Generic Name: PHENYTOIN
Brand Name: Dilantin-125
- Substance Name(s):
- PHENYTOIN
DRUG INTERACTIONS
7 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.
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.
Multiple drug interactions because of extensive plasma protein binding, saturable metabolism and potent induction of hepatic enzymes ( 7.1 , 7.2 ).
7.1 Drugs that Affect Phenytoin Concentrations Table 2 includes commonly occurring drug interactions that affect phenytoin concentrations.
However, this list is not intended to be inclusive or comprehensive.
Individual prescribing information from relevant drugs should be consulted.
The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome.
Table 2: Drugs That Affect Phenytoin Concentrations Interacting Agent Examples Drugs that may increase phenytoin serum levels Antiepileptic drugs Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate Azoles Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole Antineoplastic agents Capecitabine, fluorouracil Antidepressants Fluoxetine, fluvoxamine, sertraline Gastric acid reducing agents H 2 antagonists (cimetidine), omeprazole Sulfonamides Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim Other Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin Drugs that may decrease phenytoin serum levels Antacids Antacids may affect absorption of phenytoin.
Calcium carbonate, aluminum hydroxide, magnesium hydroxide Prevention or Management: Phenytoin and antacids should not be taken at the same time of day Antineoplastic agents (usually in combination) Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate Antiviral agents Fosamprenavir, nelfinavir, ritonavir Antiepileptic drugs Carbamazepine, vigabatrin Other Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St.
John’s wort The induction potency of St.
John’s wort may vary widely based on preparation.
, sucralfate, theophylline Drugs that may either increase or decrease phenytoin serum levels Antiepileptic drugs Phenobarbital, valproate sodium Valproate sodium and valproic acid are similar medications.
The term valproate has been used to represent these medications.
, valproic acid 7.2 Drugs Affected by Phenytoin Table 3 includes commonly occurring drug interactions affected by phenytoin.
However, this list is not intended to be inclusive or comprehensive.
Individual drug package inserts should be consulted.
The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome.
Table 3: Drugs Affected by Phenytoin Interacting Agent Examples Drugs whose efficacy is impaired by phenytoin Azoles Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole Antineoplastic agents Irinotecan, paclitaxel, teniposide Delavirdine Phenytoin can substantially reduce the concentrations of delavirdine.
This can lead to loss of virologic response and possible resistance [see Contraindications (4) ].
Neuromuscular blocking agents Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin.
Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown.
Prevention or Management: Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
Warfarin Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin Other Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D Drugs whose level is decreased by phenytoin Anticoagulants Apixaban, dabigatran, edoxaban, rivaroxaban Antiepileptic drugs The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, lacosamide Antilipidemic agents Atorvastatin, fluvastatin, simvastatin Antiplatelets Ticagrelor Antiviral agents Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite.
Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir Calcium channel blockers Nifedipine, nimodipine, nisoldipine, verapamil Other Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine 7.3 Hyperammonemia with Concomitant Use of Valproate 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.
7.4 Drug Enteral Feeding/Nutritional Preparations Interaction Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin serum levels.
It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation.
More frequent serum phenytoin level monitoring may be necessary in these patients.
7.5 Drug/Laboratory Test Interactions Care should be taken when using immunoanalytical methods to measure serum phenytoin concentrations.
OVERDOSAGE
10 The lethal dose in pediatric patients is not known.
The lethal dose in adults is estimated to be 2 to 5 grams.
The initial symptoms are nystagmus, ataxia, and dysarthria.
Other signs are tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting.
The patient may become comatose and hypotensive.
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.
Treatment: Treatment is nonspecific since there is no known antidote.
The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed.
Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins.
Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients.
In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.
DESCRIPTION
11 DILANTIN (phenytoin) is related to the barbiturates in chemical structure, but has a five-membered ring.
The chemical name is 5,5-diphenyl-2,4 imidazolidinedione, having the following structural formula: Each 5 mL of the oral suspension contains 125 mg of phenytoin, USP; alcohol, USP (maximum content not greater than 0.6 percent); banana flavor; carboxymethylcellulose sodium, USP; citric acid, anhydrous, USP; glycerin, USP; magnesium aluminum silicate, NF; orange oil concentrate; polysorbate 40, NF; purified water, USP; sodium benzoate, NF; sucrose, NF; vanillin, NF; and FD&C yellow No.
6.
Chemical Structure
HOW SUPPLIED
16 /STORAGE AND HANDLING 16.1 How Supplied DILANTIN-125 Oral Suspension is supplied as follows: Package Configuration Strength NDC 8 oz glass bottles 125 mg phenytoin/5 mL 0071-2214-20 8 oz amber polyethylene terephthalate (PET) bottles 125 mg phenytoin/5 mL 0071-2214-35 DILANTIN-125 Suspension (phenytoin oral suspension, USP), 125 mg phenytoin/5 mL contains a maximum alcohol content not greater than 0.6 percent in an orange suspension with an orange-vanilla flavor.
16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); see USP controlled room temperature.
Protect from light.
Do not freeze.
