DILANTIN- phenytoin sodium capsule, extended release
For Healthcare Providers >

1. Patient Information
2. Like Other Antiepileptic Drugs, Dilantin 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:
3. 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?
4. Dilantin 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:
5. Do Not Take Dilantin If You:
6. What Should I Avoid While Taking Dilantin?
7. What Are The Possible Side Effects Of Dilantin?
8. Active Ingredient:
9. Inactive Ingredients:
10. Dilantin May Cause Rare But Serious, Even Life-threatening, Allergic Reactions.contact Your Healthcare Provider Right Away If You Have Any Of These Symptoms After Taking Dilantin:
11. Call A Healthcare Provider Right Away If You Have Any Of These Symptoms, Especially If They Are New, Worse, Or Worry You:
12. How Can I Watch For Early Symptoms Of Suicidal Thoughts And Actions?
13. What Else Do I Need To Know About Dilantin?
14. What Is Dilantin?
15. Who Should Not Take Dilantin?
16. Before Starting Dilantin, Tell Your Healthcare Provider About All Medications You Take (including Prescription And Nonprescription Medications, Vitamins, And Herbal Medicines) And Tell Your Healthcare Provider About All Of Your Medical Conditions, Including If You:
17. How Should I Take Dilantin?
18. Dilantin 100mg:
19. Dilantin 30mg:

Patient 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 DILANTIN without consulting with their healthcare provider. DILANTIN should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus[

1.

Do not stop taking DILANTIN without first talking to your healthcare provider.

• Stopping DILANTIN 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, Dilantin 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.

Dilantin 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 DILANTIN for an extended period of time. These symptoms can be a sign of a serious allergic reaction.

Do Not Take Dilantin If You: ⮝

• Are allergic to phenytoin or any of the ingredients in DILANTIN.
  • Take DILANTIN exactly as your healthcare provider tells you.
  • Your healthcare provider will tell you how much DILANTIN to take and when to take it.
  • Your healthcare provider may change your dose if needed. Do not change your dose of DILANTIN without talking to your healthcare provider.
  • If your healthcare provider has prescribed DILANTIN oral suspension, ask your pharmacist for a medicine dropper or medicine cup to help you measure the correct amount of DILANTIN.Do notuse a household teaspoon. Ask your pharmacist for instructions on how to use the measuring device the right way.
  • Do not stop taking DILANTIN without first talking to your healthcare provider. Stopping DILANTIN suddenly can cause serious problems.

What Should I Avoid While Taking Dilantin? ⮝

• Do not drink alcohol while you take DILANTIN without first talking to your healthcare provider. Drinking alcohol while taking DILANTIN may change your blood levels of DILANTIN which can cause serious problems.
• Do not drive, operate heavy machinery, or do other dangerous activities until you know how DILANTIN affects you. DILANTIN can slow your thinking and motor skills.

What Are The Possible Side Effects Of Dilantin? ⮝

• Store DILANTIN Capsules at room temperature between 68 F to 77 F (20 C to 25 C).
• Store in tight, light-resistant containers.
• Protect from moisture.

Keep DILANTIN and all medicines out of the reach of children.General information about the safe and effective use of DILANTIN.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use DILANTIN for a condition for which it was not prescribed. Do not give DILANTIN to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about DILANTIN that is written for health professionals.

Active Ingredient: ⮝

100 mg phenytoin sodium, USP

Inactive Ingredients: ⮝

lactose monohydrate, confectioner's sugar, talc, and magnesium stearate. The capsule body contains titanium dioxide and gelatin. The capsule cap contains FD&C red No. 28, FD&C yellow No. 6, and gelatin.

For more information about DILANTIN, visit http://www.pfizer.com or call 1 800 438 1985.

LAB-0586-10.0
February 2017

Dilantin May Cause Rare But Serious, Even Life-threatening, Allergic Reactions.contact Your Healthcare Provider Right Away If You Have Any Of These Symptoms After Taking Dilantin: ⮝

• Skin rash and blisters, hives (raised bumps), fever or itching
• Swelling of your face, mouth, lips, gums, tongue or neck
• Trouble breathing

Like other antiepileptic drugs, DILANTIN, 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

If you have suicidal thoughts or actions, do not stop DILANTIN without first talking to your healthcare provider.

• Stopping DILANTIN suddenly can increase the possibility of side effects including increased seizure frequency.
• 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.

Do not stop taking DILANTIN without first talking to your healthcare provider.Stopping DILANTIN suddenly can increase the possibility of side effects including increased seizure frequency.

Use of DILANTIN during pregnancy may increase the risks of birth defects (deformed babies) or may increase seizure frequency in the mother.You should not take DILANTIN if you are pregnant or plan to become pregnant unless instructed to do so by your healthcare provider.

