These Highlights Do Not Include All The Information Needed To Use Phenytoin Oral Suspension Safely And Effectively. See Full Prescribing Information For Phenytoin Oral Suspension.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as phenytoin, during pregnancy. Physicians are advised to recommend that pregnant patients taking phenytoin 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/.

The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 grams to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. The patient may become comatose and hypotensive. Bradycardia and cardiac arrest have been reported [see Warnings and Precautions (5.6)] . Death is caused by respiratory and circulatory depression. There are marked variations among individuals with respect to phenytoin serum levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL, dysarthria and lethargy appear when the serum concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Irreversible cerebellar dysfunction and atrophy have been reported.

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 5 mL of the oral suspension contains 125 mg of phenytoin, USP; carboxymethylcellulose sodium, citric acid anhydrous, FD&C yellow no. 6, magnesium aluminum silicate, orange flavor spray dry natural and artificial, polysorbate 60, purified water, sodium benzoate, sucrose and vanilla flavored powder artificial.

Angioedema has been reported in patients treated with phenytoin in the post marketing setting. Phenytoin oral suspension should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur. Phenytoin oral suspension should be discontinued permanently if a clear alternative etiology for the reaction cannot be established.

The recommended starting dosage for adult patients who have received no previous treatment is 5 mL (125 mg/5 mL), or one teaspoonful, by mouth three times daily. Adjust the dosage to suit individual requirements, up to a maximum of 25 mL daily [see Dosage and Administration (2.4)].

What is the most important information I should know about phenytoin oral suspension?

• Do not stop taking phenytoin oral suspension without first talking to your healthcare provider.
  • Stopping phenytoin oral suspension 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).
• Like other antiepileptic drugs, phenytoin oral suspension 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:

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.

• Phenytoin oral suspension 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:

Call your healthcare provider even if the symptoms are mild or if you have been taking phenytoin for an extended period of time. These symptoms can be a sign of a serious allergic reaction.

• Phenytoin oral suspension can cause problems with your heart, including a slow heartbeat. Let your healthcare provider know right away if you have any of these symptoms:

What is phenytoin oral suspension?

Phenytoin oral suspension is a prescription medicine used to treat certain types of seizures called tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures.

Do not take phenytoin oral suspension if you:

• Are allergic to phenytoin or any of the ingredients in phenytoin oral suspension. See the end of this leaflet for a complete list of ingredients in phenytoin oral suspension.
• Have had an allergic reaction to CEREBYX (fosphenytoin), PEGANONE (ethotoin), or MESANTOIN (mephenytoin).
• Have had liver problems from taking phenytoin.
• Take delavirdine.

Before taking phenytoin oral suspension, tell your healthcare provider about all of your medical conditions, including if you:

• Have or have had depression, mood problems, or suicidal thoughts or behavior
• Have had an allergic reaction to a medicine similar to phenytoin called carboxamides, barbiturates, succinimides, and oxazolidinediones
• Have or had liver or kidney problems
• Have or had an enzyme problem called porphyria
• Have or had high blood sugar (hyperglycemia)
• Drink alcohol
• Are pregnant or plan to become pregnant. Phenytoin oral suspension may harm your unborn baby.
  • If you take phenytoin oral suspension during pregnancy, your baby is at risk for serious birth defects.
  • If you become pregnant while taking phenytoin oral suspension, the level of phenytoin in your blood may decrease, causing your seizures to become worse. Your healthcare provider may change your dose of phenytoin oral suspension.
  • If you take phenytoin oral suspension during pregnancy, your baby is also at risk for bleeding problems right after birth. Your healthcare provider may give you and your baby medicine to prevent this.
  • All women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of phenytoin oral suspension.
  • If you are of childbearing age and are not planning on getting pregnant, you should use effective birth control (contraception) while taking phenytoin oral suspension.
  • Pregnancy Registry: If you become pregnant while taking phenytoin oral suspension, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
• Are breastfeeding or plan to breastfeed. Phenytoin oral suspension can pass into breast milk. You and your healthcare provider should decide if you will take phenytoin while you are breastfeeding.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. These medicines can change the levels of phenytoin in your blood.

Taking phenytoin oral suspension with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take phenytoin oral suspension?

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

What should I avoid while taking phenytoin oral suspension?

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

What are the possible side effects of phenytoin oral suspension?

See " What is the most important information I should know about phenytoin oral suspension?"

