Phenytek

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Withdrawal Precipitated Seizure, Status Epilepticus [see Warnings and Precautions (5.1) ] • Suicidal Behavior and Ideation [see Warnings and Precautions (5.2) ] • Serious Dermatologic Reactions [see Warnings and Precautions (5.3) ] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.4) ] • Hypersensitivity [see Warnings and Precautions (5.5) ] • Cardiac Effects [see Warnings and Precautions (5.6) ] • Angioedema [see Warnings and Precautions (5.7) ] • Hepatic Injury [see Warnings and Precautions (5.8) ] • Hematopoietic Complications [see Warnings and Precautions (5.9) ] • Effects on Vitamin D and Bone [see Warnings and Precautions (5.10) ] • Exacerbation of Porphyria [see Warnings and Precautions (5.12) ] • Teratogenicity and Other Harm to the Newborn [see Warnings and Precautions (5.13) ] • Hyperglycemia [see Warnings and Precautions (5.14) ] The following adverse reactions associated with the use of PHENYTEK ® capsules were identified in clinical studies or postmarketing reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Allergic reactions in the form of rash and rarely more serious forms and DRESS have been observed, as has angioedema [see Warnings and Precautions (5.3 , 5.4 , 5.7 )] . Anaphylaxis has also been reported. There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities. Digestive System: Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia. 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 and Precautions (5.9) ] . Laboratory Test Abnormality: Phenytoin may decrease serum concentrations of thyroid hormone (T4 and T3), sometimes with an accompanying increase in thyroid-stimulating hormone (TSH), but usually in the absence of clinical hypothyroidism. Phenytoin may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose [see Warnings and Precautions (5.14) ] , alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). 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. Cerebellar atrophy has been reported, and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use [see Warnings and Precautions (5.15) ] . A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy. 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, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis [see Warnings and Precautions (5.3) ] . There have also been reports of hypertrichosis and urticaria. Special Senses: Altered taste sensation including metallic taste. Urogenital: Peyronie’s disease The most common adverse reactions are nervous system reactions, including nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

4 CONTRAINDICATIONS PHENYTEK ® capsules are contraindicated in patients with: • A history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins [see Warnings and Precautions (5.5) ] . Reactions have included angioedema. • A history of prior acute hepatotoxicity attributable to phenytoin [see Warnings and Precautions (5.8) ] . • Coadministration with delavirdine because of the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors. • Hypersensitivity to phenytoin, its ingredients, or other hydantoins ( 4 , 5.5 ) • A history of prior acute hepatotoxicity attributable to phenytoin ( 4 , 5.8 ) • Coadministration with delavirdine ( 4 )

11 DESCRIPTION Phenytoin sodium is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is 5,5-Diphenylhydantoin sodium salt, having the following structural formula: Each 200 mg or 300 mg PHENYTEK ® capsule (extended phenytoin sodium capsule, USP) for oral administration contains 200 mg or 300 mg phenytoin sodium, USP. Also contains colloidal silicon dioxide, FD&C Blue No. 1, gelatin, hydroxyethyl cellulose, magnesium oxide, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate and titanium dioxide. In addition, the imprinting ink contains black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze. Product in vivo performance is characterized by a slow and extended rate of absorption with peak blood concentrations expected in 4 to 12 hours as contrasted to prompt phenytoin sodium capsules with a rapid rate of absorption with peak blood concentration expected in 1½ to 3 hours. Meets USP Dissolution Test 3. Phenytoin Structural Formula