What Else Do I Need To Know About Dilantin? ⮝

Many drugs (including alcohol) can either increase or decrease your DILANTIN level, which can interfere with your optimum dosage. It is recommended that you avoid drinking alcoholic beverages while taking DILANTIN. It is very important to discuss all of your medications with your healthcare provider .DILANTIN may alter the results of some laboratory tests. If you require laboratory tests, you should remind your healthcare provider that you are taking DILANTIN.

It is important to practice good dental hygiene while taking DILANTIN to minimize the development of gingival hyperplasia (excessive formation of the gums over the teeth) and its complications.

Your blood may need to be tested regularly to make sure that you are taking the correct dose of DILANTIN.

What Is Dilantin? ⮝

DILANTIN is a prescription medicineused alone or with other medications to treat different types of seizures in people. DILANTIN may also be used for the prevention and treatment of seizures occurring during or following brain surgery. DILANTIN belongs to a class of prescription medicines called anticonvulsants or anti-seizure medications and affects abnormal chemical activity in the brain that may be involved in causing seizures.

DILANTIN is not effective for the treatment of seizures due to hypoglycemic or other metabolic causes. It is also not effective for absence (petit mal) seizures.

Who Should Not Take Dilantin? ⮝

Do not take DILANTIN if you are allergic or hypersensitive to any of its ingredients. The active ingredient is phenytoin.

Before Starting Dilantin, Tell Your Healthcare Provider About All Medications You Take (including Prescription And Nonprescription Medications, Vitamins, And Herbal Medicines) And Tell Your Healthcare Provider About All Of Your Medical Conditions, Including If You: ⮝

• Have or had liver disease
• Have or had porphyria (a blood disorder)
• Have or had diabetes
• Are pregnant or plan to become pregnant. Because of the potential harm to your developing baby, DILANTIN should not be taken during pregnancy unless you are told otherwise by your healthcare provider. If you discover you are pregnant, do not suddenly stop taking DILANTIN because this may lead to serious consequences for you and your baby. If you become pregnant, you should talk to your healthcare provider immediately. You should also consider enrolling in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This registry is collecting information about the safety of the use of all antiepileptic drugs during pregnancy. To enroll, call the toll free number 1-888-233-2334.
• Are breast feeding. Taking DILANTIN while breast feeding it is not recommended.
• Consume alcohol. Alcohol drinking can increase or decrease the DILANTIN level in your blood.
• Have or had Vitamin D deficiency or any other condition that causes thinning of the bones.
• Receive nutrition through a feeding tube. Patients who are receiving nutrition through a feeding tube may have lower-than-expected blood levels of DILANTIN. Do not administer DILANTIN at the same time as the feeding preparation.

How Should I Take Dilantin? ⮝

• Take DILANTIN exactly as prescribed.Your healthcare provider may need to change (adjust) the dose of DILANTIN until it is right for you. Your blood may need to be tested on a regular basis to make sure that you are taking the correct dose for proper control of your seizures. You may also need a blood test if you are switching from one form of DILANTIN to another.
• Try to take DILANTIN at the same times each day to avoid missing any doses. If you miss a dose of DILANTIN, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of DILANTIN at the same time.
• Tell your healthcare provider of any clinical condition (such as surgery) during which it is not possible to take DILANTIN orally as prescribed.
• In adults whose seizures are well controlled with divided doses of three 100-mg capsules daily, once-a-day dosing may be considered. You should discuss this possibility with your healthcare provider.
• Do not take capsules that are discolored.
• Do not stop taking DILANTIN unless your healthcare provider tells you to do so.If your treatment is stopped, it should be done gradually. If you stop taking DILANTIN suddenly or before your healthcare provider tells you, there is an increased risk of seizures.

OVERDOSE

An overdose of DILANTIN can be fatal. If you suspect an overdose,

You should avoid consuming alcoholic beverages while taking DILANTIN without first talking to your healthcare provider."

DILANTIN can cause rare but serious skin allergic reactions which can be fatal. Tell your healthcare provider and

• Keep DILANTIN out of the reach of children.
• Store DILANTIN Capsules at room temperature between 68 F (20 C) and 77 F (25 C) in tight, light-resistant containers. Protect from moisture.

General information about DILANTIN

Do not use DILANTIN for a condition for which it was not prescribed. Do not give DILANTIN to other people, even if they have the same condition. It may harm them.

This Medication Guide summarizes the most important information about DILANTIN. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about DILANTIN that was written for healthcare professionals. For more information about DILANTIN, visit http://www.pfizer.com

Dilantin 100mg: ⮝

Each capsule contains a white powder. The medium orange cap has "PD" imprinted in black ink and the white, opaque body has "DILANTIN" over "100 mg" printed in black ink.

