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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
DILANTIN-125 (NDA-008762)
(PHENYTOIN)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
03/03/2022 (SUPPL-66)
6 Adverse Reactions
Additions underlined
…
The following adverse reactions associated with the use of DILANTIN were identified in clinical studies or postmarketing reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
…
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)]. Pure red cell aplasia has also been reported.
…
7 Drug Interactions
7.2 Drugs Affected by PhenytoinAddition of the following (underlined) to Table 3 under Drugs whose level is decreased by phenytoin
Interacting Agent: Anticoagulants
Examples: Apixaban, dabigatran, edoxaban, rivaroxaban
Interacting Agent: Antiepileptic drugs
Examples: Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, lacosamide
Interacting Agent: Antiplatelets
Examples: Ticagrelor
New subsection added
Concomitant administration of phenytoin and valproate has been associated with an increased risk of valproate-associated hyperammonemia. Patients treated concomitantly with these two drugs should be monitored for signs and symptoms of hyperammonemia.
02/16/2021 (SUPPL-65)
5 Warnings and Precautions
5.3 Serious Dermatologic ReactionsAdditions underlined
…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 DILANTIN 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.
7 Drug Interactions
Additions underlined
Phenytoin is extensively bound to plasma proteins and is prone to competitive displacement. Phenytoin is primarily metabolized by the hepatic cytochrome P450 enzyme CYP2C9 and to a lesser extent by CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism.
…
8 Use in Specific Populations
8.7 Use in Patients with Decreased CYP2C9 FunctionNew subsection added
Patients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g., *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g.,*1/*1). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses of phenytoin to maintain similar steady-state concentrations compared to normal metabolizers. If early signs of dose-related central nervous system (CNS) toxicity develop, serum concentrations should be checked immediately [see Clinical Pharmacology (12.5)].
07/12/2019 (SUPPL-63)
4 Contraindications
Additions and/or revisions underlined:
A history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins. Reactions have included angioedema.
5 Warnings and Precautions
5.3 Serious Dermatologic Reactions
Additions and/or
revisions underlined:
DILANTIN
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). The
onset of symptoms is usually within 28 days but can occur later. DILANTIN
should be discontinued at the first sign of a rash, unless the rash is clearly
not drug-related. If signs or symptoms suggest 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.
Newly added subsection:
5.7 Angiodema
Angioedema has been reported in patients treated with DILANTIN in the post marketing setting. DILANTIN should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur. DILANTIN should be discontinued permanently if a clear alternative etiology for the reaction cannot be established.
6 Adverse Reactions
Addition of ‘angioedema’ to the bulleted line listing.
Additions underlined:
Body as a Whole: Allergic reactions in the form of rash and rarely more serious forms and DRESS have been observed, as has angioedema …
Skin and Appendages: … 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. There have also been reports of hypertrichosis and urticaria.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONNewly added information:
Serious Dermatologic Reactions
Advise patients of the early signs and symptoms of severe cutaneous adverse reactions and to report any occurrence immediately to a physician.
Angioedema
Advise patients to discontinue DILANTIN and seek immediate medical care if they develop signs or symptoms of angioedema, such as facial, perioral, or upper airway swelling
10/18/2018 (SUPPL-62)
5 Warnings and Precautions
5.6 Cardiac Effects(Additions and/or revisions are underlined)
Cases of bradycardia and cardiac arrest have been reported in DILANTIN-treated patients, both at recommended phenytoin doses and levels, and in association with phenytoin toxicity. Most of the reports of cardiac arrest occurred in patients with underlying cardiac disease.
6 Adverse Reactions
(Additions and/or revisions are underlined)
The following serious adverse reactions are described elsewhere in the labeling:
Cardiac Effects
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Cardiac Effects
Counsel patients that cases of bradycardia and cardiac arrest have been reported, both at recommended phenytoin doses and levels, and in association with phenytoin toxicity. Patients should report cardiac signs or symptoms to their healthcare provider.
(Additions and/or revisions are underlined)
4. DILANTIN can cause problems with your heart, including a slow heartbeat. Let your healthcare provider know right away if you have any of these symptoms:
dizziness
tiredness
feeling like your heart is beating slowly or skipping beats
10/31/2017 (SUPPL-61)
8 Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
Risk Summary
In humans, prenatal exposure to phenytoin (the active metabolite of CEREBYX) 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 …
… The background risk of major birth defects and miscarriage for the indicated population is unknown.
