Review of Phenytoin, a Best Pill for Seizures

Seizure disorders, which are also known as epilepsies, can range in severity from life-threatening and disabling to mild and benign.[1] In epilepsy, the normal brain activity becomes disturbed, causing strange sensations, emotions and behavior or sometimes convulsions, muscle spasms and loss of consciousness.

The diagnosis of epilepsy requires having two or more seizures.[2] Patients who experience a single seizure because of a high fever (called a febrile seizure) or head injury do not necessarily have epilepsy. According to the Centers for Disease Control and Prevention, approximately 3 million adults and 470,000 children in the U.S. have active seizure disorders.[3] The text box below identifies the major types of epilepsy.

Medications are the mainstay of treatment for most patients with seizure disorders, and more than two dozen such drugs have been approved by the Food and Drug Administration (FDA).[4] Here we review one of the oldest seizure drugs, phenytoin (DILANTIN, PHENYTEK). Patients using the drug need to be aware of its many potentially serious adverse effects.

Major Types of Seizures

Seizures are classified into the following two groups:

1. Generalized seizures, which affect both sides of the brain:
   • Absence seizures, sometimes called petit mal seizures, can cause rapid blinking or a few seconds of staring into space.
   • Tonic-clonic seizures, also called grand mal seizures, can make a person cry out, lose consciousness, fall to the ground, have muscle jerks or spasms in the arms and legs, and make a person feel tired after the seizure resolves.
2. Focal seizures, which occur in just one area of the brain. These seizures also are called partial seizures:
   • Simple focal seizures affect a small part of the brain. These seizures can cause twitching or a change in sensation, such as a strange taste or smell.
   • Complex focal seizures can make a person with epilepsy confused or dazed. The person will be unable to respond to questions or direction for up to a few minutes.
   • Secondary generalized seizures begin in one part of the brain but then spread to both sides of the brain. In other words, the person first has a focal seizure, followed by a generalized seizure.

Source: Centers for Disease Control and Prevention, Types of Seizures, January 17, 2018, https://www.cdc.gov/epilepsy/about/types-of-seizures.htm.

Phenytoin
Approved uses
Introduced in the 1930s, phenytoin is one of the oldest epilepsy drugs.[5] It was first approved by the FDA in 1953[6] and is used as a first-line agent to treat two types of seizures: generalized (tonic-clonic or grand mal) seizures and partial (focal) seizures.[7]

Patients taking phenytoin should adhere strictly to the prescribed dosing schedule and inform the prescribing health care professional of any situation in which it is not possible to take the drug as prescribed (for example, before, during or after surgery). Sudden discontinuation of the drug or rapid dosage reduction can result in status epilepticus, a medical emergency characterized by prolonged seizures.

Adverse effects[8]

Phenytoin can cause severe, sometimes fatal skin adverse reactions (including conditions known as Stevens-Johnson syndrome and toxic epidermal necrolysis). Certain patients of Asian ancestry are at greatest risk of these adverse events. Symptoms of these skin disorders usually begin within 28 days of starting the drug but can occur later. Patients should notify their physicians immediately if a skin rash develops while taking phenytoin.

Epilepsy drugs, including phenytoin, increase the risk of suicidal thoughts or behavior. Patients using these drugs should be monitored for new or worsening depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior.

A condition known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome has been reported in patients using phenytoin. DRESS syndrome also is known as multi-organ hypersensitivity and in some cases has been fatal. Symptoms of DRESS syndrome include fever, rash, swollen lymph nodes and facial swelling. The disorder can cause inflammation of the liver, kidneys, heart and muscles.

Cases of abnormally slow heart rate and cardiac arrest have been reported in patients treated with phenytoin. Most of the cases of cardiac arrest occurred in patients who already had heart disease.

Chronic use of phenytoin has been associated with decreased bone mineral density (osteopenia, osteoporosis and osteomalacia) and bone fractures. Importantly, the drug can decrease vitamin D levels, which may lead to vitamin D deficiency.

Phenytoin has caused serious harm to human infants born to mothers who took the drug during pregnancy. Such infants have been born with cleft palate, damage to the heart, a small head, and mental deficiency. There also have been reports of cancer in children whose mothers took phenytoin during pregnancy. Because of the potential for serious adverse effects to the fetus, this drug should not be used by pregnant women.