2 DOSAGE AND ADMINISTRATION • Adult starting dose in patients who have received no previous treatment is one 100 mg extended phenytoin sodium capsule three times a day, with dose adjustments as necessary. For most adults, the satisfactory maintenance dose will be one capsule three to four times a day. An increase, up to two capsules three times a day may be made, if necessary. ( 2.1 ) • Adult once-a-day dose: If seizure control is established with divided doses of three 100 mg extended phenytoin sodium capsules daily, once-a-day dosage with 300 mg PHENYTEK ® capsules may be considered. ( 2.1 ) • Adult loading dose: reserved for patients in a clinic or hospital setting who require rapid steady-state serum levels and where intravenous administration is not desired. Refer to full prescribing information. ( 2.1 ) • Pediatric starting dose is 5 mg/kg/day in two to three equally divided doses, with dosage adjustments as necessary, up to a maximum of 300 mg daily. Maintenance dosage is 4 to 8 mg/kg/day. ( 2.2 ) • Serum blood level determinations may be necessary for optimal dosage adjustments—the clinically effective serum total concentration is 10 to 20 mcg/mL (unbound phenytoin concentration is 1 to 2 mcg/mL). ( 2.3 ) 2.1 Adult Dosage Divided Daily Dosage The recommended starting dose for adult patients who have received no previous treatment is one 100-mg extended phenytoin sodium capsule by mouth three times daily. Adjust the dosage to suit individual requirements up to a maximum of two capsules three times a day. For most adults, the satisfactory maintenance dosage will be one capsule three to four times a day. Once-a-Day Dosage In adults, if seizure control is established with divided doses of three 100-mg extended phenytoin sodium capsules daily, once-a-day dosage with 300 mg of PHENYTEK ® capsules may be considered. Studies comparing divided doses of 300 mg with a single daily dose of this quantity indicated absorption, peak serum levels, biologic half-life, difference between peak and minimum values, and urinary recovery were equivalent. Once-a-day dosage offers a convenience to the individual patient or to nursing personnel for institutionalized patients and is intended to be used only for patients requiring this amount of drug daily. A major problem in motivating noncompliant patients may also be lessened when the patient can take this drug once a day. However, patients should be cautioned not to miss a dose, inadvertently. Only PHENYTEK ® capsules are recommended for once-a-day dosing. Inherent differences in dissolution characteristics and resultant absorption rates of phenytoin due to different manufacturing procedures and/or dosage forms preclude such recommendation for other phenytoin products. When a change in the dosage form or brand is prescribed, careful monitoring of phenytoin serum levels should be carried out. Loading Dose Some authorities have advocated use of an oral loading dose of phenytoin in adults who require rapid steady-state serum levels and where intravenous administration is not desirable. This dosing regimen should be reserved for patients in a clinic or hospital setting where phenytoin serum levels can be closely monitored. Patients with a history of renal or liver disease should not receive the oral loading regimen. Initially, one gram of PHENYTEK ® capsules is divided into three doses (400 mg, 300 mg, 300 mg) and administered at two-hour intervals. Normal maintenance dosage is then instituted 24 hours after the loading dose, with frequent serum level determinations. 2.2 Pediatric Dosage The recommended starting dosage for pediatric patients is 5 mg/kg/day by mouth in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily in divided doses. A recommended daily maintenance dosage is usually 4 to 8 mg/kg/day in equally divided doses. Children over 6 years and adolescents may require the minimum adult dosage (300 mg/day). 2.3 Dosage Adjustments Dosage should be individualized to provide maximum benefit. In some cases, serum blood level determinations may be necessary for optimal dosage adjustments. 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. Therapeutic effect without clinical signs of toxicity occurs more often with serum total concentrations between 10 and 20 mcg/mL (unbound phenytoin concentrations between 1 and 2 mcg/mL), although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin. In patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of unbound phenytoin concentrations may be more relevant [see Dosage and Administration (2.5) ] . 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. 2.4 Switching Between Phenytoin Formulations The free acid form of phenytoin is used in DILANTIN-125 ® Suspension and DILANTIN ® Infatabs ® . PHENYTEK ® capsules and parenteral phenytoin are formulated with the sodium salt of phenytoin. 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. 2.5 Dosing in Patients with Renal or Hepatic Impairment or Hypoalbuminemia Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients [see Warnings and Precautions (5.11) and Use in Specific Populations (8.6) ] . 2.6 Geriatric Dosage Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required [see Clinical Pharmacology (12.3) ] . 2.7 Dosing during Pregnancy Decreased serum concentrations of phenytoin may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations should be performed during pregnancy, and the phenytoin sodium dosage should be adjusted as necessary. Postpartum restoration of the original dosage will probably be indicated [see Use in Specific Populations (8.1) ] .Because of potential changes in protein binding during pregnancy, the monitoring of phenytoin serum levels should be based on the unbound fraction.

1 INDICATIONS AND USAGE PHENYTEK ® capsules (extended phenytoin sodium capsules) are indicated for the treatment of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery. PHENYTEK ® CAPSULES are indicated for the treatment of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery. ( 1 )

10 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, blurred vision, nausea, and vomiting. The patient may become comatose and hypotensive. Bradycardia and cardiac arrest have been reported [see Warnings and Precautions (5.6) ] . Death is caused by respiratory and circulatory depression. There are marked variations among individuals with respect to phenytoin serum 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 serum 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. Irreversible cerebellar dysfunction and atrophy have been reported. 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.