Phenytoin oral suspension may cause other serious side effects including:

• Liver problems.
• Low blood count which could increase your chance of getting infections, bruising, bleeding and increased fatigue.
• Softening of your bones (osteopenia, osteoporosis, and osteomalacia) can cause your bones to break (fractures).
• High blood sugar (hyperglycemia).
• High levels of phenytoin in your blood that could cause confusion also known as delirium, psychosis or a more serious condition that affects how your brain works (encephalopathy).

Call your healthcare provider right away, if you have any of the symptoms listed above. The most common side effects of phenytoin oral suspension include:

Phenytoin can cause overgrowth of your gums. Brushing and flossing your teeth and seeing a dentist regularly while taking phenytoin oral suspension can help prevent this from happening.

These are not all of the possible side effects of phenytoin oral suspension.

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

How should I store phenytoin oral suspension?

• Store phenytoin oral suspension at room temperature between 68°F to 77°F (20°C to 25°C).
• Protect from light.
• Do not freeze.

Keep phenytoin oral suspension and all medicines out of the reach of children.

General information about the safe and effective use of phenytoin oral suspension.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use phenytoin oral suspension for a condition for which it was not prescribed. Do not give phenytoin oral suspension 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 phenytoin oral suspension that is written for health professionals.

What are the ingredients in phenytoin oral suspension?

Active ingredient: phenytoin, USP

Inactive ingredients: carboxymethylcellulose sodium, citric acid anhydrous, FD&C yellow no. 6, magnesium aluminum silicate, orange flavor spray dry natural and artificial, polysorbate 60, purified water, sodium benzoate, sucrose and vanilla flavored powder artificial.

PACKAGED BY

Pharmaceutical

Associates, Inc.

Greenville, SC 29605

www.paipharma.com

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

Revised: April 2020

Phenytoin Oral Suspension USP, 125 mg phenytoin/5 mL is supplied as follows:

NDC 0121-0892-63: 4 mL unit dose cup

NDC 0121-0892-50: Case contains 50 unit-dose cups of 4 mL (NDC 0121-0892-63).

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 mg/kg to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dosage (300 mg/day) [see Dosage and Administration (2.3)].

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 (2.7)] .

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.

Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These events may be part of the spectrum of DRESS or may occur in isolation [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, phenytoin should be immediately discontinued and not readministered.

Phenytoin oral suspension is contraindicated in patients with:

• A history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins [see Warnings and Precautions (5.5)]. Reactions have included angioedema.
• A history of prior acute hepatotoxicity attributable to phenytoin [see Warnings and Precautions (5.8)].
• 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.

Cases of bradycardia and cardiac arrest have been reported in phenytoin-treated patients, both at recommended phenytoin doses and levels, and in association with phenytoin toxicity [see Overdosage (10)] . Most of the reports of cardiac arrest occurred in patients with underlying cardiac disease.

The following serious adverse reactions are described elsewhere in the labeling:

• Withdrawal Precipitated Seizure, Status Epilepticus [see Warnings and Precautions (5.1)]
• Suicidal Behavior and Ideation [see Warnings and Precautions (5.2)]
• Serious Dermatologic Reactions [see Warnings and Precautions (5.3)]
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.4)]
• Hypersensitivity [see Warnings and Precautions (5.5)]
• Cardiac Effects [see Warnings and Precautions (5.6)]
• Angioedema [see Warnings and Precautions (5.7)]
• Hepatic Injury [see Warnings and Precautions (5.8)]
• Hematopoietic Complications [see Warnings and Precautions (5.9)]
• Effects on Vitamin D and Bone [see Warnings and Precautions (5.10)]
• Exacerbation of Porphyria [see Warnings and Precautions (5.12)]
• Teratogenicity and Other Harm to the Newborn [see Warnings and Precautions (5.13)]
• Hyperglycemia [see Warnings and Precautions (5.15)]

The following adverse reactions associated with the use of phenytoin were identified in clinical studies or postmarketing reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: Allergic reactions in the form of rash and rarely more serious forms and DRESS have been observed as has angioedema [see Warnings and Precautions (5.3, 5.4, 5.7)] . Anaphylaxis has also been reported.

There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities.

Digestive System: Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia.

Hematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease have been reported [see Warnings and Precautions (5.9)].

Laboratory Test Abnormality: Phenytoin may decrease serum concentrations of thyroid hormone (T4 and T3), sometimes with an accompanying increase in thyroid-stimulating hormone (TSH), but usually in the absence of clinical hypothyroidism. Phenytoin may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose [see Warnings and Precautions (5.15)], 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 (5.16)].

