Phenytoin

Phenytoin formerly known as diphenylhydantoin, is the most commonly used major anti-epileptic agent. Phenytoin is used to control certain type of seizures, and to treat and prevent seizures that may begin during or after surgery to the brain or nervous system. Phenytoin works by decreasing abnormal electrical activity in the brain. Phenytoin was first approved for use in the United States in 1946, and currently more than 3 million prescriptions are filled yearly. Current indications for phenytoin are treatment and prevention of generalized tonic-clonic (grand mal) seizures and complex partial seizures and management of status epilepticus. Phenytoin is available generically in oral and parenteral formulations.

Since its discovery in 1908, phenytoin has become one of the most well-studied anticonvulsants ¹⁾. With an average monthly cost of $30, it has also become one of the most widely used anticonvulsants, listed on the World Health Organization’s List of Essential Medicines.

Phenytoin is available only with your doctor’s prescription.

Phenytoin comes as an extended-release (long-acting) capsule, a chewable tablet, and a suspension (liquid) to take by mouth. Oral forms include tablets and capsules of 100 to 300 mg, including extended release formations for once daily dosing. Commercial names include Dilantin. Chewable tablets and oral suspensions are available for pediatric use. The chewable tablet and suspension are usually taken two or three times a day. The recommended dose of phenytoin for chronic use is 100 mg three times daily. The extended-release capsules are usually taken 1 to 4 times a day. Take phenytoin at around the same time(s) every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take phenytoin exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor will start you on a low dose of phenytoin and gradually increase your dose, not more often than once every 7 to 10 days.

Different phenytoin products are absorbed by the body in different ways and cannot be substituted for one another. If you need to switch from one phenytoin product to another, your doctor may need to adjust your dose. Each time you receive your medication, check to be sure that you have received the phenytoin product that was prescribed for you. Ask your pharmacist if you are not sure that you received the right medication.

Shake the liquid well before each use to mix the medication evenly. Use an accurate measuring device to be sure you receive the correct amount of medication. Ask your doctor or pharmacist if you have any questions about how to measure your dose.

Swallow the extended-release capsules whole; do not split, chew, or crush them. Do not take capsules that are discolored.

You may chew the chewable tablets thoroughly before swallowing them, or you may swallow them whole without chewing.

If you are receiving formula or supplements through a feeding tube, talk to your doctor about when you should take phenytoin. You will need to allow some time between receiving your feedings and taking phenytoin.

Phenytoin may help control your condition but will not cure it. Continue to take phenytoin even if you feel well. Do not stop taking phenytoin without talking to your doctor, even if you experience side effects such as unusual changes in behavior or mood. If you suddenly stop taking phenytoin, your seizures may worsen. Your doctor will probably decrease your dose gradually.

Phenytoin may be used with other seizure medicines. Keep using all of your seizure medicines unless your doctor tells you otherwise. Do not change brands or dosage forms of phenytoin without first checking with your doctor. Different products may not work the same way. If you refill your medicine and it looks different, check with your pharmacist.

Phenytoin common side effects include dizziness, ataxia, nausea, gum hyperplasia and rash (which can occur in 10% of patients). Phenytoin has major effects on metabolism of other medications, and patients should be provided specific advice about other medications that can be used during long term phenytoin therapy.

Normal phenytoin level

Phenytoin is available in oral and intravenous (IV) formulations. The oral form is completely absorbed after ingestion. Its absorption is rapid with peak plasma concertation at 1.5 to 3 hours for the immediate release formulation and 4 to 12 hours for the extended-release formulation. However, due to its effects of reducing gastrointestinal (GI) motility and its poor water solubility, absorption tends to be delayed in oral overdose with peak concentrations occurring at up to 24 to 48 hours ²⁾.

Due to its poor water solubility, parenteral phenytoin is mixed with propylene glycol and alcohol and is only recommended for IV use. It needs to be administered slowly to prevent the adverse effects of rapid propylene glycol toxicity, usually over 45 minutes to an hour. Peak phenytoin concentrations occur 20 to 35 minutes after the completion of the infusion. Fosphenytoin is a water-soluble prodrug of phenytoin that can be administered intramuscularly (IM) or IV but needs to be converted enzymatically by phosphatase in the body to the active phenytoin compound. Intravenous fosphenytoin peaks within minutes, but the active phenytoin takes 34 to 42 minutes after completion of the IV infusion to reach peak plasma concentrations. If given by intramuscular route peak is delayed to 1.5 to 3.0 hours. Therefore, neither route results in rapid seizure control in status epilepticus.

Phenytoin has a narrow therapeutic window, between 10-20 mg/L. Serum concentrations of phenytoin are monitored by measuring the total phenytoin concentration. However, phenytoin is generally 90% bound to plasma proteins (mostly albumin), and only its unbound form is pharmacologically active. A greater fraction of the drug is unbound in neonates and pregnant patient, a patient with hypoalbuminemia of any cause (renal failure, hepatic failure, malnutrition) and uremia. Patients with decreased protein binding capacity may display symptoms of toxicity despite normal total phenytoin levels. Phenytoin is distributed in all tissues and becomes firmly tissue-bound with a large volume of distribution. The level of unbound phenytoin may be calculated using the corrected Winter-Tozer formula:

• Corrected Phenytoin Levels (mg/dl): Serum Phenytoin Level (milligrams/Liter)
• (0.25 x albumin [grams/deciliter]) +0.1

Some literature may use 0.29 as the albumin coefficient to improve accuracy depending on whether the sample was run at room temperature or body temperature.