7 DRUG INTERACTIONS Phenytoin is extensively bound to plasma proteins and is prone to competitive displacement. Phenytoin is primarily metabolized by the hepatic cytochrome P450 enzyme CYP2C9 and to a lesser extent by 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. Monitoring of phenytoin serum levels is recommended when a drug interaction is suspected. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes. Multiple drug interactions because of extensive plasma protein binding, saturable metabolism and potent induction of hepatic enzymes. ( 7.1 , 7.2 ) 7.1 Drugs that Affect Phenytoin Concentrations Table 2 includes commonly occurring drug interactions that affect phenytoin concentrations. However, this list is not intended to be inclusive or comprehensive. Individual prescribing information from relevant drugs should be consulted. 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. Table 2: Drugs That Affect Phenytoin Concentrations Interacting Agent Examples Drugs that may increase phenytoin serum levels Antiepileptic drugs Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate Azoles Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole Antineoplastic agents Capecitabine, fluorouracil Antidepressants Fluoxetine, fluvoxamine, sertraline Gastric acid reducing agents H 2 antagonists (cimetidine), omeprazole Sulfonamides Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim Other Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin Drugs that may decrease phenytoin serum levels Antacids Antacids may affect absorption of phenytoin. Calcium carbonate, aluminum hydroxide, magnesium hydroxide Prevention or Management: Phenytoin and antacids should not be taken at the same time of day Antineoplastic agents usually in combination Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate Antiviral agents Fosamprenavir, nelfinavir, ritonavir Antiepileptic drugs Carbamazepine, vigabatrin Other Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John’s wort The induction potency of St. John’s wort may vary widely based on preparation. , sucralfate, theophylline Drugs that may either increase or decrease phenytoin serum levels Antiepileptic drugs Phenobarbital, valproate sodium, valproic acid 7.2 Drugs Affected by Phenytoin Table 3 includes commonly occurring drug interactions affected by phenytoin. However, this list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. 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. Table 3: Drugs Affected by Phenytoin Interacting Agent Examples Drugs whose efficacy is impaired by phenytoin Azoles Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole Antineoplastic agents Irinotecan, paclitaxel, teniposide Delavirdine Phenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance [see Contraindications (4) ] . Neuromuscular blocking agents Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Prevention or Management: Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher. Warfarin Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin Other Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D Drugs whose level is decreased by phenytoin Antiepileptic drugs The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine Antilipidemic agents Atorvastatin, fluvastatin, simvastatin Antiviral agents Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: 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 Calcium channel blockers Nifedipine, nimodipine, nisoldipine, verapamil Other Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine 7.3 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 serum 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. 7.4 Drug/Laboratory Test Interactions Care should be taken when using immunoanalytical methods to measure serum phenytoin concentrations.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The precise mechanism by which phenytoin exerts its therapeutic effect has not been established but is thought to involve the voltage-dependent blockade of membrane sodium channels resulting in a reduction in sustained high-frequency neuronal discharges. 12.3 Pharmacokinetics Absorption For PHENYTEK ® capsules, peak serum levels occur 4 to 12 hours after administration. Steady-state therapeutic levels are achieved at least 7 to 10 days (5-7 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 5-7 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. Distribution Phenytoin is extensively bound to serum plasma proteins. Elimination The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 hours. Metabolism Phenytoin is primarily metabolized by the hepatic cytochrome P450 enzyme CYP2C9 and to a lesser extent by CYP2C19. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable at high serum 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. 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 serum 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. Excretion 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. Specific Populations Age: Geriatric Population 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). Since phenytoin clearance is decreased slightly in elderly patients, lower or less frequent dosing may be required [see Dosage and Administration (2.6) ] . Sex/Race Gender and race have no significant impact on phenytoin pharmacokinetics. Renal or Hepatic Impairment Increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia has been reported. Pregnancy It has been reported in the literature that the plasma clearance of phenytoin generally increased during pregnancy, reached a peak in the third trimester and returned to the level of pre-pregnancy after few weeks or months of delivery. Drug Interaction Studies Phenytoin is primarily metabolized by the hepatic cytochrome P450 enzyme CYP2C9 and to a lesser extent by CYP2C19. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes [see Drug Interactions (7.1, 7.2)] . 12.5 Pharmacogenomics CYP2C9 activity is decreased in individuals with genetic variants such as the CYP2C9*2 and CYP2C9*3 alleles. Carriers of variant alleles, resulting in intermediate (e.g., *1/*3, *2/*2) or poor metabolism (e.g., *2/*3, *3/*3) have decreased clearance of phenytoin. Other decreased or nonfunctional CYP2C9 alleles may also result in decreased clearance of phenytoin (e.g., *5, *6, *8, *11). The prevalence of the CYP2C9 poor metabolizer phenotype is approximately 2-3% in the White population, 0.5-4% in the Asian population, and < 1% in the African American population. The CYP2C9 intermediate phenotype prevalence is approximately 35% in the White population, 24% in the African American population, and 15-36% in the Asian population [see Warnings and Precautions (5.3) and Use in Specific Populations (8.7) ] .

