Phenytoin is the generic name of a widely used antiepileptic drug (AED). In the United States, phenytoin is known by the brand names Dilantin and Phenytek (an extended-release form). In the UK, the brand name is Epanutin.

Sometimes the savings from using generic medications instead of brand-name products are large, but with other products the price differences are rather small. Investigate before deciding whether the savings are worth any possible problems. What's important is that both the doctor and the patient should know what the pharmacy is dispensing and have control over what type of medication is used.

Patients who switch from brand-name Dilantin to generic phenytoin possibly risk having more seizures or side effects during the changeover, because of differences in absorption or metabolism. Switching from one company's generic phenytoin to another company's may have similar risks. So can switching from generic phenytoin to Dilantin.

All these risks are not fully known. For some patients the effects of changing from one type to another are very small. Some use generic phenytoin successfully by always using the same company's product. Then the dosage can be adjusted to achieve the best results.

Dilantin
Tablet
Dilantin 30mg

30-mg (clear)
Capsules with a pink band

Dilantin 100mg Old

100-mg (clear) Kapseal -- Original to be discontinued
Capsules with an orange band

Dilantin 100mg New

100-mg New look -- to replace Kapseal
Capsules half orange and half white

Dilantin 50mg Chewable

Dilantin Chewable Infatabs 50-mg (yellow, triangular, scored)

Those who have trouble swallowing capsules (especially small children) may use tablets instead. They are flavored and chewable, but they also can be swallowed whole.

Liquid Solution

Dilantin-125 suspension 125 mg per 5 mL (orange)
Liquid has an orange-vanilla flavor. It is given in doses of 5 milliliters (mL), which is about equal to a teaspoon.

Epanutin
Phenytek
Tablet
Phenytek 200mg

200 mg This capsule has a dark blue cap and blue body, imprinted with "Bertek" (the name of the company that makes Phenytek) and "670".

phenytek_300.gif

300 mg Both halves of this capsule are the same shade of blue. They are imprinted with "Bertek" and "750". The 300-mg capsule is the one used most often.

Each capsule actually contains white tablets (two in the 200-mg capsule and three in the 300-mg capsule). Do not take these tablets separately.

Indications

Phenytoin is indicated for use as an anticonvulsant drug in people of all ages. Evidence supporting efficacy of phenytoin as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types:

  • Partial seizures
  • Primary generalized tonic-clonic seizures (grand mal)

Phenytoin is best used for partial-onset seizures. It generally is not effective against generalized-onset absence seizures or infantile spasms.

Phenytoin has limited value in clonic, myoclonic, and atonic seizures and in the Lennox-Gastaut syndrome. It may control the tonic-clonic component of the syndrome.

Forms

Various companies make and sell phenytoin or phenytoin sodium. In the United States, it is generally available in three forms:

  • 100-mg capsules
  • 125 mg/5mL suspension
  • 50 mg/mL injectable solution
How to take and store Phenytoin?

Capsules should be swallowed whole, not chewed or broken open. They should be stored at a temperature below 86°F (30°C) and protected from light and moisture. Capsules that are discolored should not be used.

The suspension should be stored at room temperature, between 68º and 77ºF (20°-25°C), and should be protected from light and from freezing. Remind patients to shake the bottle well just before measuring and to use an accurate measuring device.

All forms of phenytoin can be taken either with food or without food, but patients should be advised to be consistent. Taking it with food lengthens the time for absorption but produces higher concentrations.

Missed Doses

Advise patients to take a forgotten dose immediately. If it is almost time for the next dose, they should either skip the forgotten dose (rather than taking a double dose) or make it up with the next 2 or 3 doses.

Patients who often forget doses may benefit from using a special pillbox or watch with an alarm. Switching to a once-a-day extended-release form (in the U.S., Phenytek) may also help with compliance.

Mechanisms of actions of Phenytoin

In chemical structure, phenytoin is related to the barbiturates.

The mechanism of action is not definitely known, but extensive research strongly suggests that its main mechanism is to block frequency-, use- and voltage-dependent neuronal sodium channels, and therefore limit repetitive firing of action potentials.