A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.

Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis [see Warnings and Precautions (5.3)] . There have also been reports of hypertrichosis and urticaria.

Special Senses: Altered taste sensation including metallic taste.

Urogenital: Peyronie's disease

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.

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 mg/kg/day to 8 mg/kg/day in equally divided doses. Children over 6 years and adolescents may require the minimum adult dosage (300 mg/day).

Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required [see Clinical Pharmacology (12.3)] .

Phenytoin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity [see Contraindications (4) and Warnings and Precautions (5.7)] . Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to phenytoin.

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 mcg/mL and 20 mcg/mL (unbound phenytoin concentrations of 1 mcg/mL to 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 (2.6)].

With recommended dosages, a period of seven to ten days may be required to achieve phenytoin steady-state blood levels, and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days.

Phenytoin oral suspension is indicated for the treatment of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures.

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.

SHAKE WELL BEFORE USING.

NOTE: Due to the viscous nature of this product, an overage is added in each unit-dose container in order to deliver 4 mL.

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Protect from light. Do not freeze.

• 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 phenytoin oral suspension 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)
• Cardiac Effects: Bradycardia and cardiac arrest have been reported. (5.6)
• Angioedema: Discontinue immediately if symptoms of angioedema such as facial, perioral, or upper airway swelling occur. (5.7)
• Hepatic Injury: Cases of acute hepatotoxicity have been reported with phenytoin oral suspension. If this occurs, immediately discontinue. (4, 5.8)
• Hematopoietic Complications: If occurs, follow-up observation is indicated and an alternative antiepileptic treatment should be used. (5.9)

• Adult starting dose in patients who have received no previous treatment is 5 mL three times daily, with dose adjustments as necessary, up to 25 mL daily. (2.2)
• 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 mg/kg/day to 8 mg/kg/day. (2.3)
• Serum blood level determinations may be necessary for optimal dosage adjustments-the clinically effective serum total concentration is 10 mcg/mL to 20 mcg/mL (unbound phenytoin concentration is 1 mcg/mL to 2 mcg/mL). (2.1)

Decreased serum concentrations of phenytoin may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations should be performed during pregnancy, and the phenytoin 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.

Phenytoin oral suspension is available as a 125 mg phenytoin/5 mL oral suspension of orange color with an orange-vanilla flavor.

• Pregnancy: Prenatal exposure may increase the risks for congenital malformations and other adverse developmental outcomes. (5.13, 8.1)
• Renal and/or Hepatic Impairment or Hypoalbuminemia: Monitor unbound phenytoin concentrations in these patients. (8.6)

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.

Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs of DRESS [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.

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.

Advise patients to read the FDA-approved patient labeling (Medication Guide).

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.

Antiepileptic drugs (AEDs), including phenytoin, 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.

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing phenytoin 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.

Phenytoin can cause severe cutaneous adverse reactions (SCARs), which may be fatal. Reported reactions in phenytoin-treated patients have included toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and Drug Reaction with Eosinophelia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.4)] . The onset of symptoms is usually within 28 days, but can occur later. Phenytoin oral suspension should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest a severe cutaneous adverse reaction, 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 SCARs.

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.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.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.

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 central nervous system (CNS) toxicity develop, serum levels should be checked immediately.

Care should be taken when using immunoanalytical methods to measure serum phenytoin concentrations.

Delivers 4 mL

NDC 0121-0892-63

PHENYTOIN ORAL

SUSPENSION USP

100 mg/4 mL

SHAKE WELL

NOT FOR PARENTERAL USE

Package Not Child-Resistant

Rx ONLY

Pkg. by: Pharmaceutical Associates, Inc.

Greenville, SC 29605

SEE INSERT

A0892631021

FOR ORAL ADMINISTRATION ONLY; NOT FOR PARENTERAL USE

A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A household teaspoon or tablespoon is not an adequate measuring device.

The free acid form of phenytoin is used in phenytoin oral suspension and phenytoin chewable tablets. Phenytoin extended capsules and parenteral phenytoin are formulated with the sodium salt of phenytoin. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa.

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.

Phenytoin may cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental 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.

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.

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.

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.

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.

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 not belonging to the hydantoin chemical class.

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.

Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients [see Warnings and Precautions (5.11) and Use in Specific Populations (8.6)].