Corrected Phenytoin Levels in patients with:

Hypoalbuminemia (mg/dl):

• Serum Phenytoin Level (milligrams/Liter)
• (0.20 x albumin [grams/deciliter]) +0.1

One to 5% of phenytoin is excreted unchanged in the urine. The remainder is metabolized by the hepatic P450 enzyme system, predominantly CYP2C9 and CYP 2C19, and induces CYP3A4, which account for many of its drug-drug interactions. All its metabolites are inactive. At plasma concentrations less than 10 mg/L, elimination follows first-order kinetics, and the rate of elimination is proportional to the drug concentration. With increasing plasma concentrations, the half-life increases as the kinetics approach zero-order. Following saturation of the system, elimination follows zero order kinetics with the same amount of drug eliminated for a given amount of time, irrespective of plasma concentration. Subsequently, the normal average half-life of 22 hours can become significantly prolonged with marked overdose.

Phenytoin mechanism of action

Phenytoin is a voltage-gated, sodium channel blocker, stabilizing the inactive state of the sodium channel and prolonging the neuronal refractory period. Phenytoin acts on the sodium channels on both neuronal and cardiac tissue. In the central nervous system, it targets neurons with high-frequency activity (as observed in seizures), with the majority of its actions on the motor cortex. Phenytoin is believed to be based upon stablization of neuronal membranes caused by an increase in the efflux and decrease in the influx of sodium ions across GABA regulated sodium channels. This prevents the spread of a seizure’s focal point and reduces the activity of brain stem regions responsible for the tonic phase of a tonic-clonic seizure. In cardiac tissue, phenytoin shortens cardiac action potentials and prolongs the refractory period between them.

Phenytoin special precautions

Before taking phenytoin:

• tell your doctor and pharmacist if you are allergic to phenytoin, other hydantoin medications such as ethotoin (Peganone) or fosphenytoin (Cerebyx), or any other medications. Also tell your doctor if you are allergic to carbamazepine (Carbatrol, Equetro, Tegretol, others), or if your doctor chose not to treat you with carbamazepine because laboratory testing showed that you have an inherited risk factor that makes it more likely that you will have an allergic reaction to carbamazepine. This risk factor may also increase the chance that you will have an allergic reaction to phenytoin.
• tell your doctor if you are taking delavirdine (Rescriptor). Your doctor will probably tell you not to take phenytoin if you are taking this medication.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: albendazole (Albenza); amiodarone (Nexterone, Pacerone); anticoagulants (‘blood thinners’) such as warfarin (Coumadin, Jantoven); antifungal medications such as fluconazole (Diflucan), ketoconazole (Nizoral), itraconazole (Onmel, Sporanox), miconazole (Oravig), posaconazole (Noxafil), and voriconazole (Vfend); certain antivirals such as efavirenz (Sustiva, in Atripla), indinavir (Crixivan), lopinavir (in Kaletra), nelfinavir (Viracept), ritonavir (Norvir, in Kaletra), and saquinavir (Invirase); bleomycin; capecitabine (Xeloda); carboplatin; chloramphenicol; chlordiazepoxide (Librium, in Librax); chlorpropamide (Diabinese); cholesterol medications such as atorvastatin (Lipitor, in Caduet), fluvastatin (Lescol), and simvastatin (Zocor, in Vytorin); cisplatin; clozapine (Fazaclo, Versacloz); cyclosporine (Gengraf, Neoral, Sandimmune); diazepam (Valium); digoxin (Lanoxin); disulfiram (Antabuse); doxorubicin (Doxil); doxycycline (Doryx, Vibramycin); fluorouracil; fluoxetine (Prozac, Sarafem, in Symbyax, others); fluvoxamine (Luvox); folic acid; fosamprenavir (Lexiva); furosemide (Lasix); H2 antagonists such as cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid), and ranitidine (Zantac); hormonal contraceptives (birth control pills, patches, rings, or injections); hormone replacement therapy (HRT); irinotecan (Camptosar); isoniazid (Laniazid, in Rifamate, in Rifater); medications for mental illness and nausea; other medications for seizures such as carbamazepine (Carbatrol, Equetro, Tegretol, others), ethosuximide (Zarontin), felbamate (Felbatol), lamotrigine (Lamictal), methsuximide (Celontin), oxcarbazepine (Trilepta), phenobarbital, topiramate (Topamax), and valproic acid (Depakene); methadone (Dolophine, Methadose); methotrexate (Otrexup, Rasuvo); methylphenidate (Daytrana, Concerta, Metadate, Ritalin); mexiletine; nifedipine (Adalat, Afeditab), nimodipine (Nymalize), nisoldipine (Sular); omeprazole (Prilosec); oral steroids such as dexamethasone, methylprednisolone (Medrol), prednisolone, and prednisone (Rayos); paclitaxel (Abraxane, Taxol); paroxetine (Paxil, Pexeva); praziquantel (Biltricide); quetiapine (Seroquel); quinidine (in Nuedexta); reserpine ; rifampin (Rifadin, Rimactane, in Rifamate, in Rifater); salicylate pain relievers such as aspirin, choline magnesium trisalicylate, choline salicylate, diflunisal, magnesium salicylate (Doan’s, others), and salsalate; sertraline (Zoloft); sucralfate (Carafate); sulfa antibiotics; teniposide (Vumon); theophylline (Elixophyllin, Theo-24); ticlopidine; tolbutamide; trazodone; verapamil (Calan, Verelan, in Tarka); vigabatrin (Sabril); and vitamin D. Your doctor may need to change the doses of your medications or monitor you more carefully for side effects.
• tell your doctor if you are taking antacids that contain calcium, magnesium, or aluminum (Maalox, Mylanta, Tums, others). Your doctor may tell you to allow some time to pass between taking the antacid and taking phenytoin.
• tell your doctor what herbal products you are taking, especially St. John’s wort.
• tell your doctor if you have ever developed a liver problem while taking phenytoin. Your doctor will probably tell you not to take phenytoin again.
• tell your doctor if you drink or have ever drunk large amounts of alcohol and if you have or have ever had diabetes, porphyria (condition in which certain natural substances build up in the body and may cause stomach pain, changes in thinking or behavior, or other symptoms), or kidney or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. You should not become pregnant while you are taking phenytoin. Talk to your doctor about effective birth control methods that you can use during your treatment. If you become pregnant while taking phenytoin, call your doctor. Phenytoin may harm the fetus.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking phenytoin.
• you should know that this medication may cause dizziness and problems with coordination. Do not drive a car or operate machinery until you know how this medication affects you.
• talk to your doctor about the safe use of alcohol while you are taking this medication.
• you should know that your mental health may change in unexpected ways and you may become suicidal (thinking about harming or killing yourself or planning or trying to do so) while you are taking phenytoin. A small number of adults and children 5 years of age and older (about 1 in 500 people) who took anticonvulsants such as phenytoin to treat various conditions during clinical studies became suicidal during their treatment. Some of these people developed suicidal thoughts and behavior as early as one week after they started taking the medication. There is a risk that you may experience changes in your mental health if you take an anticonvulsant medication such as phenytoin, but there may also be a risk that you will experience changes in your mental health if your condition is not treated. You and your doctor will decide whether the risks of taking an anticonvulsant medication are greater than the risks of not taking the medication. You, your family, or your caregiver should call your doctor right away if you experience any of the following symptoms: panic attacks; agitation or restlessness; new or worsening irritability, anxiety, or depression; acting on dangerous impulses; difficulty falling or staying asleep; aggressive, angry, or violent behavior; mania (frenzied, abnormally excited mood); talking or thinking about wanting to hurt yourself or to end your life; withdrawing from friends and family; preoccupation with death and dying; giving away prized possessions; or any other unusual changes in behavior or mood. Be sure that your family or caregiver knows which symptoms may be serious so they can call the doctor if you are unable to seek treatment on your own.
• talk to your doctor about the best way to care for your teeth, gums, and mouth during your treatment with phenytoin. It is very important that you care for your mouth properly to decrease the risk of gum damage caused by phenytoin.

Tell your doctor right away if you or your child develop a fever, rash, swollen, painful, or tender lymph glands in the neck, armpit, or groin, unusual bleeding or bruising, or yellow eyes or skin after using Phenytoin. These may be symptoms of a serious and life-threatening condition called drug reaction with eosinophilia and systemic symptoms (DRESS).

Phenytoin may cause liver damage. Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, vomiting, or yellow eyes or skin.

Phenytoin can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.
Check with your doctor immediately if you notice any unusual bleeding or bruising, black, tarry stools, blood in the urine or stools, or pinpoint red spots on your skin.
Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.
Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.
Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.
Avoid contact sports or other situations where bruising or injury could occur.

Phenytoin may decrease bone mineral density. A low bone mineral density can cause weak bones or osteoporosis. If you or your child have any questions about this ask your doctor.

Phenytoin may affect blood sugar levels. If you or your child notice a change in the results of your blood or urine sugar tests or if you have any questions, check with your doctor.

Phenytoin may cause some people to be agitated, irritable, or display other abnormal behaviors. It may also cause some people to have suicidal thoughts and tendencies or to become more depressed. If you, your child, or your caregiver notice any of these side effects, tell your or your child’s doctor right away.

In some patients (usually younger patients), tenderness, swelling, or bleeding of the gums (gingival hyperplasia) may appear soon after phenytoin treatment is started. To help prevent this, brush and floss your teeth carefully and regularly and massage your gums. Also, see your dentist every 6 months to have your teeth cleaned. If you have any questions about how to take care of your teeth and gums, or if you notice any tenderness, swelling, or bleeding of your gums, check with your doctor or dentist.