Dilantin 30mg: ⮝

Each capsule contains a white powder. The small pale pink opaque cap has "PD" imprinted in black ink and the white, opaque body has "Dilantin 30 mg" printed in black ink.

1. Highlights Of Prescribing Information
2. Recent Major Changes
3. Indications And Usage
4. Dosage And Administration
5. Dosage Forms And Strengths
6. Contraindications
7. Warnings And Precautions
8. Adverse Reactions
9. Drug Interactions
10. Use In Specific Populations
11. 1 Indications And Usage
12. 2 Dosage And Administration
13. 3 Dosage Forms And Strengths
14. 4 Contraindications
15. 5 Warnings And Precautions
16. 6 Adverse Reactions
17. 7 Drug Interactions
18. 8 Use In Specific Populations
19. 10 Overdosage
20. 11 Description
21. 12 Clinical Pharmacology
22. 13 Nonclinical Toxicology
23. 16 How Supplied/storage And Handling
24. Phenytoin Sodium
25. Repackaging Information
26. Principal Display Panel - 100mg
27. Description
28. Clinical Pharmacology
29. Warnings
30. Precautions
31. Overdosage
32. How Supplied
33. Principal Display Panel - 30 Mg Capsule
34. Phenytoin Sodium Er 30 Mg Capsules
35. Principal Display Panel

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use DILANTIN safely and effectively. See full prescribing information for DILANTIN .

DILANTIN (phenytoin sodium) Extended Capsules, for oral use
Initial U.S. Approval: 1953

Recent Major Changes ⮝

Warnings and Precautions (5.11)

11/2016

Indications And Usage ⮝

DILANTIN is 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)

Dosage And Administration ⮝

• Adult starting dose in patients who have received no previous treatment is one 100 mg DILANTIN extended 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 DILANTIN extended capsules daily, once-a-day dosage with 300 mg DILANTIN extended 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 20 mcg/mL (unbound phenytoin concentration is 1 2 mcg/mL). (2.3)

Dosage Forms And Strengths ⮝

DILANTIN is available as 30 mg and 100 mg extended phenytoin sodium capsules.(3)

Contraindications ⮝

• Hypersensitivity to phenytoin, its ingredients, or other hydantoins (4)
• A history of prior acute hepatotoxicity attributable to phenytoin (4, 5.6)
• Coadministration with delavirdine (4)

Warnings And Precautions ⮝

• Withdrawal Precipitated Seizure: May precipitate status epilepticus. Dose reductions or discontinuation should be done gradually. (5.1)
• Suicidal Behavior and Ideation: Monitor patients for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. (5.2)
• Serious Dermatologic Reactions: Discontinue DILANTIN 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. (5.3)
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity: If signs or symptoms of hypersensitivity are present, evaluate the patient immediately. Discontinue if an alternative etiology cannot be established. (5.4)
• Hepatic Injury: Cases of acute hepatotoxicity have been reported with DILANTIN. If this occurs, immediately discontinue. (4, 5.6)
• Hematopoietic Complications: If occurs, follow-up observation is indicated and an alternative antiepileptic treatment should be used. (5.7)

Adverse Reactions ⮝

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 Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions ⮝

Multiple drug interactions because of extensive plasma protein binding, saturable metabolism and potent induction of hepatic enzymes. (7.1, 7.2)

Use In Specific Populations ⮝

• Pregnancy: Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. (5.11, 8.1)
• Renal and/or Hepatic Impairment or Hypoalbuminemia: Monitor unbound phenytoin concentrations in these patients. (8.6)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 7/2017

1 Indications And Usage ⮝

DILANTIN is 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.

2 Dosage And Administration ⮝

2.1 Adult Dosage

Divided daily dosage:

The recommended starting dose for adult patients who have received no previous treatment is one 100-mg DILANTIN (extended phenytoin sodium capsule, USP) 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 DILANTIN (extended phenytoin sodium capsules, USP) daily, once-a-day dosage with 300 mg of DILANTIN (extended phenytoin sodium capsules, USP) 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 DILANTIN (extended phenytoin sodium capsules, USP) 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 DILANTIN (extended phenytoin sodium capsules, USP) 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. DILANTIN extended capsules and parental DILANTIN 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 (5.9) 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 DILANTIN 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.

3 Dosage Forms And Strengths ⮝

DILANTIN extended phenytoin sodium capsules are available as:

• 30 mg: size 4 hemispherical Coni-Snap capsule with a white opaque body and pale pink opaque cap containing a white powder. Capsule is imprinted with black rectified radial print, "PD" on cap and "DILANTIN 30 mg" on body.
• 100 mg: hard, filled No. 3 capsules with a white, opaque body and a medium orange cap containing a white powder. Capsule is imprinted with black rectified radial print, "PD" on cap and "DILANTIN 100 mg" on body.