12.1 Mechanism of Action The precise mechanism by which phenytoin exerts its therapeutic effect has not been established but is thought to involve the voltage-dependent blockade of membrane sodium channels resulting in a reduction in sustained high-frequency neuronal discharges.

12.3 Pharmacokinetics Absorption For PHENYTEK ® capsules, peak serum levels occur 4 to 12 hours after administration. Steady-state therapeutic levels are achieved at least 7 to 10 days (5-7 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 5-7 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. Distribution Phenytoin is extensively bound to serum plasma proteins. Elimination The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 hours. Metabolism Phenytoin is primarily metabolized by the hepatic cytochrome P450 enzyme CYP2C9 and to a lesser extent by CYP2C19. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable at high serum 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. 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 serum 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. Excretion 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. Specific Populations Age: Geriatric Population 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). Since phenytoin clearance is decreased slightly in elderly patients, lower or less frequent dosing may be required [see Dosage and Administration (2.6) ] . Sex/Race Gender and race have no significant impact on phenytoin pharmacokinetics. Renal or Hepatic Impairment Increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia has been reported. Pregnancy It has been reported in the literature that the plasma clearance of phenytoin generally increased during pregnancy, reached a peak in the third trimester and returned to the level of pre-pregnancy after few weeks or months of delivery. Drug Interaction Studies Phenytoin is primarily metabolized by the hepatic cytochrome P450 enzyme CYP2C9 and to a lesser extent by CYP2C19. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes [see Drug Interactions (7.1, 7.2)] .

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3 DOSAGE FORMS AND STRENGTHS PHENYTEK ® CAPSULES (extended phenytoin sodium capsules, USP) are available containing 200 mg or 300 mg of phenytoin sodium, USP. • The 200 mg capsules have a dark blue opaque cap and a blue opaque body. The hard-shell gelatin capsules are filled with two white to off-white round tablets. The capsules are rectified radial printed with BERTEK over 670 in black ink on both the cap and the body. • The 300 mg capsules have a blue opaque cap and a blue opaque body. The hard-shell gelatin capsules are filled with three white to off-white round tablets. The capsules are rectified radial printed with BERTEK over 750 in black ink on both the cap and the body. PHENYTEK ® capsules are available as 200 mg or 300 mg extended phenytoin sodium capsules. ( 3 )

Phenytek extended phenytoin sodium PHENYTOIN SODIUM PHENYTOIN FERROSOFERRIC OXIDE SILICON DIOXIDE D&C YELLOW NO. 10 FD&C BLUE NO. 1 FD&C BLUE NO. 2 FD&C RED NO. 40 GELATIN, UNSPECIFIED MAGNESIUM OXIDE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE POVIDONE, UNSPECIFIED PROPYLENE GLYCOL SODIUM LAURYL SULFATE TITANIUM DIOXIDE HYDROXYETHYL CELLULOSE (2000 MPA.S AT 1%) SHELLAC dark blue opaque blue opaque BERTEK;670 Phenytek phenytoin sodium PHENYTOIN SODIUM PHENYTOIN FERROSOFERRIC OXIDE SILICON DIOXIDE D&C YELLOW NO. 10 FD&C BLUE NO. 1 FD&C BLUE NO. 2 FD&C RED NO. 40 GELATIN, UNSPECIFIED MAGNESIUM OXIDE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE POVIDONE, UNSPECIFIED PROPYLENE GLYCOL SODIUM LAURYL SULFATE TITANIUM DIOXIDE HYDROXYETHYL CELLULOSE (2000 MPA.S AT 1%) SHELLAC blue opaque BERTEK;750

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis [see Warnings and Precautions (5.9) ] 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 serum 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 160 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.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis [see Warnings and Precautions (5.9) ] 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 serum 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 160 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.