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including phenytoin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, 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. Phenytoin should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as phenytoin, during pregnancy. Physicians are advised to recommend that pregnant patients taking phenytoin 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/.

The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 grams to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. The patient may become comatose and hypotensive. Bradycardia and cardiac arrest have been reported [see Warnings and Precautions (5.6)] . Death is caused by respiratory and circulatory depression. There are marked variations among individuals with respect to phenytoin serum levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL, dysarthria and lethargy appear when the serum concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Irreversible cerebellar dysfunction and atrophy have been reported.

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 5 mL of the oral suspension contains 125 mg of phenytoin, USP; carboxymethylcellulose sodium, citric acid anhydrous, FD&C yellow no. 6, magnesium aluminum silicate, orange flavor spray dry natural and artificial, polysorbate 60, purified water, sodium benzoate, sucrose and vanilla flavored powder artificial.

Angioedema has been reported in patients treated with phenytoin in the post marketing setting. Phenytoin oral suspension should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur. Phenytoin oral suspension should be discontinued permanently if a clear alternative etiology for the reaction cannot be established.

The recommended starting dosage for adult patients who have received no previous treatment is 5 mL (125 mg/5 mL), or one teaspoonful, by mouth three times daily. Adjust the dosage to suit individual requirements, up to a maximum of 25 mL daily [see Dosage and Administration (2.4)].

What is the most important information I should know about phenytoin oral suspension?

• Do not stop taking phenytoin oral suspension without first talking to your healthcare provider.
  • Stopping phenytoin oral suspension 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).
• Like other antiepileptic drugs, phenytoin oral suspension 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:

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.

• Phenytoin oral suspension 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:

Call your healthcare provider even if the symptoms are mild or if you have been taking phenytoin for an extended period of time. These symptoms can be a sign of a serious allergic reaction.

• Phenytoin oral suspension can cause problems with your heart, including a slow heartbeat. Let your healthcare provider know right away if you have any of these symptoms:

What is phenytoin oral suspension?

Phenytoin oral suspension is a prescription medicine used to treat certain types of seizures called tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures.

Do not take phenytoin oral suspension if you:

• Are allergic to phenytoin or any of the ingredients in phenytoin oral suspension. See the end of this leaflet for a complete list of ingredients in phenytoin oral suspension.
• Have had an allergic reaction to CEREBYX (fosphenytoin), PEGANONE (ethotoin), or MESANTOIN (mephenytoin).
• Have had liver problems from taking phenytoin.
• Take delavirdine.

Before taking phenytoin oral suspension, tell your healthcare provider about all of your medical conditions, including if you:

• Have or have had depression, mood problems, or suicidal thoughts or behavior
• Have had an allergic reaction to a medicine similar to phenytoin called carboxamides, barbiturates, succinimides, and oxazolidinediones
• Have or had liver or kidney problems
• Have or had an enzyme problem called porphyria
• Have or had high blood sugar (hyperglycemia)
• Drink alcohol
• Are pregnant or plan to become pregnant. Phenytoin oral suspension may harm your unborn baby.
  • If you take phenytoin oral suspension during pregnancy, your baby is at risk for serious birth defects.
  • If you become pregnant while taking phenytoin oral suspension, the level of phenytoin in your blood may decrease, causing your seizures to become worse. Your healthcare provider may change your dose of phenytoin oral suspension.
  • If you take phenytoin oral suspension during pregnancy, your baby is also at risk for bleeding problems right after birth. Your healthcare provider may give you and your baby medicine to prevent this.
  • All women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of phenytoin oral suspension.
  • If you are of childbearing age and are not planning on getting pregnant, you should use effective birth control (contraception) while taking phenytoin oral suspension.
  • Pregnancy Registry: If you become pregnant while taking phenytoin oral suspension, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
• Are breastfeeding or plan to breastfeed. Phenytoin oral suspension can pass into breast milk. You and your healthcare provider should decide if you will take phenytoin while you are breastfeeding.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. These medicines can change the levels of phenytoin in your blood.

Taking phenytoin oral suspension with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take phenytoin oral suspension?

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

What should I avoid while taking phenytoin oral suspension?

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

What are the possible side effects of phenytoin oral suspension?

See " What is the most important information I should know about phenytoin oral suspension?"