Before you have any medical tests, tell the medical doctor in charge that you or your child are taking Phenytoin. The results of some tests may be affected by Phenytoin.

Phenytoin may cause drowsiness, trouble thinking, or trouble in controlling movements. Do not drive or do anything else that could be dangerous until you know how Phenytoin affects you.

Avoid drinking alcohol while you are using Phenytoin.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Phenytoin in pregnancy

US FDA pregnancy category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Administration of phenytoin to pregnant animals resulted in teratogenicity (increased incidences of fetal malformations) and other developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple animal species at clinically relevant doses. There are no controlled data in human pregnancy.

• An increased risk of congenital abnormalities (“fetal hydantoin syndrome”) has been associated with the use of phenytoin in epileptic women during pregnancy.
• The overall incidence of neonate malformations for offspring of mothers treated with anti-seizure medications is approximately 10%, or 2 to 3 fold the incidence in the general population (although a definite causal relationship has not been established).
• Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took Phenytoin alone or in combination with other antiepileptic drugs during pregnancy.
• There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.

Using phenytoin while you are pregnant can harm your unborn baby. When ingested by pregnant women, a range of vascular and skeletal anomalies have been reported ³⁾. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

Phenytoin in breastfeeding

There are no adequate studies in women for determining infant risk when using phenytoin during breastfeeding. Weigh the potential benefits against the potential risks before taking phenytoin while breastfeeding.

• Because of the low levels of phenytoin in breastmilk, amounts ingested by the infant are small and usually cause no difficulties when used alone except for rare idiosyncratic reactions. Breastfeeding during monotherapy does not appear to adversely affect infant growth or development.
• Combination therapy with sedating anticonvulsants or psychotropics may result in infant sedation or withdrawal reactions.
• In one case report, maternal phenytoin dosage requirements decreased as breastfeeding was discontinued.

Phenytoin interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking phenytoin, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using phenytoin with any of the following medicines is not recommended. Your doctor may decide not to treat you with phenytoin or change some of the other medicines you take.

• Artemether
• Atazanavir
• Boceprevir
• Cobicistat
• Daclatasvir
• Darunavir
• Dasabuvir
• Delamanid
• Delavirdine
• Doravirine
• Elbasvir
• Elvitegravir
• Grazoprevir
• Isavuconazonium
• Lorlatinib
• Lurasidone
• Maraviroc
• Ombitasvir
• Paritaprevir
• Piperaquine
• Praziquantel
• Ranolazine
• Rilpivirine
• Ritonavir
• Telaprevir
• Tenofovir Alafenamide

Using phenytoin with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abemaciclib
• Abiraterone Acetate
• Acalabrutinib
• Afatinib
• Alfentanil
• Aluminum Carbonate, Basic
• Aluminum Hydroxide
• Aluminum Phosphate
• Amiodarone
• Apazone
• Apixaban
• Apremilast
• Aprepitant
• Aripiprazole
• Axitinib
• Beclamide
• Bedaquiline
• Benzhydrocodone
• Bictegravir
• Bosutinib
• Brexpiprazole
• Brigatinib
• Buprenorphine
• Bupropion
• Cabozantinib
• Calcifediol
• Calcium Carbonate
• Carbamazepine
• Cariprazine
• Ceritinib
• Chlorpheniramine
• Cisatracurium
• Clarithromycin
• Clofazimine
• Clozapine
• Cobimetinib
• Codeine
• Copanlisib
• Crizotinib
• Cyclophosphamide
• Dabigatran Etexilate
• Dasatinib
• Deferasirox
• Deflazacort
• Desogestrel
• Diazepam
• Diazoxide
• Dienogest
• Digoxin
• Dihydrocodeine
• Dihydroxyaluminum Aminoacetate
• Dihydroxyaluminum Sodium Carbonate
• Dolutegravir
• Doxorubicin
• Doxorubicin Hydrochloride Liposome
• Dronedarone
• Drospirenone
• Duvelisib
• Eliglustat
• Encorafenib
• Enzalutamide
• Eravacycline
• Erdafitinib
• Erlotinib
• Eslicarbazepine Acetate
• Estradiol
• Ethinyl Estradiol
• Ethosuximide
• Ethynodiol
• Etonogestrel
• Etravirine
• Everolimus
• Exemestane
• Ezogabine
• Fentanyl
• Fluvastatin
• Fosaprepitant
• Fosnetupitant
• Fostamatinib
• Gefitinib
• Gestodene
• Gilteritinib
• Glasdegib
• Glecaprevir
• Halothane
• Hemin
• Hydrocodone
• Ibrutinib
• Idelalisib
• Ifosfamide
• Imatinib
• Infliximab
• Irinotecan
• Irinotecan Liposome
• Itraconazole
• Ivabradine
• Ivacaftor
• Ivosidenib
• Ixabepilone
• Ixazomib
• Ketoconazole
• Lacosamide
• Lamotrigine
• Lapatinib
• Larotrectinib
• Ledipasvir
• Letermovir
• Levonorgestrel
• Lidocaine
• Linagliptin
• Lopinavir
• Macimorelin
• Macitentan
• Magaldrate
• Magnesium Carbonate
• Magnesium Hydroxide
• Magnesium Oxide
• Magnesium Trisilicate
• Manidipine
• Meperidine
• Mestranol
• Methadone
• Methotrexate
• Miconazole
• Midostaurin
• Mifepristone
• Naloxegol
• Neratinib
• Netupitant
• Nifedipine
• Nilotinib
• Nimodipine
• Nintedanib
• Norethindrone
• Norgestimate
• Norgestrel
• Olaparib
• Orlistat
• Osimertinib
• Oxcarbazepine
• Oxycodone
• Paclitaxel
• Palbociclib
• Paliperidone
• Panobinostat
• Pazopanib
• Pentazocine
• Perampanel
• Pibrentasvir
• Ponatinib
• Posaconazole
• Quetiapine
• Regorafenib
• Reserpine
• Ribociclib
• Rifampin
• Rivaroxaban
• Rocuronium
• Roflumilast
• Rolapitant
• Romidepsin
• Saquinavir
• Sertraline
• Simeprevir
• Sofosbuvir
• Sonidegib
• Sorafenib
• Stiripentol
• St John’s Wort
• Sufentanil
• Tacrolimus
• Tamoxifen
• Tasimelteon
• Temsirolimus
• Tezacaftor
• Theophylline
• Thiotepa
• Ticagrelor
• Tofacitinib
• Tolvaptan
• Trabectedin
• Tramadol
• Triclabendazole
• Ulipristal
• Valbenazine
• Vandetanib
• Velpatasvir
• Vemurafenib
• Venetoclax
• Vilazodone
• Vincristine
• Vincristine Sulfate Liposome
• Vinflunine
• Vorapaxar
• Voriconazole
• Vortioxetine
• Voxilaprevir