Data
Human Data
Meta-analyses using data from published observational studies and registries have estimated an approximately 2.4-fold increased risk for any major malformation in children with prenatal phenytoin exposure compared to controls. An increased risk of heart defects, facial clefts, and digital hypoplasia has been reported. The fetal hydantoin syndrome is a pattern of congenital anomalies including craniofacial anomalies, nail and digital hypoplasia, prenatal-onset growth deficiency, and neurodevelopmental deficiencies.
Animal Data
…
08/15/2017 (SUPPL-59)
6 Adverse Reactions
Additions and/or revisions underlined:
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 …
11/30/2016 (SUPPL-57)
4 Contraindications
(additions and/or revisions are underlined)
A history of prior acute hepatotoxicity attributable to phenytoin
Coadministration with delavirdine because of the potential for …
5 Warnings and Precautions
PLR Conversion:
(revised subsection title)
(Additions and/or revisions are underlined)
DILANTIN may cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse development outcomes.
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 …
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.
(Additions and/or revisions are underlined)
A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be caused by limited enzyme availability and lack of induction; it appears to be genetically determined. If early signs of dose-related CNS toxicity develop, serum levels should be checked immediately.
(Additions and/or revisions are underlined)
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.
(Newly added section)
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.
6 Adverse Reactions
PLR Conversion (Additions and/or revisions are underlined):
The following serious adverse reactions are described elsewhere in the labeling:
Withdrawal Precipitated Seizure, Status Epilepticus
Suicidal Behavior and Ideation
Serious Dermatologic Reactions
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity
Hypersensitivity
Hepatic Injury
Hematopoietic Complications
Effects on Vitamin D and Bone
Exacerbation of Porphyria
Teratogenicity and Other Harm to the Newborn
Hyperglycemia
The following adverse reactions associated with the use of DILANTIN were identified in clinical studies or postmarketing reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug.
Laboratory Test Abnormality: Phenytoin may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose, 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. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.
Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. There have also been reports of hypertrichosis.
7 Drug Interactions
PLR Conversion (Additions and/or revisions are underlined):
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.
(Additions and/or revisions are underlined)
Table 1 includes commonly occurring drugs interactions that affect phenytoin concentrations. However, this list is not intended to be inclusive or comprehensive. Individual prescribing information from relevant drugs should be consulted.
The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome.
Table 1: Drugs That Affect Phenytoin Concentrations (Newly added table; please refer to label).
(Additions and/or revisions are underlined)
Table 2 includes commonly occurring drug interactions affected by phenytoin. However, this list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted.
The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome.
Table 2: Drugs Affected by Phenytoin (Newly added table; please refer to label)
(Additions and/or revisions are underlined)
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 …
(Additions and/or revisions are underlined)
Care should be taken when using immunoanalytical methods to measure serum phenytoin concentrations.
8 Use in Specific Populations
8.1 Pregnancy(PLLR Conversion)
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as DILANTIN, during pregnancy. Physicians are advised to recommend that pregnant patients taking Dilantin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/
Risk Summary
In humans, prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. An increased incidence of major malformations (such as orofacial clefts and cardiac defects) and abnormalities characteristic of fetal hydantoin syndrome (dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities [including microcephaly], and cognitive deficits) has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.
Administration of phenytoin to pregnant animals resulted in an increased incidence of fetal malformations and other manifestations of developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple species at clinically relevant doses.
In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (including phenytoin) during pregnancy is about 10%, or two- to three-fold that in the general population.
Clinical Considerations
Disease-associated maternal risk
An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage. However, postpartum restoration of the original dosage will probably be indicated.
Fetal/Neonatal Adverse Reactions
A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.
Data
Animal data
Administration of phenytoin to pregnant rats, rabbits, and mice during organogenesis resulted in embryofetal death, fetal malformations, and decreased fetal growth. Malformations (including craniofacial, cardiovascular, neural, limb, and digit abnormalities) were observed in rats, rabbits, and mice at doses as low as 100, 75, and12.5 mg/kg, respectively.
(PLLR Conversion)
Risk Summary
Phenytoin is secreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DILANTIN and any potential adverse effects on the breastfed infant from DILANTIN or from the underlying maternal condition.