At usual levels, there is little or no change in normal patterns of firing. At high or toxic levels, however, phenytoin can impair the function of healthy neurons.

Clinical Pharmacology of Phenytoin

Absorption
The rate of absorption depends on the formulation. Generic forms of phenytoin may not be exactly equivalent to Dilantin pharmacologically.

The most common form of phenytoin is 100-mg capsules. This form has a slow and extended rate: peak plasma levels are reached in 4 to 12 hours for brand-name Dilantin. If the capsules are taken with food, peak levels will be reached over a period of 24 hours, but the availability is not affected. Approximately 85% of the administered dose is absorbed.

When the phenytoin suspension is used, the peak level occurs more quickly, within about 1½ to 3 hours.

Phenytoin is also prepared in a parenteral form. The standard injectable phenytoin is slowly absorbed. A related drug, fosphenytoin (Cerebyx), is also given parenterally. It is rapidly converted to phenytoin in the body. With Cerebyx, therapeutic levels are achieved within 10 minutes and peak levels within 90 minutes.

Distribution and metabolism
Phenytoin is 69% to 96% bound to plasma proteins (average 90%), and metabolized in the liver.

At low concentrations, elimination is proportional to the concentration. But as the concentration rises to therapeutic levels, the enzyme system in the liver can become saturated and elimination occurs at a constant rate despite the dose (zero order kinetics). The effect is that a small increase in the dose sometimes causes a large change in the level of free phenytoin in the blood.

Most phenytoin is excreted in the urine in the form of inactive metabolites. The half-life is about 22 hours, with a range of 7 to 42 hours. The half-life is shorter in children and longer in the elderly.

Because phenytoin is metabolized in the liver, people with liver disease should be treated with caution. They may have to be started at a lower dose and have their dosage increased more slowly.

Steady state
Steady state is reached after 5 to 8 days (5 to 7 half lives) of taking a stable dose of phenytoin. The dose that a patient takes should not be increased until steady state has been reached (or some time later), so that the effects of the previous dosage can be assessed.

Efficacy of Phenytoin

Phenytoin is highly effective and may be the most commonly used antiepileptic medication in North America. Its effectiveness in controlling seizures has been extensively studied in careful scientific trials in great numbers of patients.

Many studies have compared phenytoin with other antiepileptic medications for the treatment of newly diagnosed epilepsy. For instance, one study of 622 adults compared phenytoin with carbamazepine, primidone, and phenobarbital. All four medications were about equally effective in controlling tonic-clonic seizures. Overall, phenytoin and carbamazepine were the most successful of these four medications, largely because they caused fewer intolerable side effects than primidone or phenobarbital. The choice between phenytoin and carbamazepine will be influenced by individual needs and responses.

A similar British study of newly diagnosed epilepsy included valproate instead of primidone. Again, the efficacy of the four medications in stopping seizures was about equal. (Overall, 27% of patients had no seizures and 75% had had none for at least 1 year by the end of a 3-year follow-up.) The medications differed in the number of patients who needed to have the medication withdrawn because of intolerable side effects, however. The lowest rate of withdrawal (3%) was reported for patients taking phenytoin.

Another study compared phenytoin with valproate in treating a group of patients with newly diagnosed generalized tonic-clonic, clonic, or tonic seizures. Of the patients treated with phenytoin, 76% had no seizures during the study period after a therapeutic blood level was reached. The comparable figure for the patients who took valproate was 82%.

Phenytoin is best used for partial-onset seizures. It generally is not effective against generalized-onset absence seizures or infantile spasms. It has limited value in clonic, myoclonic, and atonic seizures and in the Lennox-Gastaut syndrome. It may control the tonic-clonic component of the syndrome.

If phenytoin alone does not fully control the patient's seizures, a combination of phenytoin and another medication may be more effective. Many doctors start with a combination of phenytoin and carbamazepine, but a number of newly developed medications are also available. Sometimes a series of combinations must be tried before finding what is best for the individual patient.