ANDA040298

Phenytek

extended phenytoin sodium

0378-2670

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL – 200 mg NDC 0378-2670-93 PHENYTEK ® (extended phenytoin sodium capsules, USP) 200 mg PHARMACIST: Dispense the accompanying Medication Guide to each patient. Rx only 30 Capsules Each capsule contains: Phenytoin sodium, USP 200 mg Pediatric Dosage: Initially, 5 mg/kg daily in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. See package insert for complete prescribing information. Keep this and all medication out of the reach of children. Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light and moisture. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Made in India Mylan.com RMX2670H Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Keep container tightly closed. Code No.: MH/DRUGS/25/NKD/89 Phenytek (extended phenytoin sodium capsules, USP) 200 mg Bottle Label

Warnings and Precautions ( 5.3 ) 2/2021

17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling ( Medication Guide ). Administration Information: Advise patients taking phenytoin 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. Advise patients not to use capsules which are discolored. Withdrawal of Antiepileptic Drugs: Advise patients not to discontinue use of PHENYTEK ® capsules without consulting with their healthcare provider. PHENYTEK ® capsules should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus [see Warnings and Precautions (5.1) ] . Suicidal Ideation and Behavior: Counsel patients, their caregivers, and families that AEDs, including PHENYTEK ® capsules, may increase the risk of suicidal thoughts and behavior and advise them 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 [see Warnings and Precautions (5.2) ] . Serious Dermatologic Reactions: Advise patients of the early signs and symptoms of severe cutaneous adverse reactions and to report any occurrence immediately to a physician [see Warnings and Precautions (5.3) ] . Potential Signs of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Other Systemic Reactions: Advise patients 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, facial swelling, and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. Advise the patient that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, advise the patient that these signs and symptoms should be reported even if mild or when occurring after extended use [see Warnings and Precautions (5.3 , 5.4 , 5.5 , 5.8 , 5.9 ) ] . Cardiac Effects: Counsel patients that cases of bradycardia and cardiac arrest have been reported, both at recommended phenytoin doses and levels, and in association with phenytoin toxicity. Patients should report cardiac signs or symptoms to their healthcare provider [see Warnings and Precautions (5.6) and Overdosage (10) ] . Angioedema: Advise patients to discontinue PHENYTEK ® capsules and seek immediate medical care if they develop signs or symptoms of angioedema, such as facial, perioral, or upper airway swelling [see Warnings and Precautions (5.7) ] . Effects of Alcohol Use and Other Drugs and Over-the-Counter Drug Interactions: Caution patients against the use of other drugs or alcoholic beverages without first seeking their physician’s advice [ Drug Interactions (7.1 , 7.2) ] . Inform patients that certain over-the-counter medications (e.g., antacids, cimetidine, and omeprazole), vitamins (e.g., folic acid), and herbal supplements (e.g., St. John’s wort) can alter their phenytoin levels. Hyperglycemia: Advise patients that PHENYTEK ® capsules may cause an increase in blood glucose levels [see Warnings and Precautions (5.14) ] . Gingival Hyperplasia: Advise patients of the importance of good dental hygiene in order to minimize the development of gingival hyperplasia and its complications. Neurologic Effects: Counsel patients that PHENYTEK ® capsules may cause dizziness, gait disturbance, decreased coordination and somnolence. Advise patients taking PHENYTEK ® capsules not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with PHENYTEK ® capsules. Use in Pregnancy: Inform pregnant women and women of childbearing potential that use of PHENYTEK ® capsules during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), cardiac defects, dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits. When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using PHENYTEK ® capsules, keeping in mind that there is a potential for decreased hormonal contraceptive efficacy [see Drug Interactions (7.2) ] . Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breastfeeding or intend to breastfeed during therapy [see Use in Specific Populations (8.1 , 8.2) ] . Encourage patients 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 [see Use in Specific Populations (8.1) ] .

