twice-daily dosing. Dosing twice a day is preferable in children. PHT sodium is marketed as 30- and 100-mg capsules. PHT acid is absorbed more rapidly and is available as a 50-mg chewable tablet and as 30-mg/5-mL and 125-mg/5-mL oral suspensions for children and adults.
PHT is also available in a parenteral formulation dissolved in propylene glycol at pH 10 that can be diluted in normal saline or half-normal saline (2 to 10 µg/mL) to avoid tissue reactions and to facilitate administration with routine intravenous (i.v.) techniques (14,15). This parenteral form of PHT should not be administered by the intramuscular route. Crystalline precipitation in the muscle after intramuscular PHT injection results in a marked delay in absorption and tissue necrosis (16). The prodrug, fosphenytoin, is water soluble and is much less irritating to tissue, so it is a clinically preferable formulation.
INDICATIONS FOR USE
In North America, PHT remains the most commonly used AED. PHT is a drug of choice in patients with simple and complex partial seizures and in those with generalized tonic and tonic-clonic seizures. It is ineffective in absence seizures and is of limited value in clonic, myoclonic, and atonic or akinetic seizures. In the epilepsy syndromes, PHT is most effective in symptomatic or secondary epilepsy manifested by partial and secondary generalized seizures. Its role in primary or genetic epilepsy characterized by generalized tonic-clonic convulsions has not been studied in randomized clinical tests.
In patients with absence, myoclonus, and tonic-clonic seizures, PHT is of value as adjunctive therapy if other drugs fail to control the tonic-clonic seizures. PHT also is effective in young adults with primary epilepsy and tonic-clonic seizures only (9). Ramsay et al. (17) reported both
valproic acid (VPA) and PHT to be efficacious in patients with primary epilepsy with spike-and-wave electroencephalographic discharge and tonic-clonic seizures.
PHT is usually not effective in infantile spasms and is of limited value in the Lennox-Gastaut syndrome; it is effective only in the tonic-clonic component of the syndrome. It is not effective as a monotherapeutic agent in the progressive myoclonic epilepsies and has been reported to worsen Baltic myoclonic epilepsy (18,19).
The use of PHT is often recommended after head trauma, intracranial neurosurgical procedures, and hemorrhagic stroke. However, double-blind studies do not demonstrate the efficacy of PHT in preventing epilepsy after stroke or supratentorial neurosurgical procedures. PHT does prevent early seizures after severe head trauma (20), nor is it useful in the prevention of alcohol withdrawal seizures (21).
After phenobarbital, PHT is the drug of choice in neonatal seizures when the drug is administered by the i.v. route (22). Fosphenytoin is the clear choice of formulations because of difficult parenteral accessibility and tissue toxicity of PHT. Therapeutic plasma PHT levels are difficult to maintain after oral administration in neonates because of erratic and sometimes incomplete absorption. PHT is generally well tolerated in children, adolescents, adults, and the elderly. However, elderly patients often are receiving multiple drugs, and PHT enhances the metabolism of these drugs. The doses of theophylline, warfarin, digoxin, steroids, and other drugs commonly used by adults and the elderly must be increased when PHT is concurrently administered. Because of the nonlinear kinetics of PHT, careful monitoring after an increase in dose in elderly patients is especially important.
PHT (as PHT or the prodrug fosphenytoin) is considered by many epilepsy specialists in the United States to be a drug of choice in the treatment of status epilepticus, as well as in acute and serial seizures (23, 24, 25, 26, 27, 28). In conjunction with a rapid-acting benzodiazepine, PHT is valuable for treating status epilepticus or other acute seizures because it is available in an easily administered i.v. solution. It relatively rapidly penetrates the blood-brain barrier to achieve therapeutic concentrations at the site of action. PHT controls seizures in most cases, and it has a time span of action that permits follow-up oral administration to maintain a therapeutic response. Respiratory or cardiac depression does not occur with careful administration (usually 50 mg/min for normal adults), and no major changes are observed in the neurologic examination. PHT does not potentiate central nervous system depression produced by previously administered agents (e.g., benzodiazepines or barbiturates). The delay in action resulting from the slow rate of administration is reason to coadminister a benzodiazepine when rapid control of seizures is needed.