Phenytoin has often been prescribed to prevent seizures in patients who have suffered a serious brain injury. However, a 2-year study to determine the efficacy of phenytoin in preventing seizures after head trauma demonstrated only short-term benefit. Patients who were given phenytoin instead of placebo had fewer seizures (but not lower mortality) during the first week but not over a longer period. These researchers also found that severely injured patients experienced negative cognitive effects while taking the phenytoin.

Status epilepticus and other acute seizures are often treated with a solution of phenytoin given intravenously. Within 20 minutes, 60% to 80% of patients will respond. A related medication, fosphenytoin (Cerebyx), is also effective for this purpose and can also be given by an intramuscular injection.

Common side effects of Phenytoin

Dose-related side effects
The most common side effects are neurotoxic and dose-related. They include:

  • sedation
  • impaired memory
  • slurred speech
  • nystagmus
  • decreased coordination
  • confusion
  • dizziness
  • headache

If these problems do not diminish within several days, a reduction in the dose of phenytoin often will solve the problem. Problems with sedation also may be helped by splitting the dose or giving the largest dose at bedtime.

The most common side effects of long-term use affect appearance. About 20% to 40% of these patients notice a problem with gingival hyperplasia. This effect appears to be dose-related and is more common in children than in adults. Its occurrence and its associated problems can be minimized by good dental care, including vigorous brushing, daily flossing, and regular dental care. It usually resolves within a few months if phenytoin is discontinued.

Other appearance-related side effects of long-term use of phenytoin include

  • hirsutism
  • acne
  • coarseness of facial features

Hirsutism is more of a problem for people with light complexions. It can be controlled with hair removal creams. Most acne can be treated effectively with facial hygiene, antibiotics, ointments, or lotions.

Dyskinesias, including chorea, dystonia, tremor, and asterixis, may be caused by phenytoin. Also, a small number of patients report sensory peripheral polyneuropathy.

Cerebellar atrophy may be another long-term effect of phenytoin, especially if high doses are used. Damage severe enough to produce significant problems is uncommon, however.

Idiosyncratic reactions
Rash is a common allergic reaction seen in about 5% to 7% of those who use phenytoin. This reaction usually occurs early in the course of therapy, within 5 to 17 days after the initial dose. Most patients will need to stop taking phenytoin and replace it with a different antiepileptic medication. The rash itself may require treatment with an antihistamine or steroid if it is severe.

Serious Side effects of Phenytoin

Long-term use of phenytoin has been found to cause osteomalacia. Bone disease is even more likely if a combination of antiepileptic drugs is used. Patients taking phenytoin should be advised to remain physically active, take vitamin D supplements, and eat foods rich in calcium. Because some sources of calcium (such as antacids and supplements like Tums and Os-Cal) reduce absorption of phenytoin, they should not be taken within about 2 hours after the phenytoin. This restriction does not apply to food sources of calcium such as dairy products. Many doctors now recommend bone-density studies for anyone taking phenytoin.

A number of reports have suggested a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Patients should be instructed to report fever, rash, and swollen, tender lymph glands. In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.

Serious forms of dermatitis are seen rarely, including bullous, exfoliative, or purpuric dermatitis, lupus erythematosus, Stevens-Johnson syndrome, and toxic epidermal necrolysis. It has been estimated that 2.3 to 4.5 people out of each 10,000 who take phenytoin are hospitalized for treatment of rash.

Other Uses of Phenytoin

Phenytoin appears to have some efficacy in treating trigeminal neuralgia and other cranial neuralgias. The evidence is not based on controlled studies, however, and carbamazepine should be considered the first choice for these disorders. If carbamazepine is not effective, phenytoin may be added.

Phenytoin also has been used for neuropathic conditions including diabetic neuropathy and Fabry's disease but its efficacy appears to be modest. It may potentiate other analgesic agents and is well tolerated.

Phenytoin Contraindications

Patients who are allergic to phenytoin or other hydantoins should not take it.

Caution should be exercised when prescribing phenytoin for patients taking other medications, since interactions are common and dosage adjustments may be required.