Medication Guide PHENYTEK ® CAPSULES (extended phenytoin sodium capsules, USP) (fen′ i toin soe′ dee um) What is the most important information I should know about PHENYTEK ® CAPSULES? 1. Do not stop taking PHENYTEK ® CAPSULES without first talking to your healthcare provider. • Stopping PHENYTEK ® CAPSULES suddenly can cause serious problems. • Stopping a seizure medicine suddenly can cause you to have seizures more often or seizures that will not stop (status epilepticus). 2. Like other antiepileptic drugs, PHENYTEK ® CAPSULES 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 in activity and talking (mania) • Other unusual changes in behavior or mood 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. 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. 3. PHENYTEK ® CAPSULES can cause a type of serious allergic reaction that may affect different parts of the body such as your liver, kidneys, blood, heart, skin or other parts of your body. These can be very serious and cause death. Call your healthcare provider right away if you have any or all of these symptoms: • Fever • Rash • Swollen lymph glands • Swelling of your face, eye, lips, or tongue • Trouble swallowing or breathing • Sore throat • Sores in your mouth • Bruise easily • Purple or red spots on your skin • Increase infections • Not wanting to eat (anorexia) • Nausea • Vomiting • Yellowing of the skin and the white part of your eyes (jaundice) Call your healthcare provider even if the symptoms are mild or if you have been taking PHENYTEK ® CAPSULES for an extended period of time. These symptoms can be a sign of a serious allergic reaction. 4. PHENYTEK ® CAPSULES can cause problems with your heart, including a slow heartbeat. Let your healthcare provider know right away if you have any of these symptoms: • dizziness • tiredness • feeling like your heart is beating slowly or skipping beats • chest pain What are PHENYTEK ® CAPSULES? PHENYTEK ® CAPSULES are a prescription medicine used to treat certain types of seizures called tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures. Do not take PHENYTEK ® CAPSULES if you: • Are allergic to phenytoin or any of the ingredients in PHENYTEK ® CAPSULES. See the end of this leaflet for a complete list of ingredients in PHENYTEK ® CAPSULES. • Have had an allergic reaction to CEREBYX ® (fosphenytoin), PEGANONE ® (ethotoin), or MESANTOIN ® (mephenytoin). • Have had liver problems from taking phenytoin. • Take delavirdine. Before taking PHENYTEK ® CAPSULES, tell your healthcare provider about all of your medical conditions, including if you: • Have or have had depression, mood problems, or suicidal thoughts or behavior • Have had an allergic reaction to a medicine similar to PHENYTEK ® CAPSULES called carboxamides, barbiturates, succinimides, and oxazolidinediones • Have or had liver or kidney problems • Have or had an enzyme problem called porphyria • Have or had high blood sugar (hyperglycemia) • Drink alcohol • Are pregnant or plan to become pregnant. Phenytoin sodium may harm your unborn baby. • If you take PHENYTEK ® CAPSULES during pregnancy, your baby is at risk for serious birth defects. • If you become pregnant while taking PHENYTEK ® CAPSULES, the level of phenytoin sodium in your blood may decrease, causing your seizures to become worse. Your healthcare provider may change your dose of PHENYTEK ® CAPSULES. • If you take PHENYTEK ® CAPSULES 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 PHENYTEK ® CAPSULES. • If you are of childbearing age and are not planning on getting pregnant, you should use effective birth control (contraception) while taking PHENYTEK ® CAPSULES. • Pregnancy Registry: If you become pregnant while taking PHENYTEK ® CAPSULES, 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. • Are breastfeeding or plan to breastfeed. Phenytoin sodium can pass into breast milk. You and your healthcare provider should decide if you will take PHENYTEK ® CAPSULES while you are breastfeeding. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. These medicines can change the levels of phenytoin sodium in your blood. Taking PHENYTEK ® CAPSULES 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 PHENYTEK ® CAPSULES? • Take PHENYTEK ® CAPSULES exactly as your healthcare provider tells you. • Your healthcare provider will tell you how many PHENYTEK ® CAPSULES to take and when to take them. • Your healthcare provider may change your dose if needed. Do not change your dose of PHENYTEK ® CAPSULES without talking to your healthcare provider. • Do not stop taking PHENYTEK ® CAPSULES without first talking to your healthcare provider. Stopping PHENYTEK ® CAPSULES suddenly can cause serious problems. What should I avoid while taking PHENYTEK ® CAPSULES? • Do not drink alcohol while you take PHENYTEK ® CAPSULES without first talking to your healthcare provider. Drinking alcohol while taking PHENYTEK ® CAPSULES may change your blood levels of phenytoin sodium which can cause serious problems. • Do not drive, operate heavy machinery, or do other dangerous activities until you know how PHENYTEK ® CAPSULES affect you. PHENYTEK ® CAPSULES can slow your thinking and motor skills. What are the possible side effects of PHENYTEK ® CAPSULES? See “ What is the most important information I should know about PHENYTEK ® CAPSULES?” PHENYTEK ® CAPSULES may cause other serious side effects including: • Liver problems. • Low blood count which could increase your chance of getting infections, bruising, bleeding and increased fatigue • Softening of your bones (osteopenia, osteoporosis, and osteomalacia) can cause your bones to break (fractures). • High blood sugar (hyperglycemia). • High levels of phenytoin sodium in your blood that could cause confusion also known as delirium, psychosis or a more serious condition that affects how your brain works (encephalopathy). Call your healthcare provider right away, if you have any of the symptoms listed above. The most common side effects of PHENYTEK ® CAPSULES include: • Irregular movement of the eye (nystagmus) • Problems with movement and balance (ataxia) • Slurred speech • Decrease in coordination • Drowsiness (somnolence) • Confusion PHENYTEK ® CAPSULES can cause overgrowth of your gums. Brushing and flossing your teeth and seeing a dentist regularly while taking PHENYTEK ® CAPSULES can help prevent this from happening. These are not all of the possible side effects of PHENYTEK ® CAPSULES. 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 PHENYTEK ® CAPSULES? • Store PHENYTEK ® CAPSULES at room temperature between 20° to 25°C (68° to 77°F). • Store in tight, light-resistant containers. • Protect from light and moisture. Keep PHENYTEK ® CAPSULES and all medicines out of the reach of children. General information about the safe and effective use of PHENYTEK ® CAPSULES. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PHENYTEK ® CAPSULES for a condition for which they were not prescribed. Do not give PHENYTEK ® CAPSULES to other people, even if they have the same symptoms that you have. They may harm them. You can ask your pharmacist or healthcare provider for information about PHENYTEK ® CAPSULES that is written for health professionals. What are the ingredients in PHENYTEK ® CAPSULES? PHENYTEK ® CAPSULES 200 mg and 300 mg: Active ingredient: phenytoin sodium Inactive ingredients: colloidal silicon dioxide, FD&C Blue No. 1, gelatin, hydroxyethyl cellulose, magnesium oxide, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate and titanium dioxide. In addition, the imprinting ink contains black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze. Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A. For more information about PHENYTEK ® CAPSULES, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX). This Medication Guide has been approved by the U.S. Food and Drug Administration The brands listed are trademarks of their respective owners. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Manufactured by: Mylan Laboratories Limited Hyderabad — 500 096, India 75078334 Revised: 11/2021 MX:PHTK:R2m/MX:MG:PHTK:R2m