DOSAGE AND ADMINISTRATION
In patients with newly diagnosed epilepsy, PHT therapy can be initiated at a dose of 4 to 7 mg/kg given once or twice daily. Children require higher doses (mg/kg/day) than do adults, and it is usually preferable to give the drug at 12-hour intervals. Most adults can take PHT once daily, either in the morning or in the evening. Our practice with adults is to give PHT once a day if the dose is 400 mg/day or less and twice a day if it is >400 mg/day. A survey of 220 adults receiving stable PHT doses showed an average daily dose of 342 mg/day (B. Joe Wilder and J. R. McLean, unpublished data). After initiation of therapy, steady state is achieved in 1 to 3 weeks because of the wide variation in metabolism among individual patients and the nonlinear kinetics of PHT. Therefore, monitoring for PHT-dose-plasma level relationships should be delayed for 2 to 3 weeks. When PHT levels are in the low to intermediate target range (8 to 15 µg/mL), increases in the dose should be made, aided by follow-up blood level monitoring. Our practice is to use the 30-mg capsules for dose increases. In general, an increase in the PHT dose of 10 mg/day will result in an approximately 1 µg/mL increase in the plasma PHT level of a patient with a level of 10 µg/mL and in a 3 µg/mL increase in a patient with a 20 µg/mL level because of saturating kinetics. This should be kept in mind when one changes the daily dose of PHT.
If seizure frequency makes a more rapid achievement of therapeutic levels desirable, PHT can be loaded orally or by the i.v. route. Oral loading can be achieved by giving 15 mg/kg in three doses at 1-hour intervals. A maintenance dose of 4 to 7 mg/kg can be given daily thereafter. The low target range of the plasma PHT level is achieved 8 to 12 hours after the loading dose (29). An i.v. loading dosage of 15 mg/kg gives immediate therapeutic levels. Our practice is to mix PHT 50 mg/mL in normal saline to a dilution of approximately 5 mg/mL and to administer it slowly over 1 to 2 hours (14,15). After oral or i.v. loading doses, transient vertigo and nausea may rarely occur.
The i.v. administration of PHT should not exceed a rate of 50 mg/min. PHT depresses the Purkinje conduction system of the heart, and slowing of the pulse rate and a drop in blood pressure may occur with rapid administration. Rarely, transient diastolic pauses may occur. The i.v. administration of PHT should be done with care in patients with heart block. The propylene glycol, alcohol, and a pH adjusted to 12, used to bring PHT into solution, may be responsible for some of the toxicity observed during rapid i.v. administration.
In young children, PHT suspension (30 mg/5 mL and 125 mg/5 mL) in individually packaged doses should be used. PHT is poorly soluble, and in large bottles, dosing errors are made because of too little or too much PHT in an individual teaspoon or tablespoon dose.
Older children can be treated with 50-mg chewable tablets. Twice-a-day administration is preferable in children. Metabolism is faster in children than in adults, and the sodium PHT in the suspension and in chewable tablets is absorbed faster. Thus, peaking of plasma PHT levels after large single daily doses may cause transient toxicity.
The accepted therapeutic plasma PHT level ranges from 10 to 30 µg/mL (40 to 80 µmol/L) (30). However, this range should only be viewed as a guide; proper management depends on the clinical response (31). Patients with partial seizures require a higher dose and higher serum PHT levels to achieve seizure control than do patients with generalized tonic-clonic seizures (32).
Any factors or substances that interfere with the solubility of PHT in the intestinal tract will retard or prevent its complete absorption. Anecdotal reports of altered absorption of PHT with the concurrent administration of antacids and other drugs are probably reliable. In some patients, absorption may be defective (33), particularly under certain conditions. For example, a marked absorption defect was observed in a pregnant woman during her second and third trimesters (B. Joe Wilder and E. Ramsay, unpublished data). Dosage requirements of PHT increased from 400 to 1,300 mg/day, with large quantities of drug excreted in the feces.
Status Epilepticus and Acute Seizures
PHT is commonly used in acute treatment of serial seizures to achieve prompt control and with a benzodiazepine to treat status epilepticus (Treiman et al.) For the treatment of status epilepticus and other acute seizures, concentrations of 5 to 20 mg of PHT per milliliter of normal saline can be administered at a rate of 50 mg/min without producing significant adverse clinical effects. Care must be taken to prevent extravasation from the vein, because severe tissue reaction may occur (34,35). A mild decrease in blood pressure or slowing of the pulse occasionally occurs, and this can be controlled by decreasing the rate of administration (25,27). An infusion rate exceeding 50 mg/min may produce a decrease in blood pressure and slowing of the pulse rate (23). Respiratory depression does not occur in patients receiving i.v. loading doses of 10 to 20 mg/kg of PHT. Asystole may occur after bolus i.v. injection. Subjective side effects resulting from i.v. loading are rare. Vertigo and nausea may occur. Except for nystagmus, the neurologic examination is unchanged.
