Phenytoin (oral)

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# Overview
Phenytoin (oral) is an anticonvulsant that is FDA approved for the treatment of generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery.   Common adverse reactions include morbilliform eruption, rash, constipation, gingival enlargement, nausea, vomiting, ataxia, coordination problem, nystagmus, slurred speech, confusion, feeling nervous.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### Seizure, During and following neurosurgery
- Dilantin Infatabs (Phenytoin Chewable Tablets, USP) are indicated for prevention and treatment of seizures occurring during or following neurosurgery.
- Dosing information
- Chewable Tablets (Infatabs(R))
- a) Adults without previous treatment may be started on 100 milligrams (mg) (2 tablets) 3 times daily and dose should be adjusted to individual needs. The usual maintenance dose is 300 to 400 mg/day. An increased to 600 mg/day (12 tablets) may be made if necessary.

### Seizure, Generalized Tonic-Clonic and Complex Partial (psychomotor and temporal lobe) Seizures
- Dilantin Infatabs (Phenytoin Chewable Tablets, USP) are indicated for the control of generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures.
- Dosing information
- General Information:
- a)In epilepsy, dosage should be individualized to achieve maximal benefit, including serum level monitoring (optimal control of seizures without clinical signs of toxicity occurs most often with serum levels between 10 to 20 micrograms/milliliter). A period of 7 to 10 days is required to achieve steady-state blood levels; dose adjustments should not be instituted at intervals shorter than 7 to 10 days.
- b) Guidelines for dosing adjustments based on phenytoin plasma concentrations have been proposed for adults with epilepsy without clinically significant renal or hepatic disease: for plasma phenytoin concentrations less than 7 micrograms/milliliter, a dosage increase of 100 milligrams/day is recommended; for plasma concentrations between 7 and 12 micrograms/milliliter, the dose may be increased by 50 milligrams/day; if the plasma concentration is greater than 12 micrograms/milliliter, the dose may increased by 30 milligrams/day. Dosage increases when the plasma level is above 16 micrograms/milliliter should only be done with caution as even a small increase may result in toxicity. These recommendations resulted in therapeutic concentrations in the majority of patients followed.
- c) Since phenytoin is metabolized in the liver by a saturable enzyme system, serum concentrations are not related linearly to the daily dose and small increases in the dose may produce substantial increases in serum levels, even when the levels are in the therapeutic range, after saturation of metabolizing enzymes occur.
- Chewable Tablets:
- a) Patients who have not received previous treatment may be started on 100 milligrams (2 tablets) orally 3 times daily. The dose should be adjusted to individual patient needs. The usual maintenance dose 300 to 400 mg/day. An increase to 600 mg/day (12 tablets) may be made if necessary.
- Oral Suspension:
- a) For the suspension, the recommended dosage for the treatment of seizures in patients with no previous treatment is 1 teaspoonful or 5 milliliters (125 milligrams) 3 times daily. It is then individualized to the patient. An increase to 5 teaspoonfuls (625 milligrams) divided into 3 doses may be made.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Phenytoin in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Phenytoin in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)

### Seizure, During and following neurosurgery
- Dosing information
- The initial dose is 5 milligrams/kilogram (mg/kg) orally per day divided equally into 2 or 3 doses to a subsequent maximum of 300 mg/day. The usual maintenance dose of 4 to 8 mg/kg/day is instituted 24 hours after the loading dose. Children over the age of 6 years may require the minimum adult dose of 300 mg/day.

### Seizure, Generalized Tonic-Clonic and Complex Partial (psychomotor and temporal lobe) Seizures
- Dosing information
- IV route:
- Maintenance doses for the treatment of seizure disorders in infants and children are 4 to 7 milligrams/kilogram intravenously divided in 2 doses.
- For neonates, loading doses of 15 milligrams/kilogram (mg/kg) intravenously have been used. With maintenance doses of 2 mg/kg every 12 hours given for preterm infants and 4 to 5 mg/kg given every 12 hours for term infants. Maintenance doses start 12 hours after loading doses.
- Phenytoin metabolism increased dramatically in a newborn infant, requiring repeated serum concentration levels, several loading doses and unusually large maintenance doses to produce therapeutic serum levels above 10 micrograms/milliliter. From postnatal days 8 to 13, serum levels declined despite constant doses of 9 milligrams/kilogram/day. Maintenance doses of 25 milligrams/kilogram/day (in four divided doses) produced therapeutic levels. The authors suggest that these changes in pharmacokinetics are related to maturation of metabolism of phenytoin and concurrent administration of phenobarbital or both, and emphasize the importance of serum concentration measurements in newborn infants.
- Oral route:
- The initial recommended oral dosage of phenytoin suspension or chewable tablets or phenytoin sodium extended-release capsules is 5 milligrams/kilogram (mg/kg) per day (in 2 or 3 divided doses). Dosage should be individualized up to 300 mg daily. In infants and children, usual maintenance doses are 4 to 8 mg/kg/day, in 2 or 3 divided doses. Children over the age of 6 years may require the minimum adult dose of 300 mg/day.
- In studies based on Michaelis-Menten pharmacokinetics, children in younger age groups require larger doses/kilogram/day than older children. The average milligram/kilogram/day (mg/kg) dose required to achieve a phenytoin level of 15 micrograms/milliliter was as follows: 0.5 to 3 years of age, 9.7 mg/kg/day; 4 to 6 years of age, 7.5 mg/kg/day; 7 to 9 years of age, 7 mg/kg/day; 10 to 16 years of age, 6 mg/kg/day.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Phenytoin in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Phenytoin in pediatric patients.