8.5 Geriatric Use Phenytoin clearance tends to decrease with increasing age [see Clinical Pharmacology (12.3) ] . Lower or less frequent dosing may be required [see Dosage and Administration (2.6) ] .

8.4 Pediatric Use 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 dosage (300 mg/day) [see Dosage and Administration (2.2) ] .

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as PHENYTEK ® capsules, during pregnancy. Physicians are advised to recommend that pregnant patients taking PHENYTEK ® capsules enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the tollfree 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/ Risk Summary In humans, prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Prenatal phenytoin exposure is associated with an increased incidence of major malformations, including orofacial clefts and cardiac defects. In addition, the fetal hydantoin syndrome, a pattern of abnormalities including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy [see Data ] . There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. Administration of phenytoin to pregnant animals resulted in an increased incidence of fetal malformations and other manifestations of developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple species at clinically relevant doses [see Data ] . In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Disease-Associated Maternal Risk An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage [see Dosage and Administration (2.3 , 2.7) ] . However, postpartum restoration of the original dosage will probably be indicated [see Clinical Pharmacology (12.3) ] . Fetal/Neonatal Adverse Reactions 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. Data Human Data Meta-analyses using data from published observational studies and registries have estimated an approximately 2.4-fold increased risk for any major malformation in children with prenatal phenytoin exposure compared to controls. An increased risk of heart defects, facial clefts, and digital hypoplasia has been reported. The fetal hydantoin syndrome is a pattern of congenital anomalies including craniofacial anomalies, nail and digital hypoplasia, prenatal-onset growth deficiency, and neurodevelopmental deficiencies. Animal Data Administration of phenytoin to pregnant rats, rabbits, and mice during organogenesis resulted in embryofetal death, fetal malformations, and decreased fetal growth. Malformations (including craniofacial, cardiovascular, neural, limb, and digit abnormalities) were observed in rats, rabbits, and mice at doses as low as 100, 75, and 12.5 mg/kg, respectively.