Using phenytoin with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acetaminophen
• Acetazolamide
• Acyclovir
• Amitriptyline
• Amprenavir
• Aripiprazole Lauroxil
• Atorvastatin
• Betamethasone
• Bexarotene
• Bleomycin
• Busulfan
• Capecitabine
• Carboplatin
• Caspofungin
• Chloramphenicol
• Cimetidine
• Ciprofloxacin
• Cisplatin
• Clobazam
• Clopidogrel
• Colesevelam
• Cortisone
• Cyclosporine
• Dexamethasone
• Dicumarol
• Digitoxin
• Diltiazem
• Disopyramide
• Disulfiram
• Doxepin
• Doxifluridine
• Felbamate
• Fluconazole
• Fludrocortisone
• Fluorouracil
• Fluoxetine
• Fluvoxamine
• Folic Acid
• Fosamprenavir
• Ginkgo
• Imipramine
• Isoniazid
• Levodopa
• Levomethadyl
• Levothyroxine
• Lithium
• Methoxsalen
• Methsuximide
• Midazolam
• Nafimidone
• Nelfinavir
• Nilutamide
• Nisoldipine
• Ospemifene
• Pancuronium
• Paroxetine
• Phenprocoumon
• Piperine
• Prednisolone
• Prednisone
• Progabide
• Quinidine
• Quinine
• Remacemide
• Rifapentine
• Risperidone
• Rufinamide
• Sabeluzole
• Shankhapulshpi
• Simvastatin
• Sirolimus
• Sulfamethizole
• Sulfamethoxazole
• Sulfaphenazole
• Sulthiame
• Tegafur
• Telithromycin
• Tenidap
• Tiagabine
• Ticlopidine
• Ticrynafen
• Tirilazad
• Tizanidine
• Tolbutamide
• Topiramate
• Trazodone
• Triamcinolone
• Trimethoprim
• Tubocurarine
• Valacyclovir
• Valproic Acid
• Vecuronium
• Verapamil
• Vigabatrin
• Viloxazine

Other Interactions

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using phenytoin with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use phenytoin, or give you special instructions about the use of food, alcohol, or tobacco.

• Enteral Nutrition
• Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of phenytoin. Make sure you tell your doctor if you have any other medical problems, especially:

• Acute hepatoxicity (liver problem) from previous phenytoin use—Should not be used in patients with this condition.
• Bone problems (eg, osteomalacia, osteoporosis) or
• Depression or mental illness, history of or
• Diabetes or
• Heart disease or
• Lymphadenopathy (lymph node problems) or
• Porphyria (an enzyme problem) or
• Vitamin D deficiency—Use with caution. May make these conditions worse.
• Hypoalbuminemia (low albumin in the blood) or
• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal from the body.

Phenytoin uses

Phenytoin is used to control seizures (convulsions) in the treatment of epilepsy. Phenytoin is also used to prevent and treat seizures that occur during brain surgery.

• Seizures (non-emergent use): Control of generalized tonic-clonic and complex partial (psychomotor, temporal lobe) seizures; prevention and treatment of seizures occurring during or following neurosurgery (capsule, chewable tablet, and injection only).
• Status epilepticus (injection only): Treatment of generalized tonic-clonic status epilepticus.