4 Contraindications ⮝

DILANTIN is contraindicated in patients with:

• A history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins [see Warnings and Precautions (5.5)].
• A history of prior acute hepatotoxicity attributable to phenytoin [see Warnings and Precautions (5.6)].
• 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.

5 Warnings And Precautions ⮝

5.1 Withdrawal Precipitated Seizure, Status Epilepticus

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 anticonvulsant medication arises, this should be done gradually. However, 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 drug not belonging to the hydantoin chemical class.

5.2 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including DILANTIN, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (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 1000 Patients	Drug Patients with Events Per 1000 Patients	Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients	Risk Difference: Additional Drug Patients with Events Per 1000 Patients
Epilepsy	1.0	3.4	3.5	2.4
Psychiatric	5.7	8.5	1.5	2.9
Other	1.0	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 DILANTIN 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.

5.3 Serious Dermatologic Reactions

Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. DILANTIN should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms [see Warnings and Precautions (5.4)].

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.

5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including DILANTIN. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. DILANTIN should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

5.5 Hypersensitivity

DILANTIN and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity [see Contraindications (4)]. Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to DILANTIN.

5.6 Hepatic Injury

Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with DILANTIN. These events may be part of the spectrum of DRESS or may occur in isolation [see Warnings and Precautions (5.4)]. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, DILANTIN should be immediately discontinued and not readministered.

5.7 Hematopoietic Complications

Hematopoietic complications, some fatal, have occasionally been reported in association with administration of DILANTIN. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression.

There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs of DRESS [see Warnings and Precautions (5.4)].

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.

5.8 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.

5.9 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.

5.10 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.

5.11 Teratogenicity and Other Harm to the Newborn

DILANTIN may cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse development outcomes [see Use in Specific Populations (8.1)].

Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), and abnormalities characteristic of fetal hydantoin syndrome, including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits, have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have been several reported cases of malignancies, including neuroblastoma.

The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs, including phenytoin, during pregnancy is about 10%, or two- to three-fold that in the general population.

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.

5.12 Slow Metabolizers of Phenytoin

A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be caused by limited enzyme availability and lack of induction; it appears to be genetically determined. If early signs of dose-related CNS toxicity develop, serum levels should be checked immediately.

5.13 Hyperglycemia

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.

5.14 Serum Phenytoin Levels above Therapeutic Range

Serum levels of phenytoin sustained above the therapeutic range may produce confusional states referred to as "delirium," "psychosis," or "encephalopathy," or rarely irreversible cerebellar dysfunction and/or cerebellar atrophy. Accordingly, at the first sign of acute toxicity, serum levels should be immediately checked. Dose reduction of phenytoin therapy is indicated if serum levels are excessive; if symptoms persist, termination is recommended.

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)]
• Hepatic Injury [see Warnings and Precautions (5.6)]
• Hematopoietic Complications [see Warnings and Precautions (5.7)]
• Effects on Vitamin D and Bone [see Warnings and Precautions (5.8)]
• Exacerbation of Porphyria [see Warnings and Precautions (5.10)]
• Teratogenicity and Other Harm to the Newborn [see Warnings and Precautions (5.11)]
• Hyperglycemia [see Warnings and Precautions (5.13)]

The following adverse reactions associated with the use of DILANTIN 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 [see Warnings and Precautions (5.3, 5.4)]. 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 (5.7)].

Laboratory Test Abnormality: 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 [see Warnings and Precautions (5.13)], 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 (5.14)].

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, Stevens-Johnson syndrome, and toxic epidermal necrolysis [see Warnings and Precautions (5.3)]. There have also been reports of hypertrichosis.

Investigations: Thyroid function test abnormal.

Special Senses: Altered taste sensation including metallic taste.

Urogenital: Peyronie's disease

7 Drug Interactions ⮝

Phenytoin is extensively bound to 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. Monitoring of phenytoin serum levels is recommended when a drug interaction is suspected.

Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes.

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
* Antacids may affect absorption of phenytoin. The induction potency of St. John's wort may vary widely based on preparation.
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	H2 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*	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 , 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
* The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable
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*	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, 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.

8 Use In Specific Populations ⮝

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 DILANTIN, during pregnancy. Physicians are advised to recommend that pregnant patients taking DILANTIN 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/

Risk Summary

In humans, prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse development outcomes. An increased incidence of major malformations (such as orofacial clefts and cardiac defects) and abnormalities characteristic of fetal hydantoin syndrome (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. 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 4% and 15 20%, respectively. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (including phenytoin) during pregnancy is about 10%, or two- to three-fold that in the general population.

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

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 DILANTIN and any potential adverse effects on the breastfed infant from DILANTIN 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.

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. 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.