Phenytoin Interactions with other medications

When prescribing phenytoin, question patients or family members extensively about the use of prescription and OTC medications, herbal products, vitamins, alcohol, and other substances. Interactions with phenytoin are common. Usually all necessary medications can be used, but the dosages may need to be adjusted to achieve therapeutic levels.

Effects of phenytoin on other drugs
If combination therapy using phenytoin and another antiepileptic drug (AED) is begun, the dosage of the initial AED may need to be adjusted. Similarly, if a medication previously used in combination therapy is to be stopped, the dosage of the remaining AED may need to be changed.

Phenytoin will lower the blood levels of other AEDs:

  • carbamazepine
  • clonazepam
  • lamotrigine
  • oxcarbazepine
  • tiagabine
  • topiramate
  • valproate
  • zonisamide

Phenytoin also will lower the blood levels of other types of medication:

  • acetaminophen
  • amiodarone
  • aminophylline
  • chloramphenicol
  • cholecalciferol
  • cyclosporine
  • dicoumarol
  • digoxin
  • disopyramide
  • doxycycline
  • estrogens
  • felodipine
  • folic acid
  • furosemide
  • itraconazole (large effect)
  • levodopa
  • meperidine
  • methadone
  • metronidazole
  • mexiletine
  • misonidazole
  • nisoldipine
  • oral contraceptives
  • paroxetine
  • phenobarbital (possible)
  • praziquantel
  • prednisone/prednisolone
  • psoralens
  • quetiapine
  • quinidine
  • rifampin
  • theophylline
  • topotecan
  • tirilazad
  • tricyclic antidepressants
  • vitamin D
  • warfarin (variable effect)

Phenytoin may increase the blood levels of a few other drugs:

  • phenobarbital (changes insignificant in most patients)
  • warfarin (variable effect)

Effects of other drugs on phenytoin

Some substances that are safe to use in small amounts with phenytoin can be a problem if larger amounts are used. For instance, one or two drinks of alcohol will seldom affect the level of phenytoin in any important way, but if a person who does not often consume alcohol drinks a moderate or large amount, the level of phenytoin in the blood may be significantly increased. On the other hand, a person who chronically abuses alcohol may experience decreased levels of phenytoin and be more susceptible to seizures.

Aspirin and other salicylates are generally safe to take with phenytoin at the usual doses. If more than 1500 mg per day is taken, however, the total level of phenytoin in the blood may be decreased but the free level may increase. Effects may vary.

Medications that contain calcium, including some antacids, should not be taken at the same time as phenytoin, to prevent absorption problems. They can be used, but the times should be staggered.

A few other AEDs may decrease the blood level of phenytoin:

  • carbamazepine (varies by individual)
  • phenobarbital (varies by individual)
  • valproate (variable)
  • vigabatrin

Other medications that decrease the blood level of phenytoin include:

  • alcohol (chronic abuse)
  • aminophylline
  • antacids containing calcium (if taken together)
  • ciprofloxacin
  • folic acid
  • methotrexate
  • reserpine
  • rifampin
  • sucralfate
  • vinblastine

Other AEDs that increase the blood level of phenytoin include:

  • carbamazepine (varies by individual)
  • clobazam (possible)
  • diazepam
  • ethosuximide
  • felbamate
  • methsuximide
  • oxcarbazepine
  • phenobarbital (varies by individual)
  • topiramate
  • valproate (possible)

Other medications that increase the blood level of phenytoin include:

  • alcohol (occasional moderate or large intake)
  • amiodarone
  • aspirin (more than 1500 mg/d)
  • chloramphenicol
  • chlordiazepoxide
  • cimetidine
  • dicoumarol
  • diltiazem
  • disulfiram
  • estrogens
  • fluconazole
  • fluoxetine
  • halothane
  • isoniazid
  • itraconazole
  • methylphenidate
  • metronidazole
  • miconazole & flucytosine
  • omeprazole
  • phenothiazines
  • propoxyphene
  • ranitidine
  • sertraline
  • sulfonamides
  • ticlopidine
  • tolbutamide
  • trazodone
  • trimethoprim
  • warfarin

AED Interaction Sheets: 
Seizure drugs are often affected by drug-drug interactions. Print these informative sheets for practical help.