Additional notable adverse effects of phenytoin include severe allergic reactions; angioedema (a condition characterized by swelling of the face, lips, tongue or throat and trouble breathing); liver damage, which in rare instances may lead to liver failure; blood cell abnormalities, such as low white blood cells, low platelets or anemia; and high blood sugar levels.

Phenytoin also has clinically important interactions with many other prescription and over-the-counter medications. For example, some drugs when taken concomitantly with phenytoin may increase phenytoin blood levels, potentially resulting in phenytoin toxicity. These include certain antibiotics (for example, sulfamethoxazole-trimethoprim [BACTRIM, SEPTRA, SULFATRIM PEDIATRIC]), antidepressants (for example, fluoxetine [PROZAC, SARAFEM]), antifungal drugs (for example, fluconazole [DIFLUCAN]), other epilepsy drugs (for example, topiramate [QUDEXY XR, TOPAMAX, TROKENDI XR]) and medications for decreasing stomach acid (for example, omeprazole [PRILOSEC]). Signs of phenytoin toxicity include loss of muscle coordination, involuntary repetitive eye movements, slurred speech, sleepiness and confusion. For more details, see our September 2019 article, Important Drug Interactions for the Seizure Drug Phenytoin.

What You Can Do

Before taking phenytoin, tell your doctor about all of your medical conditions, including if you:

• Have or have had depression, mood problems, or suicidal thoughts or behavior
• Have had an allergic reaction to phenytoin or to medicines chemically similar to phenytoin, including barbiturates (for example, phenobarbital [LUMINAL, SOLFOTON]), ethosuximide (ZARONTIN) and methsuximide (CELONTIN), among others
• Have or have had liver or kidney problems
• Have the inherited disorder porphyria
• Have or have had high blood sugar or diabetes
• Drink alcohol
• Are pregnant or plan to become pregnant
• Are breastfeeding or plan to breastfeed

If you need treatment with phenytoin, review a list of all of your other prescription and over-the-counter medications with your doctor to assess for potentially significant drug interactions. If you are taking phenytoin, you may need to undergo blood tests to monitor phenytoin levels after starting or stopping a new drug that may interact with phenytoin.

You should avoid drinking alcohol while taking phenytoin without first talking to your doctor. Drinking alcohol while taking phenytoin may change your blood level of the drug, which can cause serious problems.

Do not drive, operate heavy machinery, or do other dangerous activities until you know how phenytoin affects you because the drug can slow your thinking and motor skills.

Finally, call your doctor right away if you have any of the following symptoms while taking phenytoin:

• Thoughts about suicide or dying or attempts to commit suicide
• New or worse depression or anxiety
• Feeling agitated or restless
• Panic attacks
• Trouble sleeping
• New or worse irritability
• Acting aggressively or violently or being angry
• Acting on dangerous impulses
• An extreme increase in activity and talking (mania)
• Other unusual changes in behavior or mood
• Fever
• Rash, easy bruising, or purple or red spots on your skin
• Swollen lymph glands
• Swelling of your face, eyelids, lips or tongue
• Trouble swallowing or breathing
• Sore throat or sores in your mouth
• Frequent infections
• Loss of appetite, nausea or vomiting
• Yellowing of the skin and the white part of your eyes
• Dizziness, tiredness, feeling like your heart is beating slowly or skipping beats, or chest pain
• Irregular movement of the eye
• Problems with movement and balance
• Slurred speech
• Decrease in coordination
• Drowsiness
• Confusion or delirium

References

[1] National Institutes of Health, National Institute of Neurological Disorders and Stroke. Epilepsy information page. November 22, 2019. https://www.ninds.nih.gov/Disorders/All-Disorders/Epilepsy-Information-Page#disorders-r1. Accessed July 9, 2020.

[2] Ibid.

[3] Centers for Disease Control and Prevention. Epilepsy fast facts. July 31, 2018. https://www.cdc.gov/epilepsy/about/fast-facts.htm. Accessed July 9, 2020.

[4] [Personal medical knowledge]

[5] Schachter SC. Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects. UpToDate. June 3, 2020.

[6] Pfizer. Label: phenytoin (DILANTIN). August 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=8848de76-8d74-4620-bcc7-a86a596e5dd9&type=display. Accessed June 23, 2020.

[7] Schachter SC. Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects. UpToDate. June 3, 2020.

[8] Pfizer. Label: phenytoin (DILANTIN). August 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=8848de76-8d74-4620-bcc7-a86a596e5dd9&type=display. Accessed June 23, 2020.