(Additions and/or revisions are underlined)
Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dosage (300 mg/day).
(Additions and/or revisions are underlined)
Phenytoin clearance tends to decrease with increasing age. Lower or less frequent dosing may be required.
(Additions and/or revisions are underlined)
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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Newly Added Section)
Advise patients to read the FDA-approved patient labeling (Medication Guide).
Administration Information
Advise patients taking phenytoin of the importance of adhering strictly to the prescribed dosage regimen, and of informing the physician of any clinical condition in which it is not possible to take the drug orally as prescribed, e.g., surgery, etc.
Instruct patients to use an accurately calibrated measuring device when using this medication to ensure accurate dosing.
Withdrawal of Antiepileptic Drugs
Advise patients not to discontinue use of DILANTIN without consulting with their healthcare provider. DILANTIN should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus.
Suicidal Ideation and Behavior
Counsel patients, their caregivers, and families that AEDs, including DILANTIN, may increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Potential Signs of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Other Systemic Reactions
Advise patients of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy, facial swelling, and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. Advise the patient that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, advise the patient that these signs and symptoms should be reported even if mild or when occurring after extended use.
Effects of Alcohol Use and Other Drugs and Over-the-Counter Drug Interactions
Caution patients against the use of other drugs or alcoholic beverages without first seeking their physician’s advice.
Inform patients Inform patients that certain over-the-counter medications (e.g., cimetidine and omeprazole), vitamins (e.g., folic acid), and herbal supplements (e.g., St. John’s wort) can alter their phenytoin levels.
Hyperglycemia
Advise patients that DILANTIN may cause an increase in blood glucose levels.
Gingival Hyperplasia
Advise patients of the importance of good dental hygiene in order to minimize the development of gingival hyperplasia and its complications.
Neurologic Effects
Counsel patients that DILANTIN may cause dizziness, gait disturbance, decreased coordination and somnolence. Advise patients taking DILANTIN not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with DILANTIN.
Use in Pregnancy
Inform pregnant women and women of childbearing potential that use of DILANTIN during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), cardiac defects, dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits. When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using DILANTIN, keeping in mind that there is a potential for decreased hormonal contraceptive efficacy.
Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breastfeeding or intend to breastfeed during therapy.
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy.
Extensive changes; please refer to label.
Other
PLR Conversion
11/30/2016 (SUPPL-58)
4 Contraindications
(additions and/or revisions are underlined)
A history of prior acute hepatotoxicity attributable to phenytoin
Coadministration with delavirdine because of the potential for …
5 Warnings and Precautions
PLR Conversion:
(revised subsection title)
(Additions and/or revisions are underlined)
DILANTIN may cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse development outcomes.
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 …
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.
(Additions and/or revisions are underlined)
A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be caused by limited enzyme availability and lack of induction; it appears to be genetically determined. If early signs of dose-related CNS toxicity develop, serum levels should be checked immediately.
(Additions and/or revisions are underlined)
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.
(Newly added section)
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.
6 Adverse Reactions
PLR Conversion (Additions and/or revisions are underlined):
The following serious adverse reactions are described elsewhere in the labeling:
Withdrawal Precipitated Seizure, Status Epilepticus
Suicidal Behavior and Ideation
Serious Dermatologic Reactions
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity
Hypersensitivity
Hepatic Injury
Hematopoietic Complications
Effects on Vitamin D and Bone
Exacerbation of Porphyria
Teratogenicity and Other Harm to the Newborn
Hyperglycemia
The following adverse reactions associated with the use of DILANTIN were identified in clinical studies or postmarketing reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug.
Laboratory Test Abnormality: Phenytoin may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose, 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. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.
Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. There have also been reports of hypertrichosis.
7 Drug Interactions
PLR Conversion (Additions and/or revisions are underlined):
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.
(Additions and/or revisions are underlined)
Table 1 includes commonly occurring drugs interactions that affect phenytoin concentrations. However, this list is not intended to be inclusive or comprehensive. Individual prescribing information from relevant drugs should be consulted.
The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome.
Table 1: Drugs That Affect Phenytoin Concentrations (Newly added table; please refer to label).
(Additions and/or revisions are underlined)
Table 2 includes commonly occurring drug interactions affected by phenytoin. However, this list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome.