Off Label Uses

• Prevention of early (within 1 week) posttraumatic seizures following traumatic brain injury

Data from a randomized, double-blind, placebo-controlled trial in patients with serious head trauma supports the use of phenytoin to prevent posttraumatic seizures in patients who recently (within 1 week) experienced a traumatic brain injury. Phenytoin did not reduce the incidence of late (≥day 8) posttraumatic seizures.

Based on the Brain Trauma Foundation’s Guidelines for the Management of Severe Traumatic Brain Injury and the American Association of Neurology (AAN) Practice Parameter for Antiepileptic Drug Prophylaxis in Severe Traumatic Brain Injury, phenytoin is effective and recommended to decrease the risk of posttraumatic seizures occurring within the first 7 days of traumatic brain injury.

Phenytoin is also used to control irregular heartbeat. Phenytoin is now rarely used to suppress ventricular arrhythmias in patients unresponsive to lidocaine. Talk to your doctor about the risks of using phenytoin for your condition.

Phenytoin dose

The dose of phenytoin will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of phenytoin. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of phenytoin that you take depends on the strength of the phenytoin. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take phenytoin depend on the medical problem for which you are using phenytoin.

For seizures:

For oral dosage form (extended-release capsules):

• Adults—At first, 100 milligrams (mg) 3 times a day or 300 mg once a day. Your doctor may increase your dose as needed. For patients in the clinic or hospital (except with a history of liver or kidney disease), a loading dose of 1000 mg is divided into three doses (400 mg, 300 mg, 300 mg) and given every 2 hours. Then, normal maintenance dose may be started 24 hours after the loading dose.
• Children older than 6 years of age—300 mg per day. Your doctor may adjust your dose as needed.
• Children 6 years of age and younger—Dose is based on body weight and must be determined by your doctor. At first, 5 milligrams (mg) per kilogram (kg) of body weight given in 2 or 3 divided doses per day. The doctor may adjust the dose as needed.

For oral dosage form (suspension):

• Adults—At first, 5 milliliters (mL) or one teaspoonful 3 times a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 25 mL per day.
• Children older than 6 years of age—300 mg per day. Your doctor may adjust your dose as needed.
• Children 6 years of age and younger—Dose is based on age and body weight and must be determined by your doctor. At first, 5 milligrams (mg) per kilogram (kg) of body weight given in 2 or 3 divided doses per day. Your doctor may adjust your dose as needed.

For oral dosage form (tablets):

• Adults—At first, 100 milligrams (mg) 3 times a day. Your doctor may adjust your dose as needed.
• Children older than 6 years of age—300 mg per day, given in 2 or 3 divided doses per day. Your doctor may adjust your dose as needed.
• Children 6 years of age and younger—Dose is based on age and body weight and must be determined by your doctor. At first, 5 milligrams (mg) per kilogram (kg) of body weight given in 2 or 3 divided doses per day. The doctor may adjust the dose as needed.

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Phenytoin side effects

Phenytoin may cause an increase in your blood sugar. Talk to your doctor about the symptoms of high blood sugar and what to do if you experience these symptoms.

Taking phenytoin may increase the risk that you will develop osteomalacia (weakening and softening of the bones) and problems with your lymph nodes including Hodgkin’s disease (cancer that begins in the lymph system). Talk to your doctor about the risks of using this medication to treat your condition.

Phenytoin may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• difficulty falling asleep or staying asleep
• uncontrollable eye movements
• abnormal body movements
• loss of coordination
• confusion
• slowed thinking
• slurred speech
• headache
• constipation
• unwanted hair growth
• coarsening of facial features
• enlargement of lips
• overgrowth of gums
• pain or curving of the penis

Some side effects can be serious. If you experience any of the following symptoms or those listed in the SPECIAL PRECAUTIONS section, call your doctor immediately:

• swollen lymph glands
• blisters
• joint pain
• nausea
• vomiting
• yellowing of the skin or eyes
• pain in upper right part of the stomach
• excessive tiredness
• unusual bruising or bleeding
• loss of appetite
• flu-like symptoms
• fever, sore throat, rash, mouth ulcers, or easy bruising, or facial swelling
• swelling of the face, eyes, throat, tongue, or lips
• dizziness, tiredness, irregular heartbeat, or chest pain

Phenytoin may cause other side effects. Call your doctor if you have any unusual problems while you are taking phenytoin.

Phenytoin overdose symptoms may include the following:

• uncontrollable eye movements
• loss of coordination
• slow or slurred speech
• uncontrollable shaking of a part of the body
• nausea
• vomiting
• difficulty understanding reality
• coma (loss of consciousness for a period of time)
• confusion
• convulsions (occasionally)
• dizziness
• fever
• low blood pressure
• muscle rigidity or spasms
• sleepiness
• side-to-side eye movement (nystagmus)
• slurred speech
• swollen gums
• tremor (unintentional trembling)
• unsteadiness

Phenytoin toxicity

Phenytoin displays its main signs of toxicity on the nervous and cardiovascular systems. Overdose on oral phenytoin causes mainly neurotoxicity and only very rarely causes cardiovascular toxicity. On the other hand, cardiovascular toxicity is the main side effect of parenteral administration ⁴⁾.