Phenytoin effects on Children

Phenytoin has been used for many years to treat children with partial and generalized tonic-clonic seizures. It is not effective for absence seizures, so children with both tonic-clonic and absence seizures will need combination therapy. Often phenytoin is not chosen as a first-choice medication for children, however, because of troublesome effects on appearance, including gingival hyperplasia and hirsutism. The gum disorder affects almost one-half of children who take phenytoin for a prolonged period and is made worse by braces.

Nystagmus and ataxia are common when blood levels reach the top of the usual therapeutic range. Lethargy, unsteadiness in the feet and hands, dysarthria, vomiting, problems with thinking or behavior, or mood changes are other common dose-related side effects. Because of nonlinear kinetics, small increases in the dose of phenytoin can increase blood levels considerably, exacerbating these side effects.

Dosage increases should be done slowly to minimize side effects. Children usually start with a dose of 5 mg/kg per day. This is usually given in two or three equally divided doses. Most children do best at about 4 to 8 mg/kg per day. The highest dose recommended for young children is 300 mg per day, which can be given using the suspension. Children older than 6 years and adolescents may require the minimum adult dosage of 300 mg per day.

If the suspension is used, the importance of thoroughly shaking the bottle immediately before measuring must be stressed, since phenytoin is poorly soluble and dosing errors can occur.

The use of oral phenytoin is not recommended for infants because of problems with bioavailability and a narrow therapeutic index.

Phenytoin and Pregnancy

The U.S. Food and Drug Administration (FDA) lists phenytoin in Pregnancy Category D. This indicates that there is clear evidence of risk to the human fetus, but the benefits may outweigh the risk for pregnant women who have a serious condition that cannot be treated effectively with a safer drug.

The babies of women taking phenytoin have a greater than usual number of major birth defects like cleft lip, cleft palate, and heart malformations. Defects like these occur in 2-3% of all pregnancies but affect 4-7% of the babies of women taking only phenytoin. (This rate is similar to that for women taking other seizure medicines.) There is also an increased chance of minor birth defects such as short fingers and widely spaced eyes. When these babies are re-examined after several years, however, these minor defects are often undetectable or very subtle.

Women taking phenytoin used to be warned about a disorder called "fetal hydantoin syndrome," but this concept is no longer accepted. Phenytoin does not clearly differ from other seizure medicines in the type of defects that may occur.

The risk of defects is higher for women who take more than one AED and for women with a family history of birth defects.

Advise women who are capable of becoming pregnant to take 400 mcg (0.4 mg) of folic acid (folate) daily to help prevent neural tube defects. Women at high risk, such as those with a history of a neural tube defect in a previous pregnancy, should take 4000 mcg (4 mg) daily, beginning before they become pregnant.

About 20% to 35% of women have seizures more often during pregnancy because of changes in hormones or changes in how phenytoin is handled by the body. Check the blood levels of phenytoin regularly during pregnancy so that the dosage can be adjusted as needed.

No studies have been performed to demonstrate the effect of specific AEDs during labor and delivery. Possible causes of seizures include:

  • failure or inability to take medication
  • sleep deprivation
  • hyperventilation
  • stress
  • pain

Some babies born to mothers taking phenytoin have had inadequate blood clotting within the first 24 hours after birth. It is recommended that the mother be given about 10 mg of vitamin K per day during the last month of pregnancy to prevent this problem. The vitamin K given to babies when they are born may be too late to prevent this disorder.

Breast-feeding by mothers taking phenytoin should be safe for healthy, full-term newborns, although a small amount of the medication will appear in the milk. Since 90% of phenytoin is bound to plasma proteins in the mother's blood, the level in breast milk is about 10% of the level in the mother's blood.

Phenytoin effects on Seniors

Phenytoin is much more commonly used in American nursing homes than any other antiepileptic drug (AED). Some of these doses of AEDs are prescribed for conditions other than epilepsy, and some are prescribed for elderly patients who have experienced only one seizure.

Older people metabolize phenytoin more slowly than younger adults and they are often more susceptible to side effects. Lower initial doses and caution in titration are required. A total daily dose of 3 mg/kg is appropriate for many elderly patients.