# Contraindications
- Phenytoin is contraindicated in those patients with a history of hypersensitivity to phenytoin or its inactive ingredients, or other hydantoins.
- Coadministration of Dilantin is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.

# Warnings
- Effects of Abrupt Withdrawal
- Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative antiepileptic medication arises, this should be done gradually. In the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an anticonvulsant not belonging to the hydantoin chemical class.
Suicidal Behavior and Ideation
- Antiepileptic drugs (AEDs), including Dilantin Infatabs, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5100 years) in the clinical trials analyzed.
- Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing Dilantin Infatabs or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Serious Dermatologic Reactions
- Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. Dilantin should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of drug reaction with eosinophilia and systemic symptoms (DRESS syndrome/Multiorgan hypersensitivity).
- Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B*1502.
- The use of HLA-B*1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity
- Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including Dilantin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Dilantin should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Hypersensitivity
- Dilantin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS). Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to Dilantin.
- Hepatic Injury
- Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with Dilantin. These events may be part of the spectrum of DRESS or may occur in isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, Dilantin should be immediately discontinued and not readministered.
Hematopoietic System
- Hematopoietic complications, some fatal, have occasionally been reported in association with administration of Dilantin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression.
- There have been a number of reports suggesting 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. Lymph node involvement may occur with or without symptoms and signs of DRESS.
- 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.
Effects on Vitamin D and Bone
- The chronic use of phenytoin in patients with epilepsy has been associated with decreased bone mineral density (osteopenia, osteoporosis, and osteomalacia) and bone fractures. Phenytoin induces hepatic metabolizing enzymes. This may enhance the metabolism of vitamin D and decrease vitamin D levels, which may lead to vitamin D deficiency, hypocalcemia, and hypophosphatemia. Consideration should be given to screening with bone-related laboratory and radiological tests as appropriate and initiating treatment plans according to established guidelines.
Effects of Alcohol Use on Phenytoin Serum Levels
- Acute alcoholic intake may increase phenytoin serum levels while chronic alcoholic use may decrease serum levels.
Exacerbation of Porphyria
- In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease.
Usage in Pregnancy
Clinical:
- Risks to Mother. An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS, Laboratory Tests). However, postpartum restoration of the original dosage will probably be indicated.
- Risks to the Fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus.
- 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 also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two- to three-fold that in the general population. However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs.
- Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy.
- Postpartum Period. A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.
Preclinical:
- Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits.

### Precautions
- General
- The liver is the chief site of biotransformation of phenytoin; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity.
- A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined. If early signs of dose-related CNS toxicity develop, plasma levels should be checked immediately.
- Hyperglycemia, resulting from the drug's inhibitory effects on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients.
- Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated.
- Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence (petit mal) seizures are present, combined drug therapy is needed.
- Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as "delirium," "psychosis," or "encephalopathy," or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, plasma levels are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended.
Information for Patients
- Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking Dilantin. Instruct patients to take Dilantin only as prescribed.
- Patients taking phenytoin should be advised of the importance of adhering strictly to the prescribed dosage regimen, and of informing the physician of any clinical condition in which it is not possible to take the drug orally as prescribed, e.g., surgery, etc.
- Patients should be made aware of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or when occurring after extended use.
- Patients should also be cautioned on the use of other drugs or alcoholic beverages without first seeking the physician's advice.
- The importance of good dental hygiene should be stressed in order to minimize the development of gingival hyperplasia and its complications.
- Patients, their caregivers, and families should be counseled that AEDs, including Dilantin Infatabs, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334.
Laboratory Tests
- Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments. Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL).