Neurotoxicity

The neurotoxic effects are concentration dependent and can range from mild nystagmus to ataxia, slurred speech, vomiting, lethargy and eventually coma and death. Paradoxically, at very high concentrations, phenytoin can lead to seizures. Symptoms correlate well with the unbound plasma phenytoin concentration. However, this laboratory value is seldom obtained. The following is a loose correlation of side effects with total plasma phenytoin concentrations (the value obtained in most laboratories):

• Less than 10 mg/L: Rare side effects
• Ten to 20 mg/L: Occasional mild horizontal nystagmus on lateral gaze
• Twenty to 30 mg/L: Nystagmus
• Thirty to 40 mg/L: Ataxia, slurred speech, tremor, nausea, and vomiting
• Forty to 50 mg/L: Lethargy, confusion, hyperactivity
• Greater than 50 mg/L: Coma and seizures

Seizures are very rare and usually occur at very high serum concentrations. The presence of seizures in a patient with suspected phenytoin overdose should prompt the search for other coingestants.

Cardiac Toxicity

Phenytoin is a Vaughn Williams Class IB antiarrhythmic; although, it is almost never used as an antiarrhythmic anymore. Its effects on the cardiac voltage-gated sodium channels can lead to dysrhythmias as well as SA and AV nodal blocks although such effects have rarely been reported following ingestion of the oral form. In the intravenous form, the main toxicity is believed to be from its parenteral vehicle: propylene glycol. Propylene glycol is a cardiac depressant, and rapid infusions can lead to bradycardia, hypotension, and asystole. Care must be taken so that intravenous formulations of phenytoin are not administered at a rate faster than 50 mg per minute.

Other Toxicities

“Purple Glove syndrome” is a rare side effect that can occur with intravenous administration of phenytoin. It is characterized by worsening distal limb edema and discoloration which can lead to extensive skin necrosis and limb ischemia. Phenytoin hypersensitivity has also been reported, generally occurring one week to 1 month after initiation of therapy. It is characterized by a fever, rash and different internal organ involvement (hepatitis, myocarditis, pneumonitis). Chronic intake of phenytoin can lead to folate deficiency, peripheral neuropathy or a lupus-like syndrome although these effects have not been reported from acute overdoses.

Your local poison center can be reached directly by calling the national toll-free Poison Help hotline (1-800-222-1222) from anywhere in the United States. This hotline number will let you talk to experts in poisoning. They will give you further instructions.

This is a free and confidential service. All local poison control centers in the United States use this national number. You should call if you have any questions about poisoning or poison prevention. It does NOT need to be an emergency. You can call for any reason, 24 hours a day, 7 days a week.

Take the pill container with you to the hospital, if possible.

Risk factors for phenytoin toxicity

The different risk factors for phenytoin toxicity are as follows:

Change in Medications

Phenytoin toxicity can occur from an increase in the daily dose of phenytoin, changes in the formulations or brands as well as changes in the frequency of administration. It can also occur when patients are started on new medications that interact with the metabolism or binding capacity of phenytoin to plasma proteins. Due to its metabolism by CYP450 liver enzymes, multiple drug interactions can occur.

Change in Physiology

New disease states can lead to changes in the phenytoin plasma concentration. Liver cirrhosis can lead to a decrease in serum albumin as well as a decreased metabolism of phenytoin by the CYP450 pathway, both leading to increased amounts of free phenytoin in the serum. Kidney disease can also lead to hypoalbuminemia as well as uremia which decreases the percentage of bound phenytoin in the plasma. Malnutrition, malignancy, and pregnancy are other causes for phenytoin toxicity in a patient on chronic therapy without any changes in dose.

Acute Ingestion

Acute ingestion leading to overdose can be intentional or unintentional. There have also been reports of crack cocaine being adultered with phenytoin, which can lead to an unintentional overdose

Chronic Toxicity

One of the more common manifestations of chronic phenytoin ingestion is gingival hyperplasia. The cause of phenytoin-induced gingival enlargement is likely due to the direct effects of the drug and its metabolites on the gingival fibroblasts. Other factors which can contribute to phenytoin-induced gingival enlargement include adrenocortical axis suppression, alterations in the metabolism of calcium, low serum folic acid levels, and suppression of the immune system.

DRESS Syndrome

Drug reaction with eosinophilia and systemic symptoms, or DRESS syndrome, has been associated with chronic phenytoin use. This rare syndrome may occur in one out of 1000 to 10,000 users of any of the aromatic anticonvulsants, including phenytoin, carbamazepine, and lamotrigine. Onset is typically within two months of initiation of therapy and is triggered by metabolites of each agent inducing a type-IV hypersensitivity. Symptoms typically include high fever, a macular rash, and pharyngitis, and it is often mistaken early in the course for streptococcal pharyngitis. Multi-organ system involvement lymphadenopathy, liver injury, acute kidney injury and occasional encephalitis may occur. A peripheral blood smear shows eosinophilia and atypical lymphocytosis, often confusing the diagnosis with acute mononucleosis. Fatalities in the unrecognized case can be as high as 10%. Immediately discontinuation of phenytoin and the initiation of steroid treatment is key to preventing progression. A skin biopsy may be needed to confirm the diagnosis. A substitute anticonvulsant, from a non-aromatic class, should be used in place of phenytoin.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Phenytoin has been associated with both Stevens-Johnson syndrome, and its more severe manifestation toxic epidermal necrolysis (TEN). Once thought to be idiopathic, these life-threatening dermopathies have been linked to genetic variants of the human lymphocyte antigen system, and in CYP genetic variants. Mostly in Asia, patients who carry the HLAB*1502 and CYP2C9*3 genes are at high risk. If the presence of a skin and a mucosal rash is seen, immediate discontinuation of phenytoin is mandatory. Genetic testing may be advised before switching to another aromatic anticonvulsant.