Table 2: Drugs Affected by Phenytoin (Newly added table; please refer to label)
(Additions and/or revisions are underlined)
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 …
(Additions and/or revisions are underlined)
Care should be taken when using immunoanalytical methods to measure serum phenytoin concentrations.
8 Use in Specific Populations
8.1 Pregnancy(PLLR Conversion)
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as DILANTIN, during pregnancy. Physicians are advised to recommend that pregnant patients taking Dilantin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/
Risk Summary
In humans, prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. An increased incidence of major malformations (such as orofacial clefts and cardiac defects) and abnormalities characteristic of fetal hydantoin syndrome (dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities [including microcephaly], and cognitive deficits) has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.
Administration of phenytoin to pregnant animals resulted in an increased incidence of fetal malformations and other manifestations of developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple species at clinically relevant doses.
In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (including phenytoin) during pregnancy is about 10%, or two- to three-fold that in the general population.
Clinical Considerations
Disease-associated maternal risk
An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage. However, postpartum restoration of the original dosage will probably be indicated.
Fetal/Neonatal Adverse Reactions
A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.
Data
Animal data
Administration of phenytoin to pregnant rats, rabbits, and mice during organogenesis resulted in embryofetal death, fetal malformations, and decreased fetal growth. Malformations (including craniofacial, cardiovascular, neural, limb, and digit abnormalities) were observed in rats, rabbits, and mice at doses as low as 100, 75, and12.5 mg/kg, respectively.
(PLLR Conversion)
Risk Summary
Phenytoin is secreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DILANTIN and any potential adverse effects on the breastfed infant from DILANTIN or from the underlying maternal condition.
(Additions and/or revisions are underlined)
Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dosage (300 mg/day).
(Additions and/or revisions are underlined)
Phenytoin clearance tends to decrease with increasing age. Lower or less frequent dosing may be required.
(Additions and/or revisions are underlined)
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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Newly Added Section)
Advise patients to read the FDA-approved patient labeling (Medication Guide).
Administration Information
Advise patients taking phenytoin of the importance of adhering strictly to the prescribed dosage regimen, and of informing the physician of any clinical condition in which it is not possible to take the drug orally as prescribed, e.g., surgery, etc.
Instruct patients to use an accurately calibrated measuring device when using this medication to ensure accurate dosing.
Withdrawal of Antiepileptic Drugs
Advise patients not to discontinue use of DILANTIN without consulting with their healthcare provider. DILANTIN should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus.
Suicidal Ideation and Behavior
Counsel patients, their caregivers, and families that AEDs, including DILANTIN, may increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Potential Signs of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Other Systemic Reactions
Advise patients of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy, facial swelling, and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. Advise the patient that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, advise the patient that these signs and symptoms should be reported even if mild or when occurring after extended use.
Effects of Alcohol Use and Other Drugs and Over-the-Counter Drug Interactions
Caution patients against the use of other drugs or alcoholic beverages without first seeking their physician’s advice.
Inform patients Inform patients that certain over-the-counter medications (e.g., cimetidine and omeprazole), vitamins (e.g., folic acid), and herbal supplements (e.g., St. John’s wort) can alter their phenytoin levels.
Hyperglycemia
Advise patients that DILANTIN may cause an increase in blood glucose levels.
Gingival Hyperplasia
Advise patients of the importance of good dental hygiene in order to minimize the development of gingival hyperplasia and its complications.
Neurologic Effects
Counsel patients that DILANTIN may cause dizziness, gait disturbance, decreased coordination and somnolence. Advise patients taking DILANTIN not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with DILANTIN.
Use in Pregnancy
Inform pregnant women and women of childbearing potential that use of DILANTIN during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), cardiac defects, dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits. When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using DILANTIN, keeping in mind that there is a potential for decreased hormonal contraceptive efficacy.
Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breastfeeding or intend to breastfeed during therapy.
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy.
Extensive changes; please refer to label.
Other
PLR Conversion
06/16/2016 (SUPPL-55)
5 Warnings and Precautions
General- Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely irreversible cerebellar dysfunction and/or cerebellar atrophy. (addition of cerebellar atrophy).
6 Adverse Reactions
- Nervous System: Cerebellar atrophy has been reported, and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use. (addition to first paragraph)