Phenytoin by Mylan Institutional Inc. / Mylan Pharmaceuticals Inc.

NOT FOR ONCE-A-DAY DOSING

DESCRIPTION

Phenytoin is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is 5,5-Diphenylhydantoin, having the following structural formula:

Each phenytoin chewable tablet, USP for oral administration, contains 50 mg of phenytoin, USP. Also contains: colloidal silicon dioxide, compressible sugar, corn starch, D&C Red No. 30 Aluminum Lake, magnesium stearate, peppermint flavor and talc.

CLINICAL 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.

Pharmacokinetics and Drug Metabolism

Clinical studies using phenytoin chewable tablets 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 (5 to 7 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 5 to 7 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 phenytoin chewable tablets, peak levels occur 1.5 to 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 phenytoin chewable tablets 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 20 to 30 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).

INDICATIONS AND USAGE

Phenytoin chewable tablets are indicated for the control of generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery. Phenytoin serum level determinations may be necessary for optimal dosage adjustments (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY sections).

CONTRAINDICATIONS

Phenytoin chewable tablets are contraindicated in those patients with a history of hypersensitivity to phenytoin or its inactive ingredients, or other hydantoins.

Coadministration of phenytoin 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 phenytoin chewable tablets, 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 1 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 (5 to 100 years) in the clinical trials analyzed.

Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication	Placebo Patients with Events Per 1,000 Patients	Drug Patients with Events Per 1,000 Patients	Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients	Risk Difference: Additional Drug Patients with Events Per 1,000 Patients
Epilepsy	1	3.4	3.5	2.4
Psychiatric	5.7	8.5	1.5	2.9
Other	1	1.8	1.9	0.9
Total	2.4	4.3	1.8	1.9

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 phenytoin chewable tablets 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. Phenytoin 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 (see DRESS/Multiorgan Hypersensitivity below).

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 phenytoin. 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. Phenytoin should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Hypersensitivity

Phenytoin 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 phenytoin.

Hepatic Injury

Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. 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, phenytoin should be immediately discontinued and not readministered.

Hematopoietic 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.

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 2- to 3-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.

Nonclinical

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.

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. (See WARNINGS section.)

Information for Patients

Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking phenytoin. Instruct patients to take phenytoin 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 phenytoin chewable tablets, 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).

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, H 2-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 (see CONTRAINDICATIONS).
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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

See WARNINGS (Hematopoietic System) section.

In carcinogenicity studies, phenytoin was administered in the diet to mice (10, 25, or 45 mg/kg/day) and rats (25, 50, or 100 mg/kg/day) for 2 years. The incidences of hepatocellular tumors were increased in male and female mice at the highest dose. No increases in tumor incidence were observed in rats. The highest doses tested in these studies were associated with peak plasma phenytoin levels below human therapeutic concentrations.

In carcinogenicity studies reported in the literature, phenytoin was administered in the diet for 2 years at doses up to 600 ppm (approximately 90 mg/kg/day) to mice and up to 2400 ppm (approximately 120 mg/kg/day) to rats. The incidences of hepatocellular tumors were increased in female mice at all but the lowest dose tested. No increases in tumor incidence were observed in rats.

Mutagenesis

Phenytoin was negative in the Ames test and in the in vitro clastogenicity assay in Chinese hamster ovary(CHO) cells.

In studies reported in the literature, phenytoin was negative in the in vitro mouse lymphoma assay and the in vivo micronucleus assay in mouse. Phenytoin was clastogenic in the in vitro sister chromatid exchange assay in CHO cells.

Fertility

Phenytoin has not been adequately assessed for effects on male or female fertility.

Pregnancy

Teratogenic Effects. Pregnancy Category D

See WARNINGS section.

To provide information regarding the effects of in utero exposure to phenytoin chewable tablets, physicians are advised to recommend that pregnant patients taking phenytoin chewable tablets enroll in the North American Antiepileptic Drug (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 http://www.aedpregnancyregistry.org/.

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

See DOSAGE AND ADMINISTRATION section.

Geriatric Use

Phenytoin clearance tends to decrease with increasing age (see CLINICAL PHARMACOLOGY: Special Populations).

ADVERSE REACTIONS

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 dermatitis, 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

OVERDOSAGE

The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 g to 5 g. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, nausea and 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.

DOSAGE AND ADMINISTRATION

When given in equal doses, phenytoin chewable tablets 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 ® Suspensions* and phenytoin chewable tablets. 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 adjustments - the clinically effective serum level is usually 10 to 20 mcg/mL. With recommended dosage, a period of 7 to 10 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 7 to 10 days.