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. ( 5.13 , 8.1 ) • Renal and/or Hepatic Impairment or Hypoalbuminemia: Monitor unbound phenytoin concentrations in these patients. ( 8.6 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as PHENYTEK ® capsules, during pregnancy. Physicians are advised to recommend that pregnant patients taking PHENYTEK ® capsules enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the tollfree 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/ Risk Summary In humans, prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Prenatal phenytoin exposure is associated with an increased incidence of major malformations, including orofacial clefts and cardiac defects. In addition, the fetal hydantoin syndrome, a pattern of abnormalities including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy [see Data ] . There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. Administration of phenytoin to pregnant animals resulted in an increased incidence of fetal malformations and other manifestations of developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple species at clinically relevant doses [see Data ] . In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Disease-Associated Maternal Risk An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage [see Dosage and Administration (2.3 , 2.7) ] . However, postpartum restoration of the original dosage will probably be indicated [see Clinical Pharmacology (12.3) ] . Fetal/Neonatal Adverse Reactions 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. Data Human Data Meta-analyses using data from published observational studies and registries have estimated an approximately 2.4-fold increased risk for any major malformation in children with prenatal phenytoin exposure compared to controls. An increased risk of heart defects, facial clefts, and digital hypoplasia has been reported. The fetal hydantoin syndrome is a pattern of congenital anomalies including craniofacial anomalies, nail and digital hypoplasia, prenatal-onset growth deficiency, and neurodevelopmental deficiencies. Animal Data Administration of phenytoin to pregnant rats, rabbits, and mice during organogenesis resulted in embryofetal death, fetal malformations, and decreased fetal growth. Malformations (including craniofacial, cardiovascular, neural, limb, and digit abnormalities) were observed in rats, rabbits, and mice at doses as low as 100, 75, and 12.5 mg/kg, respectively. 8.2 Lactation Risk Summary Phenytoin is secreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PHENYTEK ® capsules and any potential adverse effects on the breastfed infant from PHENYTEK ® capsules or from the underlying maternal condition. 8.4 Pediatric Use 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 dosage (300 mg/day) [see Dosage and Administration (2.2) ] . 8.5 Geriatric Use Phenytoin clearance tends to decrease with increasing age [see Clinical Pharmacology (12.3) ] . Lower or less frequent dosing may be required [see Dosage and Administration (2.6) ] . 8.6 Renal and/or Hepatic Impairment or Hypoalbuminemia 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. Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients. 8.7 Use in Patients with Decreased CYP2C9 Function Patients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g., *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g., *1/*1). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses of phenytoin to maintain similar steady-state concentrations compared to normal metabolizers. If early signs of dose-related central nervous system (CNS) toxicity develop, serum concentrations should be checked immediately [see Clinical Pharmacology (12.5) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied PHENYTEK ® CAPSULES (extended phenytoin sodium capsules, USP) are available containing 200 mg or 300 mg of phenytoin sodium, USP. The 200 mg capsules have a dark blue opaque cap and a blue opaque body. The hard-shell gelatin capsules are filled with two white to off-white round tablets. The capsules are rectified radial printed with BERTEK over 670 in black ink on both the cap and the body. They are available as follows: NDC 0378-2670-93 bottles of 30 capsules NDC 0378-2670-01 bottles of 100 capsules The 300 mg capsules have a blue opaque cap and a blue opaque body. The hard-shell gelatin capsules are filled with three white to off-white round tablets. The capsules are rectified radial printed with BERTEK over 750 in black ink on both the cap and the body. They are available as follows: NDC 0378-3750-93 bottles of 30 capsules NDC 0378-3750-01 bottles of 100 capsules 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light and moisture. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. PHARMACIST: Dispense a Medication Guide with each prescription.