Phenytoin

Phenytoin is an antiseizure medicine used across multiple formulations, each with specific approved indications:

• Oral extended-release capsules (Phenytek, generic extended phenytoin sodium): tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures; prevention and treatment of seizures during or after neurosurgery
• Oral capsules (some formulations): also cover complex partial (psychomotor, temporal lobe) seizures in addition to tonic-clonic seizures and neurosurgery-related seizures
• Chewable tablets (Dilantin Infatabs, Phenytoin Infatabs, generic): generalized tonic-clonic and complex partial seizures; prevention and treatment of neurosurgery-related seizures
• Oral suspension (Dilantin-125, generic): tonic-clonic and psychomotor (temporal lobe) seizures
• Injectable phenytoin sodium (IV/IM): generalized tonic-clonic status epilepticus (life-threatening prolonged seizure); prevention and treatment of seizures during neurosurgery; short-term substitute for oral phenytoin when oral dosing is not possible

Phenytoin works by blocking sodium channels in the membranes of nerve cells in a voltage-dependent way. During a seizure, nerve cells fire abnormally fast and repeatedly. By stabilizing these channels, phenytoin reduces that sustained rapid firing — essentially calming overactive electrical activity in the brain without shutting down normal nerve function entirely.

Phenytoin is processed mainly by liver enzymes (CYP2C9, and to a lesser extent CYP2C19). This metabolism becomes saturated at higher blood levels, which means a small dose increase can cause a disproportionately large rise in blood levels. This nonlinear behavior makes careful dose adjustment and blood level monitoring especially important.

Phenytoin is available as oral extended-release capsules, chewable tablets, oral suspension, and an injectable solution — and the dosing schedule differs by form. Chewable tablets and oral suspension are NOT for once-daily dosing and are taken in divided doses throughout the day. Extended-release capsules are typically taken two to four times daily, though once-daily dosing may be possible for some adults once seizure control is established. The injectable form is administered by healthcare professionals in a clinical setting only.

• Oral suspension must be measured with a calibrated device — not a household spoon
• Chewable tablets may be chewed thoroughly or swallowed whole
• Do not switch between formulations (e.g., free acid vs. sodium salt, immediate vs. extended release) without guidance — blood levels can change significantly
• Blood level monitoring is often needed to keep phenytoin in the effective range and avoid toxicity

The most common side effects of phenytoin involve the nervous system and tend to be dose-related:

• Nystagmus — involuntary, rapid eye movements
• Ataxia — unsteady walking or poor coordination
• Slurred speech
• Drowsiness and mental confusion
• Dizziness, headache, or tremor
• Nausea, vomiting, or constipation
• Gingival hyperplasia — overgrowth of the gums
• Altered or metallic taste sensation

More serious reactions — including severe skin blistering (SJS/TEN), liver damage, dangerous drops in blood counts, and multi-organ hypersensitivity (DRESS) — require immediate medical attention. Stop the medication and seek care right away if any of these develop.

• Never stop suddenly: Abrupt discontinuation can cause status epilepticus, a prolonged and life-threatening seizure. Taper slowly under medical supervision.
• Severe skin reactions: Stevens-Johnson syndrome and toxic epidermal necrolysis can be fatal. Stop at the first sign of any rash and seek medical evaluation immediately.
• DRESS (multiorgan hypersensitivity): Fever, rash, swollen lymph nodes, and organ involvement (liver, kidneys, heart) can appear. Can be fatal — discontinue if suspected.
• Suicidal thoughts: All antiseizure drugs, including phenytoin, increase the risk of suicidal thinking and behavior. Monitor closely, especially early in treatment.
• Liver injury: Acute hepatotoxicity, including liver failure, has been reported. Jaundice or abdominal pain warrants immediate evaluation.
• Heart effects: Bradycardia (slow heart rate) and cardiac arrest have been reported, particularly with IV dosing or in patients with underlying heart disease.
• Bone health: Long-term use can lower bone density and vitamin D levels, increasing fracture risk. Screening and supplementation may be needed.
• Birth defects: Phenytoin can cause serious fetal harm, including heart defects, cleft palate, and fetal hydantoin syndrome. Discuss risks carefully with your doctor if you are pregnant or could become pregnant.