# Adverse Reactions

## Clinical Trials Experience
Body as a Whole
- Allergic reactions in the form of rash and rarely more serious forms (see Skin and Appendages paragraph below) and DRESS (see WARNINGS) have been observed. Anaphylaxis has also been reported.
- There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities.
Nervous System
- The most common adverse reactions encountered with phenytoin therapy are nervous system reactions and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, paresthesias, and headaches have also been observed. There have also been rare reports of phenytoin-induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs.
- A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.
Digestive System
- Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia.
Skin and Appendages
- Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatiti, Stevens-Johnson syndrome, and toxic epidermal necrolysis (see WARNINGS section). There have also been reports of hypertrichosis.
Hematologic and Lymphatic System
- Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease have been reported (see WARNINGS section).
Special Senses
- Altered taste sensation including metallic taste.
Urogenital
- Peyronie's disease

## Postmarketing Experience
There is limited information regarding Phenytoin (oral) Postmarketing Experience in the drug label.

# Drug Interactions
- Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19, and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected.
- The most commonly occurring drug interactions are listed below:
- Note: The list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted.
Drugs that affect phenytoin concentrations
- Drugs that may increase phenytoin serum levels, include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, miconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2-antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), ticlopidine, tolbutamide, trazodone, and warfarin.
- Drugs that may decrease phenytoin levels, include: anticancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol abuse, diazepam, diazoxide, folic acid, fosamprenavir, nelfinavir, reserpine, rifampin, ritonavir, St. John's Wort, sucralfate theophylline, and vigabatrin.
- Administration of phenytoin with preparations that increase gastric pH (e.g., supplements or antacids containing calcium carbonate, aluminum hydroxide, and magnesium hydroxide) may affect the absorption of phenytoin. In most cases where interactions were seen, the effect is a decrease in phenytoin levels when the drugs are taken at the same time. When possible, phenytoin and these products should not be taken at the same time of day.
- Drugs that may either increase or decrease phenytoin serum levels, include: phenobarbital, sodium valproate, and valproic acid. Similarly, the effect of phenytoin on phenobarbital, valproic acid, and sodium valproate serum levels is unpredictable.
- The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome.
Drugs affected by phenytoin
- Drugs that should not be coadministered with phenytoin: Delavirdine.
- Drugs whose efficacy is impaired by phenytoin include: azoles, (fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contraceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, teniposide, theophylline, and vitamin D.
- Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin.
- Phenytoin decreases plasma concentrations of active metabolites of albendazole, certain HIV antivirals (efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), anti-epileptic agents (carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, quetiapine), atorvastatin, chlorpropamide, clozapine, cyclosporine, digoxin, fluvastatin, folic acid, methadone, mexiletine,nifedipine, nimodipine, nisoldipine, praziquantel, simvastatin and verapamil.
- Phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir.
- Resistance to the neuromuscular blocking action of the non-depolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium, and cisatracurium has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
- The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome.
Drug Enteral Feeding/Nutritional Preparations Interaction
- Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin plasma levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin level monitoring may be necessary in these patients.
Drug/Laboratory Test Interactions
- Phenytoin may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT).
- Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
- To provide information regarding the effects of in utero exposure to Dilantin Infatabs, physicians are advised to recommend that pregnant patients taking Dilantin Infatabs enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website /.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Phenytoin (oral) in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Phenytoin (oral) during labor and delivery.

### Nursing Mothers
- Infant breast-feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk.

### Pediatric Use
There is no FDA guidance on the use of Phenytoin (oral) with respect to pediatric patients.

### Geriatic Use
- Phenytoin clearance tends to decrease with increasing age.

### Gender
There is no FDA guidance on the use of Phenytoin (oral) with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Phenytoin (oral) with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Phenytoin (oral) in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Phenytoin (oral) in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Phenytoin (oral) in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Phenytoin (oral) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
When given in equal doses, Dilantin Infatabs yield higher plasma levels than Dilantin Kapseals. For this reason serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form.
Dilantin Kapseals is formulated with the sodium salt of phenytoin. The free acid form of phenytoin is used in Dilantin-125 Suspension and Dilantin Infatabs. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa.
General
Not for once-a-day dosing.
Dosage should be individualized to provide maximum benefit. In some cases, serum blood level determinations may be necessary for optimal dosage adjustmentsthe clinically effective serum level is usually 1020 mcg/mL. With recommended dosage, a period of seven to ten days may be required to achieve steady-state blood levels with phenytoin and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days.
Dilantin Infatabs can be either chewed thoroughly before being swallowed or swallowed whole.
Adult Dosage
Patients who have received no previous treatment may be started on two Infatabs three times daily, and the dose is then adjusted to suit individual requirements. For most adults, the satisfactory maintenance dosage will be six to eight Infatabs daily; an increase to twelve Infatabs daily may be made, if necessary.
Dosing in Special Populations
Patients with Renal or Hepatic Disease
Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution. Unbound phenytoin concentrations may be more useful in these patient populations.
Elderly Patients
Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required.
Pediatric
Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years old and adolescents may require the minimum adult dose (300 mg/day). If the daily dosage cannot be divided equally, the larger dose should be given before retiring.