11 Description ⮝

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

Each 30 mg DILANTIN- (extended phenytoin sodium capsule, USP) for oral administration contains 30 mg phenytoin sodium, USP. Also contains lactose monohydrate, NF; confectioner's sugar, NF; talc, USP; and magnesium stearate, NF. The capsule shell cap and body components contain titanium dioxide (cap and body); gelatin (cap and body); D&C yellow No. 10 (cap); FD&C red No. 3 (cap). 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 1 to 3 hours.

Each 100 mg DILANTIN- 100 mg (extended phenytoin sodium capsule, USP) for oral administration contains 100 mg phenytoin sodium. Also contains lactose monohydrate, NF; confectioner's sugar, NF; talc, USP; and magnesium stearate, NF. The capsule body contains titanium dioxide, USP and gelatin, NF. The capsule cap contains FD&C red No. 28; FD&C yellow No. 6; and gelatin NF. 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 1 to 3 hours.

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 DILANTIN 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 metabolized by hepatic cytochrome P450 enzymes CYP2C9 and 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 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 metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes [see Drug Interactions (7.1, 7.2)].

13 Nonclinical Toxicology ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis [see Warnings and Precautions (5.7)]

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 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.

16 How Supplied/storage And Handling ⮝

Product: 68151-1019

NDC: 68151-1019-6 1 CAPSULE, EXTENDED RELEASE in a PACKAGE

Phenytoin Sodium ⮝

DILANTIN phenytoin sodium capsule, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50090-0029(NDC:0071-0369) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PHENYTOIN SODIUM (UNII: 4182431BJH) (PHENYTOIN - UNII:6158TKW0C5) PHENYTOIN SODIUM 100 mg

Inactive Ingredients Ingredient Name Strength LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) SUCROSE (UNII: C151H8M554) TALC (UNII: 7SEV7J4R1U) MAGNESIUM STEARATE (UNII: 70097M6I30) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) D&C RED NO. 28 (UNII: 767IP0Y5NH) FD&C YELLOW NO. 6 (UNII: H77VEI93A8)

Product Characteristics Color WHITE (opaque) , ORANGE (medium orange) Score no score Shape CAPSULE Size 16mm Flavor Imprint Code PD;DILANTIN;100;mg Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50090-0029-2 30 in 1 BOTTLE; Type 0: Not a Combination Product 11/28/2014

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA084349 08/27/1976

Labeler - A-S Medication Solutions (830016429)

Establishment
Name	Address	ID/FEI	Business Operations
A-S Medication Solutions		830016429	RELABEL(50090-0029) , REPACK(50090-0029)

Revised: 4/2019 Document Id: 8657e0f0-e112-44ad-a896-c3ce1b884012 34391-3 Set id: f5b7e576-49b1-4633-ab0a-6ab94922e970 Version: 11 Effective Time: 20190401 A-S Medication Solutions

Repackaging Information ⮝

Please reference the How Supplied section listed above for a description of individual tablets or capsules. This drug product has been received by Aphena Pharma - TN in a manufacturer or distributor packaged configuration and repackaged in full compliance with all applicable cGMP regulations. The package configurations available from Aphena are listed below:

Count	100mg
90	43353-131-60
120	43353-131-70
150	43353-131-75
270	43353-131-92
360	43353-131-94

Store between 20 -25 C (68 -77 F). See USP Controlled Room Temperature. Dispense in a tight light-resistant container as defined by USP. Keep this and all drugs out of the reach of children.

Repackaged by:

Cookeville, TN 38506

20120726KW

Principal Display Panel - 100mg ⮝

NDC 43353-131 - Extended Phentoin NA (Dilantin ) 100mg - Rx Only

DILANTIN phenytoin sodium capsule, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:43353-131(NDC:0071-0369) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Phenytoin Sodium (UNII: 4182431BJH) (Phenytoin - UNII:6158TKW0C5) Phenytoin Sodium 100 mg

Inactive Ingredients Ingredient Name Strength lactose monohydrate (UNII: EWQ57Q8I5X) sucrose (UNII: C151H8M554) talc (UNII: 7SEV7J4R1U) magnesium stearate (UNII: 70097M6I30) titanium dioxide (UNII: 15FIX9V2JP) D&C red No. 28 (UNII: 767IP0Y5NH) FD&C yellow No. 6 (UNII: H77VEI93A8) gelatin (UNII: 2G86QN327L)

Product Characteristics Color ORANGE (medium orange) , WHITE (white, opaque) Score no score Shape CAPSULE Size 16mm Flavor Imprint Code PD;DILANTIN;100;mg Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:43353-131-60 90 in 1 BOTTLE, PLASTIC 2 NDC:43353-131-70 120 in 1 BOTTLE, PLASTIC 3 NDC:43353-131-75 150 in 1 BOTTLE, PLASTIC 4 NDC:43353-131-92 270 in 1 BOTTLE, PLASTIC 5 NDC:43353-131-94 360 in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA084349 08/27/1976

