PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Package/Label Display Panel

Extended Phenytoin Sodium Capsules, USP

100 mg

100 Capsules

DESCRIPTION SECTION

11 DESCRIPTION

Phenytoin sodium, USP is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is 5,5-diphenyl-2,4 imidazolidinedione, having the following structural formula:


Each extended phenytoin sodium capsule, USP for oral administration contains 100 mg phenytoin sodium, USP. Each capsule also contains the following inactive ingredients: D&C Red #28, D&C Red #33, FD&C Blue #1, gelatin, hydroxypropyl cellulose, mannitol, magnesium stearate, talc and titanium dioxide. 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, USP with a rapid rate of absorption with peak blood concentration expected in 1½ to 3 hours.

Meets USP Dissolution Test 5.

CLINICAL PHARMACOLOGY SECTION

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 extended phenytoin sodium capsules, peak serum levels occur 4 to 12 hours after administration. 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.

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 (7.1, 7.2)].

12.5 Pharmacogenomics

CYP2C9 activity is decreased in individuals with genetic variants such as the CYP2C92 and CYP2C93 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% to 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% to 36% in the Asian population [see Warnings and Precautions (5.3) and Use in Specific Populations (8.7)].

INDICATIONS & USAGE SECTION

Highlight: 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. 1

1 INDICATIONS AND USAGE

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.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: Extended phenytoin sodium capsules, USP are available as 100 mg capsules. Error! Hyperlink reference not valid. (3)

3 DOSAGE FORMS AND STRENGTHS

Extended phenytoin sodium capsules, USP are available as:

**100 mg:** white opaque/light lavender opaque, hard gelatin capsules imprinted with “IP 212” on both cap and body.

CONTRAINDICATIONS SECTION

Highlight: Hypersensitivity to phenytoin, its ingredients, or other hydantoins (4, 5.5) A history of prior acute hepatotoxicity attributable to phenytoin (4, 5.8) Co-administration with delavirdine (4)

4 CONTRAINDICATIONS

Phenytoin is 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)].

•

Co-administration 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.

INFORMATION FOR PATIENTS SECTION

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 phenytoin without consulting with their healthcare provider. Phenytoin 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 extended phenytoin sodium 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 10 OVERDOSAGE].

Angioedema

Advise patients to discontinue phenytoin sodium 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 phenytoin 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 phenytoin may cause dizziness, gait disturbance, decreased coordination and somnolence. Advise patients taking phenytoin not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with phenytoin.

Use in Pregnancy

Inform pregnant women and women of childbearing potential that use of phenytoin 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 phenytoin, 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 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 8.1].

Brands listed are the trademarks of their respective owners.

Distributed by:

Amneal Pharmaceuticals LLC

Bridgewater, NJ 08807

Packaged and Distributed by:

MAJOR® PHARMACEUTICALS

Indianapolis, IN 46268 USA

Refer to package label for Distributor's NDC Number

Rev. 08-2023-09

SPL MEDGUIDE SECTION

MEDICATION GUIDE

Dispense with Medication Guide available at:

documents.amneal.com/mg/extended-phenytoin-sodium.pdf

Stopping extended phenytoin sodium 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).

Thoughts about suicide or dying

New or worse anxiety

Trouble sleeping (insomnia)

Acting on dangerous impulses

Attempts to commit suicide

Feeling agitated or restless

New or worse irritability

An extreme increase in activity and talking (mania)

New or worse depression

Panic attacks 

Acting aggressive, being angry, or violent

Other unusual changes in behavior or mood

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.

Fever 

Sore throat 

Not wanting to eat (anorexia)

Rash 

Sores in your mouth 

Nausea

Swollen lymph glands 

Bruise easily 

Vomiting

Swelling of your face, eye, lips, or tongue

Trouble swallowing or breathing

Purple or red spots on your skin

Increase infections

Yellowing of the skin and the white part of your eyes (jaundice)

dizziness

tiredness

feeling like your heart is beating slowly or skipping beats

chest pain

Are allergic to phenytoin or any of the ingredients in extended phenytoin sodium capsules. See the end of this leaflet for a complete list of ingredients in extended phenytoin sodium capsules.

Have had an allergic reaction to CEREBYX (fosphenytoin), PEGANONE (ethotoin), or MESANTOIN (mephenytoin). 

Have had liver problems from taking phenytoin.

Take delavirdine.

Have or have had depression, mood problems, or suicidal thoughts or behavior

Have had an allergic reaction to a medicine similar to extended phenytoin sodium 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. Extended phenytoin sodium capsules may harm your unborn baby.

If you take extended phenytoin sodium capsules during pregnancy, your baby is at risk for serious birth defects.

If you become pregnant while taking extended phenytoin sodium capsules, the level of phenytoin in your blood may decrease, causing your seizures to become worse. Your healthcare provider may change your dose of extended phenytoin sodium capsules.

If you take extended phenytoin sodium 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 extended phenytoin sodium capsules.

If you are of childbearing age and are not planning on getting pregnant, you should use effective birth control (contraception) while taking extended phenytoin sodium capsules.

**Pregnancy Registry:**If you become pregnant while taking extended phenytoin sodium 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 can pass into breast milk. You and your healthcare provider should decide if you will take extended phenytoin sodium capsules while you are breastfeeding.

Take extended phenytoin sodium capsules exactly as your healthcare provider tells you.

Your healthcare provider will tell you how much extended phenytoin sodium capsules to take and when to take it.

Your healthcare provider may change your dose if needed. Do not change your dose of extended phenytoin sodium capsules without talking to your healthcare provider.

Do not stop taking extended phenytoin sodium capsules without first talking to your healthcare provider. Stopping extended phenytoin sodium capsules suddenly can cause serious problems.

Do not drink alcohol while you take extended phenytoin sodium capsules without first talking to your healthcare provider. Drinking alcohol while taking extended phenytoin sodium capsules 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 extended phenytoin sodium capsules affects you. Extended phenytoin sodium capsules can slow your thinking and motor skills.

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 in your blood that could cause confusion also known as delirium, psychosis or a more serious condition that affects how your brain works (encephalopathy).

Irregular movement of the eye (nystagmus)

Slurred speech 

Drowsiness (somnolence)

Problems with movement and balance (ataxia)

Decrease in coordination 

Confusion

Store extended phenytoin sodium capsules at room temperature between 68°F to 77°F (20°C to 25°C).

Store in tight, light-resistant containers.

Protect from moisture.