### Monitoring
There is limited information regarding Monitoring of Phenytoin (oral) in the drug label.
- Description

# IV Compatibility
There is limited information regarding IV Compatibility of Phenytoin (oral) in the drug label.

# Overdosage
- The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression.
- There are marked variations among individuals with respect to phenytoin plasma levels where toxicity may occur. Nystagmus on lateral gaze usually appears at 20 mcg/mL, ataxia at 30 mcg/mL, dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery.
- Treatment:
- Treatment is nonspecific since there is no known antidote.
- The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients.
- In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.

# Pharmacology

## Mechanism of Action
Phenytoin is an antiepileptic drug which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. *Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures.

## Structure
- Dilantin is an antiepileptic drug.
- Dilantin (phenytoin) is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is 5,5-diphenyl-2,4-imidazolidinedione, having the following structural formula:
- Each Dilantin Infatab, for oral administration, contains 50 mg phenytoin, USP. Also contains: D&C yellow No. 10, Al lake; FD&C yellow No. 6, Al lake; flavor; saccharin sodium, USP; confectioner's sugar, NF; talc, USP; magnesium stearate, NF; and purified water, USP.

## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Phenytoin (oral) in the drug label.

## Pharmacokinetics
- Clinical studies using Dilantin Infatabs have shown an average plasma half-life of 14 hours with a range of 7 to 29 hours. Steady-state therapeutic levels are achieved at least 7 to 10 days (57 half-lives) after initiation of therapy with recommended doses of 300 mg/day.
- When serum level determinations are necessary, they should be obtained at least 57 half-lives after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady-state will have been achieved. Trough levels provide information about clinically effective serum level range and confirm patient compliance and are obtained just prior to the patient's next scheduled dose. Peak levels indicate an individual's threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. For Dilantin Infatabs, peak levels occur 112 3 hours after administration.
- Optimum control without clinical signs of toxicity occurs more often with serum levels between 10 and 20 mcg/mL, although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin.
- In most patients maintained at a steady dosage, stable phenytoin serum levels are achieved.
- There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, variant CYP2C9 and CYP2C19 alleles, or drug interactions which result in metabolic interference. The patient with large variations in phenytoin plasma levels, despite standard doses, presents a difficult clinical problem. Serum level determinations in such patients may be particularly helpful. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal.
- Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable at high plasma levels, small incremental doses may increase the half-life and produce very substantial increases in serum levels, when these are in the upper range. The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more.
- Clinical studies show that chewed and unchewed Dilantin Infatabs are bioequivalent, yield approximately equivalent plasma levels, and are more rapidly absorbed than 100-mg Dilantin Kapseals.
Special Populations:
Patients with Renal or Hepatic Disease:
- Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see DOSAGE AND ADMINISTRATION). Unbound phenytoin concentrations may be more useful in these patient populations.
Age:
- Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 2030 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see DOSAGE AND ADMINISTRATION).
Gender and Race:
- Gender and race have no significant impact on phenytoin pharmacokinetics.
Pediatrics:
- Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dose (300 mg/day).

## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Phenytoin (oral) in the drug label.

# Clinical Studies
There is limited information regarding Clinical Studies of Phenytoin (oral) in the drug label.

# How Supplied
- Dilantin Infatabs are supplied as:
- N 0071-0007-24Bottle of 100.
- N 0071-0007-40Unit dose (10/10's).
- Each tablet contains 50 mg phenytoin in a yellow triangular scored chewable tablet.

## Storage
- Store at room temperature between 68F to 77F (20C to 25C).
- Protect from moisture.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking Dilantin. Instruct patients to take Dilantin only as prescribed.
- Patients taking phenytoin should be advised of the importance of adhering strictly to the prescribed dosage regimen, and of informing the physician of any clinical condition in which it is not possible to take the drug orally as prescribed, e.g., surgery, etc.
- Patients should be made aware of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or when occurring after extended use.
- Patients should also be cautioned on the use of other drugs or alcoholic beverages without first seeking the physician's advice.
- The importance of good dental hygiene should be stressed in order to minimize the development of gingival hyperplasia and its complications.
- Patients, their caregivers, and families should be counseled that AEDs, including Dilantin Infatabs, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS: Pregnancy section).
Laboratory Tests
- Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments. Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL).

# Precautions with Alcohol
- Alcohol-Phenytoin (oral) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
Dilantin,
Dilantin Infatabs,
Dilantin-125.

# Look-Alike Drug Names
- A  B

# Drug Shortage Status

# Price