Labeler - Aphena Pharma Solutions - Tennessee, Inc. (128385585)

Establishment
Name	Address	ID/FEI	Business Operations
Aphena Pharma Solutions - Tennessee, Inc.		128385585	Repack(43353-131)

Revised: 6/2012 Document Id: 0bedfead-19aa-4149-ba58-4d0f189267b7 34391-3 Set id: ecab970d-83e9-4aad-92de-dbb73d7a151f Version: 1 Effective Time: 20120620 Aphena Pharma Solutions - Tennessee, Inc.

Description ⮝

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

Each Dilantin Extended Phenytoin Sodium Capsule, USP contains 30 mg phenytoin sodium, USP. Also contains lactose monohydrate,, NF; confectioner's sugar, NF; talc, USP; and magnesium stearate, NF. The capsule shell cap and body components contain Titanium Dioxide (cap and body); gelatin (cap and body); D&C yellow No. 10 (cap); FD&C red No. 3 (cap).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 1 to 3 hours.

USP dissolution test pending

and

Each Dilantin 100 mg Extended Oral Capsule contains 100 mg phenytoin sodium. Also contains lactose monohydrate, NF; confectioner's sugar, NF; talc, USP; and magnesium stearate, NF. The capsule body contains titanium dioxide, USP and gelatin, NF. The capsule cap contains FD&C red No. 28; FD&C yellow No. 6; and gelatin NF. 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 1 to 3 hours.

Clinical Pharmacology ⮝

Phenytoin is an antiepileptic drug which can be used 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.

The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 hours. 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. Trough levels provide information about clinically effective serum level range and confirm patient compliance and are obtained just prior to the patient's next scheduled dose. Peak levels indicate an individual's threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. For Dilantin capsules, peak serum levels occur 4 to 12 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, congenital enzyme deficiency, 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.

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. However, in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an antiepileptic drug not belonging to the hydantoin chemical class.

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including Dilantin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 100 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 1000 Patients	Drug Patients with Events Per 1000 Patients	Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients	Risk Difference: Additional Drug Patients with Events Per 1000 Patients
Epilepsy	1.0	3.4	3.5	2.4
Psychiatric	5.7	8.5	1.5	2.9
Other	1.0	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 Dilantin 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.

Lymphadenopathy

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 resembling serum sickness, e.g., fever, rash, and liver involvement.

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 of Alcohol Use on Phenytoin Serum Levels

Acute alcoholic intake may increase phenytoin serum levels, while chronic alcohol 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

A.

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.

B.

Risks to the Fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus.

Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two- to three-fold that in the general population. However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs.

Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy.

C.

Postpartum Period. A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.

Preclinical

Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits.

Skin reactions

Dilantin can cause rare, serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs hypersensitivity such as itching, and should seek medical advice from their physician immediately when observing any indicative signs or symptoms. The physician should advise the patient to discontinue treatment if the rash appears (see WARNINGS section regarding drug discontinuation). If the rash is of a milder type (measles-like or scarlatiniform), therapy may be resumed after the rash has completely disappeared. If the rash recurs upon reinstitution of therapy, further Dilantin medication is contraindicated. Published literature has suggested that there may be an increased, although still rare, risk of hypersensitivity reactions, including skin rash, SJS, TEN, hepatotoxicity, and Anticonvulsant Hypersensitivity Syndrome in black patients.

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 another anticonvulsive drug. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding use of drugs associated with SJS/TEN, including Dilantin, in HLA-B*1502 positive patients when alternative therapies are otherwise equally available.

Anticonvulsant Hypersensitivity Syndrome

Anticonvulsant Hypersensitivity Syndrome (AHS) is a rare drug induced, multiorgan syndrome which is potentially fatal and occurs in some patients taking anticonvulsant medication. It is characterized by fever, rash, lymphadenopathy, and other multiorgan pathologies, often hepatic. The mechanism is unknown. The interval between first drug exposure and symptoms is usually 2 4 weeks but has been reported in individuals receiving anticonvulsants for 3 or more months. Although up to 1 in 5 patients on Dilantin may develop cutaneous eruptions, only a small proportion will progress to AHS.

Patients at higher risk for developing AHS include black patients, patients who have a family history of or who have experienced this syndrome in the past, and immuno-suppressed patients. The syndrome is more severe in previously sensitized individuals. If a patient is diagnosed with AHS, discontinue the Dilantin and provide appropriate supportive measures.

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.