Phenytoin has one of the most complex drug interaction profiles of any medication — it both affects and is affected by a large number of drugs:

• Drugs that raise phenytoin levels (toxicity risk): azole antifungals (fluconazole, ketoconazole), amiodarone, omeprazole, cimetidine, isoniazid, fluoxetine, acute alcohol intake, and others
• Drugs that lower phenytoin levels (reduced seizure control): rifampin, carbamazepine, antacids (take at a different time of day), St. John's Wort, chronic alcohol abuse
• Drugs whose levels phenytoin lowers: oral contraceptives, corticosteroids, warfarin, apixaban, rivaroxaban, statins (atorvastatin, simvastatin), HIV antivirals, vitamin D, methadone, cyclosporine, digoxin, and many others
• Delavirdine (HIV medication): Contraindicated — phenytoin can cause loss of HIV control and drug resistance
• Valproate: Unpredictable two-way interaction; combination also raises ammonia levels — monitor closely
• Enteral (tube) feedings: Can reduce phenytoin absorption — do not give at the same time
• Warfarin: Interaction is unpredictable (INR may rise or fall); close monitoring required

This is not a complete list of interactions. Always talk with your doctor or pharmacist before starting, stopping, or changing any medication.

• Do not take phenytoin if you have had a prior serious allergic reaction (including angioedema) to phenytoin, its ingredients, or other hydantoin drugs
• Do not take it if you have a history of acute liver damage caused by phenytoin
• Do not take it with delavirdine (an HIV medication) — this combination is contraindicated
• Tell your doctor if you are pregnant — phenytoin causes serious birth defects and fetal harm; enroll in the NAAED Pregnancy Registry (1-888-233-2334) if you take this drug while pregnant
• Tell your doctor if you are breastfeeding — phenytoin is secreted in breast milk
• Older adults: phenytoin clears more slowly with age; lower or less frequent dosing may be needed
• Liver or kidney disease: increases the unbound (active) fraction of phenytoin in your blood; blood level monitoring based on unbound levels is important
• Low blood protein (hypoalbuminemia): similarly increases unbound phenytoin — requires careful monitoring
• People of Asian ancestry: may be at higher risk for severe skin reactions (SJS/TEN); HLA-B*1502 or CYP2C9*3 genetic testing may be considered before starting
• People with porphyria: use with caution — phenytoin has been associated with worsening this condition

Taking too much phenytoin initially causes nervous system symptoms: involuntary eye movements (nystagmus), unsteady walking (ataxia), and slurred speech, followed by tremor, drowsiness, blurred vision, nausea, and vomiting. In severe cases, a person may become unresponsive, have dangerously low blood pressure, or experience slow heart rate or cardiac arrest — and high enough doses can be fatal through respiratory and circulatory failure.

There is no specific antidote. Treatment is supportive (maintaining breathing and circulation), and hemodialysis may be considered. If overdose is suspected, contact emergency services or Poison Control immediately.

Phenytoin stabilizes overactive nerve cell membranes by blocking voltage-dependent sodium channels, reducing the sustained rapid electrical firing that characterizes seizures. This effect is selective for neurons that are firing abnormally at high frequency, which is why it controls seizures without completely suppressing normal brain activity. At toxic blood levels, these same effects extend beyond seizure control and can cause central nervous system depression, slowed heart rate, and cardiovascular instability.

After oral dosing, phenytoin is absorbed at a rate that depends on the formulation — chewable tablets reach peak blood levels in about 1.5 to 3 hours, while extended-release capsules absorb more slowly. Phenytoin binds extensively to blood proteins, which affects how much active drug is available, especially in people with liver disease, kidney disease, or low protein levels. It is broken down mainly by the liver enzyme CYP2C9 (and partly CYP2C19), with an average half-life of about 14 hours (ranging from 7 to 29 hours) — but this metabolism becomes saturated at higher doses, meaning small dose increases can cause unexpectedly large jumps in blood levels.

Steady blood levels typically take 7–10 days to establish after starting or changing a dose. The drug is excreted mainly in the urine as inactive metabolites. Clearance is reduced in older adults and in people with liver disease, and drug levels during pregnancy often change significantly — especially in the third trimester — requiring monitoring and possible dose adjustments.

Store at 20° to 25°C (68° to 77°F) . Protect from moisture.