Phenytoin Sodium
Phenytoin Sodium Prescribing Information
Warnings and Precautions (5.3) 2/2021
Extended phenytoin sodium capsules are indicated for the treatment of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery.
- Adult starting dose in patients who have received no previous treatment is one 100 mg extended phenytoin sodium capsule three times a day, with dose adjustments as necessary. For most adults, the satisfactory maintenance dose will be one capsule three to four times a day. An increase, up to two capsules three times a day may be made, if necessary.Divided daily dosage:
- Adult once-a-day dose: If seizure control is established with divided doses of three 100 mg extended phenytoin sodium capsules daily, once-a-day dosage with 300 mg extended phenytoin sodium capsules may be considered. Divided daily dosage:
- 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. Divided daily dosage:
- Pediatricstartingdoseis5mg/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.
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).
- Serum blood level determinations may be necessary for optimal dosage adjustments - the clinically effective serum total concentration is 10 to 20 mcg/mL (unbound phenytoin concentration is 1 to2mcg/mL).
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)].
Extended Phenytoin Sodium Capsules, USP 100 mg are hard gelatin capsules of size '3' with white to off white opaque cap and white to off white opaque body imprinted 'U' on cap and '379' on the body with black ink containing white to off white powder.
- Pregnancy: Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes.,5.13 Teratogenicity and Other Harm to the Newborn
Extended phenytoin sodium capsules 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.
)8.1 PregnancyPregnancy Exposure RegistryThere is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as extended phenytoin sodium capsules, during pregnancy. Physicians are advised to recommend that pregnant patients taking extended phenytoin sodium capsules enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the tollfree number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website
http://www.aedpregnancyregistry.org/Risk SummaryIn humans, prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Prenatal phenytoin exposure is associated with an increased incidence of major malformations, including orofacial clefts and cardiac defects. In addition, the fetal hydantoin syndrome, a pattern of abnormalities including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy
[see Data]. There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.Administration of phenytoin to pregnant animals resulted in an increased incidence of fetal malformations and other manifestations of developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple species at clinically relevant doses
[see Data].In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Clinical ConsiderationsDisease-associated maternal riskAn 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 ReactionsA 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.DataHuman DataMeta-analyses using data from published observational studies and registries have estimated an approximately
2.4-fold increased risk for any major malformation in children with prenatal phenytoin exposure compared to controls. An increased risk of heart defects, facial clefts, and digital hypoplasia has been reported. The fetal hydantoin syndrome is a pattern of congenital anomalies including craniofacial anomalies, nail and digital hypoplasia, prenatal-onset growth deficiency, and neurodevelopmental deficiencies.
Animal DataAdministration 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.
- Renal and/or Hepatic Impairment or Hypoalbuminemia: Monitor unbound phenytoin concentrations in these patients.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.
Extended phenytoin sodium capsules is contraindicated in patients with:
- A history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins [see. Reactions have included angioedema.]
5 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 extended phenytoin sodium capsules 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 extended phenytoin sodium capsules. If this occurs, immediately discontinue.
- Hematopoietic Complications:If occurs, follow-up observation is indicated and an alternative antiepileptic treatment should be used. (5.9)
5.1 Withdrawal Precipitated Seizure, Status EpilepticusAbrupt 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 IdeationAntiepileptic drugs (AEDs), including extended phenytoin sodium capsules, 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 PatientsRelative Risk:
Incidence of Events in Drug Patients/ Incidence in Placebo PatientsRisk Difference:
Additional Drug Patients with Events Per 1000 PatientsEpilepsy 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 extended phenytoin sodium capsules 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 ReactionsExtended Phenytoin Sodium Capsules 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 Eosinophilia and Systemic Symptoms (DRESS) [
see Warnings and Precautions (5.4)]. The onset of symptoms is usually within 28 days, but can occur later. Extended Phenytoin Sodium Capsules 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. In addition, retrospective, case-control, genome-wide association studies in patients of southeast Asian ancestry have also identified an increased risk of SCARs in carriers of the decreased function CYP2C9*3 variant, which has also been associated with decreased clearance of phenytoin. Consider avoiding extended phenytoin sodium capsules as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers
[see Use in Specific Populations (8.7)and Clinical Pharmacology (12.5)].The use of HLA-B*1502 or CYP2C9 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 HypersensitivityDrug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including extended phenytoin sodium capsules. 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. Extended phenytoin sodium capsules should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
5.5 HypersensitivityExtended phenytoin sodium capsules 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 extended phenytoin sodium capsules.5.6 Cardiac EffectsCases of bradycardia and cardiac arrest have been reported in extended phenytoin sodium capsules-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.5.7 AngioedemaAngioedema has been reported in patients treated with extended phenytoin sodium capsules in the postmarketing setting. Extended phenytoin sodium capsules should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur. Extended phenytoin sodium capsules should be discontinued permanently if a clear alternative etiology for the reaction cannot be established.
5.8 Hepatic InjuryCases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with extended phenytoin sodium capsules. 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, extended phenytoin sodium capsules should be immediately discontinued and not readministered.5.9 Hematopoietic ComplicationsHematopoietic complications, some fatal, have occasionally been reported in association with administration of extended phenytoin sodium capsules. 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.
5.10 Effects on Vitamin D and BoneThe 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.
5.11 Renal or Hepatic Impairment or HypoalbuminemiaBecause 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.
5.12 Exacerbation of PorphyriaIn view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease.
5.13 Teratogenicity and Other Harm to the NewbornExtended phenytoin sodium capsules 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.
5.14 HyperglycemiaHyperglycemia, resulting from the drug's inhibitory effects on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients.
5.15 Serum Phenytoin Levels above Therapeutic RangeSerum 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.
- A history of prior acute hepatotoxicity attributable to phenytoin [see].5.8 Hepatic Injury
Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with extended phenytoin sodium capsules. 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, extended phenytoin sodium capsules should be immediately discontinued and not readministered. - 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.