PHT rapidly penetrates the brain during i.v. infusion (27,36) and is concentrated by brain phospholipids. One hour after i.v. infusion, the brain:plasma ratio is greater than 1.5 in both experimental animals and humans (26,36).
Patients in status epilepticus or experiencing serial epileptic seizures, alcohol or drug withdrawal seizures, or seizures of undetermined origin respond promptly to i.v. PHT. Wilder (26) and Leppik et al. (25) reported that 60% to 80% of patients responded within 20 minutes after the initiation of PHT infusion. Plasma PHT levels were ≥10 µg/mL 12 hours after a mean i.v. dose of 13 mg/kg in eight of 14 patients (26). Higher levels were reached after an initial higher i.v. dose (25). Fosphenytoin, a water-soluble prodrug formulation, is preferred because of improved tolerability to tissue irritability.
Monotherapy versus Polytherapy
PHT, like other AEDs, is easier to use in a monotherapy regimen. Unfortunately, some 30% of epileptic patients are refractory to monotherapy and require polytherapy with other AEDs. PHT has been used with virtually every other AED, but there appear to be favorable combinations. The selection of a drug combination should be based on certain basic principles: Select combinations of drugs with different mechanisms of action, avoid drugs that have adverse additive effects, and avoid drugs with the potential for drug interactions. The last principle is difficult to follow with PHT, because it is an enzyme inducer of the cytochrome P450 mixed oxidase system and therefore increases the metabolic rate of other drugs also metabolized by this route.
Mirza et al. (37) showed that PHT with VPA is a favorable combination for enhancing seizure control in refractory patients. Bates et al. (38) reported that PHT and low doses of phenobarbital were efficacious in a large cohort of mentally retarded patients with refractory seizures that did not respond to monotherapy. Ultimately, the combination of drugs that works is the best. Whenever PHT is used with other AEDs, interactions may occur. With the development of newer AEDs drugs such as gabapentin, vigabatrin, lamotrigine, topiramate, levetiracetam, zonisamide, and oxcarbazepine a rational algorithm has to be developed to optimize combination therapy (39, 40, 41, 42).
Although felbamate, carbamazepine, sulfonamides, clobazam, chloramphenicol, diltiazem, cimetidine, disulfiram, isoniazid, methsuximide, and antimetabolites used in cancer chemotherapy may increase PHT levels by inhibition of metabolism. Only a few drugs interact sufficiently with PHT to necessitate a change in the dose of PHT. Antacids, large doses of salicylates, tolbutamide, and phenylbutazone may alter PHT total and free levels by altering absorption and protein binding (31,43). Felbamate increases PHT levels, and careful monitoring of PHT levels is required. With the addition of felbamate to PHT, the guiding principle should be clinical changes rather than an automatic reduction in the PHT dose. Seizures and possible status epilepticus may be precipitated by an abrupt decrease in PHT dosage (44).
The effect of PHT on other drugs may be clinically significant (33,43). Doses of dicumarol, tiagabine, zonisamide, lamotrigine, topiramate, theophylline, chloramphenicol, doxycycline, digitoxin, quinidine, dexamethasone, oral contraceptives, or folic acid may have to be increased because of enzyme induction by PHT.
Interactions are usually not seen when PHT is used in combination with phenobarbital, diazepam, or clonazepam (31). The interaction of PHT with vigabatrin is generally not clinically significant.
VPA transiently lowers PHT levels in patients whose PHT levels are less than the saturation point of the metabolizing enzymes (45), but by displacing PHT from protein binding sites, VPA increases levels of free PHT so no change in the dose of PHT is generally required. However, the increase in free PHT levels resulting from VPA displacement of PHT from protein binding sites may be sufficient to produce signs of PHT toxicity without a significant change in the total level of PHT (46). Patients should be warned that this interaction may occur; and if signs of PHT intoxication develop after the dose of VPA, free levels of PHT should be determined, and dosage adjustments of VPA should be made. Reducing the peak plasma levels of VPA by giving lower doses more frequently, giving the drug with meals to slow absorption, or use of the slow-release form will generally relieve the problem. No interactions occur when PHT is used in combination with gabapentin (44).
PHT induces the metabolism of VPA, and it markedly increases the dose of VPA needed to achieve a therapeutic serum level (47). When VPA is given with PHT or carbamazepine, the dose of VPA required to maintain therapeutic serum levels may be 50% to 100% greater than that needed with VPA monotherapy (46). PHT increases the metabolism of lamotrigine and felbamate and lowers plasma concentrations (48).