Phenytoin should be discontinued if a skin rash appears (see WARNINGS section regarding drug discontinuation). If the rash is exfoliative, purpuric, or bullous or if lupus erythematosus, Stevens-Johnson syndrome, or toxic epidermal necrolysis is suspected, use of this drug should not be resumed and alternative therapy should be considered. (See ADVERSE REACTIONS section.) If the rash is of a milder type (measles-like or scarlatiniform), therapy may be resumed after the rash has completely disappeared. If the rash recurs upon reinstitution of therapy, further phenytoin medication is contraindicated.

Published literature has suggested that there may be an increased, although still rare, risk of hypersensitivity reactions, including skin rash, SJS, TEN, hepatotoxicity, and Anticonvulsant Hypersensitivity Syndrome in black patients. (See WARNINGS section).

Phenytoin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS). Additionally, caution should be exercised if using structurally similar compounds (e.g., barbiturates, succinimides, oxazolidinediones, and other related compounds) in these same patients. 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.

Osteomalacia has been associated with phenytoin therapy and is considered to be due to phenytoin's interference with vitamin D metabolism.

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

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 also be cautioned on the use of other drugs or alcoholic beverages without first seeking the physician's advice.

Patients should be instructed to call their physician if skin rash develops.

The importance of good dental hygiene should be stressed in order to minimize the development of gingival hyperplasia and its complications.

Patients, their caregivers, and families should be counseled that AEDs, including Dilantin, 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).

Do not use capsules which are discolored.

Laboratory Tests

Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments.

Drug Interactions

There are many drugs which may increase or decrease phenytoin levels or which phenytoin may affect. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected. The most commonly occurring drug interactions are listed below:

1. Drugs which may increase phenytoin serum levels include: acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, cimetidine, diazepam, dicumarol, disulfiram, estrogens, ethosuximide, fluoxetine, H2-antagonists, halothane, isoniazid, methylphenidate, phenothiazines, phenylbutazone, salicylates, succinimides, sulfonamides, ticlopidine, tolbutamide, trazodone.
2. Drugs which may decrease phenytoin levels include: carbamazepine, chronic alcohol abuse, reserpine, and sucralfate. Moban brand of molindone hydrochloride contains calcium ions which interfere with the absorption of phenytoin. Ingestion times of phenytoin and antacid preparations containing calcium should be staggered in patients with low serum phenytoin levels to prevent absorption problems.
3. Drugs which 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.
4. Although not a true drug interaction, tricyclic antidepressants may precipitate seizures in susceptible patients and phenytoin dosage may need to be adjusted.
5. Drugs whose efficacy is impaired by phenytoin include: corticosteroids, coumarin anticoagulants, digitoxin, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, theophylline, vitamin D.

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

See WARNINGS section for information on carcinogenesis.

Pregnancy

Pregnancy Category D

See WARNINGS section.

To provide information regarding the effects of in utero exposure to Dilantin, physicians are advised to recommend that pregnant patients taking Dilantin enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website 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.

Overdosage ⮝

The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression.

There are marked variations among individuals with respect to phenytoin plasma levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL; dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery.

Treatment

Treatment is nonspecific since there is no known antidote.

The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients.

In acute overdosage, the possibility of other CNS depressants, including alcohol, should be borne in mind.

How Supplied ⮝

A size 4 hemispherical Coni Snap capsule with a white opaque body and pale pink opaque cap containing a white powder. Capsule is imprinted with black rectified radial print, "PD" on cap and "Dilantin 30 mg" on body.

Bottles of 30	NDC 54868-1486-1
Bottles of 100	NDC 54868-1486-0

Hard, filled No. 3 capsules containing a white powder. The medium orange cap having "PD" printed in black ink and the white, opaque body having "DILANTIN" over "100 mg" printed in black ink.

Bottles of 60	NDC 54868-0325-7
Bottles of 90	NDC 54868-0325-2
Bottles of 100	NDC 54868-0325-1

Rx only

LAB-0375-6.0

August 2009

Relabeling and Repackaging by;
Physicians Total Care, Inc.
Tulsa, OK 74146

Principal Display Panel - 30 Mg Capsule  ⮝

DILANTIN phenytoin sodium capsule, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:69189-3742(NDC:0071-3740) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PHENYTOIN SODIUM (UNII: 4182431BJH) (PHENYTOIN - UNII:6158TKW0C5) PHENYTOIN SODIUM 30 mg

Inactive Ingredients Ingredient Name Strength LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) SUCROSE (UNII: C151H8M554) TALC (UNII: 7SEV7J4R1U) MAGNESIUM STEARATE (UNII: 70097M6I30) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) GELATIN (UNII: 2G86QN327L) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) FD&C RED NO. 3 (UNII: PN2ZH5LOQY)