GERIATRIC USE
8.5 Geriatric Use Phenytoin clearance tends to decrease with increasing age [see Clinical Pharmacology (12.3) ] .
Lower or less frequent dosing may be required [see Dosage and Administration (2.7) ] .
DOSAGE FORMS AND STRENGTHS
3 DILANTIN-125 is available as a 125 mg phenytoin/5 mL oral suspension of orange color with an orange-vanilla flavor.
DILANTIN-125 is available as a 125 mg phenytoin/5 mL oral suspension.
( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action The precise mechanism by which phenytoin exerts its therapeutic effect has not been established but is thought to involve the voltage-dependent blockade of membrane sodium channels resulting in a reduction in sustained high-frequency neuronal discharges.
INDICATIONS AND USAGE
1 DILANTIN is indicated for the treatment of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures.
DILANTIN is indicated for the treatment of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures.
( 1 )
PEDIATRIC USE
8.4 Pediatric Use Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily.
A recommended daily maintenance dosage is usually 4 to 8 mg/kg.
Children over 6 years and adolescents may require the minimum adult dosage (300 mg/day) [see Dosage and Administration (2.3) ].
PREGNANCY
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as DILANTIN, during pregnancy.
Physicians are advised to recommend that pregnant patients taking DILANTIN enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry.
This can be done by calling the 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 Summary In 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 Considerations Disease-associated maternal risk An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics.
Periodic measurement of serum phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage [see Dosage and Administration (2.4 , 2.8) ] .
However, postpartum restoration of the original dosage will probably be indicated [see Clinical Pharmacology (12.3) ] .
Fetal/Neonatal Adverse Reactions A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero .
This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.
Data 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 Administration of phenytoin to pregnant rats, rabbits, and mice during organogenesis resulted in embryofetal death, fetal malformations, and decreased fetal growth.
Malformations (including craniofacial, cardiovascular, neural, limb, and digit abnormalities) were observed in rats, rabbits, and mice at doses as low as 100, 75, and 12.5 mg/kg, respectively.
WARNING AND CAUTIONS
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 DILANTIN at the first sign of a rash, unless the rash is clearly not drug-related.
If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.
( 5.3 ) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity: If signs or symptoms of hypersensitivity are present, evaluate the patient immediately.
Discontinue if an alternative etiology cannot be established.
( 5.4 ) • 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 DILANTIN.
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 ) 5.1 Withdrawal Precipitated Seizure, Status Epilepticus Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus.
When in the judgment of the clinician the need for dosage reduction, discontinuation, or substitution of alternative anticonvulsant medication arises, this should be done gradually.
However, in the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary.
In this case, alternative therapy should be an anticonvulsant not belonging to the hydantoin chemical class.
5.2 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including DILANTIN, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.
Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.
In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.
There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed.
Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.
The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.
The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
Table 1 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing DILANTIN or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.
Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
Behaviors of concern should be reported immediately to healthcare providers.
5.3 Serious Dermatologic Reactions 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) [see Warnings and Precautions (5.4) ].
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.
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 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.
5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/ Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including DILANTIN.
Some of these events have been fatal or life-threatening.
DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection.
Eosinophilia is often present.
Because this disorder is variable in its expression, other organ systems not noted here may be involved.
It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident.
If such signs or symptoms are present, the patient should be evaluated immediately.
DILANTIN should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
5.5 Hypersensitivity DILANTIN and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity [see Contraindications (4) 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 DILANTIN.
5.6 Cardiac Effects 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 [see Overdosage (10) ] .
Most of the reports of cardiac arrest occurred in patients with underlying cardiac disease.
5.7 Angioedema Angioedema has been reported in patients treated with DILANTIN in the postmarketing 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.
5.8 Hepatic Injury Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with DILANTIN.
These events may be part of the spectrum of DRESS or may occur in isolation [see Warnings and Precautions (5.4) ].
Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia.
The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes.
In these patients with acute hepatotoxicity, DILANTIN should be immediately discontinued and not readministered.
5.9 Hematopoietic Complications Hematopoietic complications, some fatal, have occasionally been reported in association with administration of DILANTIN.
These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression.
There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease.
Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology.
Lymph node involvement may occur with or without symptoms and signs of DRESS [see Warnings and Precautions (5.4) ].
In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.
5.10 Effects on Vitamin D and Bone The chronic use of phenytoin in patients with epilepsy has been associated with decreased bone mineral density (osteopenia, osteoporosis, and osteomalacia) and bone fractures.
Phenytoin induces hepatic metabolizing enzymes.
This may enhance the metabolism of vitamin D and decrease vitamin D levels, which may lead to vitamin D deficiency, hypocalcemia, and hypophosphatemia.
Consideration should be given to screening with bone-related laboratory and radiological tests as appropriate and initiating treatment plans according to established guidelines.
5.11 Renal or Hepatic Impairment, or Hypoalbuminemia Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients.
5.12 Exacerbation of Porphyria In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease.
5.13 Teratogenicity and Other Harm to the Newborn DILANTIN may cause fetal harm when administered to a pregnant woman.
Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse 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 Hyperglycemia Hyperglycemia, resulting from the drug’s inhibitory effects on insulin release, has been reported.