Phenytoin chewable tablets 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 phenytoin chewable tablets 3 times daily, and the dose is then adjusted to suit individual requirements. For most adults, the satisfactory maintenance dosage will be six to eight phenytoin chewable tablets daily; an increase to twelve phenytoin chewable tablets 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.

HOW SUPPLIED:

Phenytoin Chewable Tablets, USP are available containing 50 mg of phenytoin, USP.

The 50 mg tablets are pink, round, scored tablets debossed with M above the score and P50 below the score on one side of the tablet and blank on the other side. The tablets are peppermint flavored. They are available as follows:

NDC: 51079-129-06 – Unit dose blister packages of 50 (5 cards of 10 tablets each).

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
Protect from moisture.

PHARMACIST: Dispense a Medication Guide with each prescription.

MEDICATION GUIDE

PHENYTOIN CHEWABLE TABLETS, USP

(fen′ i toyn)

50 mg

Read this Medication Guide before you start taking phenytoin chewable tablets and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about phenytoin chewable tablets, ask your healthcare provider or pharmacist.

What is the most important information I should know about phenytoin chewable tablets?

Do not stop taking phenytoin chewable tablets without first talking to your healthcare provider.

Stopping phenytoin chewable tablets suddenly can cause serious problems.

Phenytoin chewable tablets can cause serious side effects including:

Like other antiepileptic drugs, phenytoin chewable tablets may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

thoughts about suicide or dying
attempts to commit suicide
new or worse depression
new or worse anxiety
feeling agitated or restless
panic attacks
trouble sleeping (insomnia)
new or worse irritability
acting aggressive, being angry, or violent
acting on dangerous impulses
an extreme increase activity and talking (mania)
other unusual changes in behavior or mood

How can I watch for early symptoms of suicidal thoughts and actions?

Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Do not stop taking phenytoin chewable tablets without first talking to a healthcare provider.

Stopping phenytoin chewable tablets suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

Phenytoin chewable tablets may harm your unborn baby.
If you take phenytoin chewable tablets during pregnancy, your baby is at risk for serious birth defects.
Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors.
If you take phenytoin chewable tablets during pregnancy, your baby is also at risk for bleeding problems right after birth. Your healthcare provider may give you and your baby medicine to prevent this.
All women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of phenytoin chewable tablets. If the decision is made to use phenytoin chewable tablets, you should use effective birth control (contraception) unless you are planning to become pregnant.
Tell your healthcare provider right away if you become pregnant while taking phenytoin chewable tablets. You and your healthcare provider should decide if you will take phenytoin chewable tablets while you are pregnant.
Pregnancy Registry: If you become pregnant while taking phenytoin chewable tablets, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
Swollen glands (lymph nodes)
Allergic reactions or serious problems which may affect organs and other parts of your body like the liver or blood cells. You may or may not have a rash with these types of reactions. Symptoms can include any of the following:
swelling of your face, eyes, lips, or tongue
trouble swallowing or breathing
a skin rash
hives
fever, swollen glands (lymph nodes), or sore throat that do not go away or come and go
painful sores in the mouth or around your eyes
yellowing of your skin or eyes
bruising or bleeding
severe fatigue or weakness
severe muscle pain
frequent infections or an infection that does not go away
loss of appetite (anorexia)
nausea or vomiting

Call your healthcare provider right away if you have any of the symptoms listed above.

What are phenytoin chewable tablets?

Phenytoin chewable tablets are a prescription medicine used to treat tonic-clonic (grand mal), complex partial (psychomotor or temporal lobe) seizures, and to prevent and treat seizures that happen during or after brain surgery.

Who should not take phenytoin chewable tablets?

Do not take phenytoin chewable tablets if you:

are allergic to phenytoin or any of the ingredients in phenytoin chewable tablets. See the end of this leaflet for a complete list of ingredients in phenytoin chewable tablets.
have had an allergic reaction to CEREBYX ®* (fosphenytoin), PEGANONE ®* (ethotoin), or MESANTOIN ®* (mephenytoin).
take delavirdine.

What should I tell my healthcare provider before taking phenytoin chewable tablets?