Reduced elimination also extends the half-life of phenytoin for elderly patients, so that many do well taking phenytoin just once a day.

Declining serum albumin levels in many elderly people mean that the unbound phenytoin concentration may be higher than expected in relationship to the total drug concentration, The total drug level thus may be poorly correlated with clinical response. An appropriate therapeutic range may be 5–15 mcg/mL rather than the 10–20 mcg/mL suggested for young adults.

Variations in gastrointestinal function may affect absorption and mean that blood levels may fluctuate even if the patient is taking a steady dosage of the same formulation.

Another difficulty with the use of phenytoin in seniors is its large number of interactions with other medications, including many commonly used by elderly patients. Changes in dosages of both medications are often required.

Some common side effects of phenytoin, such as imbalance, may exacerbate pre-existing problems of seniors, and their greater risk of injury from falls or other accidents makes this an area of concern. Phenytoin also may affect cognitive functioning at higher levels.

Phenytoin Dosing and titration

In young adults, phenytoin should be started at 4–5 mg/kg per day (200–300 mg/d, in one or two doses) and titrated by increments of 30 mg to 100 mg per day, with at least 7–10 days between changes. Elderly patients generally require a lower initial dose (3 mg/kg per day) and especially cautious titration.

The average maintenance dose as monotherapy for adults is 4–7 mg/kg per day (300-600 mg/d). The package insert for brand-name Dilantin indicates that this amount is usually given in three or four doses, though it notes that some patients do well on one daily dose of 300 mg, using the capsule form. Once-daily dosing also can be achieved using Phenytek, an extended-release form of phenytoin.

In children over 6, the usual maintenance dose is 4–8 mg/kg per day, usually in two doses. The form of phenytoin in the suspension is absorbed faster than the form in phenytoin capsules, so once-daily dosing with the suspension is likely to cause toxicity.

A therapeutic blood level of phenytoin is general considered to be 10-20 mcg/mL (lower for seniors), but adjustments should depend on clinical response. At higher levels, small increments in dose may produce large increments in blood level because of saturating kinetics.

If therapeutic levels need to be reached quickly, a loading dose can be administered orally or parenterally. An oral loading dose consists of four doses (400 mg, 300 mg, 300 mg) given at 2-hour intervals in a clinic or hospital, where serum levels can be closely monitored. A normal maintenance dose is begun 24 hours later.

Algorithm for dosing phenytoin (Dilantin, Phenytek)

Phenytoin Package insert

In the United States, companies that manufacture medicines are required to publish certain kinds of information about each product. This document is commonly known as a "package insert" because it is usually included with each package of the medicine.

You can also read these documents (also called "prescribing information") online. The package insert for Dilantin (phenytoin) is available at:

Some of the information may differ in other countries.

To learn how to read and understand a package insert, see How to read a package insert.

Phenytoin References for Professionals

Abstracts of articles relevant to this topic are available through PubMed, a service of the National Library of Medicine.

Here are links to some articles relevant to this subject:

Mattson, RH, Cramer, JA, et al. Comparison of carbamazepine, phenobarbital, phenytoin and primidone in partial and secondarily generalized tonic clonic seizures. N Engl J Med 313:145-151, 1985. PMID: 3925335.

Overall, phenytoin and carbamazepine were shown to be the first choices for a single medication to treat adults with newly diagnosed partial seizures, generalized tonic-clonic seizures, or both.

Heller AJ, Chesterman P, Elwes RD, et al. Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial. J Neurol Neurosurg Psychiatry 1995 Jan;58(1):44-50. PMID: 7823066.

Four medications were similar in their ability to control seizures, but phenytoin had the lowest rate of intolerable side effects.

Wilder BJ, Ramsay RE, Murphy JV, Karas BJ, Marquardt K, Hammond EJ. Comparison of valproic acid and phenytoin in newly diagnosed tonic-clonic seizures. Neurology 1983 Nov;33(11):1474-6. PMID: 6415511.

Valproic acid was slightly more effective than phenytoin in controlling generalized tonic-clonic seizures.