When PHT is combined with primidone, the plasma primidone level falls and the level of phenobarbital rises, giving a marked increase in the ratio of phenobarbital to primidone (46,49). This combination should generally be avoided because of resulting phenobarbital toxicity.
PHT induces the metabolism of carbamazepine; and when the two drugs are used in combination, the dose of carbamazepine required is higher than when carbamazepine is given alone. Carbamazepine inhibits the metabolism of PHT (46,50) and increases plasma PHT levels. An extensive review of PHT interactions is given in Chapter 59.
Dysfunction of the ocular and cerebellovestibular systems may occur at plasma PHT levels higher than the usual therapeutic range of 10 to 30 µg/mL. Nystagmus and ataxia appear at plasma PHT levels >30 µg/mL; dysarthria, lethargy, and mental changes occur at levels >30 to 40 µg/mL; and stupor occurs at levels >40 to 60 µg/mL (30,31). Because the neurologic effects of PHT are usually dose related, reduction of the dose should eliminate them.
Other adverse effects of PHT may be hypersensitivity reactions, such as rash, fever, abnormal liver function, lymphadenopathy, eosinophilia, blood dyscrasias, renal failure, and serum sickness-like illness (51). Other systemic adverse effects include the following: gingival hyperplasia (19,52, 53); hirsutism; hematologic reactions and folate deficiency including megaloblastic anemia (53), neonatal coagulation defects (54), aplastic anemia, granulocytosis, and thrombopenia; thyroid dysfunction (55,56); and decrease in serum immunoglobulin A (57, 58, 59). An extensive review of the toxicity of PHT, as well as its cognitive effects and teratogenicity, is given in Chapter 63.
CLINICAL USE: OTHER HYDANTOINS
With the availability of newer-generation AEDs, the use of other hydantoins such as ethotoin and mephenytoin is only of historical interest. There is probably a very limited role in the use of other drugs in the treatment of epilepsy because of better efficacy and tolerance of the newer agents.
Ethotoin is an approved drug by the United States Food and Drug Administration for the treatment of complex partial and tonic-clonic seizures. It is ineffective against other seizure types. Clinical efficacy has been determined through uncontrolled clinical trials (60,61).
In a study of 17 patients with refractory seizures, 16 patients responded favorably to adjunctive therapy with ethotoin (60). Control, however, was not defined. The number of patients was small and represented a very heterogeneous population. No adverse effects were reported.
A retrospective study of 46 patients with intractable seizures reported a >50% seizure reduction in approximately 51% of the patients (61). This was reduced to about 25% for the last 3 months of the study. Ten patients experienced side effects including allergy, gastrointestinal effects, weight loss, psychiatric effects, tremors, and ataxia. Gingival hyperplasia was not observed. Other side effects observed in six patients included leukopenia, pseudolymphoma, elevated liver enzymes, and, in one patient, choreoathetosis. Although the clinical experience is limited, it is generally believed that the risk of congenital anomalies and malformations is similar to the incidences associated with PHT (62).
Therapy should be initiated with doses ≤1,000 mg. The optimal dose is in the range of 3,000 to 4,000 mg and initially should be administered in four to six divided doses. Once steady-state levels are achieved, administration can be reduced to three daily doses.
After many decades of use, PHT remains a drug of choice for the treatment of partial (simple and complex) and generalized tonic-clonic seizures. It is not effective in absence or myoclonic seizures or infantile spasms. PHT is effective in neonatal seizures, but adequate blood levels may be difficult to maintain with the oral preparation. PHT is considered by many clinicians to be a drug of choice for the treatment of acute seizures and status epilepticus. In this case, its action is enhanced by the simultaneous use of diazepam or lorazepam.
Drug interactions may occur when PHT is used concurrently with other drugs, including some AEDs. Generally, PHT induces the metabolism and increases the dose requirements of other drugs, and caution is indicated when PHT is used in combination with other drugs.
The acute toxic effects of PHT (e.g., nystagmus, ataxia, and incoordination) are dose related. Individual variation can result in adverse effects over a wide range of blood PHT levels. Thus, the response to therapy must be judged clinically, with “therapeutic” or “toxic” blood PHT levels used as general guidelines to treatment. The clinical uses of ethotoin and mephenytoin in the treatment of epilepsy are limited.
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13b. Bill PA, Vigonius W, Pohlman H, et al. A double-blind clinical treal of oxcarbazepine versus phenytoin in adults with previously untreated epilepsy. Epilepsy Res 1997;27:195-204.
43a. Treiman DM, Meier PD, et al. Treatment of status epilepticus. N Engl J Med 1998;339:792-798.