Phenytoin toxicity symptoms

Phenytoin toxicity symptoms may include the following:

• uncontrollable eye movements
• loss of coordination
• slow or slurred speech
• uncontrollable shaking of a part of the body
• nausea
• vomiting
• difficulty understanding reality
• coma (loss of consciousness for a period of time)
• confusion
• convulsions (occasionally)
• dizziness
• fever
• low blood pressure
• muscle rigidity or spasms
• sleepiness
• side-to-side eye movement (nystagmus)
• slurred speech
• swollen gums
• tremor (unintentional trembling)
• unsteadiness

Phenytoin toxicity treatment

There is no specific antidote for phenytoin toxicity, and the hallmark of treatment is supportive care. Your health care provider will measure and monitor the your vital signs, including temperature, pulse, breathing rate, and blood pressure. Blood tests will be done to check phenytoin levels. Symptoms will be treated as appropriate. You may receive:

• Activated charcoal
• Airway support, including oxygen, breathing tube through the mouth (intubation), and ventilator (breathing machine)
• Blood and urine tests
• Chest x-ray
• EKG (electrocardiogram, or heart tracing)
• Fluids through the vein (intravenous or IV)
• Laxative
• Medicines to treat symptoms

The management of phenytoin toxicity should initially proceed along the lines of accepted treatment of general overdoses. The airway should be assessed, and advanced airway management initiated in patients that cannot maintain their airway or respiratory drive. The circulation should be assessed and abnormalities in vital signs addressed. Hypotension can be treated with an initial bolus of isotonic solution. If unresponsive to fluid administration, vasopressors can be initiated with norepinephrine or dopamine being preferred. Bradycardia can also be managed according to standard advanced cardiac life support protocols including atropine, epinephrine and if needed, transcutaneous or transvenous pacing. Consultation with a medical toxicologist is highly recommended ⁵⁾.

Other symptoms of overdose can be managed according to standards of care. Antiemetics can be administered in cases of nausea and vomiting. Seizures can be controlled by following the normal seizure protocols with benzodiazepines as the first like medications followed by phenobarbital or levetiracetam for persistent or recurrent seizures.

Activated charcoal reliably binds phenytoin and prevents absorption. In acute ingestions, one dose of activated charcoal may be of benefit especially in large acute overdoses as phenytoin slows GI (gastrointestinal) motility and absorption is delayed. Activated charcoal is also of benefit in acute ingestions of extended-release tablets. Activated charcoal is not recommended if there is a depressed mental state. The role of multi-dose activated charcoal is controversial. Some studies have shown increased clearance rates although no clinical benefit or improvement in patient outcomes could be demonstrated. Induced emesis, gastric lavage, and whole bowel irrigation are not recommended for phenytoin overdose.

Despite high-plasma protein binding by phenytoin, the drug can be removed by hemodialysis with moderate effectiveness. However, clinical benefits are controversial. Due to the high-risk nature of hemodialysis, the effectiveness of supportive treatment, and the self-limited nature of acute overdoses, hemodialysis is rarely recommended and should only be used in extreme situations after consultation with a medical toxicologist. One guideline by the EXTRIP group advises the consideration of hemodialysis in cases of coma, and possibly in incapacitating ataxia; however, no specific serum concentration threshold can be used as a sole reason to perform dialysis.

Phenytoin toxicity prognosis

How well a person does depends on the severity of the overdose and how quickly treatment is received. If there has been prolonged coma and shock (damage to multiple internal organs), a more serious outcome is possible.

Deaths are rare from phenytoin ingestion alone. Most reported cases involve ingestion of other substances along with phenytoin. Fatal cases of single phenytoin ingestions typically involve serum concentrations of greater than 125 mg/L.

Disposition of patients is made on an individual basis. Patients requiring ventilatory support, hemodynamically unstable patients or patients with abnormal ECGs should be admitted to a monitored setting. Patients with mild to moderate overdoses, normal mentation, normal ECGs without any hypotension, bradycardia, or arrhythmias can be safely admitted to a bed without cardiac monitoring.

Serum phenytoin levels should be repeated and trended. Decreasing levels of serum phenytoin in a patient that can ambulate without assistance and has someone at home who can assist with activities of daily living until all symptoms of toxicity have resolved may be safely discharged home. Adequate follow-up should be arranged. All patients with intentional overdoses should receive a psychiatric consultation while hospitalized.