Before you take phenytoin chewable tablets, tell your healthcare provider if you:

have or had liver disease
have or had porphyria
have or had diabetes
have or have had depression, mood problems, or suicidal thoughts or behavior
are pregnant or plan to become pregnant. If you become pregnant while taking phenytoin chewable tablets, the level of phenytoin in your blood may decrease, causing your seizures to become worse. Your healthcare provider may change your dose of phenytoin chewable tablets.
are breast-feeding or plan to breast-feed. Phenytoin can pass into breast milk. You and your healthcare provider should decide if you will take phenytoin chewable tablets or breast-feed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Taking phenytoin chewable tablets with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take phenytoin chewable tablets?

Take phenytoin chewable tablets exactly as prescribed. Your healthcare provider will tell you how many phenytoin chewable tablets to take.
Your healthcare provider may change your dose. Do not change your dose of phenytoin chewable tablets without talking to your healthcare provider.
Phenytoin can cause overgrowth of your gums. Brushing and flossing your teeth and seeing a dentist regularly while taking phenytoin chewable tablets can help prevent this.
If you take too many phenytoin chewable tablets, call your healthcare provider or local Poison Control Center right away.
Do not stop taking phenytoin chewable tablets without first talking to your healthcare provider. Stopping phenytoin chewable tablets suddenly can cause serious problems.

What should I avoid while taking phenytoin chewable tablets?

Do not drink alcohol while you take phenytoin chewable tablets without first talking to your healthcare provider. Drinking alcohol while taking phenytoin chewable tablets may change your blood levels of phenytoin which can cause serious problems.

Do not drive, operate heavy machinery, or do other dangerous activities until you know how phenytoin chewable tablets affect you. Phenytoin chewable tablets can slow your thinking and motor skills.

What are the possible side effects of phenytoin chewable tablets?

See “ What is the most important information I should know about phenytoin chewable tablets?”.

Phenytoin chewable tablets may cause other serious side effects including:

Softening of your bones (osteopenia, osteoporosis, and osteomalacia). This can cause broken bones.

Call your healthcare provider right away, if you have any of the symptoms listed above.

The most common side effects of phenytoin chewable tablets include:

problems with walking and coordination
slurred speech
confusion
dizziness
trouble sleeping
nervousness
tremor
headache
nausea
vomiting
constipation
rash

These are not all the possible side effects of phenytoin chewable tablets. For more information, ask your healthcare provider or pharmacist.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store phenytoin chewable tablets?

Store phenytoin chewable tablets at room temperature between 20° to 25°C (68° to 77°F). Protect from moisture.

Keep phenytoin chewable tablets and all medicines out of the reach of children.

General information about phenytoin chewable tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use phenytoin chewable tablets for a condition for which it was not prescribed. Do not give phenytoin chewable tablets to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about phenytoin chewable tablets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about phenytoin chewable tablets that was written for healthcare professionals.

For more information about phenytoin chewable tablets, call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

What are the ingredients in phenytoin chewable tablets?

The 50 mg tablets are pink, round, scored tablets debossed with M above the score and P50 below the score on one side of the tablet and blank on the other side.

Active ingredient: 50 mg phenytoin, USP

Inactive ingredients: colloidal silicon dioxide, compressible sugar, corn starch, D&C Red No. 30 Aluminum Lake, magnesium stearate, peppermint flavor and talc.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

*The brands listed are trademarks of their respective owners.

Manufactured by:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Distributed by:
Mylan Institutional Inc.
Rockford, IL 61103 U.S.A.

S-11355 R2
8/16

PRINCIPAL DISPLAY PANEL - 50 mg

NDC: 51079-129-06

Phenytoin
Chewable
Tablets, USP
50 mg

50 Tablets (5 x 10)

Each tablet contains:
Phenytoin, USP 50 mg

Dosage and Use: Pediatric patients, 5 mg/kg
daily in two or three equally divided doses
initially, with subsequent dosage individualized
to a maximum of 300 mg daily. See Medication
Guide and package insert for full prescribing
information.

NOT FOR ONCE-A-DAY DOSING

Chewable, flavored for pediatric patients.
Phenytoin chewable tablets can be either chewed
thoroughly before being swallowed or swallowed
whole. Store so that pediatric patients cannot
eat these flavored tablets as candy.

Store at 20° to 25°C (68° to 77°F). [See
USP Controlled Room Temperature.]
Protect from moisture.

Manufactured by:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Rx only

S-11354 R2

Distributed by:

Mylan Institutional Inc.

Rockford, IL 61103 U.S.A.

This unit dose package is not child resistant.

For institutional use only.

Keep this and all drugs out of the reach of children.

This container provides light-resistance.

See window for lot number and expiration date.