Product Characteristics Color WHITE (opaque) , PINK (pale pink opaque) Score no score Shape CAPSULE Size 14mm Flavor Imprint Code PD;Dilantin;30;mg Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:69189-3742-1 1 in 1 DOSE PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA084349 09/14/2015

Labeler - Avera McKennan Hospital (068647668)

Establishment
Name	Address	ID/FEI	Business Operations
Avera McKennan Hospital		068647668	relabel(69189-3742) , repack(69189-3742)

Revised: 12/2015 Document Id: 1a2b8914-4ff8-4e63-9713-6012d9bd8f49 34391-3 Set id: 5554a280-0490-4235-9c8c-bea141db6884 Version: 1 Effective Time: 20151203 Avera McKennan Hospital

Phenytoin Sodium Er 30 Mg Capsules ⮝

DILANTIN phenytoin sodium capsule, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68151-1019(NDC:0071-3740) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PHENYTOIN SODIUM (UNII: 4182431BJH) (PHENYTOIN - UNII:6158TKW0C5) PHENYTOIN SODIUM 30 mg

Inactive Ingredients Ingredient Name Strength LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) SUCROSE (UNII: C151H8M554) TALC (UNII: 7SEV7J4R1U) MAGNESIUM STEARATE (UNII: 70097M6I30) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) FD&C RED NO. 3 (UNII: PN2ZH5LOQY)

Product Characteristics Color WHITE (opaque) , PINK (pale pink opaque) Score no score Shape CAPSULE Size 14mm Flavor Imprint Code PD;Dilantin;30;mg Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68151-1019-6 1 in 1 PACKAGE; Type 0: Not a Combination Product 08/27/1976

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA084349 08/27/1976

Labeler - Carilion Materials Management (079239644)

Establishment
Name	Address	ID/FEI	Business Operations
Carilion Materials Management		079239644	REPACK(68151-1019)

Revised: 7/2017 Document Id: c536d481-cc6d-4d3e-8d1d-accbec36c4dc 34391-3 Set id: 4f918d15-908e-4c3a-94d6-71370da9a116 Version: 4 Effective Time: 20170706 Carilion Materials Management

Principal Display Panel ⮝

Rx only

Dilantin
(Extended Phenytoin
Sodium Capsules, USP)

30 mg

Rx only

Dilantin
(phenytoin sodium)
Extended Oral Capsule

100 mg

DILANTIN phenytoin sodium capsule, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:54868-1486(NDC:0071-3740) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PHENYTOIN SODIUM (UNII: 4182431BJH) (PHENYTOIN - UNII:6158TKW0C5) PHENYTOIN SODIUM 30 mg

Inactive Ingredients Ingredient Name Strength LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) SUCROSE (UNII: C151H8M554) TALC (UNII: 7SEV7J4R1U) MAGNESIUM STEARATE (UNII: 70097M6I30) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) GELATIN (UNII: 2G86QN327L) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) FD&C RED NO. 3 (UNII: PN2ZH5LOQY)

Product Characteristics Color white (opaque) , pink (pale pink opaque) Score no score Shape CAPSULE Size 14mm Flavor Imprint Code PD;Dilantin;30;mg Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:54868-1486-0 100 in 1 BOTTLE, PLASTIC 2 NDC:54868-1486-1 30 in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA084349 08/19/2003

DILANTIN phenytoin sodium capsule, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:54868-0325(NDC:0071-0369) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PHENYTOIN SODIUM (UNII: 4182431BJH) (PHENYTOIN - UNII:6158TKW0C5) PHENYTOIN SODIUM 100 mg

Inactive Ingredients Ingredient Name Strength LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) SUCROSE (UNII: C151H8M554) TALC (UNII: 7SEV7J4R1U) MAGNESIUM STEARATE (UNII: 70097M6I30) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) D&C RED NO. 28 (UNII: 767IP0Y5NH) FD&C YELLOW NO. 6 (UNII: H77VEI93A8) GELATIN (UNII: 2G86QN327L)

Product Characteristics Color orange (medium orange) , white (white, opaque) Score no score Shape CAPSULE Size 16mm Flavor Imprint Code PD;DILANTIN;100;mg Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:54868-0325-1 100 in 1 BOTTLE, PLASTIC 2 NDC:54868-0325-2 90 in 1 BOTTLE, PLASTIC 3 NDC:54868-0325-7 60 in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA084349 01/27/1995

Labeler - Physicians Total Care, Inc. (194123980)

Establishment
Name	Address	ID/FEI	Business Operations
Physicians Total Care, Inc.		194123980	relabel, repack

Revised: 3/2010 Document Id: c239fe20-4f79-4610-8e05-e6e0f52c509d 34391-3 Set id: 1fd75c5a-f56b-42a2-aa4a-9cd0344d0a6f Version: 2 Effective Time: 20100304 Physicians Total Care, Inc.