Phenytoin oral suspension may cause other serious side effects including:

• Liver problems.
• Low blood count which could increase your chance of getting infections, bruising, bleeding and increased fatigue.
• Softening of your bones (osteopenia, osteoporosis, and osteomalacia) can cause your bones to break (fractures).
• High blood sugar (hyperglycemia).
• High levels of phenytoin in your blood that could cause confusion also known as delirium, psychosis or a more serious condition that affects how your brain works (encephalopathy).

Call your healthcare provider right away, if you have any of the symptoms listed above. The most common side effects of phenytoin oral suspension include:

Phenytoin can cause overgrowth of your gums. Brushing and flossing your teeth and seeing a dentist regularly while taking phenytoin oral suspension can help prevent this from happening.

These are not all of the possible side effects of phenytoin oral suspension.

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

How should I store phenytoin oral suspension?

• Store phenytoin oral suspension at room temperature between 68°F to 77°F (20°C to 25°C).
• Protect from light.
• Do not freeze.

Keep phenytoin oral suspension and all medicines out of the reach of children.

General information about the safe and effective use of phenytoin oral suspension.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use phenytoin oral suspension for a condition for which it was not prescribed. Do not give phenytoin oral suspension 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 phenytoin oral suspension that is written for health professionals.

What are the ingredients in phenytoin oral suspension?

Active ingredient: phenytoin, USP

Inactive ingredients: carboxymethylcellulose sodium, citric acid anhydrous, FD&C yellow no. 6, magnesium aluminum silicate, orange flavor spray dry natural and artificial, polysorbate 60, purified water, sodium benzoate, sucrose and vanilla flavored powder artificial.

PACKAGED BY

Pharmaceutical

Associates, Inc.

Greenville, SC 29605

www.paipharma.com

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

Revised: April 2020

Phenytoin Oral Suspension USP, 125 mg phenytoin/5 mL is supplied as follows:

NDC 0121-0892-63: 4 mL unit dose cup

NDC 0121-0892-50: Case contains 50 unit-dose cups of 4 mL (NDC 0121-0892-63).

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 mg/kg to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dosage (300 mg/day) [see Dosage and Administration (2.3)].

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 (2.7)] .

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.

Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These events may be part of the spectrum of DRESS or may occur in isolation [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, phenytoin should be immediately discontinued and not readministered.

Phenytoin oral suspension is contraindicated in patients with:

• A history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins [see Warnings and Precautions (5.5)]. Reactions have included angioedema.
• A history of prior acute hepatotoxicity attributable to phenytoin [see Warnings and Precautions (5.8)].
• 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.

Cases of bradycardia and cardiac arrest have been reported in phenytoin-treated patients, both at recommended phenytoin doses and levels, and in association with phenytoin toxicity [see Overdosage (10)] . Most of the reports of cardiac arrest occurred in patients with underlying cardiac disease.

The following serious adverse reactions are described elsewhere in the labeling:

• Withdrawal Precipitated Seizure, Status Epilepticus [see Warnings and Precautions (5.1)]
• Suicidal Behavior and Ideation [see Warnings and Precautions (5.2)]
• Serious Dermatologic Reactions [see Warnings and Precautions (5.3)]
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.4)]
• Hypersensitivity [see Warnings and Precautions (5.5)]
• Cardiac Effects [see Warnings and Precautions (5.6)]
• Angioedema [see Warnings and Precautions (5.7)]
• Hepatic Injury [see Warnings and Precautions (5.8)]
• Hematopoietic Complications [see Warnings and Precautions (5.9)]
• Effects on Vitamin D and Bone [see Warnings and Precautions (5.10)]
• Exacerbation of Porphyria [see Warnings and Precautions (5.12)]
• Teratogenicity and Other Harm to the Newborn [see Warnings and Precautions (5.13)]
• Hyperglycemia [see Warnings and Precautions (5.15)]

The following adverse reactions associated with the use of phenytoin were identified in clinical studies or postmarketing reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: Allergic reactions in the form of rash and rarely more serious forms and DRESS have been observed as has angioedema [see Warnings and Precautions (5.3, 5.4, 5.7)] . Anaphylaxis has also been reported.

There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities.

Digestive System: Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia.

Hematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease have been reported [see Warnings and Precautions (5.9)].

Laboratory Test Abnormality: Phenytoin may decrease serum concentrations of thyroid hormone (T4 and T3), sometimes with an accompanying increase in thyroid-stimulating hormone (TSH), but usually in the absence of clinical hypothyroidism. Phenytoin may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose [see Warnings and Precautions (5.15)], 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 (5.16)].