Phenytoin may also raise the serum glucose level in diabetic patients.
5.15 Serum Phenytoin Levels above Therapeutic Range Serum levels of phenytoin sustained above the therapeutic range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely irreversible cerebellar dysfunction and/or cerebellar atrophy.
Accordingly, at the first sign of acute toxicity, serum levels should be immediately checked.
Dose reduction of phenytoin therapy is indicated if serum levels are excessive; if symptoms persist, termination is recommended.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Medication Guide).
Administration Information Advise patients taking phenytoin of the importance of adhering strictly to the prescribed dosage regimen, and of informing the physician of any clinical condition in which it is not possible to take the drug orally as prescribed, e.g., surgery, etc.
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 [see Warnings and Precautions (5.1) ] .
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 [see Warnings and Precautions (5.2) ] .
Serious Dermatologic Reactions Advise patients of the early signs and symptoms of severe cutaneous adverse reactions and to report any occurrence immediately to a physician [see Warnings and Precautions (5.3) ] .
Potential Signs of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Other Systemic Reactions Advise patients of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions.
These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy, facial swelling, and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice.
Advise the patient that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician.
In addition, advise the patient that these signs and symptoms should be reported even if mild or when occurring after extended use [see Warnings and Precautions (5.3 , 5.4 , 5.5 , 5.8 , 5.9) ] .
Cardiac Effects Counsel patients that cases of bradycardia and cardiac arrest have been reported, both at recommended phenytoin doses and levels, and in association with phenytoin toxicity.
Patients should report cardiac signs or symptoms to their healthcare provider [see Warnings and Precautions (5.6) and Overdosage (10) ] .
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 [see Warnings and Precautions (5.7) ] .
Effects of Alcohol Use and Other Drugs and Over-the-Counter Drug Interactions Caution patients against the use of other drugs or alcoholic beverages without first seeking their physician’s advice [see Drug Interactions (7.1 , 7.2) ] .
Inform patients that certain over-the-counter medications (e.g., antacids, cimetidine, and omeprazole), vitamins (e.g., folic acid), and herbal supplements (e.g., St.
John’s wort) can alter their phenytoin levels.
Hyperglycemia Advise patients that DILANTIN may cause an increase in blood glucose levels [see Warnings and Precautions (5.14) ] .
Gingival Hyperplasia Advise patients of the importance of good dental hygiene in order to minimize the development of gingival hyperplasia and its complications.
Neurologic Effects Counsel patients that 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 [see Drug Interactions (7.2) ].
Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breastfeeding or intend to breastfeed during therapy [see Use in Specific Populations (8.1 , 8.2) ] .
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant.
This registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1) ] .
DOSAGE AND ADMINISTRATION
2 • Adult starting dose in patients who have received no previous treatment is 5mL 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 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 to 20 mcg/mL (unbound phenytoin concentration is 1 to 2 mcg/mL).
( 2.1 ) 2.1 Important Administration Instructions 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.
2.2 Adult Dosage 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) ].
2.3 Pediatric Dosage The recommended starting dosage for pediatric patients is 5 mg/kg/day by mouth in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily in divided doses.
A recommended daily maintenance dosage is usually 4 to 8 mg/kg/day in equally divided doses.
Children over 6 years and adolescents may require the minimum adult dosage (300 mg/day).
2.4 Dosage Adjustments Dosage should be individualized to provide maximum benefit.
In some cases, serum blood level determinations may be necessary for optimal dosage adjustments.
Trough levels provide information about clinically effective serum level range and confirm patient compliance, and are obtained just prior to the patient’s next scheduled dose.
Peak levels indicate an individual’s threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration.
Therapeutic effect without clinical signs of toxicity occurs more often with serum total concentrations between 10 and 20 mcg/mL (unbound phenytoin concentrations of 1 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.
2.5 Switching Between Phenytoin Formulations The free acid form of phenytoin is used in DILANTIN-125 Suspension and DILANTIN Infatabs.
DILANTIN extended capsules and parenteral DILANTIN are formulated with the sodium salt of phenytoin.
Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa.
2.6 Dosing in Patients with Renal or Hepatic Impairment or Hypoalbuminemia Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients [see Warnings and Precautions (5.11) and Use in Specific Populations (8.6) ].
2.7 Geriatric Dosage Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required [see Clinical Pharmacology (12.3) ] .
2.8 Dosing during Pregnancy Decreased serum concentrations of phenytoin may occur during pregnancy because of altered phenytoin pharmacokinetics.
Periodic measurement of serum phenytoin concentrations should be performed during pregnancy, and the DILANTIN dosage should be adjusted as necessary.
Postpartum restoration of the original dosage will probably be indicated [see Use in Specific Populations (8.1) ].
Because of potential changes in protein binding during pregnancy, the monitoring of phenytoin serum levels should be based on the unbound fraction.