A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.

Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis [see Warnings and Precautions (5.3)] . There have also been reports of hypertrichosis and urticaria.

Special Senses: Altered taste sensation including metallic taste.

Urogenital: Peyronie's disease

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.

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 mg/kg/day to 8 mg/kg/day in equally divided doses. Children over 6 years and adolescents may require the minimum adult dosage (300 mg/day).

Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required [see Clinical Pharmacology (12.3)] .

Phenytoin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity [see Contraindications (4) and Warnings and Precautions (5.7)] . Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to phenytoin.

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 mcg/mL and 20 mcg/mL (unbound phenytoin concentrations of 1 mcg/mL to 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 (2.6)].

With recommended dosages, a period of seven to ten days may be required to achieve phenytoin steady-state blood levels, and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days.

Phenytoin oral suspension is indicated for the treatment of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures.

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.

SHAKE WELL BEFORE USING.

NOTE: Due to the viscous nature of this product, an overage is added in each unit-dose container in order to deliver 4 mL.

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Protect from light. Do not freeze.

• 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 phenytoin oral suspension 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)
• Cardiac Effects: Bradycardia and cardiac arrest have been reported. (5.6)
• Angioedema: Discontinue immediately if symptoms of angioedema such as facial, perioral, or upper airway swelling occur. (5.7)
• Hepatic Injury: Cases of acute hepatotoxicity have been reported with phenytoin oral suspension. If this occurs, immediately discontinue. (4, 5.8)
• Hematopoietic Complications: If occurs, follow-up observation is indicated and an alternative antiepileptic treatment should be used. (5.9)

• Adult starting dose in patients who have received no previous treatment is 5 mL three times daily, with dose adjustments as necessary, up to 25 mL daily. (2.2)
• 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 mg/kg/day to 8 mg/kg/day. (2.3)
• Serum blood level determinations may be necessary for optimal dosage adjustments-the clinically effective serum total concentration is 10 mcg/mL to 20 mcg/mL (unbound phenytoin concentration is 1 mcg/mL to 2 mcg/mL). (2.1)

Decreased serum concentrations of phenytoin may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations should be performed during pregnancy, and the phenytoin 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.

Phenytoin oral suspension is available as a 125 mg phenytoin/5 mL oral suspension of orange color with an orange-vanilla flavor.

• Pregnancy: Prenatal exposure may increase the risks for congenital malformations and other adverse developmental outcomes. (5.13, 8.1)
• Renal and/or Hepatic Impairment or Hypoalbuminemia: Monitor unbound phenytoin concentrations in these patients. (8.6)

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.

Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs of DRESS [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.

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.

Advise patients to read the FDA-approved patient labeling (Medication Guide).

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.

Antiepileptic drugs (AEDs), including phenytoin, 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.

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing phenytoin 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.

Phenytoin can cause severe cutaneous adverse reactions (SCARs), which may be fatal. Reported reactions in phenytoin-treated patients have included toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and Drug Reaction with Eosinophelia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.4)] . The onset of symptoms is usually within 28 days, but can occur later. Phenytoin oral suspension should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest a severe cutaneous adverse reaction, 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 SCARs.

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.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.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.

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 central nervous system (CNS) toxicity develop, serum levels should be checked immediately.

Care should be taken when using immunoanalytical methods to measure serum phenytoin concentrations.

Delivers 4 mL

NDC 0121-0892-63

PHENYTOIN ORAL

SUSPENSION USP

100 mg/4 mL

SHAKE WELL

NOT FOR PARENTERAL USE

Package Not Child-Resistant

Rx ONLY

Pkg. by: Pharmaceutical Associates, Inc.

Greenville, SC 29605

SEE INSERT

A0892631021

FOR ORAL ADMINISTRATION ONLY; NOT FOR PARENTERAL USE

A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A household teaspoon or tablespoon is not an adequate measuring device.

The free acid form of phenytoin is used in phenytoin oral suspension and phenytoin chewable tablets. Phenytoin extended capsules and parenteral phenytoin are formulated with the sodium salt of phenytoin. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa.

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.

Phenytoin may cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental 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.

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.

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.

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.

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.

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 not belonging to the hydantoin chemical class.

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.

Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients [see Warnings and Precautions (5.11) and Use in Specific Populations (8.6)].

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including phenytoin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, 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. Phenytoin should be discontinued if an alternative etiology for the signs or symptoms cannot be established.